Rotashield FOIA info, aka, how can we manipulate the numbers to make it look safe?

Walt: Yesterday, Rima shared with me a copy of a draft MMWR article which contained a one sentence report of postlicensure surveillance data from the Northern California Kaiser. If I understand that data correctly, they, like the VAERS data, are not reassuring and I recommend that they not be presented as they are now in the current draft of the MMWR article.

Jane Orient, M.D.
Association of American Physicians and Surgeons, Inc.
1601 N. Tucson Blvd., Suite 9
Tucson, Arizona 85716-3450

Dear Dr. Orient:

This letter is in response to your Freedom of Information Act (FOIA) request of October 4.

We received your check for $56.20. Enclosed are documents you requested.

Under authority of the Freedom of Information Act at 5 U.S.C. 552(b) (6) and the Department’s implementing regulation at 45 CFR 5.67, names and other information, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy, have been deleted from these documents.

Under authority of 5 U.S.C. 552(b) (2) of the Freedom of Information Act and 45 CFR 5.63 of the Department’s implementing regulations, we are withholding internal information such as conference call bridge numbers. This information relates solely to the internal personnel rules and practices of this agency.

We are withholding predecisional internal communications. Release of this type of material would interfere with the agency’s deliberative process. This decision is based upon the Freedom of Information Act at 5 U.S.C. 552(b) (5) and the Department’s implementing regulation at 45 CFR 5.66(a).

You have the right to appeal this decision to deny you full access to agency records. Should you wish to do so, send your appeal, within 30 days from the date you receive this letter, to the Deputy Assistant Secretary for Public Affairs (Media), U.S. Department of Health and Human Services, Room 17A-46, 5600 Fishers Lane, Rockville, Maryland 20857. Please mark both your appeal letter and envelope “FOIA Appeal.”

We may have additional releasable records. If you are interested in receiving these, let our office know and we’ll prepare an invoice as soon as we know what is available.

Portions of documents generated by either the Food and Drug Administration (FDA) or the National Institutes of Health (NIH) were deleted from these records. You should contact those agencies directly for any further information.

Sincerely yours,

Lynn Armstrong
Office of Communication
(404) 639-7270


From: Wharton, Melinda
Sent: Wednesday, June 30, 1999 3:15 PM
To: Murphy, Trudy; Prevots, Rebecca; Zanardi, Lynn; Vitek, Charles; Livengood, John; Massoudi, Mehran; Nelson, Rick
Cc: Reynolds, Barbara S.; Allen, Curtis
Subject: discussions at CSTE

Although I didn’t have a chance to get any more states recruited (didn’t see anyone from Indiana), we did discuss rotavirus vaccine issues over lunch yesterday, thanks to Sandy. Basically a good, constructive, supportive discussion. Folks from a number of states were there (MN, OH, OR, TN, NM, NJ are the ones I remember). We talked about everything from press response (lots of concern about when this hits the press) to how controls should be selected. They made the following suggestions:

1. There needs to be clarity an in process for ANY change in recommendations. Need to make clear that with publicity we expect additional cases, that the recommendation currently is that the vaccine still be used, but in the event that that changes, we will let people know immediately. There is concern about a lot of “local” decisions being made on the fly in lieu of a coordinated CDC response.

2. I told them that I was anticipating that the story would appear in the “trade tabloids” and maybe AAP in the July issues, and that these might be published before the MMWR story came out. Someone suggested we get those publication dates, and I’ve already talked to Barbara Reynolds about that — she was going to try to have someone follow up on that.

3. There was a lot of conversation about “doing it fast” and “doing it right,” and the tension between those competing priorities. Dave Fleming suggested that once the cases are ascertained from hospital discharge data that the FIRST step (before reviewing hospital charts, radiology reports, or anything else) should be obtaining vaccination histories (and if that means interviewing providers and/or parents, administering the complete questionnaire at the same time — he was not advocating going back to a given source). There was general agreement that this was feasible and reasonable. These cases in vaccinated children would be tallied and could lead to public health action if warranted.

4. We need a procedure for handling “stimulated reports” in states participating in the study (and other states, for that matter). Once the MMWR article comes out, or press coverage that the state health dept is participating in the study, there will be providers or parents calling in “that happened to my child,” but the child may have been the only child hospitalized at Hospital A for intussusception in the last 4 years, and the case would NOT have been ascertained. We didn’t talk a lot about what that procedure should be, other than to say that the cases should be tabulated, but not included in the study. Approaches might be for the state file a VAERS report; for the state to encourage the person calling to file a VAERS report (not optimal); or to actually use the study questionnaire in case by chance the child’s name DOES come up (so they don’t have to call back and then the parent thinks the state is incompetent because they didn’t ask all these questions three weeks ago when they reported the case the first time). This needs some thought and discussion.

5. Local health dept folks need some information on the benefits of rotavirus vaccine, and on the issue generally, because they will get asked questions.

6. An EIS officer said it was “awkward” that they knew about the study and their state immunization program folks DIDN’T — which is when I realized that we hadn’t pursued that channel simultaneously in either the EIP states or Epi-aid states (obviously in some states it’s all the same folks, but in some it isn’t). I don’t know where we are with state contact at this point, but if we haven’t followed up with the immunization programs in the states where we are trying to get things launched, I think we should. Rick, is that something you could do?

7. There was some discussion about control selection, much of which echoed discussions we’ve had here (i.e., need to age match, but don’t want to match on much else, and birth certificate info is not going to be available at the state level in a timely way in all areas). Karen White from MN suggested using COUNTY level birth certificate matches (many of the advantages of using state data, but she thought this might be feasible in all states, since most of the delay is NOT in getting the information to the county, but getting it from the county to the state). Also would facilitate age-matching, since most counties would have enough births this would be easy, while many hospitals might not. Seems like a reasonable alternative to me but I have no idea whether all areas could do it. Probably some more discussion about selecting controls in order, and we will need very clear instructions on how EXACTLY it is to be done, once that decision is made.

8. I told them about the issue at NCK of admitting dx vs discharge dx, and people thought that infants transferred to surgical services might very well receive discharge diagnoses of “s/p bowel resection” or something (which is what I would guess happened with the NC K). There was interest in trying to do some validation in some places where it was feasible, and someone from MN called one of their pediatric hospitals right after the discussion to ask if they could check admitting dx vs discharge dx. This is an issue which deserves some more discussion (and it’s actually even worse than we thought – NCK found ANOTHER non-ascertained case by reviewing the barium enemas done on infants, that didn’t show up from EITHER discharge or admission codes, according to the msg Steve Black left today).

I also made a note to send out the updated background material. Does someone have a group code to send it out?


From: Wharton, Melinda
Sent: Thursday, June 10, 1999 11:48 AM
To: Livengood, John
Subject: expected rates

Expected rates for 300,000- 1,200,000 first doses. if it looks okay, please forward to Walt -.



RateLower 95% CIUpper 95% CI
expected rate among children <12 months of age0.0003890.0003310.000456
Assuming number of first doses administered300,000
Number of infants <12 months of age in U.S.4,000,000
Expected number of cases of intussusception among infants <12 months of age (annual)1,5561,3241,824
Proportion of infants receiving first dose0.075
Expected number of cases of intussusception among infants receiving first dose116.799.3136.8
Expected number of cases of intussusception among infants within I week of first dose2.21.92.6
RateLower 95% CIUpper 95% CI
expected rate among children <12 months of age0.0003890.0003310.000456
Assuming number of first doses administered600,000
Number of infants <12 months of age in U.S.4,000,000
Expected number of cases of intussusception among infants <12 months of age (annual)1,5561,3241,824
Proportion of infants receiving first dose0.15
Expected number of cases of intussusception among infants receiving first dose233.4198.6273.6
Expected number of cases of intussusception among infants within 1 week of first dose4.53.85.3
RateLower 95% CIUpper 95% CI
expected rate among children <12 months of age0.0003890.0003310.000456
Assuming number of first doses administered900,000
Number of infants <12 months of age in U.S.4,000,000
Expected number of cases of intussusception among infants <12 months of age (annual)1,5561,3241,824
Proportion of infants receiving first dose0.225
Expected number of cases of intussusception among infants receiving first dose350.1297.9410.4
Expected number of cases of intussusception among infants within 1 week of first dose6.75.77.9
RateLower 95% CIUpper 95% CI
expected rate among children 12 months of age0.0003890.0003310.000456
Assuming number of first doses administered1,200,000
Number of infants <12 months of age in U.S.4,000,000
Expected number of cases of intussusception among infants <12 months ofage (annual)1,5561,3241,824.
Proportion of infants receiving first dose0.3
Expected number of cases of intussusception among infants receiving first dose466.8397.2547.2
Expected number of cases of intussusception among infants within 1 week of first dose9.07.610.5

From: Wharton, Melinda
Sent: Monday, June 14, 1999 5:22 PM
To: Kramarz, Piotr
Cc: Livengood, John
Subject: FW: Intussusception Questions that need answers
Importance: High

See the second set of questions about VAERS. Is this something that you all already have put together somewhere?

ThanksOriginal Message

From: Nowak, Glen
Sent: Monday, Junel4, 1999 1:56 PM
To: Livengood, John; Wharton, Melinda; Schwartz, Ben (NIP)
cc: Cordero, Jose; Landry, Martin; Nichols, Bill; Orenstein, Walt; Reynolds, Barbara S.; Thompson, Charlis J.
Subject: Intussusception Questions that need answers
Importance: High

Barbara Reynolds, Charlis Thompson and I have identified some of the key questions that the media are likely to raise. Though you might have already identified these, here’s our suggestions:

  • Do the VAERS reports/numbers mean that the vaccine caused the reaction that was reported?
  • What is VAERS? How does it work? Is it a good system (i.e., valid and reliable) for determining if a vaccine causes serious adverse reactions? What are its strengths? What are its weaknesses?
  • Has CDC investigated other adverse reactions involving vaccines? Which ones? What did those investigations entail?
  • What is intussusception? How is it caused? How serious is it? Can it cause/lead to death?
  • How many infants have received the rotavirus vacine?
  • Was this an adverse event detected in the prelicensure trials?
  • Why wasn’t intussusception noted on the rotavirus VIS? Will it now be added?
  • What other common side effects or adverse reactions are associated with rotavirus vaccine?
  • What action is the CDC taking?
  • Did the CDC take similar action for hepatitis B vaccine? (Why not?)
  • Why is CDC taking this action now?
  • Should parents continue to immunize their children against rotavirus while this investigation is underway?
  • How long will the investigation take?
  • What will happen if the CDC does find evidence of a causal relationship between the rotavirus vaccine and intussusception?
  • How frequently or often would this (inussusception) or any other serious adverse effect have to occur, before the CDC takes major action (e.g., suspending the recommendation)?

I realize this is a fairly long list, with many difficult questions, but given these are the ones most likely to be asked, it’s better to be prepared in advance. Let me know if you have questions or need additional information.

From: Wharton, Melinda
Sent: Thursday, June 17,1999 9:40 AM
To: Anderson, Larry
Cc: Livengood, John
Subject: RE: rotavirus vaccines

I tried to call you yesterday –I could quibble with you about details (the VAERS data are alarming for a number of reasons, and given the known problems with completeness of reporting to passive surveillance systems, are consistent with an incidence markedly in excess to that expected by chance alone) but I don’t disagree with your bottom line concern. That said, it’s anybody’s guess how this is going to turn out. We’ll see what happens this afternoon. Even if ACIP supports the current plan of action (continuing to use the vaccine while we collect more data), I’m not sure what will happen if we get another 50 reports to VAERS next week, after this hits the press. At the moment, we’re just taking this one day at a time.

MelindaOriginal Message
From: Anderson, Larry
Sent: Wednesday, June 16, 1999 1:24 PM
To: Wharton, Melinda; Livengood, John
cc: ‘Joseph Bresee’; Schonberger, Larry; Khabbaz, Rima
Subject: rotavirus vaccines

I am concerned about possible directions for communications from CDC and some less than enthusiastic support for rotavirus vaccines. I hope the luke warm support for rotavirus vaccines by some does not detract from appropriate interpretation of the data. Since I am about to leave for vacation, I wanted to put in my two cents worth. I will also be in close contact with Joe.

My read of the data is that:

1. the rate in the Kaiser study (only reasonable data) and VEERS data (pretty difficult to have much confidence in rates) both suggest no increase in intussuception with rotavirus vaccination.

2. given the small number of patients in Kaiser study and unknown numerator and denominator for VEERS data and, previous questions regarding intussuception with the vaccine, we can not be sure that rotavirus vaccination does not occasionally cause intussuception and must do further studies.

3. Given that the data to date is neutral or no increased risk, vaccination should proceed as before. It is reassuring 4 that intussuception is not life threatening illness (rarely requires surgery with present medical practice according the pediatricians among us). It would not be good to stop a vaccination program that can have substantial public health impact on the basis of data that raises a question but does not show a problem.



From: Wharton, Melinda
Sent: Wednesday, June 23, 1999 10:41 AM
To: Livengood, John

Sorry it took me so long to get this right — had the wrong numbers of doses in the original calculations, but I think this is right. Bottom line: with these assumptions (equal rates of vaccine use early on to later, which I’m sure is wrong) and a baseline rate of 0.4 per 1,000, the expected number of cases among vaccines is 1.14, and within one week of any dose is 0.127. The intervals for the one case that has been reported to VAERS is 14 or 15 days, but the kid with the polyp (not reported to VAERS) was (I think) 8 days. The child that has been reported to VAERS but not included in the cases analyzed to date had a 3-4 day interval.

Mike said that they (NCK) are working on the person-time, and I clearly scared him this morning when I sent him an earlier (wrong) version of this. So they will be leaning on NCK to do it, as well, if only to show me wrong. I did tell him we couldn’t include the NCK data without person-time, but if we got it we could put it in the body of the report.

Expected rates of intussusception among RRV-TV (recipients, Northern California Kaiser

Dose 1 9,860
Dose2 5,207
Dose3 1,613
Total 16,680

No. dose 1

Total infant-months 34,510.0
Total infant-years 2875.8
Expected rate among infants per infant-year 0.000389
Expected cases among vaccine recipients 1.12
Total doses of vaccine administered 16,680
Expected rate among infants per infant-week 0.0000076538
Expected number of cases within one week of any dose 0.127

From: Schonberger, Larry
Sent: Wednesday, June 23, 1999 3:40 PM
To: Orenstein, Walt
Cc: Livengood, John; Cordero, Jose; Khabbaz, Rirna; Wharton, Melinda; Bresee, Joseph
Subject: RE: Comments on the draft MMWR article about intussusception and rotavirus vaccine

Walt: Yesterday, Rima shared with me a copy of a draft MMWR article which contained a one sentence report of postlicensure surveillance data from the Northern California Kaiser. If I understand that data correctly, they, like the VAERS data, are not reassuring and I recommend that they not be presented as they are now in the current draft of the MMWR article.

First, let me update you on the background incidence of intussusception from New York based on information I asked Bob Holman to obtain for us. For the seven year period, 1991 through 1997, (note that we have added two more years of data) there were 972 hospitalizations of infants under 1 year of age coded for intussusception. Using census estimates of the population under 1 year of age in New York for each of the 7 years in the study, we can estimate the denominator as 99 million person weeks of risk, hence the estimated rate in infants in New York becomes 0.98 hospitalizations for intussusception per 100,000 person weeks of risk.

With regard to the Northern California Kaiser data, I will assume from the current draft MMWR article that Kaiser had, on average, a population of 27,860 children under 1 year of age that were followed for 23 weeks beginning December 1, 1998 and that 9,860 of these children received RRV-TV during this 23 week period. As I know you well understand, the timing of vaccinations is critical for calculating incidence rates. If the number of vaccinations administered was stable each week throughout the period, for example, then the incidence rate for vaccinees based on the 2 cases becomes 1.76 cases per 100,000 person weeks of risk. If the number of vaccinations administered increased over time such that, for example, the average vaccination was given only after 60% of the 23 week period had passed, instead of by the midpoint of the period, then the incidence rate for vaccinees based on the 2 cases becomes 2.2 cases per 100,000. Because the person week denominator is larger for the unvaccinated population, the background incidence rate for this population remains relatively stable with either of the assumptions above at about 1.1 cases per 100,000 person weeks.

When I spoke to Melinda Wharton this morning, she mentioned that if one extended the time period of the analysis of the Kaiser data by 1 week, the numerator for the vaccinees would include case number 12 of the MMWR Table. Such a case would, of course, increase the overall incidence rate among vaccinees and would add to the one week post vaccination incidence rate, the period of most concern based on cases reported through VAERS. Of course, the one week extension of the Kaiser followup study period could also change the numbers of people vaccinated and possibly the numbers of unvaccinated cases, but again, with what I would consi reasonable assumptions about how these numbers might change, the Kaiser study data are not reassuring to me. As important as the Kaiser data may be, the way they are presented in the MMWR is at least as important. Botheserve more attention. The current draft could be misinterpretted by some as CDC’s not fully appreciating the importance of using person-time analyses and assessing intervals between vaccinations and onsets.

Let me suggest that you give me a call when you get a chance during your hectic schedule. My pager is 404 716- 2271. Thanks. Larry S.—Onginal Message—-
From: Schonberger, Larry
Sent: Thursday, June 17, 1999 8:10 PM
To: Orenstein, Walt
cc: Livengood, John; Cordero, Jose; Khabbaz, Rima; Schonberger, Larry
Subject: Comments on the rotavirus vaccine associated intussusception data and protocol

Walt: John and Rima both mentioned that you had wanted me to look at the key data on the association between rotavirus vaccine and intussusception and provide you with some feedback. I am not an expert on intussusception but clearly risk factors for this illness that might also influence likelihood of receipt of vaccine are factors that would be good to identify early. I will assume that there are no such overwhelming confounders, that the estimate of the number of first doses administered is 1.2 million (that is; 1.8 million vaccinations distributed, 1.5 million administered including 0.3 million second or third doses, and that there has been a decision that vaccinations will continue at least until John Livengood et al can obtain epidemiologic data to better define whether there is an etiologic association between vaccination and intussusception and if so the magnitude of any risk.

Because I have more raw data from the New York State study (all hospitalizations between 1991 and 1995), I will use these data as my estimate of the background rates of intussusception for the entire country. This study yields higher background rates than the ones I believe you have been using but I do not think this will significantly alter our main conclusions.

The estimated background incidence rate in New York in terms of cases per 100,000 person weeks of risk for those under 1 year of age is approximately 0.97. From the New York data, the background incidence rate for the specific age group 2 months through 6 months of age is estimated to be about 21 % higher than this overall rate, or 1.18 cases per 100,000 person weeks of risk. The 2 months through 6 months of age period represents the most likely period when an infant would receive rotavirus vaccinations.

Using the above relatively high background estimates, nationally the 1.2 million first doses should produce an estimated 11 (if the 0.97 rate above is used) to 14 cases (if the 1.18 rate above is used) of intussusception in children under 1 year of age in the 1 week period after a first dose of rotavirus vaccine; I understand that the VAERS system has identified at least 9 such cases whose diagnoses have been confirmed. If the sensitivity of VAERS reporting were 64% to 77% these ascertained cases would not suggest that there existed a true excess of cases in this critical period of concern. If this sensitivity of reporting, however, were 50% and there were in fact 18 cases of intussusception (9 more not yet identified), then we would estimate that nationally there were between about 3 to 5 extra cases of intussusception per million first doses of vaccine. Similarly, if the sensitivity of VAERS were 10%, then we would estimate that there were between 63 and 65 extra cases per million first doses of vaccine. These analyses are not reassuring.

Despite the signal from VAERS about a potential problem with first doses, in the follow-up study that is currently being planned, I agree with broadening our concern to any dose of rotavirus vaccine. I say this despite my suspicion that for a variety of reasons we might expect that if there were a risk of intussusception after receipt of rotavirus vaccine then that risk would be more apparent after first doses than after subsequent doses. The risk period of key concern Is appropriately the one week period after receipt of any of the doses of vaccine and, as may be planned for the follow-up study, there will and should be analyses of data by risk windows slightly longer than 1 week as well.

Do I agree with the case-control methodology? Yes, because a) we need cases from a huge population, b) there are problems with pinning down appropriate denominators and C) there likely is wide variability in vaccine coverage in different geographic areas. However, I would anticipate that completing such a case-control study would take considerable time and effort before it would likely provide us with data about whether there is really an increased vaccine-related risk of intussusception, and if so, some information about the magnitude of this risk.

Since children are still being vaccinated, I would suggest that we do the case-control study but break one of the usual rules of such studies and focus initially on just ascertaining cases from throughout the country and determining their vaccination status. We can begin to identify the controls and prepare for their eventual inclusion into the case- control study, but initially give the case ascertainment almost exclusive priority. The justification for this would be to hasten determination of whether there is likely a risk and particularly to hasten detection of a relatively large risk should it exist. For example, you might arbitrarily set in advance some arbitrary number of new cases in the first week after a rotavirus vaccine that, if ascertained in this initial case ascertainment effort, would lead you to temporarily halt the vaccination program or to at least put out more information about the fact that some risk exists.

One negative consequence of initially working up cases without simultaneously working up the controls is our potentially creating a systematic bias in the histories of vaccination; that is, controls will potentially be interviewed about their vaccination history months after their matched case will have been. Given that we would plan to confirm the histories of vaccinations by checking physician records, this systematic bias is less worrisome to me and probably does not outweigh the benefits of our focusing on quickly ascertaining as many cases of intussusception as possible. This latter ascertainment could also include tapping into data of health maintenance organizations or other institutions that might have local unvaccinated and vaccinated denominators that would facilitate interpretations of risk.

In the cooperative, NIP/DVRD study of GBS in 1990-91, DVRD actually took primary responsibility for the HMO aspect of case ascertainment and provided an additional EIS Officer to help out with other case ascertainment efforts. A similar type of cooperative arrangement might be considered for this investigation too, although I have not really discussed this with Dr. Larry Anderson. Since Dr. Anderson’s group, I suspect, would be interested in the possiblity that even should rotavirus vaccine trigger some instances of intussusception, this might be similarly true for wild rotavirus disease as well. Longer term follow-up of large numbers of vaccine-recipients might show, for example, some long term protective effect of the vaccine against developing intussusception in the period during which recipients would be relatively protected from the wild rotavirus disease. The HMOs might give Larry Anderson’s group some opportunity to look for evidence of this hypothetical possibility though longer term follow- up of vaccine recipients.

The tremendous work involved in conducting the case-control study argues for not wasting too much effort on cases and controls who by their date of birth would be at no or extremely low risk of receiving rotavirus vaccine. The current protocol, for example, does not exclude children who were born between December 1997 and April 1998 even though these children will have been beyond the recommended age for vaccination during the likely period when vaccine would have been available for the infants who could become cases in the follow-up study period, November 1998 -June 1999. Although it is true not all physicians will necessarily follow ACIP recommendations on the age group to vaccinate and possibly begin to vaccinate infants 7 months old or older, I suggest excluding these children from the case-control study.

In summary, the current data are not reassuring to me. A rotavirus vaccine-related risk of intussusception on the order of magnitude discussed above would not be surprising and should be ruled out as quickly as reasonably can be done. Although the uncertainties about denominators argues for the case-control methodology, the need for a more rapid assessment argues for initially focusing almost exclusively on case ascertainment nationally and taking advantage of any subgroup denominators that may exist, as in large HMOs. A decision should be made early about what number of vaccine-associated intussusception cases would lead you to recommend temporarily halting rotavirus vaccinations or to revise information provided to parents deciding whether to vaccinate their infants. Get Larry Anderson’s group involved in some of the HMO case ascertainment aspects of the study. Drop birth cohorts from the case-control study who would have been too old to have likely received rotavirus vaccine by the time the vaccine became reasonably available.

Hope these comments are helpful.
Larry S.

From: Wharton, Melinda
Sent: Friday, June 25, 1999 9:15AM
To: Livengood, John
Subject: RE: MMWR

I got the changes and they’re good (and I think readable). Only other thing I was thinking about was explicitly stating that the expected number of cases within one week of vaccine in the prelicensure trials was <1. That can be calculated from the data in the report, and it will be an obvious omission if it is not there.

“However, three of five cases among vaccinated children occurred with onsets of 6-7 days of receipt of rotavirus vaccine; based on observed background rates of intussusception, <1 cases was expected during that period.”

The other thing I’m getting an ulcer about is how this whole thing was presented to AClP. Would the outcome have been different if we had pointed out that the cases within one week were 10-fold higher than expected, and that the NCK data (including the next week) also were » expected, even if n=1? Should we tell them now, before this goes to print?

Steve Black called me last night; they will be extending the period of analysis to May 17, so it will include the 3rd case. Anyway, I’ll make the edits and get it off to Dr. Koplan.

Melinda—-Original Message
From: Livengood, John
Sent: Friday, June 25,1999 8:31 AM
To: Wharton, Melinda
Subject: MMWR

I arn faxing the 2 pages with final cornrnents. Please make these last changes (for this round) and send to Jeff, cc Martha, Dixie and Walt Jose Roger and me. Note should say this is the draft for his comments. preliminary review by NClD/FDA, but not final approval. Will add NCK data if it becomes available early next week. ask for comments by Monday (noon?) and inquire how and when to sent to Mr. THurm. Reminder that this will need to go to MMWR by Wed to be published 7/9 due to shortened holiday week.


From: Glass, Roger
Sent: Friday, September 03, 1999 10:47 AM
To: Adams, Melissa; Speers, Marjorie
Cc: Shefer, Abigail; Rodewald, Lance; Glass, Roger; Livengood, John; Anderson, Larry
Subject: RE: \HSREB-N IP\Rotavirus-ethics\rotavirus_ethics.wpd

Melissa and Abigail,

I read over the Ethics discussion and was pleased by the way you have approached the alternatives but not sure that the data presented is in fact correct. Below are some issues for consideration:

1. Are your numerical estimates of IS cases related to RV plausible? On page 5, you suggest that 6000 children per year would develop intussusception over baseline with continued use of the vaccine and 37 deaths. The excess risk of IS noted in the studies quoted above refer to excess risk in the week or 3 weeks after immunization– not to an excess for an entire year or a child’s first years of life which would be much less. Consequently, in the Kaiser study, 9000 vaccinated children had 2 episodes in the 3 weeks after vaccination–that might be extapolated to about 2/10,000 or 200/million or 800 total for the US birth cohort of 4 million. So the estimate of 6000 seems very high. I might ask how that figure was obtained.

2. Knowledge of intussusception might radically change outcome. If physicians were informed to think about IS as a complicaton, the risks of surgery or death might be significantly diminished. In many settings, few children end up in surgery and the risk of a fatality is low ( on the order of 1/500) or several deaths from excess vaccine related cases. Clearly, knowledge of more precise figures can alter the direction of the assessment.

3. In India, 100,000 children will die of RV each year (about 1 in 300 children born) so a vaccine that has a low risk of IS (say 2/10,000) and a smaller risk of fatal IS would still be a life-saver. At issue is replacing one fatal risk which we induce by vaccine for a greater risk that we prevent. Can we ethically deny a vaccine from these children given that their risk of fatal rotavirus is so great? Should we test these vaccines further in developing countries given the risk that we will soon learn for American kids? Knowing that intussusception is a complication that could require surgery for repair or be fatal, could we test a vaccine in India in a setting where surgery is available (eg. catchment area of a hospital) and in a setting where health workers visit, educate and bring in vaccinees who present on day 3-10 with symptoms of obstruction?

4. On page 2, you state a number of complications associated with RV but don’t mention intussusception. In 4 studies at least, 8-38% of IS cases have RV detected in stool or antibodies in sera. So RV vaccines may well protect against this outcome. Causality still has to be addressed and this will be difficult to do but not impossible. The bottom line is that the vaccine may well diminish this adverse event.

All vaccine testing of live oral vaccines has stopped because of fear of litigation and risks of complications. The current vaccines could well be life-savers in developing countries and during the 6-8 years it may take to develop the next generation of rotavirus vaccines, 4-6 million children will die of rotavirus diarrhea–some 2000 per day. Any ethical review should address the potential considerations for considering continued use of the vaccine in developing countries.

Happy to discuss this further but I think that the piece as presented should highlight these developing country issues and put more appropriate estimates on the extent of the IS problem in the US or leave these blank until we have more accurate information.

Look forward to opening a dialogue on these ethical considerations. Hope these comments help.

Roger I. Glass, M.D., Ph.D.
Chief, Viral Gastroenteritis Section
Division of Viral & Rickettsial Diseases
MailStop G04
Centers for Disease Control & Prevention
1600 Clifton Rd., NE
Atlanta, GA 30333 USA
+1 1-404-639-3577
+1-404-639-3645 (FAX)
Original Message
From: Adams, Melissa
Sent: Wednesday, September 01,1999 5:01 PM
To: Speers, Marjorie
Cc: Shefer, Abigail; Glass, Roger; Rodewald, Lance
Subject: RE: \HSREB-N I P\Rotavirus-ethics\rotavirus_ethics .wpd

Sorry for the delayed response, Marjorie. I wanted to check w/folks here to see how much time they needed for review before sending it to your shop. I thought that Abby would be sending you something today, but Roger Glass stopped by this afternoon and made a compelling arguement that the document should include something about the potential impact on developing countries of a decision to not recommend the vaccine. [The risk of death from diarrhea is much different in developing countries than in the U.S. A decision to not recommend the vaccine would very likely halt the development of competing products by other manufacturers. Without competition, a cheap vaccine will not become available and the potential spill-over benefit to children in developing countries will not be achieved.] I’ve asked Abby to talk w/Roger and incorporate his comments. We plan to have something to you tomorrow.

Original Message
From: Speers, Marjorie
Sent: Monday, August 30,1999 11:20 AM
To: Adams, Melissa
Subject: RE: \HSREB-N I P\Rotavirus-eth ics\rotavirus_ethics .wpd

Any sense on when a draft will be available?

Marjorie A. Speers, Ph.D.
Deputy Associate Director for Science
1600 Clifton Rd, NE MS D50
Atlanta, GA 30333
404 639-7341 (fax)

Original Message
From: Adams, Melissa
Sent: Monday, August 30, 1999 11:13 AM
To: Speers, Marjorie
Subject: RE: \HS REB-N I P\Rotavirus-ethics\rotavirus_ethics .wpd

Thanks for your helpful comments. Work on the document continues apace here. Stay tuned!

Original Message
From: Speers, Marjorie
Sent: Monday, August 23, 1999 10:39 PM
To: Adams, Melissa
Cc: Rodewald, Lance; Shefer, Abigail; Bernier, Roger; Snider, Dixie
Subject: RE: \HSREB-N I P\Rotavirus-ethics\rotavirus_ethics .wpd

I looked over the outline. The outline structure looks well thought out and to cover the major issues. I am more likely to be helpful once you have a draft of text. Here are some ideas for you to consider:

1. The ethical principles you have chosen are those used to guide research. They are focussed on the individual because the ethicists, at the time, were thinking about biomedical research and psychological research, two areas where the emphasis is on the individual. You may want to consider adding another principle which guides public health – balancing societal good with individual good. Although this principle may not be as relevant to the rotavirus vaccine, I think it should be discussed because we view immunization programs as public health programs.

2. Following on the former, you should discuss herd immunity or that lack of it.

3. When discussing the ethical principles, I would consider them from the viewpoints of children, parents, and providers.

4. When the ethicists were debating ethical prinicples over 25 years ago, there was a lively debate about including children in research. The basic premise is that children cannot give consent because they lack the mental decision making capacity to do so. Thus, we get “assent”, general agreement, from children and “permission” from their parents. During the debate 25 years ago, one theologian argued that children should never be included in research because they cannot consent. Another theologian argued that parents could consent on behalf of their children because parents would act in the best interests of their children. A compromise was reached. Children could be involved in only minimal risk research or research that held the prospect of direct benefit to the child. Riskier research should not undertaken except under special circumstances. You may recall that Tom Murray mentioned once during the call that parents are acting on behalf on their children. He was speaking from some of the work he has done on this topic. But what I think you may want to consider is whether there is a conflict of interest for parents to give permission for their child to receive the vaccine when a major benefit of the vaccine is to the parent (in terms of reducing lost work time). This, to me, is one of the interesting, hard ethical issues with this vaccine. It may come up when you discuss autonomy and whether having parents be informed and consent obviates the potential harmful effects.

5. There hasn’t been much discussion about the balancing of the 3 or 4 ethical principles; however it seems that autonomy is held a bit higher than the rest. Further, Western thinking seems to suggest that part of what makes an activity ethical is having the people involved appropriately informed and make a decision to participate. During the AzT trial debate, Peter Lurie argued that informed consent can never make an unethical activity ethical. One approach would be to discuss whether the rotavirus vaccination program in general is ethical and then to suggests that potential harms could be minimized through informed consent.

6. Consider comparing the rotavirus vaccine to other immunizations as appropriate. I found the comparison to OPV/IPV and pertussis helpful.

Original Message
From: Adams, Melissa
Sent: Thursday, August 19, 1999 4:20 PM
To: Speers, Marjorie
Cc: Rodewald, Lance; Shefer, Abigail; Bernier, Roger
Subject: L :\HS RE B-NI P\Rotavirus-ethics\rotavirus_ethics .wpd

Marjorie — attached is proposed outline for the rotavirus ethics paper. We would value your comments. Abby will return on Monday and begin to develop the manuscript.

— Melissa

From: Wharton, Melinda
Sent: Wednesday, July 14,1999 3:42 PM
To: Livengood, John; Orenstein, Walt; Cordero, Jose
Subject: FW: Possible Association of Intussusception with Rotavirus VaccinationOriginal Message
From: Murphy, Trudy
Sent: Wednesday, July 14, 1999 3:01 PM
To: Livengood, John; Wharton, Melinda; Yacovone, Edward; Bresee, Joseph;
Massoudi, Mehran; Nelson, Rick; Prevots, Rebecca; Zanardi, Lynn Subject: FW: Possible Association of Intussusception with Rotavirus Vaccination


Original Message
From: AAP Office of the Executive Director [mailto:EXECOFFICE@AAP.ORG]
Sent: Wednesday, July 14,1999 1:55 PM
Subject: Possible Association of Intussusception with Rotavirus

Possible Association of Intussusception with Rotavirus Vaccination (Committee on Infectious Diseases)

New information indicates there may be an increased risk of intussusception during the first few weeks after receipt of the licensed tetravalent rotavirus vaccine (RRV-TV), RotaShield. Currently available data are very limited and are based on passive reporting to the Vaccine Adverse Event Reporting System (VAERS), a post-licensure study of adverse events at Northern California Kaiser, and active case finding in two states. Results thus should be considered preliminary. To date, the Centers for Disease Control and Prevention (CDC) has received reports of 23 cases of intussusception following receipt of doses 1, 2, or 3 of RRV-TV. The number of children who have received RRV-TV is unknown, however, the observed rate of intussusception among vaccine recipients during the first 3 weeks after immunization appears to be greater than expected, with the highest rate during the first week following vaccination. These initial data suggest that intussusception occurs at a younger age in vaccine recipients than in unvaccinated children.

The results of an ongoing case-control study of intussusception following rotavirus vaccination, conducted by the CDC, are anticipated to be available in a few months. At that time, a re-evaluation of the health risks and costs of rotavirus vaccination versus the health risks and costs of natural rotavirus infection will be performed. Since the seasonal risk of natural rotavirus infection in the United States will be very low during the next few months, the AAP is making the following interim recommendations:

1. Clinicians temporarily should suspend administration of rotavirus vaccine to unimmunized and partially immunized children, pending collection and evaluation of additional information.

2. Parents or guardians of children who have received RRV-TV within a period of approximately 3 weeks should be advised to promptly contact their physician if signs or symptoms compatible with intussusception develop.

3. All cases of intussusception which occur following administration of RRV-TV should be reported to VAERS (800-822-7967;

From: Wharton, Melinda
Sent: Thursday, July 15, 1999 5:01 PM
To: Schmitt, Tom
Subject: FW: AP Story on rotavirusFrom: Thompson, Charlis J.
Sent: Thursday, July 15, 1999 4:46 PM
To: Orenstein, Walt,; Wharton, Melinda
Cc: Nowak, Glen; Allen, Curtis; Hibbs, Beth; Livengood, John; Reynolds, Barbara S.
Subject: FW: AP Story on rotavirus

CDC recommends suspending use of diarrhea vaccine
4:39 p.m. ET (2040 GMT) July 15, 1999

By Patricia J. Mays, Associated Press

ATLANTA (AP) – The government is recommending that doctors temporarily stop giving children a diarrhea vaccine because at least 20 infants have developed a bowel obstruction.

The Centers for Disease Control and Prevention said Thursday that RotaShield, the vaccine against rotavirus, has not been conclusively linked to bowel obstruction, but early studies show it may increase the risk.

The obstruction occurs when one part of the bowel becomes enfolded within another. Symptoms include vomiting, bloody stools and abdominal pain. Surgery is often needed to clear the blockage if it isn’t caught early.

The CDC recommended suspending use of the vaccine in all children – including those who have begun the three- dose series – until November so health officials can conclude additional studies. Following the CDC’s move, the American Academy of Pediatrics issued the same recommendation.

It’s enough to make us worry,” said Dr. Melinda Wharton, head of the CDC’s child vaccine preventable diseases branch. “We’re fortunate that rotavirus is a seasonal disease so we can postpone vaccination for a few months.”

Rotavirus, an intestinal infection, is the leading cause of severe diarrhea in children under 5 in the United States. Each year, an estimated 3 million American children are sickened, 50,000 are hospitalized, and 20 die. The disease primarily occurs in winter and spring.

The vaccine’s manufacturer, Philadelphia-based Wyeth-Ayerst Laboratories, said 1 million infants have been vaccinated with RotaShield since it received government approval in August. The three-dose series is given at ages 2 months, 4 months, and 6 months.

Before its approval by the Food and Drug Administration, five cases of the bowel obstruction were reported for every 10,000 vaccine recipients.

As a result, the bowel obstruction was listed as a potential adverse reaction on the package insert. The CDC said it is still investigating, but based on the early findings so far, it appears that the bowel obstruction rate may be higher than expected.

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COVID, the madness, the sham, the scam, the fear mongering to control the people.

It has been a crazy year, and the madness continues. Culminating into a poisonous, gene altering shot they are trying to push on the masses. Sweden joins Germany, France and 15 other countries in suspending AstraZeneca’s vaccine due to blood clot issues.

 a 49-year-old woman had died as a result of severe coagulation disorder after taking the shot, and that a 35-year-old had developed blood clots in the lungs, but was recovering. Both had received vaccines from the same batch, the authorities said.

Danish authorities said on March 10 that one person who had clots after receiving the vaccine had died.

And similar concerns have been seen with the Moderna and Pfizer vaccines…

Specifically, Whelan was concerned that the new mRNA vaccine technology utilized by Pfizer and Moderna has “the potential to cause microvascular injury (inflammation and small blood clots called microthrombi) to the brain, heart, liver and kidneys in ways that were not assessed in the safety trials.”

While Whelan did not dispute the vaccines’ potential to quickly arrest the spread of the virus (assuming that the vaccines prove to actually prevent transmission — also not assessed in the clinical trials), he cautioned that “it would be vastly worse if hundreds of millions of people were to suffer long-lasting or even permanent damage to their brain or heart microvasculature as a result of failing to appreciate in the short-term an unintended effect of full-length spike protein-based vaccines on other organs.”

Unfortunately, Whelan’s concerns were not acknowledged, and the agency instead relied on the limited clinical trial data. The VRBPAC endorsed the use of the Pfizer vaccine on Dec. 10. The following day, the FDA issued the first COVID-19 vaccine emergency use authorization allowing the Pfizer-BioNTech COVID-19 vaccine to be widely distributed in individuals 16 and older without calling for the additional studies that Whelan felt were critical to assure safety of the vaccine, especially in children.

What many have failed to realize is that the body is self-healing if we stop abusing it with wrong food, the processed garbage disguised as “food”. The alcohol, the bakery items, most anything that has a label is going to impede your body’s ability to function as intended. The best prevention for any illness is to eat the right food, mostly fruits, some greens, vegetables, seeds and nuts. If you were stuck in nature with no tools to work with, what would you be eating? Would you be running down animals and crushing them and killing them and savoring their flesh and bones and blood? That is what a wolf may do, or an animal intended to eat meat, however, humans do not savor raw flesh and blood and bones (unperverted humans, I should say). We would be choosing the brightly colored sweet fruits, that can be eaten as is. Those are the foods we were meant to eat, as is, no prep. Just as a wolf does not prep their prey, nor should we. I changed my diet over 9 years ago and haven’t been sick since. I have intentionally exposed myself to others with covid to prove my point. It’s the terrain, not the germ. Contagion has never been proved. I no longer get sick no matter if I am exposed or not, simply because I keep my terrain healthy by feeding my body proper food. We live in harmony with germs, (most of the time), we are home to trillions of them. When our bodies are healthy and in balance, we thrive. When we eat wrong foods, skimp on sleep and exercise, we put our bodies out of balance. The germs come in to clean up the toxic state we have built up, and the resulting symptoms of release are given a label of disease, such as cold, flu, covid, diabetes, cancer….Cancer being the end state of the body being overwhelmed with toxins, it can no longer eliminate faster than it accumulates.

When you understand that it’s the terrain, not the germ (see Bechamp or Pasteur) you will see why masks are useless and vaccines are dangerous, poisonous to the body/blood. Vaccines only increase the toxic load in your body.

“When you enter into a healing crisis, and your body is throwing off toxins, these “germs” appear out of your very substance, to help eliminate, process and break down these toxins. Germs have absolutely no causal relationship to disease. But germs do appear to help your clean out, because put quite simply, your disease is your cure!”

Dr. William P. Trebing, author of Good-Bye Germ Theory,” page 154

“The entire fabric of the germ theory of disease rests upon assumptions which not only have not been proved, but which are incapable of proof, and many of them can be proved to be the reverse of truth. The basic one of the unproven assumptions, wholly due to Pasteur, is the hypothesis that all the so-called infections and contagious disorders are caused by germs.”

M.L. Leverson, M.D.

“…Viruses are simply the excretions of a toxic cell. [guilty by association]. Viruses are pieces of DNA or RNA, with a few other proteins. They butt out from the cell. They happen when the cell is poisoned. They are not the cause of anything.”

Dr. Thomas Cowan, M.D., comment on Rudolf Steiner’s insights

“If the Germ Theory were true, no one would be alive to believe it.”

B.J. Palmer, D.C.

“We agree with those members of the profession who hold that no germ causes tuberculosis. Germs do not cause any disease. Further, we agree that there is more harm in the fear of germs than there is in the germs themselves.”

Simon Louis Katzoff, M.D., author of Timely Truths on Human Health 1921

“Germs seek their natural habitat: diseased tissue, rather than being the cause of diseased tissue.” [again, guilty by association]

Rudolf Virchow

“The general public have been told that we do not become ill except when germs penetrate into from without. The germ theory of disease is ridiculous.”

E. Douglas Hume, author of Bechamp or Pasteur, A Lost Chapter in the History of Biology

“The most serious, even fatal, disorders may be provoked by the injection of living organisms into the blood; organisms which, existing in the organs proper to them, fulfill necessary and beneficial functions-chemical and physiological-but injected into the blood, into a medium not intended for them, provoke redoubtable manifestations of the gravest morbid phenomena.

Microzymas, morphologically identical, may differ functionally, and those proper to one species cannot be introduced into an animal of another species, or even into another center of activity in the same animal, without serious danger.”

The Blood and Its Third Anatomical Element


So ditch the mask, avoid the vaccine like the plague.  If you want good health, you just need to focus on eating real food and ditching the foods that build disease.  You can see the irony everywhere you look, people obviously in a state of poor health but demanding you wear a mask to protect them, while they continue loading their grocery cart full of ding dongs and twinkies, sugar filled cereal, pastries and chips and sodas. 

In good health. 

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Seven-Step Recipe for Generating Interest in, and Demand for, Flu (or any other) Vaccination

Glen Nowak, then-acting director of media relations at the CDC. Nowak gave the presentation at the National Influenza Vaccine Summit in 2004, co-sponsored by the CDC and the American Medical Association (AMA). In a nutshell, Nowak’s presentation focused on how to use the media to create fear and anxiety to promote vaccination and increase vaccine uptake in the U.S.

A section of his presentation titled “Getting Ready for 2004-2005: Lessons (Re-) Learned [Including the Seven-Step Recipe for Generating Interest in, and Demand for, Flu (or any other) Vaccination  included the following statements:


  • Getting medical experts and public health authorities to “publicly … state concern and alarm (and predict dire outcomes) — and urge influenza vaccination”
  • Publishing media articles and reports saying “that influenza is causing severe illness and/or affecting lots of people, helping foster the perception that many people are susceptible to a bad case of influenza” and “framing of the flu season in terms that motivate behavior (e.g., as ‘very severe,’ ‘more severe than last or past years,’ ‘deadly’)

You can view the entire slideshow here:

Click to access CDC_2004_flu_nowak.pdf

May want to download it in case the link disappears.

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Measles virus for cancer therapy

Since links have a way of going bad, I am copying the page here along with the current link.
. Author manuscript; available in PMC 2014 Feb 17.
Published in final edited form as:
Curr Top Microbiol Immunol. 2009; 330: 213–241.
PMCID: PMC3926122
PMID: 19203112

Measles virus for cancer therapy

Stephen J. Russell, M.D., Ph.D. and Kah Whye Peng, Ph.D.


Measles virus offers an ideal platform from which to build a new generation of safe, effective oncolytic viruses. Occasional “spontaneous” tumor regressions have occurred during natural measles infections, but common tumors do not express SLAM, the wild-type MV receptor, and are therefore not susceptible to the virus. Serendipitously, attenuated vaccine strains of measles virus have adapted to use CD46, a regulator of complement activation that is expressed in higher abundance on human tumor cells than on their non transformed counterparts. For this reason, attenuated measles viruses are potent and selective oncolytic agents showing impressive antitumor activity in mouse xenograft models. The viruses can be engineered to enhance their tumor specificity, increase their antitumor potency and facilitate noninvasive in vivo monitoring of their spread. A major impediment to the successful deployment of oncolytic measles viruses as anticancer agents is the high prevalence of pre-existing anti measles immunity, which impedes bloodstream delivery and curtails intratumoral virus spread. It is hoped that these problems can be addressed by delivering the virus inside measles-infected cell carriers and/or by concomitant administration of immunosuppressive drugs. From a safety perspective, population immunity provides an excellent defense against measles spread from patient to carers and, in fifty years of human experience, reversion of attenuated measles to a wild type pathogenic phenotype has not been observed. Clinical trials testing oncolytic measles viruses as an experimental cancer therapy are currently underway.

Oncolytic Viruses

Viruses that replicate selectively in neoplastic tissues (oncolytic viruses) hold considerable promise as novel therapeutic agents for the treatment of human malignancies and many such agents are currently under investigation, both in preclinical studies and in human clinical trials.[] The existence of viruses was not recognized until the turn of the 19th century, but ever since that time, they have continued to attract considerable interest as possible agents of tumor destruction.[] Clinical observations suggested that, given the right set of conditions, cancers would sometimes regress during naturally acquired virus infections.[] Clinical trials were therefore conducted in which a variety of different human and animal viruses were administered to cancer patients.[] Most often, these viruses were arrested by the host immune system and did not significantly impact tumor growth.[] However, in a few immunosuppressed patients, the infection “took” and tumors regressed, although all too often, this was associated with unacceptable morbidities due to infection of normal tissues. Attempts to address the specificity problem continued throughout the 1950s and 1960s but the results, although encouraging, were not compelling, and with the advent of anticancer chemotherapy, the concept of using replication competent viruses as anticancer agents was largely eclipsed.[] However, by the 1980s it was clear that even the combination of surgery, radiotherapy, and anticancer chemotherapy was failing to substantially impact cancer mortality and with the advent of modern virology accompanied by powerful reverse genetic systems, there came a resurgence of interest in oncolytic viruses.[] During the past two decades, oncolytic virotherapy has reestablished itself as a respectable field of research and there are new numerous ongoing early phase clinical trials testing a wide variety of oncolytic viruses representing many virus families.[]

Why Attenuated Measles Viruses are Attractive Oncolytic Agents

Safety concerns arising from the use of oncolytic viruses for human cancer therapy can be divided into two areas: risk to the patient and risk to the population.[] To minimize risk to the patient, an ideal oncolytic virus should be selective for the tumor, nonpathogenic for normal host tissues, non-persistent and genetically stable. To minimize risk to the population, in addition to the above characteristics, the virus should be non-transmissible and preferably derived from a virus to which the population is generally immune.[]

Attenuated measles viruses fulfill the above requirements. During the past fifty years, live attenuated measles viruses have been administered as vaccines to more than a billion people and the safety record has been outstanding.[] [] Very occasionally, in people with severely compromised immune functions, the viral vaccine has propagated and caused disease in the recipient. However, even in this extreme circumstance, as in the case of an HIV-infected patient with virtually no CD4 lymphocytes who succumbed to measles pneumonia nine months after vaccination,[] there was no evidence that the offending virus had reverted to a pathogenic phenotype capable of spreading and causing disease in normal people.

Tumor Targeting through CD46 Density Discrimination

Wild-type pathogenic and attenuated measles viruses have different receptor tropisms.[] Most importantly, attenuated vaccines strains such as MV-Edm are capable of using CD46 as a cell entry receptor.[] Wild-type measles viruses do not, in general, use CD46 as a cell entry receptor, but acquire the CD46 tropism during tissue culture adaption via a mutation in the H-attachment protein coding sequence that changes the amino acid at position 481 in the H-protein, from asparagine to tyrosine.[] Attenuated measles virus strains carrying this mutation are typically selected when wild-type measles stocks are applied to CD46 positive SLAM negative cell monolayers (for example, Vero cells).[] CD46, also known as membrane cofactor protein, is ubiquitously expressed by all human cells except erythrocytes. [] CD46 plays an important role in protecting autologous cells from complement attack by serving as a cofactor for Factor I-mediated inactivation of C3b and C4b, thus blocking the complement cascade at the C3 activation stage. [] Fortuitously for those wishing to use attenuated measles as a oncolytic agent, CD46 is frequently overexpressed on human cancer cells compared with their normal non-transformed counterparts, possibly as a mechanism to protect the cancer cells from complement mediated lysis.[] Overexpression of CD46 has been documented in gastrointestinal, hepatocellular, colorectal, endometrial, cervical, ovarian, breast, renal, and lung carcinomas, also in leukemias and multiple myeloma, and has been found to limit the therapeutic potential of monoclonal antibody therapy.[]

CD46 mediates not only the attachment and entry of attenuated measles viruses, but also drives the process of virus induced cell-to-cell fusion between a virus infected cell and its neighboring cells. Using engineered Chinese hamster ovary (CHO) cells expressing a range of CD46 densities, it was shown that intercellular fusion between infected and uninfected cells was minimal at low CD46 receptor density, but increased dramatically above a threshold CD46 expression level.[] Virus entry, by contrast, increased progressively with increasing CD46 receptor density, showing no dramatic all-or-nothing threshold effects. Thus, at low CD46 receptor densities typical of normal cells, attenuated measles virus is able to infect but intercellular fusion is negligible. At higher CD46 receptor densities typical of tumor cells, infection leads to extensive intercellular fusion (the classical cytopathic effect of measles virus) culminating in a dramatically increased level of cell killing.[] In one recent study, the levels of CD46 expression on myeloma cells was found to be much higher (49,130 per cell) than levels on corresponding normal bone marrow cells (7,340 per cell) from 38 myeloma patients.[] Potent cytopathic effects of extensive intercellular fusion were observed in the myeloma cells after measles infection, but not in the normal bone marrow cells (Figure 1). Also, the extent of measles virus induced cell fusion varied from patient to patient, but correlated with CD46 expression levels on the myeloma cells, colony forming assays demonstrated that measles was not cytotoxic to the normal bone marrow progenitor cells.[] Discrimination between cells with high and low CD46 receptor densities provides a compelling basis for the oncolytic specificity of attenuated measles viruses and establishes them as a highly promising CD46 targeted cancer therapeutic agent.[]

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Object name is nihms551378f1.jpg

Attenutated measles virus preferentially targets CD46 which is overexpressed on cancer cells, including multiple myeloma cells. (A) Cytospin of a bone marrow aspirate showing myeloma cells. (B) Bone marrow aspirates obtained from myeloma patients were separated into plasma cells (myeloma) and non-plasma cells (all normal hemapoietic cells in the marrow). Cells were stained with an anti-CD46 antibody and the numbers of CD46 receptors/cell were determined using BD-QuantiBrite Beads.[] Primary myeloma cells express 7-fold higher CD46 receptors than normal non-plasma cells in the bone marrow. (C) Primary myeloma cells expressing high levels of CD46 receptors (shown on the left) are more susceptible to the cytopathic effects of measles induced syncytial formation compared to normal bone marrow cells isolated from the same bone marrow aspirates [].

There may be additional factors contributing to the tumor specificity of attenuated measles virus besides CD46 receptor density. One possible contributing factor could be a higher intrinsic membrane fusogenicity in tumor cells, making them more likely to undergo intercellular fusion when infected by measles virus, regardless of the surface density of CD46.[] Another factor might be that there are deficiencies in the innate antiviral responses of tumor cells that render them more highly susceptible to virus infection. [] For example, the interferon-α/β and RNA-dependent protein kinase response pathways are often impaired in tumor cells but not in normal cells, and this is the mechanism underlying the tumor selectivity of a number of RNA viruses currently being tested for cancer therapy, such as vesicular stomatitis virus and reovirus.[] These same innate viral control mechanisms may also serve, albeit to a lesser extent, to control the propagation of attenuated measles viruses.

Safety to Population

The main public safety concern associated with the therapeutic use of an oncolytic virus is accidental emergence of a new viral pathogen capable of epidemic spread in the human population.[] Serious epidemics arise when pathogenic viruses gain access to susceptible populations under conditions which favor transmission between individual members of the population. In selecting a virus from which to develop an oncolytic antitumor agent for human use, consideration should be given to its mutability, potential pathogenicity, potential transmissibility, and prevalence in the population. As mentioned above, even though the measles vaccine has been given to more than one billion people over the past fifty years, there has never been yet a documented reversion to wild-type measles.[] Moreover, in contrast to viruses such as influenza which are inheritantly unstable, requiring new vaccines every year, measles virus has remained very stable and has been effectively controlled by essentially the same vaccine for decades.[] Even if one considers the worst case scenario wherein an attenuated measles virus used for cancer therapy might revert back to wild-type pathogenic strain, the risk of virus transmission from patients to carers and then into the population is limited by the high prevalence of anti-measles immunity. At the current time because of the successful childhood measles vaccination programs which give lifelong protection, more than 80% of the people in the world are currently measles immune.[] For this reason, attenuated measles viruses raise significantly fewer safety concerns than oncolytic viruses derived from other virus families.

Oncolytic Activity of Wild-Type and Attenuated (Vaccine Strain) Measles Viruses

Occasional “spontaneous” tumor regressions of Hodgkin’s disease and Burkitt’s lymphoma have been documented after measles infections.[] Perhaps the most compelling was the case history of an 8-year old African boy who presented to a clinic in Uganda with a four month history of painless right orbital swelling. A biopsy specimen of the right retroorbital tumor was histologically diagnostic of Burkitt’s lymphoma but at the time of planned initiation of therapy, he was noted to have a generalized measles rash. On the same day, the right orbital tumor was noted to be regressing and because of the presumed measles infection, he was given no chemotherapy for the Burkitt’s lymphoma. During the course of the next two weeks, his rash disappeared and he seroconverted to measles. At the same time, the tumor regressed completely and remained in complete remission for at least four months after the measles infection in the absence of antineoplastic therapy. The mechanism underlying the rapid tumor regression that was observed in this remarkable case history was never elucidated but Burkitt’s lymphomas are known to express high levels of SLAM and are therefore susceptible to infection by wild-type measles viruses.[] The timing of the regression, coinciding with the period during which measles virus burden and measles-induced immunosuppression are at their peak, supports the contention that the tumor cells were directly destroyed by the virus.

It could be argued on the basis of case histories such as the one described above that there would be some value to treating cancer patients with a wild-type pathogenic strain of measles. However, there are strong safety and efficacy arguments against this. From a safety perspective, measles is a serious and unpleasant illness which is highly transmissible to non-immune subjects and is sometimes fatal.[] Regarding efficacy, as discussed previously, most human malignancies lack receptors for wild-type measles viruses[] and therefore, are not even theoretically susceptible to its possible oncolytic actions. Attenuated vaccine strains of measles virus, by contrast, have far greater appeal as possible oncolytic agents for intentional administration to human cancer patients. Most of the measles vaccine strains in current use belong to the Edmonston lineage which comprises a number of closely interrelated laboratory-adapted substrains derived from a 1954 clinical isolate (from the throat of a child named David Edmonston) that has been passaged extensively in tissue culture, resulting in a loss of pathogenicity.[] The MV-Edm vaccine was initially licensed in 1963 but was found to be reactogenic, causing fever and rash in measles-naïve children.[] The virus was passaged further in other cells, including chick embryo fibroblasts, giving rise to more highly attenuated vaccine strains, including MV-Moraten which was licensed as Attenuvax in the United States in 1968 and the Edmonston-Zagreb strain (MV-EZ), a strain which has been used extensively in Europe.[] In contrast to wild-type measles viruses, all the laboratory-adapted Edmonston strains of measles virus have acquired the ability to use CD46 as a receptor to mediate virus entry and intercellular fusion.[]

Preclinical studies to test the oncolytic potential of attenuated Edmonston lineage viruses were first conducted at the turn of the 20th century using a genetically modified derivative of the Edmonston-B strain (MV-Edm tag) that was rescued from a molecular clone of the viral genome and was subsequently amplified on Vero cells.[] The Edm-tag strain and its genetically engineered derivatives (see below) were found to be selectively destructive to human tumor cells in culture[] and showed promising antitumor activity in several mouse xenografts models of different human malignancies including lymphoma, multiple myeloma, ovarian, colorectal, breast, liver cancer and glioma.[] However, clinical testing of these engineered measles strains presented considerable logistic challenges, including the need to develop new manufacturing processes, validate the clinical products, and perform extensive toxicology testing to confirm their safety. For these reasons, there was a strong impetus to take the simple path and explore the possibility of using agents that had already been approved for human use, such as the Moraten and Edmonston-Zagreb measles vaccines, as oncolytic agents for cancer therapy. For this reason, the oncolytic potential of the commercially available Moraten measles vaccine was tested in a murine intraperitoneal model of human ovarian cancer and was compared with the efficacy of a recombinant MV-Edm tag derived viral strain.[] In vitro, the Moraten strain was able to infect human ovarian cancer cells, but caused intercellular fusion with greatly delayed kinetics compared to the MV-Edm tag strain. However, in vivo studies in ovarian cancer models showed that both viruses had equivalent antitumor potency causing significant prolongations in survival after intraperitoneal administration of a total dose of 106 infectious units.[] Unfortunately, since the Moraten vaccine is packaged and sold commercially in doses of only 103 TCID50 it was considered impractical to proceed to a clinical trial in which, it was anticipated, MV-Moraten doses in excess of 108 TCID50 (i.e., 100,000 times the vaccination dose) would be required for oncolytic efficacy.

While there have been no human studies evaluating the oncolytic potential of the MV-Moraten vaccine strain, a Phase I clinical study using the Edmonston-Zagreb vaccine strain was conducted in Zurich in patients with cutaneus T-cell lymphoma.[] A total of five patients were enrolled in this study and the Edmonston-Zagreb vaccine strain of measles virus was administered directly into accessible cutaneous tumors for up to a total of four doses. Each virus injection was preceded by two subcutaneous injections of interferon-alpha (9 million units subcutaneously), at 72 hours and 24 hours previously. This was a dose escalation study with a minimum intratumoral dose of 100 TCID50 and a maximum dose of 1,000 TCID50of the MV-Edmonston-Zagreb virus. The treatment was very well tolerated and five of six MV-injected lesions showed clear regression. In two of the patients distant non-injected lesions improved, but they remained unchanged in the other three of five. In all five patients there was a slight increase in the anti-measles antibody titer after therapy. These very promising data were published in October 2005 and follow-on studies are eagerly awaited.[]

Engineering Attenuated Measles Viruses to Enhance Their Utility as Oncolytic Agents

A reverse genetic system for the generation of recombinant measles viruses derived from MV-Edm tag was first reported in 1996.[] This opened the door for the generation of recombinant measles viruses encoding additional transcription units as well as the engineering of viral structural and nonstructural protein coding sequences to modulate virus biology (Figure 2). Genome engineering has therefore emerged as an important approach whereby new versions of the MV-Edm tag virus can be generated as a way to enhance its performance in cancer therapy. Efforts to date have focused on the generation of recombinant viruses whose in vivo spread can be noninvasively monitored as well as the generation of viruses that can more effectively combat host innate immune responses or that can more accurately recognize and destroy neoplastic tissues. Each of these approaches is discussed separately below.

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Genetic engineering of attenuated measles virus for cancer therapy. (A) The virus can be engineered to express soluble marker proteins (eg. MV-CEA) which are secreted into the circulation, thus enabling noninvasive monitoring of the profiles of viral gene expression over time by sampling body fluids[]. (B) The virus can be engineered to express the sodium iodide symporter (MV-NIS) which concentrates radioiodine in the infected cell, thus enabling noninvasive monitoring of the sites of MV infection by gamma camera, SPECT-CT or PET-CT imaging.[] Virotherapy can also be enhanced by a timely dose of beta-emitting I-131 to result in synergistic killing of MV infected tumors. (C) Arming of the virus with genes (e.g. P-gene from wild-type measles) that enable the virus to combat the innate antiviral immunity []. (D) Targeting virus entry, the H glycoprotein of measles virus can accommodate addition of large polypeptides (eg. Single-chain antibodies) as C-terminal extensions on the H protein. Mutations in the H protein that ablate fusion via CD46 and SLAM have been identified and incorporated in the retargeted viruses. The displayed ligand redirects binding of the virus to the new receptor to mediate virus entry and syncytial formation via the targeted receptor.[]

Noninvasive monitoring of measles virus spread

Pharmacokinetics describes the fate of a drug in the body including its absorption, distribution, biotransformation, and excretion. Unfortunately, pharmacokinetic issues have not been adequately addressed in previous human virotherapy studies and this is proving to be a significant impediment to the intelligent clinical development of these agents. Ideally, it should be possible to noninvasively monitor the in vivo spread and elimination of an oncolytic virus in a treated cancer patient, and to determine the profile of viral gene expression over time. In the absence of data on virus kinetics, it is not possible to know whether a failed response to therapy is due to lack of infection, inadequate virus spread, weakened cytopathic effect, or premature virus elimination. Noninvasive monitoring should therefore be an integral component of human studies of oncolytic measles viruses and has the potential to facilitate the tailoring of virotherapy protocols for individual patients.

Two approaches have been taken to facilitate in vivo monitoring of the spread of oncolytic measles viruses (Figure 2). In the first approach, additional transcription units coding for soluble marker peptides were inserted into the viral genome.[] It was reasoned that ideal marker peptides should be non immunogenic with no biological function and a constant circulation half life. They should also be efficiently secreted from virus infected cells into the blood stream. The soluble extracellular domain of human carcinoembryonic antigen (CEA) and the β–subunit of human chorionic gonadotrophin (βhCG) were therefore chosen for this approach. Oncolytic measles viruses expressing each of these transgenes from an additional transcription unit inserted upstream of the N gene were constructed.[] The marker peptides did not compromise virus replication and the kinetics of virus propagation in CD46 transgenic mice could be easily followed by measuring concentrations of the virally encoded marker peptides in serum. When mice bearing human tumor xenografts were challenged with the trackable viruses, different kinetic profiles of marker gene expression could be correlated with distinct therapeutic outcomes.[] In subsequent studies, the MV-CEA virus was shown to retain its potent oncolytic activity in preclinical models of ovarian cancer[] and subsequently in brain cancer[] which provided the impetus for its advancement to Phase I clinical testing in patients with each of these malignancies (see below).

While virally encoded soluble marker peptides do provide for noninvasive monitoring of the total burden of virus infected cells and tissues in the body, they do not provide any anatomical information about the location of virus infected cells (Figure 2). To this end, a second recombinant measles virus was generated coding for the human thyroidal sodium iodide symporter (NIS).[] NIS is a membrane ion channel expressed on thyroid follicular cells which efficiently transports iodine (required for thyroxin production) into cells against its concentration gradient.[] Thyroidal NIS expression has been exploited for more than fifty years in clinical practice for thyroid imaging (with I-123) or ablation (with I-131) and for systemic therapy of well differentiated thyroid malignancies.[] MV-NIS infected cells are able to concentrate radioactive iodine from the bloodstream, enabling the status of an infection to be monitored by serial noninvasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging using I-123 or I-124 as tracers respectively.[] The approach has been used for noninvasive monitoring of intratumoral virus propagation in preclinical models of multiple myeloma, pancreatic, hepatocellular, and ovarian carcinoma, and has further been used to enhance the therapeutic potency of measles virotherapy by judiciously timed administration of the β-emitting radioiodine isotope I-131.[] Interestingly the recombinant measles virus in which NIS was inserted between the H and L cistrons is able to propagate as efficiently as the MV-Edm tag strain from which it was derived and is potently oncolytic even in the absence of I-131.[] Based on these favorable characteristics, the MV-NIS virus has been advanced to Phase I clinical testing in patients with multiple myeloma (see below)

The interaction of a replicating measles virus with tumor cells and with the host immune system represents a complex dynamical system that can be analyzed mathematically as a problem in population dynamics.[] The outcome of this type of therapy depends in a complex way on the intricate interactions between the various populations involved and modeling of the kinetics of virotherapy may aid in improved understanding of treatment outcomes and in the design of improved therapeutic protocols. Mathematical models of cancer virotherapy with recombinant measles viruses and of radiovirotherapy using the combination of MV-NIS and radioactive I-131 have been developed and provide a reasonably good fit to experimental data.[]

Arming the Virus to Combat Innate Immunity

Pathogenic measles viruses are capable of combating the cellular innate immune response. They do this by means of the P/VC proteins encoded in the phospho protein (P) transcription unit.[] The P and V proteins are particularly implicated in measles immune evasion and have been shown to inhibit interferon-induced STAT nuclear translocation and to suppress STAT1 and STAT2 phosphorylation.[] Attenuated measles viruses are typically mutated in their P and V proteins and are therefore unable to efficiently suppress innate immune responses. [] As a consequence, wild-type measles isolates induce significantly lower release of interferon upon infecting peripheral blood lymphocytes when compared to attenuated strains.[]

As a general rule, tumor cells are thought to have defects in their interferon response pathways such that they are unable to mount effective innate antiviral responses.[] However, this is not an absolute deficiency. Oncolytic measles viruses derived from the MV-Edm tag infectious clone were shown to induce significantly higher levels of interferon in both normal and tumor cells when compared to a wild-type measles virus.[] Moreover, pretreatment of tumor cells with interferon prior to measles infection did significantly compromise viral gene expression. Based on these observations, a chimeric measles virus based on the Edm-tag platform, but armed with a wild-type P-gene, was generated and evaluated both in vitro and in vivo for antineoplastic activity.[] As expected, the chimeric virus exhibited a reduced capacity to induce interferon in infected cells, and when intravenously administered to SCID mice bearing human myeloma xenografts, showed greater oncolytic potency. This study served to emphasize that oncolytic measles viruses can be subject to control by the innate immune defenses of human tumor cells and may therefore be more effective when engineered to rearm them with wild-type proteins that silence the innate immune response. This engineering strategy does raise the legitimate concern that rearming an attenuated measles virus with a wild-type P-gene to permit more effective immune evasion may generate a more pathogenic agent and thereby compromise patient safety. However, measles virus virulence and pathogenicity are known to be complex and does not depend solely on P/V/C proteins.[] Clinical testing of oncolytic measles viruses that have been engineered to more effectively combat the innate intracellular immune response is not currently being pursued. However, depending upon the clinical outcomes (i.e., efficacy versus toxicity) of ongoing clinical trials which are using highly attenuated measles viruses, there may be a good rationale for testing such fortified viruses in the future.

Engineering Measles Virus Tropism

At this time, measles is still the only virus that can be efficiently retargeted through a broad range of cellular receptors without significant reductions in entry efficiency.[] However, while the retargeting of measles virus entry is without question an extraordinary technical triumph, its utility has yet to be proven. The original rationale for attempting to redirect the tropisms of oncolytic measles viruses was the incorrect assumption that, because it is expressed ubiquitously, CD46 would not be tumor selective. However, as outlined previously, the oncolytic strains of measles virus in current use do efficiently discriminate between the high density of CD46 expressed on tumor cells and the lower densities of this receptor present on non-transformed cells.[] As such, these viruses already discriminate and selectively destroy cancer cells by targeting CD46. For this reason, unless significant toxicities arising from collateral damage to normal tissues are encountered in ongoing clinical studies using the non-targeted viruses MV-CEA and MV-NIS in patients with ovarian cancer, glioma, and multiple myeloma, it will be difficult to justify the use of fully retargeted viruses. However, it is possible that certain tumor types will prove to have lower levels of CD46 receptor expression, in which case there may be a stronger case for using viruses with alternative, engineered receptor tropisms. In addition, for intravenously administered viruses, the ability to interact with the lumenal surface of vascular endothelial cells lining tumor blood vessels might lead to significant enhancements in virus uptake at sites of tumor growth.

Initial efforts to engineer foreign polypeptides into the measles virus coat were focused on the Fusion (F) protein. But even small modifications to the extreme N-terminus of this protein completely destroyed its ability to provide fusion support (Morling F and Russell SJ, unpublished). In contrast to the F protein, the Hemagglutinin (H), a type II membrane glycoprotein, was able to tolerate the insertion of large polypeptides sequences at or close to its extreme C-terminus without compromising its ability to be incorporated into virus particles and to provide fusion support functions. Building upon this observation, recombinant viral genomes coding for chimeric H-glycoproteins with a variety of different C-terminal extensions were constructed and rescued as recombinant infectious viral particles. In this way, it was possible to display a wide variety of different ligands on the viral surface, including growth factors (human EGF and IGF 1), single-chain antibodies (against CEA CD38, CD20, EGF receptor, and others), single-chain T cell receptors, and snake venom peptides such as Echistatin. [] In each case the recombinant viruses were shown to display multiple copies of the respective polypeptides on the surface and were endowed not only with new binding specificities, but also with expanded tropisms. Thus each recombinant virus was able to bind and enter cells via its targeted receptor and thereafter to drive the process of intercellular fusion between the infected cell and neighboring receptor positive cells.

Having determined that the tropisms of recombinant measles viruses could be expanded by surface display of cell binding polypeptides, the next step was to engineer the underlying H-protein to ablate the natural virus tropisms for CD46 and SLAM. [] Several different mutations known to interfere with binding to either CD46[] or SLAM[] were therefore engineered into an H-expression construct coding for a chimeric H-protein displaying a single-chain antibody against CD38. Numerous different permutations of CD46 and SLAM ablating mutations were tested in a screening system, wherein the H-expression constructs were co-transfected with an F-expression plasmid into cells expressing receptors for CD46, SLAM, or CD38 respectively.(Nakamura T and Russell SJ, unpublished) In this way, a construct with mutations at residues 481 (Y to A) and 533 (R to A) was found to efficiently mediate antibody targeted cell fusion, even when the displayed domain was replaced with single-chain antibodies recognizing alternative cellular targets (EGFR and EGFRvIII).[] Subsequently, these fully retargeted H-coding sequences were engineered into recombinant measles virus genomes and the corresponding viruses were recovered.[] In each case, recombinant viruses displaying single-chain antibodies on a doubly ablated H-protein displayed the expected (fully retargeted) host range properties and could be used to mediate targeted destruction of tumors expressing the appropriate cognate receptor in living mice.

One technical issue associated with the rescue and propagation of fully retargeted viruses was the requirement that the targeted receptor should be expressed on the cells being used as a substrate for virus growth. This was addressed in two ways, either by generating Vero cells expressing the targeted receptors[] or, alternatively, by means of a pseudo receptor system using Vero-α His cells expressing a membrane anchored single-chain antibody that recognizes a hexahistidine peptide (H6).[] The H6 peptide was then incorporated at the extreme C-terminus of the chimeric H-proteins of fully retargeted viruses, such that they could be efficiently rescued and propagated on the Vero-α His cells.[] This system has subsequently been used to generate fully retargeted viruses displaying single-chain antibodies with diverse receptor specificities. At the current time, the list includes viruses retargeted to CD38, EGFR, EGFRvIII, α-folate receptor, HER2/neu, CD20, CD19, CD52, prostate specific membrane antigen (PSMA) and the myeloma antigens HM1.24 and Wue-1. (Russell SJ, unpublished) [] Interestingly, where tested, the new tropisms conferred on measles viruses by displayed scFvs are stably maintained during multiple serial virus passages without reversion to native receptor usage. While one conclusion from the aforementioned studies is that measles virus has a remarkably flexible and adaptable entry mechanism that can utilize multiple alternative cellular receptors, it has also become apparent that there can be significant differences in the efficiency of virus entry and intercellular fusion depending on the precise specificity and affinity of the displayed ligand. To further explore the relationship between the affinity of a displayed ligand for its targeted receptor and the behavior of the retargeted viruses, a panel of six recombinant HER2/neu retargeted measles viruses was generated displaying a panel of single-chain antibodies with identical HER2/neu receptor specificities but with dissociation constants ranging from 1.6 × 10−6M to 1.5 × 10−11 M.[] Comparisons of the infectivities and cytopathic effects of these viruses on a panel of cell lines expressing different surface densities of the HER2/neu receptor gave quite unexpected results, showing that there was a functional threshold affinity level above which infection and intercellular fusion proceeded with equal efficiency, even when affinity increased over 1,000-fold above the threshold level. Below the threshold, infection was minimal. This affinity threshold was shown to correlate inversely with receptor density such that higher affinities were required to fuse cells with lower receptor densities. Thus, depending on their receptor affinities, retargeted measles viruses are able to discriminate efficiently between cells expressing different densities of a targeted receptor.[]

Several in vivo therapy studies have been published in which fully retargeted viruses have been administered to mice bearing human tumor xenografts by intratumoral, intraperitoneal, or intravenous routes resulting in retardation of tumor growth and prolongation of survival. Examples include the use of measles viruses targeted to EGF receptor in ovarian cancer and glioma models, viruses targeted to the α-folate receptor in an ovarian cancer model, EGFRvIII targeted viruses for glioma, and CD38 or CD20 targeted viruses for the treatment of two different mouse lymphoma models.[] In general, the retargeted viruses showed at least equivalent antitumor activity compared to the parental MV-Edm tag strain, but with reduced capacity to cause damage to the brains of CD46 transgenic mice.

As discussed previously, it is still an open question whether fully retargeted measles viruses can offer therapeutic advantages over the CD46 specific viruses that are currently undergoing clinical testing. However, it is hoped that measles viruses that can interact more efficiently with markers expressed on the lumenal surfaces of the endothelial cells lining tumor blood vessels will more efficiently localize to sites of tumor growth when infused into the bloodstream. Exploratory studies using measles viruses displaying αvβ3 integrin binding peptides (cyclic RGD and Echistatin) as extensions of their H proteins have shown that they can, at least, interact with the lumenal surface of developing neovessels in the chick chorioallantoic membrane and that they can be transcystosed across the vascular endothelium of these vessels into the interstitial space (Peng KW and Russell SJ, unpublished).

Clinical Translation of Recombinant Oncolytic Measles Viruses

Of the recombinant measles viruses discussed in the previous section, two (MV-CEA and MV-NIS) are currently being administered to cancer patients in Phase I clinical trials. MV-CEA is being infused into the peritoneal cavities of patients with advanced treatment refractory ovarian cancer, and in a second trial, is being administered into the tumor bed after surgical excision of high-grade tumors of the brain. MV-NIS is being administered intravenously to patients with advanced treatment refractory multiple myeloma. Approval for these clinical protocols was, in each case, preceded by a detailed FDA review of the clinical protocol design, the manufacturing process, the purity, identity, and sterility of the manufactured product, the results of preclinical efficacy studies, and the results of comprehensive toxicology and biodistribution studies conducted in appropriate animal models.


Based on the doses of MV-CEA and MV-NIS that were required to mediate tumor regression in mouse xenograft models of human cancer, it was projected that doses of virus in the region of 109 TCID50 would be required for clinical efficacy. A single dose of the Moraten measles vaccine contains somewhere between 103 and 104 TCID50 and existing manufacturing processes used by major measles vaccine suppliers were unsuitable for the generation of high titer viral stocks required for oncolytic applications.[] A new process was therefore developed for the scaled manufacture and partial purification of oncolytic measles viruses using the immortal Vero cell line as substrate. Manufacture of clinical grade lots of both MV-CEA and MV-NIS was then completed in a pilot manufacturing facility at Mayo Clinic Rochester, adhering to the principles of Good Manufacturing Practices (GMP).

Choice of Animal Models for Toxicology Studies

Because they are derived from attenuated laboratory adapted strains of measles virus, the host range properties of MV-CEA and MV-NIS are quite distinct from those of wild-type pathogenic measles virus strains. As mentioned previously, these viruses efficiently exploit CD46 as a receptor for binding, cell entry and cell fusion and this receptor usage is a critical factor influencing the choice of an appropriate animal model for pharmacology and toxicology studies. As for other vaccine strains of measles viruses, because they are highly attenuated (i.e., non pathogenic) there is no model in which to study their pathogenesis. The three animal models that have proven to be of some considerable value for FDA mandated preclinical studies of biodistribution and toxicity are Rhesus monkeys (Old World primates), squirrel monkeys (New World primates), and interferon α/β receptor knockout CD46 transgenic mice.

CD46 transgenic mouse models were originally created in the hope that they might facilitate the study of measles virus pathogenesis. [] However dissemination of viruses belonging to the Edmonston lineage has only ever been observed in CD46 mice lacking the interferon α/β receptor (IFNARko xCD46-Ge).[] These mice express human CD46 in a tissue distribution that mimics the pattern of CD46 expression in humans, including low to absent of expression on erythrocytes.[] After intranasal challenge with MV-tag the animals showed local virus replication in the respiratory epithelium followed by dissemination via the lymph node system, similar to the pattern of wild-type measles virus dissemination in the human host.[] Infection of cells of the monocyte macrophage lineage is prominent in this model.[]

An alternative and better established model for the study of measles virus pathogenesis is the Rhesus monkey which, like other Old World non-human primates, develops a measles-like illness when challenged with wild-type measles virus.[] However, Rhesus monkeys do not provide, by any means, a perfect model in which to test the virulence of tissue culture adapted measles viruses that use CD46 as a receptor.[] Previous studies have shown repeatedly that Rhesus monkey virulence studies of attenuated measles viruses are not predictive of their reactogenicity (i.e., the ability to cause measles-like illness) in humans.[] Numerous attenuated measles viruses have been tested in primates during the development of new measles virus vaccines []and despite the fact that they have scored completely negative in this Macaque-virulence test, they have proven to be reactogenic in humans, causing a morbilliform rash, often accompanied by fever and malaise in a high percentage of recipients.[] The key deficiency of the Macaque-virulence model is that the tissue distribution of CD46 in Macaque differs significantly from humans. Most importantly, CD46 is abundant on Macaque red blood cells, but is absent from human red blood cells.[] CD46 binding strains of measles virus, therefore, are agglutinated on Macaque, but not human red blood cells, an interaction that most likely impedes virus dissemination in the primates. The Macaque model was therefore considered to be suboptimal for toxicity studies in which recombinant measles viruses are administered into the bloodstream, but was considered relevant when studying the toxicity of intracerebral MV-CEA (see below).

Unlike Old World primates, New World primates, such as the squirrel monkey (Saimiri sciureus) express a truncated CD46 molecule to which MV-Edm does not attach.[] The red cells of New World monkeys are, therefore, not agglutinated by attenuated measles viruses but these animals do get a measles-like illness when challenged with wild-type measles virus, making them an informative model in which to test the toxicities of oncolytic measles viruses arising from their interactions with the wild-type measles receptor SLAM. Squirrel monkeys challenged with wild-type measles virus develop a classical measles-like illness characterized by fever, coryza rash, immunosuppression, and subsequent recovery.[]

Pharmacology / Toxicology Testing of MV-CEA and MV-NIS

To support the first clinical protocol, a Phase I trial of intraperitoneal administration of MV-CEA in patients with recurrent ovarian cancer, the formal biodistribution and toxicology studies were conducted in IFNARko xCD46-Ge mice.[] The key findings were that MV-CEA administered into the peritoneal cavity efficiently infected peritoneal macrophages and these trafficked to abdominal draining lymph nodes, as well as to the marginal zones of the spleen. CEA expression peaked between days 2 and 5 and returned to baseline by day 10, due to virus elimination. There was no evidence of virus shedding in the urine or respiratory secretions, but there was some evidence for long-term persistence of viral genomes in the spleens of infected animals. Measles viruses encoding different marker genes were also employed for biodistribution studies and green fluorescent protein proved to be highly informative. Mesothelium and ovarian surface epithelium were remarkably resistant to infection but peritoneal macrophages were susceptible. Large numbers of infected macrophages could be detected in the greater omentum concentrated in “milky spots”. Infected macrophages were also identified outside the peritoneal cavity at diaphragmatic stomata along lymphatic vessels and in the parathymic lymph nodes. Eventually, the cells escaped into the blood stream and could be identified in the marginal zones of the white pulp of the spleen.

In toxicology studies, MV-CEA was administered into the peritoneal cavity (maximum dose 107 TCID50) and the animals were closely monitored for activity level, general appearance, body weight, key hematological and biochemical parameters, and serum CEA levels (Peng KW, Myers RM and Russell SJ, unpublished). Necropsies were conducted on days 14, 28, and 91 after virus administration and all organs were sent for histopathological analysis. The study was essentially negative with no significant toxicities encountered at any dose level. Dose response studies in a SKOV3.ip1 intraperitoneal ovarian cancer xenograft model revealed that the virus was equally effective over a wide range of dose levels, from 6 × 107 down to 6 × 103 TCID50. Analysis of CEA profiles in the treated mice was highly informative, illustrating the variability of virus kinetics at different dose levels. The highest doses of virus were associated with higher initial levels of tumor cell killing, but the final outcome of MV-CEA therapy at all dose levels was a partial equilibrium between virus and tumor, resulting in significant slowing of tumor growth and enhanced survival of the mice[].

In support of the Phase I brain cancer study of intratumoral and/or resection cavity administration of MV-CEA in patients with recurrent glioblastoma multiforme, toxicology studies were conducted both in IFNARko xCD46-Ge mice and in Rhesus monkeys.[] In both cases, the virus was delivered by intracerebral inoculation and animals were carefully observed for signs of neurological impairment or other organ damage. MV-Edm is known to be neuropathogenic in measles-naïve IFNARko xCD46-Ge mice and the animals were therefore pre-immunized by intraperitoneal administration of MV-GFP for one month prior to the initiation of toxicology. The animals were closely monitored for 90 days after intracerebral inoculation with MV-CEA but there was no evidence for neurotoxicity, neither clinically nor upon histological examination of brain sections at various timepoints after virus administration. For toxicity testing in monkeys, five adult measles-immune Rhesus Macaques received intracerebral injections of MV-CEA (105 or 106 TCID50) or vehicle control into the frontal lobe on days 1 and 5. The animals were monitored closely thereafter. Monitoring studies included clinical observation, analysis of blood samples, throat swabs, and cerebral-spinal fluid and MRI imaging of the brain. There was no evidence in this study for MV-CEA-mediated neurotoxicity.

In support of the Phase I clinical trial testing intravenous administration of MV-NIS, with or without cyclophosphamide, in patients with multiple myeloma, preclinical pharmacology and toxicology studies were conducted in SCID mice bearing subcutaneous myeloma xenografts, non-tumor bearing IFNARkoxCD46-Ge mice, and in measles-naïve squirrel monkeys.[] Dose response studies conducted in the KAS-6/1 myeloma xenograft model demonstrated that a single intravenous dose of 4 × 106 TCID50 per kilogram of MV-NIS was the minimum dose that reliably led to tumor regression and prolongation of survival. Toxicity studies in IFNARko xCD46-Ge mice were negative up to a single intravenous dose of 4 × 108 TCID50 per kilogram. A single dose of cyclophosphamide given prior to virus administration did significantly impede the antiviral immune response in this model, leading to delayed virus elimination. Virus associated toxicities were not observed in measles-naïve squirrel monkeys, even at very high intravenous doses of 108 TCID50 per kilogram of MV-NIS given alone or in combination with cyclophosphamide. Viral mRNA was detected in cheek swabs harvested from the squirrel monkeys on days 1, 2, 8, 15, and 22 after MV-NIS administration and copy numbers were higher at all timepoints in the cyclophosphamide treated animals with peak levels seen on day 8. Based on these studies, a safe starting dose of MV-NIS for the clinical protocol was set at 1.5 by 104 TCID50 per kilogram (106 TCID50 per patient) increasing to a maximum of 1.5 × 107 TCID50 per kilogram (109 TCID50 per patient) with a single-dose of 10 milligrams per kilogram cyclophosphamide administered 24 hours earlier by intravenous infusion.

Current Status of Clinical Trials

Each of the three Phase I clinical trials discussed above is progressing satisfactorily. The first patient to receive a recombinant measles virus had advanced ovarian cancer and received a series of six intraperitoneal infusions of MV-CEA starting in July 2004. To date, 20 patients have been treated in the ovarian cancer study at seven dose levels (103 to 109 TCID50). The study is progressing satisfactorily and the results will be published in the near future. Two patients with glioblastoma multiforme have so far been enrolled into the intracerebral MV-CEA study and six patients with multiple myeloma have been enrolled for intravenous administration of MV-NIS at two dose levels (106 TCID50 and 107 TCID50). Each of these clinical studies is progressing satisfactorily but detailed reports of the trial outcomes will not be published until the trials have been completed.

Enhancing the Efficacy of Oncolytic Measles Viruses: Immune Evasion and Immune Suppression

For successful virotherapy of disseminated malignancies, oncolytic measles viruses will have to be delivered via the bloodstream. Optimal treatment outcomes will require efficient delivery via the bloodstream to sites of tumor growth and this should be followed by efficient intratumoral spread, leading to tumor destruction. Each of these processes can be severely constrained by anti-measles immunity; delivery by humoral immunity, and spread by cell mediated immunity (Figure 3). Considerable attention has therefore been focused on the use of cells as delivery vehicles to circumvent the humoral anti-measles immune response, and on the use of immunosuppressive drugs to combat cell mediated anti-measles immunity. These two approaches are discussed below.

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Considerations for future improvements of measles virotherapy. Ideally, intravascularly administered viruses will reach the tumor sites to result in infection of tumor cells, viral spread and elimination of the tumors. However, anti-measles antibodies can potentially inhibit delivery of the viruses and viral spread in the infected tumor can be inhibited by cell mediated immunity. To combat these barriers to successful therapy, virus infected cell carriers can be exploited to act as Trojan horses to deliver virus to the tumor sites and cell mediated immunity can be controlled by judicious use of immunosuppressive agents such as cyclophosphamide.

Use of Cell Carriers to Deliver Oncolytic Measles Viruses to Sites of Tumor Growth

Irrespective of the presence of antiviral antibodies, many intravenously administered viruses are sequestered in the microcirculations of lung, liver, and spleen, where they are phagocytosed by macrophages.[] It is the small percentage of intravenously administered viruses escaping this fate that infect the tumor tissue and mediate the regressions that are seen in preclinical models. However, these viruses are highly vulnerable to the neutralizing activities of antiviral antibodies, which have a dramatic titer dependent effect on the speed of virus inactivation.[] Also, antibody titers increase progressively with each successive exposure to the virus.[] Because of prior measles infection or measles vaccination, approximately 90% of Americans have protective titers of anti-measles antibodies which may limit the therapeutic efficacy of systemically administered measles viruses.[] In contrast to the general population, patients with multiple myeloma have profound suppression of their humoral immune-responses and low antibody titers to measles virus, making them ideal candidates for systemic oncolytic measles virus therapy.[] However, most patients suffering from other cancers do have healthy protective titers of anti-measles antibodies. The protective properties of anti-measles antibodies were well demonstrated in the pre-vaccination era when serum from convalescing measles patients was used as post-exposure prophylaxis for children at risk.[] Interestingly, serotherapy was only effective if administered within six days of measles virus exposure, indicating that it cannot prevent the cell associated viremia and dissemination of measles virus via the bloodstream that occurs towards the end of the incubation period (days 10–14 after initial exposure, coincident with the prodromal symptoms and rash).[] Importantly, cell free viremia has not been recorded in natural measles infections.[] The virus enters via the respiratory tract, migrates locally to lymphoid tissues and then enters the bloodstream, only inside cells, typically monocytes or lymphocytes which transport it to distant sites where it causes the typical rash and other disease features.[]

On the basis of the above insights into how measles virus can travel via the bloodstream, even the presence of antiviral antibodies, there is considerable interest in the use of infected cell carriers to deliver oncolytic measles viruses to sites of tumor growth.[] Not only does this approach have the potential to avoid neutralization by antiviral antibodies, but might also prevent mislocalization of the virus in liver and spleen, as well as aiding extravasation from tumor blood vessels. In vitro studies demonstrated that in contrast to infection by naked virions, heterofusion between infected cell carriers and tumor cells was more resistant to antibody neutralization. [] Moreover, systemic and intraperitoneal injection of measles infected cells successfully transferred infection in vivo to sites of tumor growth (using xenograft models of lymphoma, hepatocellular carcinoma, and multiple myeloma) even in the presence of neutralizing antibodies.[] Monocytes, endothelial progenitor cells, and T lymphocytes were also shown to have potential as measles virus carriers, but considerable optimization of the approach is required since, to date, the enhancements in efficacy that have been achieved using this approach have been very small.

Combination Therapy with Oncolytic Measles Viruses and Immunosuppressive Drugs

There are many drugs with immunosuppressive properties currently being used in the clinic, either for the treatment of autoimmune disease or to suppress the rejection of transplanted organs. Their profiles of activity vary, some being more effective against a particular subset of lymphocytes with others having a broader spectrum of activity. While there is a strong rationale for combining immunosuppressive therapy with oncolytic measles virotherapy, progress in this research endeavor has been hampered by the lack of suitable animal models in which a measles susceptible tumor is allowed to grow in a measles susceptible animal with an intact immune system. However, despite the lack of suitable experimental models, attempts have nevertheless been made to determine whether cyclophosphamide might be capable of suppressing anti-measles immune responses and thereby enhancing its therapeutic potency.

Cyclophosphamide is known to be highly toxic to proliferating lymphocytes and can modulate both primary and anamnestic immune responses to a variety of antigenic challenges, including virus infection.[] Precise effects vary with the dose of antigen, the dose of cyclophosphamide, and the timing of cyclophosphamide administration relative to the antigenic challenge.[] Suppression of B-cell and T-cell responses is most pronounced when cyclophosphamide is administered at the same time or within three days following antigen challenge, but is also seen when the drug is administered one or two days before exposure to antigen, particularly when higher doses of cyclophosphamide are used.[] When a single dose of cyclophosphamide was administered to IFNARko xCD46-Ge mice a few hours prior to intraperitoneal or intravenous injection of MV-CEA or MV-NIS, respectively, elimination of the viruses was substantially delayed and the primary anti-measles antibody response was suppressed. A similar delay in virus elimination was observed when squirrel monkeys were pretreated with cyclophosphamide prior to infusion of MV-NIS and these data provided part of the justification for the ongoing MV-NIS clinical trial in which, in later cohorts, the patients will be pretreated with cyclophosphamide before they receive the virus.[] Additional preclinical studies were conducted in which cyclophosphamide was compared with other immunosuppressive agents and found to be substantially superior to dexamethasone, an equipotent but less toxic than whole-body irradiation (Myers RM, Peng KW, Russell SJ, unpublished).

Toward the development of an informative immunoincompetent murine model to experimentally test the role of immunosuppressive agents in measles virus therapy, a CEA retargeted measles virus was used to treat a CEA positive murine colon adenocarcinoma implanted in syngeneic C57BL/6 mice.[] This targeted virus was also armed with the prodrug convertase purine nucleotide phosphorylase (PNP). Systemic delivery of MV-PNP-anti CEA had no substantial oncolytic activity, but in combination with the prodrug, 6-methyl purine-2’-deoxyroboside, it was therapeutic, revealing synergistic affects between virus and prodrug. Immunosuppression with cyclophosphamide was shown to retard the appearance of measles neutralizing antibodies and also to enhance oncolytic efficacy.

Current Status and Future Prospects

Measles virotherapy has recently emerged as a safe and highly promising experimental approach to the treatment of human cancer. Clinical testing is still at an early stage and it remains possible that efficacy will be limited by preexisting anti-measles immunity. However, ongoing research emphasizing the use of engineered viruses, infected cell carriers, and supplemental therapy within immunosuppressive drugs is already offering viable strategies to enhance the potency of these agents, even in the face of preexisting anti-measles immunity.


Dr. Stephen Russell and Dr. Kah-Whye Peng are supported by funds from the NIH/NCI (CA100634 and CA129966 to Dr. Stephen Russell and CA118488 to Dr. Kah-Whye Peng). A grant from the Rapid Access to Intervention Development (RAID) Program of the NCI supported the manufacture of MV-NIS and toxicology studies in transgenic mice and squirrel monkeys. Efforts of numerous individuals including clinical collaborators (Drs. Evanthia Galanis, Angela Dispenzieri, Lynn C Hartmann, David Dingli), members of the virus manufacturing facility (Drs. Mark Federspiel and Linda Gregory, Guy Griesmann, Kirsten Langfield, Julie Sauer, Sharon Stephan, Henry Walker, Troy Wegman, Cindy Whitcomb) and members of the pharmacology/toxicology group (Rae Myers, Suzanne Greiner, Mary Harvey, Pam Ryno, Nathan Jenks, Emily Mader) are gratefully acknowledged.

Contributor Information

Stephen J. Russell, Mayo Clinic Department of Molecular Medicine, 200 1st Street SW, Rochester, MN 55905, Phone: 507-824-8384, Fax: 507-284-8388, ude.oyam@rjs.

Kah Whye Peng, Mayo Clinic Department of Molecular Medicine, 200 1stStreet SW, Rochester, MN 55905, Phone: 507-824-8357, Fax: 507-284-8388, ude.oyam@hak.gnep.


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118. Ungerechts G, et al. Lymphoma chemovirotherapy: CD20-targeted and convertase-armed measles virus can synergize with fludarabine. Cancer Res. 2007;67(22):10939–10947. [PubMed[]
119. Paraskevakou G, et al. Epidermal growth factor receptor (EGFR)-retargeted measles virus strains effectively target EGFR- or EGFRvIII expressing gliomas. Mol Ther. 2007;15(4):677–686. [PubMed[]
120. Allen C, et al. Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity. Cancer Res. 2006;66(24):11840–11850. [PubMed[]
121. Ungerechts G, et al. An immunocompetent murine model for oncolysis with an armed and targeted measles virus. Mol Ther. 2007;15(11):1991–1997. [PubMed[]
122. Mrkic B, et al. Measles virus spread and pathogenesis in genetically modified mice. Journal of Virology. 1998;72(9):7420–7427. [PMC free article] [PubMed[]
123. Oldstone MB, et al. Measles virus infection in a transgenic model: virus-induced immunosuppression and central nervous system disease. Cell. 1999;98(5):629–640. [PubMed[]
124. Manchester M, Rall GF. Model Systems: transgenic mouse models for measles pathogenesis. Trends Microbiol. 2001;9(1):19–23. [PubMed[]
125. Mrkic B, et al. Lymphatic dissemination and comparative pathology of recombinant measles viruses in genetically modified mice. J Virol. 2000;74(3):1364–1372. [PMC free article] [PubMed[]
126. Kemper C, et al. Membrane cofactor protein (MCP; CD46) expression in transgenic mice. Clin Exp Immunol. 2001;124(2):180–189. [PMC free article] [PubMed[]
127. Peng KW, et al. Biodistribution of oncolytic measles virus after intraperitoneal administration into Ifnar-CD46Ge transgenic mice. Hum Gene Ther. 2003;14(16):1565–1577. [PubMed[]
128. Kobune F, et al. Nonhuman primate models of measles. Lab Anim Sci. 1996;46(3):315–320.[PubMed[]
129. van Binnendijk RS, et al. Viral replication and development of specific immunity in macaques after infection with different measles virus strains. J Infect Dis. 1994;170(2):443–448. [PubMed[]
130. Auwaerter PG, et al. Measles virus infection in rhesus macaques: altered immune responses and comparison of the virulence of six different virus strains. J Infect Dis. 1999;180(4):950–958. [PubMed[]
131. Takeda M, et al. Measles virus attenuation associated with transcriptional impediment and a few amino acid changes in the polymerase and accessory proteins. J Virol. 1998;72(11):8690–8696.[PMC free article] [PubMed[]
132. Kobune F, Sakata H, Sugiura A. Marmoset lymphoblastoid cells as a sensitive host for isolation of measles virus. J Virol. 1990;64(2):700–705. [PMC free article] [PubMed[]
133. Aldous IR, et al. Vaccination aginst measles. III. Clinical trial in British children. Br Med J. 1961;2(5262):1250–1253. [PMC free article] [PubMed[]
134. Collard P, et al. Vaccination against measles. II. Clinical trial in Nigerian children. Br Med J. 1961;2(5262):1246–1250. [PMC free article] [PubMed[]
135. Katz SL, et al. Studies on an attenuated measles-virus vaccine. VIII. General summary and evaluation of the results of vaccine. N Engl J Med. 1960;263:180–184. [PubMed[]
136. Schwarz AJ, et al. Experimental vaccination against measles. I. Tests of live measles and distemper vaccine in monkeys and two human volunteers under laboratory conditions. J Am Med Assoc. 1960;173:861–867. [PubMed[]
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142. Myers RM, et al. Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide. Clin Pharmacol Ther. 2007;82(6):700–710.[PMC free article] [PubMed[]
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Modified AAP Vaccine Decline Form

Child’s Name ____________________________________________________ Child’s ID#____________________

Parent’s/Guardian’s Name(s)



My child’s health care provider ______________________________, has advised me that my child (named above) should receive the following vaccines:

Vaccine Recommended Declined Date
Hepatitis B  Y / N  Y / N ____/_____/____
DTaP  Y / N  Y / N ____/_____/____
DT or Td  Y / N  Y / N ____/_____/____
Haemophilus influenza type B (Hib)  Y / N  Y / N ____/_____/____
Pneumococcal conjugate vaccine  Y / N  Y / N ____/_____/____
Polio vaccine (IPV)  Y / N  Y / N ____/_____/____
Measles, mumps, rubella MMR-II  Y / N  Y / N ____/_____/____
Varicella (chickenpox)  Y / N  Y / N ____/_____/____
Influenza (flu)  Y / N  Y / N ____/_____/____
Meningococcal  Y / N  Y / N ____/_____/____
Hepatitis A  Y / N  Y / N ____/_____/____
Rotavirus  Y / N  Y / N ____/_____/____
HPV  Y / N  Y / N ____/_____/____
Other________________________  Y / N  Y / N ____/_____/____

I have read the Centers for Disease Control and Prevention’s (CDC) Vaccine Information Sheet(s) (VIS) explaining the vaccine(s) and the disease(s) for which each vaccine is intended. I have had the opportunity to discuss this with my child’s health care provider, who has answered all of my questions regarding the recommended vaccine(s) to the best of their ability.

    I understand the following:
● The intended purpose of the recommended vaccine(s)
● The known risks and alleged benefits of the recommended vaccine(s)
● If my child does receive the vaccine(s), the consequences may include:
-Contracting the illness the vaccine should have prevented.
– Transmitting the disease to others.
-Chronic illness and/or death.
-Suffering from any of the adverse events listed in the package insert and possibly adverse events not yet listed and/or associated with the vaccine. The outcomes of these adverse events may include one or more of the following: illness requiring hospitalization, death, brain damage, meningitis, seizures, and deafness. Other severe and permanent effects from these vaccines are possible as well.
● If my child does not receive the recommended vaccines, possible adverse outcomes are the same as listed above for a child that does receive the vaccines.
● I understand the need to keep my child at home or in qualified care anytime the child exhibits symptoms of contagious diseases.
● My health care provider, the American Academy of Pediatrics, the American Academy of Family Physicians, and the Centers for Disease Control and Prevention have all strongly recommended that the vaccine(s) be given based on the “information” they have been given by the drug companies producing the vaccines.
I have declined consent for the vaccine(s) recommended for my child, as indicated above, by circling the appropriate mark under the column titled “Declined.” I know that I may re-address this issue with my health care provider at any time, and that I may change my mind as personal beliefs are subject to evolve and change over time. I acknowledge that I have read this document in its entirety and fully understand it.

Parent/Guardian Signature







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Miscellaneous Links and Information

The Clinical Impact of Adverse Event Reporting


Another major concern with any spontaneous reporting system is underreporting of adverse events (16, 30-32). It has been estimated that rarely more than 10% of serious ADRs, and 2-4% of non-serious reactions, are reported to the British spontaneous reporting program (30). A similar estimate is that the FDA receives by direct report less than 1% of suspected serious ADRs(32). This means that cases spontaneously reported to any surveillance program, which comprise the numerator, generally represent only a small portion of the number that have actually occurred. The effect of underreporting can be somewhat lessened if submitted reports, irrespective of number, are of high quality.  LINK NO LONGER VALID

I had to redo the search for the information and was able to locate it here,    LINK NO LONGER VALID    This link valid as of 3/11/2019.  Due to the links disappearing, this is a pdf that I will copy/paste here to ensure sustainability.

Special Communications
Introducing MEDWatch

2768 JAMA, June 2, 1993-Vol 269, No. 21
A New Approach to Reporting Medication and Device Adverse Effects and Product Problems
David A. Kessler, MD, for the Working Group

UNFORTUNATELY, many health professionals do not think to report adverse events that might be associated with medications or devices to the Food and Drug Administration (FDA) or to the manufacturer. That needs to change, and the FDA is taking steps to encourage that to happen.
Reports from health professionals of adverse events or product quality problems are essential to ensure the safety of drugs, biologicals, medical devices, and other products regulated by the FDA once they are introduced into the US market.
Even the large, well-designed clinical trials that are conducted to gain premarket approval cannot uncover every problem that can come to light once a product is widely used. A new drug application, for example, typically includes safety data on several hundred to several thousand patients. If an adverse event occurs in perhaps one in 5000 or even one in 1000 users, it could be missed in clinical trials but pose a serious safety problem when released to the market.
Moreover, patients taking marketed drugs in conjunction with other drugs may experience interactions not revealed during the premarketing phase. (1)
In response to voluntary reports from physicians to the FDA or the manufacturer, the FDA has issued warnings, made labeling changes, required manufacturers to conduct postmarketing studies, and ordered product withdrawals that have ultimately prevented patient deaths and suffering.
Adverse drug reports from physicians,for example, prompted the FDA to determine that torsades-de-pointes ventricular arrhythmias could occur when the antihistamine terfenadine (Seldane) was taken in combination with the antifungal medicine ketoconazole or the antibiotic erythromycin.(2) This episode also increased recognition that individual variability in drug metabolism can account for significant differences in patient responsel and underscored the importance of postmarketing studies and physician observations and reports.
Other examples of FDA actions prompted by reports of adverse events include the 1986 recall of suprofen,(3) the 1991 alert to health professionals on potentially fatal latex hypersensitivitY,(4) the 1992 boxed warning and alert to physicians regarding use of angiotensin-converting enzyme inhibitors during the second and third trimesters of pregnancy,(5) and, most recently, the recall of temafloxacin. (6)
Just as reports enable us to respond to serious adverse events, lack of reporting can delay problem detection. Silicone breast implants are one example. Although these devices have been on the market for some 30 years, only recently has evidence accumulated about a possible association with autoimmune-like disorders.(7,8)
If reports from physicians who diagnosed autoimmune-like disorders in patients with breast implants had been received years ago, the possible connection might have been
identified much earlier.
Aside from adverse events associated with specified vaccines (listed in the National Childhood Vaccine Injury Act )(9), most reporting by health providers is voluntary. Manufacturers of drugs and devices and device distributors are required to report adverse events, (10, ll)  and soon manufacturers of biologicals will face similar requirements.

Device manufacturers and distributors are also required to report to the FDA product problems that may cause death or serious injury if the malfunction were to recur. (11)   Health care facilities are required to report certain adverse events
associated with devices. (11) However, these groups, like the FDA, depend on
health care professionals’ surveillance and voluntary reporting.
Although the FDA receives many adverse event reports, these probably represent only a fraction of the serious adverse events encountered by providers.
A recent review article (l2) found that between 3% and 11% of hospital admissions could be attributed to adverse drug reactions. Only about 1% of serious
events are reported to the FDA, according to one study. (13)      (my note, the emphasis and color mine)
There are probably several reasons why some serious events are not reported to either the FDA or the manufacturer. First, when confronted with an unexpected outcome of treatment, physicians may not consider drug-induced or device-induced disease, but
rather consider the event to be related to the course of the disease.
Unfortunately, this may be due to the limited training medical students receive
in clinical pharmacology and therapeutics. A 1985 survey of US medical schools
found that only 14% of them had required courses in core skills and principles of therapeutic decision making and clinical pharmacology. Of the remainder, 87% taught only a few hours of clinical pharmacology, and most of the teaching occurred in the early years of medical training.(14)
Another factor inhibiting physician reporting is that it is not an ingrained practice-it is not in the culture of US medicine to notify the FDA about adverse events or product problems. In other countries such as the United Kingdom, adverse drug reporting is more frequent. (15) A patchwork of reporting forms and systems may make it difficult
to file reports in the United States and may discourage even the most conscientious professionals. Finally, physicians may be unclear as to what adverse reactions should be reported to the FDA.
Mindful of these problems, the FDA has just completed an overhaul of the adverse event reporting system. This month we are announcing our new system called MEDWatch: The FDA Medical Products Reporting Program_ (Adverse events associated with vaccines
will continue to be reported through the Vaccine Adverse Event Reporting System [VAERS], a joint program of the FDA and the Centers for Disease Control and Prevention.(9)
This new system encourages health care professionals to regard reporting as a fundamental professional and public health responsibility. It was developed with the enthusiastic support of the medical community, and its success will depend on close cooperation among the FDA, the medical community, and industry to identify and report adverse events and problems with medications and devices.
The FDA recognizes that the confidentiality of the identities of both providers who report adverse events and patients is an important concern of health professionals. To encourage reporting, the FDA carefully protects the identities of providers who report and patients contained in FDA records and will not release such information to the
public. Unfortunately, during the course of litigation manufacturers have increasingly been asked to reveal the identities of those reporting adverse events and, in some cases, even the identities of patients. The FDA believes that maintaining the confidentiality of these individuals is extremely important, and it has participated in a number of court cases vigorously opposing release of the names of those involved in adverse event reports. To date, we have been successful in maintaining the confidentiality of this
information in all the cases in which we have been involved. Nevertheless, we
are considering whether additional actions may be appropriate to further strengthen our ability to safeguard the confidentiality of this information.
Our goal in introducing MEDWatch is to underscore the responsibility of providers to identify and report adverse events that may be related to FDA regulated products. To that end, we want to (1) make it easier for providers to report serious events, (2) make it clear to physicians and others what types of reports the FDA wants to receive, (3) more widely disseminate information on the FDA’s actions that have resulted from adverse event and product problem reporting, and (4) increase physician understanding and awareness of drug- and device-induced disease.
Under the MEDWatch program, the separate forms previously used to report adverse drug reactions, drug quality product problems, device quality product problems, and adverse reactions to medical devices have been consolidated into a single, one-page reporting form for health professionals. This form can also be used to report problems with other FDA-regulated products, such as dietary supplements, cosmetics, medical foods, and infant formulas.
In addition to making reporting easier for providers, using one form for both device and drug problems should also help the health care community to detect, and the FDA to investigate, adverse events.

One example of how this form might facilitate investigation was the FDA’s
discovery that the latex-cuffed barium enema tips used to perform many barium enema procedures provoked life-threatening allergic responses in some patients. (4) When the problem was first recognized, practitioners typically believed that patients were reacting to the barium sulfate or to other medications used in the procedure, and therefore adverse incidents were initially reported as barium sulfate reactions to the Center for Drugs. The new one-page form asks reporters to indicate concomitant devices as well as the suspect drug and other drugs used in the procedures. Using the new form might have decreased the follow-up time required by FDA officials, the time needed to identify latex
as the problem, and the time until the medical community was alerted.

The unified reporting form  will be available in several publications, including the Physicians’ Desk Reference, the FDA Medical Bulletin, and AMA Drug Evaluations. A 24-hour-a-day, 7-day-a-week toll-free number, (800) FDA-1088, is also now available for providers who want to request forms or obtain the new FDA Desk Guide to Adverse
Event and Product Problem Reporting.
Providers will no longer be expected to send different reports for devices and
medications to different addresses at the FDA; there will now be a single mailing
address for these reports.

In addition, health professionals will be able to report
electronically by computer by calling (800) FDA-7737 and responding to the questions that appear on the screen. Reports can be also sent to the FDA by fax ([800] FDA-0178) or by regular mail using the self-mailer included in the form.
In addition to reporting adverse events to the FDA, reports can also be sent to manufacturers, which are required by law to forward reports to the FDA. (10, 11)  If the event has occurred in a health care facility, reports of problems with medical devices should also be filed with that facility, which legally must report device problems to the FDA and/or the manufacturer. (11)
The Joint Commission on Accreditation of Healthcare Organizations also has standards for monitoring and reporting adverse medication and device events. (16)
Individual institutions may have their own procedures and guidelines for monitoring and reporting adverse events within the institution; physicians can obtain that
information from the pharmacy and therapeutics committee or the institutional risk manager at their institution.
Physicians should report when there is a suspicion that the drug or device may be related to a serious adverse effect; they are not expected to establish the connection or even to wait until evidence seems compelling. Reports should be alert of possible associations. Combined with other reports, follow-up, and results of epidemiologic studies or new
studies undertaken, the FDA can evaluate these initial suspicions.
On the other hand, the FDA does not want providers to report every adverse reaction observed; this would not be practical for the practitioner or useful to the FDA. The FDA’s goal is to increase reporting of serious events, not all adverse events. What should be reported are those cases in which the physician suspects that an FDA-regulated product was associated with a serious outcome– death, a life-threatening condition, initial
or prolonged hospitalization, disability, or congenital anomaly, or when intervention was required to prevent permanent impairment or damage.
Although traditionally problems with devices are associated with products that are defective or malfunction, adverse events can occur with a device even when
no malfunction or defect is recognized, for example, hypersensitivity to latex (4)
or dialyzer germicides. (17)

Especially important to report are adverse effects from medications or devices that have been on the market for a relatively short time—about 3 years or less—because that is when the most critical problems are discovered. Since most serious adverse events are observed in the hospital setting, (18) practitioners should be especially diligent about reporting these events.
The FDA should also be informed promptly of product quality problems such as defective devices, inaccurate or unreadable product labeling, packaging or product mix-up, contamination or stability problems, and particulate matter in injectable products. In 1990, a total of 38 drug recalls resulted: from reporting of such problems. (19) While pharmacists or risk managers are often the ones in a position to observe these problems, physicians who become aware of such problems should bring them to the FDA’s attention by calling (800) FDA-1088 and submitting a report.
One recent example of the importance of this type of report is the possible link reported between hyperkalemia observed in two patients in a medical center intensive care unit and two enteral feeding products. The university’s laboratory analysis demonstrated that the products had a potassium content about twice that specified on the label. The FDA follow-up of this report revealed that all product lines of the manufacturer contained potassium values of 150% to 250% of the declared amount. Because these products are frequently used as a sole source of nutrition, and sometimes in patients with compromised renal function, the FDA initiated a recall of the product.
MEDWatch is aimed at facilitating reporting by providers, but we also want to better inform providers about regulatory actions taken by the FDA in response to reports. We believe this information will not only be useful to physicians and others, but that it will also encourage serious adverse event reporting by demonstrating the value of the
information. The FDA will therefore take a more aggressive stance in reporting back to providers.
As part of MEDWatch, the FDA hopes to heighten physician awareness of drug- and device-induced disease. Our educational efforts will include a focus on issues such as the importance of the problem, mechanisms of adverse drug and device reactions, and how to evaluate possible adverse events. As part of that effort we plan to hold a conference for health care professionals and FDA officials to help poise practitioners to
recognize drug- and device-induced problems when they occur, and thereby increase participation in the MEDWatch program.
MEDWatch is an important program that we hope will significantly improve our ability to monitor the safety of products we regulate and to take necessary actions swiftly and effectively. Perhaps most important, we hope MEDWatch will encourage an increased sense of responsibility among physicians and other health care providers about reporting adverse events and product problems. We are eager to work closely with the medical community to ensure the program’s success.
Leaders of the Working Group include the following: Sharon Natanblut, MPA; Dianne Kennedy, MPH, RPh; Eliot Lazar, MD; Peter Rheinstein, MD, JD, MS. Members of the Working Group include Chuck Anello, SeD; Dave Barash, RPh; Ilisa Bernstein, PhannD; Ross Bolger, RPh; Kay Cook, JD; Mary Pat Couig, RN, MPH; JetTy Donlon, MD, PhD; Joyce Johnson, DO, MA; Catherine Lorraine, JD; Tom McGinnis, RPh; John Nazario, RPh; Stuart Nightingale, MD; Carl Peck, MD; Mary Pendergast, JD; Suresh Rastogi, PhD; Chet Reynolds, MBA; Renie Schapiro, MPH; Linda Tollefson, DVM; Ann Wion, JD.

1. Peck CC, Temple R, Collins JM. Understanding consequences of concurrent therapies..lAMA. 1993; 269:1550-1552.
2. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazoleinteraction: pharmacokinetic and electrocardiographic consequences. .lAMA. 1993;269:1513-1550.
3. Rossi AC, Bosco L, Faich GA, Tanner A, Temple R. The impOltance ofadverse reaction reporting by physicians: suprofen and the flank pain syndrome. .lAMA. 1988;259:1203-1204.
4. Stehlin D. When rubber rubs the wrong way. FDA Consumer. 1992;26:17-21.
5. Gelb LN, ed. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull. 1992;22(1):2.
6. Rheinstein PH. Reporting of adverse events: a key to postmarketing drug safety. Am Fam Phys. 1992;46:873-875.
7. Press RI, Peebles CL, Kumagai Y, Ochs RL, Tan EM. Antinuclear autoantibodies in women with silicone breast implants. Lancet. 1992;340:1304-1307.8. Dunn KW, Hall PN, Khoo CTK. Breast implant materials: sense and safety. Br .I Plast Surg. 1992; 45:315-321.
9. Nightingale SL. New system for reporting of vaccine adverse events. .lAMA. 1990;264:2863.
10. Johnson JM, Barash D. A review of postmarketing adverse drug experience reporting requirements. Food Drug Cosmetic Law J. 1991;46:665­671.
11. Medical Devices; Medical Device, User Facility, Distributor, and Manufacturers’ Reporting, Certification, and Registration. Rockville, Md: Dept of  Health and Human Services, Food and Drug Administration; 1991:60024-60039. 21 CFR parts 803 and 807 (docket No. 91N-0295).
12. Beard K. Adverse reactions as a cause of hospital admissions in the aged. [h~lg Aging. 1992;2:356-367.

13. Scott HD, Rosenbaum SE, Waters WJ, et al.Rhode Island physicians’ recognition and reporting of adverse drug reactions. RIMed J. 1987;70:311­316.
14. Griffin JP, Weber JCP. Voluntary systems of adverse reaction reporting, part II. Adv [h~l React Ac Pois Rev. 1986;1:23-55.
15. Nierenberg DW. Clinical pharmacology instruction for all medical students. Clin Pharm Ther. 1986;40:483-487.
16. Accreditation Manual, 199:>. Oakbrook Terrace, Ill: Joint Commission on Accreditation of Healthcare Organizations; 1993.
17. Gelb LN. Precautions needed for dialyzer germicides. FDA Med Bull. 1993;23(1):7.
18. Kennedy DL,JohnsonJM, Nightingale SS. Monitoring of adverse drug events in hospitals. .lAMA. 1991;266:2878.
19. Bolger G, Goetsch R. Monitoring drug product quality. Am Pharm. 1992;NS32:47-50.


Probable Mechanism of DPT vaccine induced neurological damage

Link no longer working, will attempt to find a new one.  That is one reason why it’s important to copy the information from the link, as this seems to happen a lot!

Probable Mechanism of DPT vaccine induced neurological damage:

In implicating pertussis vaccination in the evolution of subsequent neurological residua, a careful consideration of the mechanism for vaccine-induced brain damage plays an important supporting role. Pertussis toxin has been shown to alter cellular signaling. It also affects the catecholaminergic and GABAergic systems in the brain. In addition, a direct, endotoxin-mediated attack on the endothelial cells could create a local defect of the blood-brain barrier. It is being seen that a combination of one or more bacterial toxins, asphyxia, Co2 retention and loss of cerebral autoregulation is responsible for neurological symptoms.

Encephalopathy manifests with alteration of sensorium or generalized or focal seizures that persist for more than a few hours. Occurrence of hypotensive-hyporesponsive shock or post-vaccination encephalopathy is a contra-indication of further doses of the pertussis component. This should be explained to the guardians. Other manifestations that indicate occurrence of encephalopathy include: seizures with or without fever occurring within 3 days of immunization and persistent, severe, inconsolable screaming or crying for 3 or more hours within 48 hours of immunization. Usually, these are not associated with permanent sequel. Previously, occurrence of these events also meant withdrawal of pertussis component from doses to be received in future. However, it is now recommended that all factors should be considered while advising regarding DPT vaccination in future in these children.

Association of severe reactions made the whole- cell pertussis vaccine highly unpopular among many communities and countries and spurred research for safer vaccines. Some European countries even went to the extent of withdrawing (whole-cell) pertussis vaccination; only to find an increased incidence of and increased morbidity due to pertussis amongst infants and young children in the community. An acellular pertussis vaccine (Designated as aP) is now available in several countries including India. It contains purified, inactivated components of B. pertussis. The acellular vaccine is as potent as the whole cell vaccine, but it is still associated with neurological complications described with whole-cell vaccine, albeit at a much lower frequency. It is also credited with lesser incidence of local side effects as well as decreased incidence of severe reactions like seizures and hypotensive episodes. However, the vaccine is expensive and it is unlikely that it would be included in the Indian National immunization schedule in near future.

Optimization of vaccine responses in early life: the role of delivery systems and immunomodulators.

Link working as of 10/20/16

Virus-induced autoimmunity may play a causal role in autism

Personally, I think a lot of the autoimmune problems our children are suffering from today are vaccine induced.

Puzzling associations between childhood infections and the later occurrence of asthma and atopy

There are data to suggest that measles, hepatitis A, and Mycobacterium tuberculosis infection in early life may prevent the subsequent development of atopic diseases.

Link working as of 10/20/16

Unlike hepatitis B and hepatitis C, hepatitis A causes no long-term liver damage and usually does not cause death. There is no chronic carrier state with hepatitis A. Having had the disease produces lifelong immunity from future hepatitis A infection.

Increased susceptibility to measles in infants in the United States.

link working as of 10/20/16


Hepatitis B virus transmission between children in day care.

link working as of 10/20/16

Duration of hepatitis B immunity in low risk children receiving hepatitis B vaccinations from birth.

link working as of 10/20/16

How safe is the Hep B vaccine?

link not working will try to find a new one

Pertussis resurgence in Canada largely caused by a cohort effect. \

link working as of 10/20/16


link not working , will try to find a new one


Comparison of tissue reactions produced by Haemophilus pleuropneumoniae vaccines made with six different adjuvants in swine.

link working as of 10/20/16

Based on the growing number of children allergic to peanuts, I tried to find out if any type of peanut oil was used in the vaccines. From what I could find, it may be used in vaccines for animals, but I have not yet found conclusive evidence that it’s used in vaccines for people. This is something I am still interested in getting to the bottom of. Update 10/20/16   I have since read that peanut oil is used in childhood vaccines. Will update with links as I find the information to back this up.

UPDATE: 10/20/16

I found this but have not had time to do my own research into the information however I see that there are several references listed.  It would make sense, as you never heard of peanut allergies 20 plus years ago, but then way back when I went to school, allergies and asthma were quite rare as well.

– Dr Tim O’Shea

Have you ever wondered why so many kids these days are allergic to peanuts? Where did this allergy come from all of a sudden?

Before 1900, reactions to peanuts were unheard of. Today almost a 1.5 million children in this country are allergic to peanuts.

What happened? Why is everybody buying EpiPens now?

Looking at all the problems with vaccines during the past decade, [2] just a superficial awareness is enough to raise the suspicion that vaccines might have some role in the appearance of any novel allergy among children.

But reactions to peanuts are not just another allergy. Peanut allergy has suddenly emerged as the #1 cause of death from food reactions, being in a category of allergens able to cause anaphylaxis. This condition brings the risk of asthma attack, shock, respiratory failure, and even death. Primarily among children.

Sources cited in Heather Fraser’s 2011 book The Peanut Allergy Epidemic suggest a vaccine connection much more specifically. We learn that a class of vaccine adjuvants – excipients – is a likely suspect in what may accurately be termed an epidemic. [1]


Task Force on Safer Childhood Vaccines: Final Report and Recommendations

No surprise this link isn’t working anymore.  Will attempt to find another

Interagency Vaccine Group Meeting on the Development of CDC’s ISO Scientific Agenda – Final 3/21/08


Dose discrepancies between the Physicians’ Desk Reference and the medical literature, and their possible role in the high incidence of dose-related adverse drug events.

Because the PDR was originally developed as a promotional device, there is no mechanism by which all clinically relevant dose-response data or important postrelease discoveries are regularly and rapidly incorporated into it.

link working as of 10/20/16

Epidemiology. 1997 Nov;8(6):678-80 Is infant immunization a risk factor for childhood asthma or allergy?

Kemp T, Pearce N, Fitzharris P, Crane J, Fergusson D, St George I, Wickens K, Beasley R.

Department of Medicine, Wellington School of Medicine, New Zealand.

The Christchurch Health and Development Study comprises 1,265 children born in 1977. The 23 children who received no diphtheria/pertussis/tetanus (DPT) and polio immunizations had no recorded asthma episodes or consultations for asthma or other allergic illness before age 10 years; in the immunized children, 23.1% had asthma episodes, 22.5% asthma consultations, and 30.0% consultations for other allergic illness. Similar differences were observed at ages 5 and 16 years. These findings do not appear to be due to differential use of health services (although this possibility cannot be excluded) or con-founding by ethnicity, socioeconomic status, parental atopy, or parental smoking.

link working as of 10/20/16

Burton Press Release Expertly Misleads Both The Press And The Public

by Rich Greenaway

On May 1, 2003 a press release originating from the office of Congressman Dan Burton (R-IN) indicated that he would join a panel of scientists, medical researchers, and parents who were convening from across the nation in Chicago, IL to present evidence from recently or soon-to-be released studies linking autism with the mercury-based preservative thimerosal. Part of the premise for Representative Burton’s press release was his statement that the 2003 Physicians Desk Reference (PDR) showed that there are three vaccine manufacturers who are still making childhood vaccines with full doses {his term} of thimerosal. Specifically, his press release of May 1, 2003 stated:

“The 2003 Physicians’ Desk Reference shows that there are three vaccine manufacturers who are still making childhood vaccines with full doses of thimerosal. These are as follows: the Diphtheria-Tetanus-acellular-Pertussis (DTaP) manufactured by Aventis-Pasteur in multi-dose vials contains 25 micrograms of mercury; the Haemophilus-influenza-Type b (Hib TITER) in multi-dose vials manufactured by Wyeth contains 25 micrograms of mercury; and the pediatric hepatitis B vaccine manufactured by Merck contains 12.5 micrograms of mercury. These vaccines represent approximately half of the childhood vaccines currently available for use in the United States.”

After reading the press release, ECBT immediately went into full research mode to find out if Burton’s information was true. Were thimerosal-containing childhood vaccines still listed in the 2003 PDR and did that mean that they were still available in the marketplace? We found out that only one truth was contained in the above quote from Congressman Burton’s press release. That one and only truth is that the above mentioned thimerosal-containing formulations of the childhood vaccines are still listed in the 2003 PDR. The fallacies or misleading points in his statement are “that there are three vaccine manufacturers who are still making childhood vaccines with full doses of thimerosal”; that “these {thimerosal-containing} vaccines represent approximately half of the childhood vaccines currently available for use in the United States.” The reality is that the thimerosal-containing formulations of those vaccines listed in Burton’s press release are no longer in manufacture or distribution in the United States and haven’t been for years. Nor are they available for use in the United States.

In an effort to better understand how a vaccine could be listed in the most current PDR showing that it contains thimerosal when it is no longer manufactured as such, we contacted PDR directly and asked how the information in their reference books is kept current.

The PDR is published yearly by Thomson Healthcare in Montvale, NJ. Manufacturers pay to have their products listed in the PDR and a free copy of the PDR is distributed to office-based physicians. Not all medical products are found in the PDR because a manufacturer may decide for whatever reason not to list a product. Product information found in the PDR comes directly from the manufacturer and is identical to the latest package labeling as approved by the FDA for that product. No changes to content are made by PDR. PDR may reformat the layout of the information but final formatting and content is approved by the manufacturer before PDR goes to print to insure that PDR’s reformatting does not change the content from the original.

Manufacturers have flexibility to make changes to the information on their product in the PDR without submission of those changes to FDA if the new information is considered a “negative” change. Negative changes include new warnings about their product, or new findings that would reflect negatively on its use. Changes of information that would be considered “positive” include information that would further promote or serve to increase use of the product and those changes must be submitted through FDA for approval before they can be inserted into the next PDR edition.

Manufacturers can decide at any time to discontinue production, however, once a manufacturer makes such a decision it is not uncommon for them to keep the information in the PDR for at least a couple of years. The reasons for doing this are varied. Having unexpired product still available in the market, or a recommendation from legal council that a product listing be maintained are but two of the many potential reasons why essentially outdated information may still be maintained in the PDR. In the case involving this press release, three vaccine manufacturers sited by Burton decided to continue to list descriptions of products in the PDR that they have removed from the U.S. market. ECBT is not privileged to know their reasoning for doing this. We just hope that in the future, Congressman Burton will first investigate further before using misleading information like this as such a major focal point in his press release.  (link no longer works)

Pediatric Neurologist comments on Vaccine Reactions  Link no longer working however all the congressional hearings links appear to be working

I believe this info came from one of the congressional hearing links appear to work just fine and you can Ctrl F to search for Dr Kinsbourne’s comments.



Mr. Cummings. Have there been any published peer review studies that show a link between hepatitis B vaccine and conditions such as multiple sclerosis and SIDS? Dr. Orenstein. There have been case reports that have suggested that this is a possibility, and that’s why we are doing more comprehensive research. The people who are developing these illnesses after vaccination have very, very severe illnesses; there’s no question that these are terrible tragedies. The problem is that there are people who develop these same kinds of tragedies, these same kinds of illnesses in the absence of vaccination. And that’s why we’re engaged, we and others are engaged in substantial research to try and see whether the vaccine increases the risk over what would be expected.

Scroll down to almost the bottom of the page & look for these statements:






Workshop on neurologic complications of pertussis and pertussis vaccination.

  1. Vaccines are not standardized between manufacturers.
  2. For a given manufacturer, vaccines are not standard from one batch to the next.
  3. Unless the vaccine is properly prepared and refrigerated, its potency and reactivity varies with shelf life.

In fact, the whole question of vaccine detoxification has never been systematically investigated.

Listed in order of increasing severity, observed adverse reactions include irritability, persistent, unusually high pitched crying, somnolence, seizures, a shock-like “hypotensive, hyporesponsive” state, and an encephalopathy. Since the neurologic picture is not specific for pertussis vaccination, its temporal relationship to the vaccination is the critical variable for determining causation. Although the majority of seizures following pertussis vaccination are associated with fever, it was the consensus of the neurologists attending the workshop, that these do not represent febrile convulsions, but are non-benign convulsions.

link working as of 10/20/16

Sudden Infant Death Syndrome — United States, 1983-1994

My note, please pay close attention to the timing of the deaths and in particular, even after the back to sleep campaign, while overall death rates were reduced, the timing of the deaths did not change.

Link working as of 10/20/16

RECALLS AND FIELD CORRECTIONS: BIOLOGICS — CLASS II PRODUCT Platelets. Recall #B-441-2. CODE Unit #90028. MANUFACTURER Memorial Blood Center of Minneapolis, Minneapolis, Minnesota. RECALLED BY Manufacturer, by telephone June 1, 1992. Firm-initiated recall complete. DISTRIBUTION Minnesota. QUANTITY 1 unit. REASON Blood product, which tested repeatedly reactive for the antibody to hepatitis B core antigen (anti-HBC), was distributed for transfusion.    link no longer working

Conflicts of Interest in Vaccine Policy Making Majority Staff Report Committee on Government Reform U.S. House of Representatives June 15, 2000

Reconstituted vaccines may become contaminated with staphylococcus and other

organisms from improper handling. Once this happens, a chemical called a toxin is

produced that may be deadly if injected.

FLUMIST MEETING link working as of 10/20/2016

Dangerous Prescription  

This gives good insight as to what goes on behind the scenes and how they want “yes” men.

Typing of human enteroviruses by partial sequencing of VP1.    Link no longer valid will try to find a new one

Calling the Shots:

Immunization Finance Policies and Practices (2000) Institute of Medicine

WOW, this site compares vaccines used

1985 vs. 2000 vs. what they expect to be in use by

2020 link working as of 10/20/16

History of the vaccine schedule:     link working as of 10/20/16

keep in mind vaccine makers were relieved of liability in 1986, and look at the jump in vaccine production after they were free & clear!

Increased levels of active pertussis toxin may aid a pertussis vaccine to pass the mouse body weight gain test. link working as of 10/20/16

Tuberculosis (TB) STATS

see how it’s declined without widespread vaccination. This may answer the question, what will happen if we stop vaccinating…there was a spike in cases for a short period of time as shown in the graph in the link below, then cases continued to drop. This has been happening since as far back as the 1950’s . Another graph: TB Case Rates in the US by Race/Ethnicity, Selected Years 1993-2011 shows that the cases are absolute lowest in White, in the middle are Hispanic, Black and American Indian or Alaska Native, high mid-range (and looks like tracking didn’t start til mid 90’s is Native Hawaiian/Other Pacific Islanders, and Asians top the charts in the highest amount of cases.

There is a vaccine for TB but it is not given to the masses, just in certain high risk conditions such as persons residing in congregate settings such as hospitals, prisons and homeless shelters, and a decline in resources for TB control.

The following document was written to provide the general public with information on the epidemiology (mortality, morbidity and burden) of tuberculosis in the United States and worldwide.

Despite popular misconceptions that tuberculosis (TB) is a disease of the past, it continues to pose a significant threat to public health. Worldwide, one-third of the total population is infected; 9 million are ill and nearly 1.5 million people die from TB each year.

In the United States, TB is much less common, with just over 10,500 people sick in 2011; however, it continues to cause disproportioned illness in certain populations such foreign-born persons and those with weak immune systems. Therefore, it remains imperative for the United States government and other agencies to maintain focus on eradicating TB through surveillance, treatment and prevention in the United States, as well as, worldwide.

In 1904, the American Lung Association began as an organization committed to eradicating TB, a contagious airborne infection caused by an organism called Mycobacterium tuberculosis and spread through the air from one person to another. More than a hundred years later, the American Lung Association continues to be at the forefront by supporting much needed research examining the links between the disease and other lung diseases and risk factors

This next link shows the # of cases going as far back as 1953, can you believe # of cases dropped from 84,304 in 1953 to 23,846 in 1983 to 9,421 in 2014.   How amazing that this disease has been on a steady decline the past 60 plus years WITHOUT A MAGIC BULLET VACCINE! So how do they explain the decline in absence of widespread vaccination? I will give you a hint, the very same reasons for all the other infectious diseases were on a decline before a vaccine was introduced, and they just continued to decline yet credit is given to the vaccine. No vaccine to credit here as no is given to the masses as it is NOT YET required for school entry, but no doubt that will change in time.

“Disease control resulted from improvements in sanitation and hygiene, the discovery of antibiotics, and the implementation of universal childhood vaccination programs.”

However, TB has never been included in the universal childhood vaccination program, yet it has still been on a steady decline in spite of that.


FAST STATS:   Good reference site


Weighing the risks and benefits of vaccination.

The following summarizes this author’s current thoughts regarding veterinary vaccines and their safety: 1. Every licensed animal vaccine is probably effective, but also produces some adverse effects. 2. Prelicensing studies of vaccines are not specifically designed to detect adverse vaccine reactions. 3. An improved system of national postmarketing surveillance is required to identify most adverse vaccine reactions that occur at low and moderate frequency. 4. Even a good postmarketing surveillance system is unlikely, however, to detect delayed adverse vaccine reactions, and the longer the delay the less likely they will be associated with vaccination. 5. Analytic epidemiologic (field) studies are the best way to link vaccination with delayed adverse reactions, but these are often hindered by incomplete vaccination histories in medical records in veterinary practice and by a lack of veterinarians in industry trained in epidemiologic methods. 6. Each licensed veterinary vaccine should be subjected to a quantitative risk assessment, and these should be updated on a regular basis as new information becomes available. 7. Risk assessment should be used to identify gaps in information regarding the safety and efficacy of vaccines, and appropriate epidemiologic studies conducted to fill these gaps that contribute to the uncertainty in risk estimates. 8. Risk assessment is an analytical process that is firmly based on scientific considerations, but it also requires judgments to be made when the available information is incomplete. These judgments inevitably draw on both scientific and policy considerations. 9. Representatives from industry, government, veterinary medicine, and the animal-owning public should be involved in risk management, that is, deciding between policy options. The controversy regarding vaccine risks is intensifying to the point that some animal owners have stopped vaccinating their animals. They offer as justification the belief that current vaccines are “just too dangerous.” Some owners report that since they completely stopped vaccinating their animals, they have been healthy. What they fail to realize is that a high percentage of animal owners are responsible and do vaccinate their animals, thus providing “herd immunity” protection to the unvaccinated animals whom they contact. The solution to the vaccine controversy is not to abandon vaccination as an effective means of disease prevention and control, but rather to encourage vaccine research to answer important questions regarding safety and to identify the biological basis for adverse reactions. Key questions to be answered include these: What components of vaccines are responsible for adverse reactions? What is the genetic basis for susceptibility to adverse health effects in animals? How can susceptible individuals be identified? Do multivalent vaccines cause a higher rate of adverse reactions than monovalent vaccines? Is administration of multiple doses of monovalent vaccines really any safer than administering a single multivalent vaccine? These and other vaccine-related questions deserve our attention as veterinarians so we can fulfill our veterinary oath to relieve animal suffering and “above all else, do no harm.”

PMID: 9890055 linking working as of 10/20/16


Information obtained via the Freedom of Information Act, watch how they discuss the adverse events related to the Rotashield vaccine, and basically decide to let more children be damaged while they decide if they should pull it off the market. Some appear quite concerned, but the end result is to let more children get hurt before they stop the madness… link no longer valid, too bad as this was a great read. Could only find this, not sure if the other info is out there anymore. Maybe under the licensing info, may look for it when I have a chance.

Rotavirus Vaccine On October 15, 1999, American Home Products Corp. abruptly pulled the RotaShield vaccine off the market because of a link to intussusception in infants. Writing in The Wall Street Journal (Oct. 18, 1999), Gardiner Harris stated: “Over the past year, two babies died, 53 had surgery and another 47 required medical care after receiving American Home’s RotaShield vaccine and then developing bowel obstructions.” On October 26, 1999 it was further reported in the WSJ that the rotavirus vaccine (RotaShield) “would have killed 12 to 20 infants a year — about as many lives as it was predicted to save — if it had been given to every American infant, according to an emergency government study.” This prompted a member of the vaccine-advisory panel of the CDC, Dr. Charles Helms, to admit, “We have got a bit of a black eye here and a possible problem with the future confidence of vaccines.”

Indeed the withdrawal of RotaShield is the first time a vaccine for a common childhood illness has been taken off the market in the United States after having received FDA approval. The article also goes on to state that the FDA may have also lapsed by the fact that it was not aware of a 1989 test of a similar vaccine in China, in which a number of babies also suffered intussusception. It also elucidated the fact that while intussusception can usually be cured with enemas, in the case of vaccinated infants, surgery was required because of the severity of these cases in which part of the bowel had infarcted and had to be removed.

The paper also quoted Roger Glass, “a top CDC researcher who was involved in both the China trial and RotaShield’s approval.” Apparently remaining skeptical about the link, Dr. Glass was quoted as saying: “I am concerned that by throwing out this vaccine or damning it with the intussusception issue, we’ll lose the opportunity to examine whether it could be a lifesaver in developing countries as well as a major preventer of hospitalization in the U.S.”

Indeed the RotaShield withdrawal marks another setback for American Home, based in Madison, N.J. which has also recently agreed to pay as much as $4.83 billion to settle diet-pill litigation.


Let’s look at vaccine schedules, then and now:  link no longer valid, but found this one.  Once again they moved the information and changed the link…

Vaccine Schedule

In the early 1950s, there were four vaccines: diphtheria, tetanus, pertussis and smallpox. Because three of these vaccines were combined into a single shot (DTP), children received five shots by the time they were 2 years old and not more than one shot at a single visit.

By the mid-1980s, there were seven vaccines: diphtheria, tetanus, pertussis, measles, mumps, rubella and polio. Because six of these vaccines were combined into two shots (DTP and MMR), and one, the polio vaccine, was given by mouth, children still received five shots by the time they were 2 years old and not more than one shot at a single visit.

Since the mid-1980s,  (my note, once the vaccine makers were made immune from lawsuits) many vaccines have been added to the schedule. Hib vaccine was added in the late-1980s. In the 1990s, hepatitis B and varicella vaccines were added and the polio vaccine shot (IPV) replaced the oral polio vaccine (OPV). In the year 2000, the pneumococcal vaccine was added. Now, children could receive as many as 20 shots by 2 years of age and five shots in a single visit!

(Dec of 2002, a 5 in 1 combo shot was licensed, Pediarix. Should a child have a reaction, it will be virtually impossible to determine which of the 5 were the cause.)

And more vaccines are to come. By 2005, it is likely that children will also be recommended to receive a meningococcal vaccine, the influenza vaccine and the hepatitis A vaccine, all given as shots.



For me, I think the first place to begin is with hard numbers–Just how many cases of all these vax-diseases do we get here in the united states? (by the way, if you are out of the us I recommend you search your country’s online stats)

This is one of the hardest to find pages at the cdc… the way that I actually found this page was by accident. I had called the CDC to find out about hib cases and I got a doctor and he sent me to this page…

if you download the current issue it gives you the most up-to-date stat that the cdc has on the reportable diseases by the way, the stats are at the end of the document. Anyway, I would start there first.

But just to give you an idea: Here are the hard numbers for 2004. This is what I found for the last week of the year….. this is the total amount of cases reported to the CDC for 2004…..

Total reported cases to the cdc:

Disease Cases

Diptheria 0 Measles 37 Mumps 236 Rubella 12 Congenital rubella 0 Tetanus 26 Hib (under 5) Sero b-16 Non sero b-114 Unknown b-156

Out of a population of 295 million people in the united states!!

Remember it is a cumulative list… it is not that many cases per week. It’s the year to date.

I will say that critics of the CDC will say that the numbers don’t reflect all the cases since sometimes the cases are so mild they don’t even get reported or people don’t even go to the doctors because the symptoms are so manageable.

also….if you want to know how many people died of a disease–go to this link. plug in the disease.  You will be shocked by how small a number it is.

More stats to consider

Polio has been eradicated in the western hemisphere and western Europe. As of 2003 there were around 700 cases of polio world wide and they were primarily in hot spots in India, Pakistan and sub Sahara Africa.     link no longer valid

And then there is the data on vaccine injuries…kept by US dept of health. Basically a summery of the most dangerous vaxes…here is a link that contains that link plus more:…us_vaccines.htm    link no longer valid



A doctor is supposed to give you the inserts whenever they give your child a shot….I must say, from what I understand that usually for some reason doesn’t happen…. Anyway, here is a link to those inserts  link working as of 10/20/16


topic: Timeline of Thimerosal Controversy (note–from Motherjones)…p_timeline.html link valid as of 10/20/16


How to Raise a Healthy Child in Spite of Your Doctor by Robert S. Mendelsohn (Paperback)…=glance&s=books

Confessions of a Medical Heretic by Robert S. Mendelsohn (Paperback)…g=UTF8&v=glance

Vaccines: Are They Really Safe and Effective by Neil Z. Miller, et al (Paperback)…=glance&s=books

Smart Medicine for a Healthier Child: A Practical A-To-Z Reference to Natural and Conventional Treatments for Infants and Children by Janet Zand, et al (Paperback)  I should say, this book is pro-vax..which I am not thrilled about…but the other stuff is very, very helpful)…=glance&s=books


Decreases In Disease Risks

Today, vaccine-preventable diseases are at or near record lows. By virtue of their absence, these diseases are no longer reminders of the benefits of vaccination. At the same time, approximately 15,000 cases of adverse events following vaccination are reported in the United States each year (these include both true adverse reactions and events that occur coincidentally after vaccination). This number exceeds the current reported incidence of vaccine-preventable childhood diseases. As a result, parents and providers in the United States are more likely to know someone who has experienced an adverse event following immunization than they are to know someone who has experienced a reportable vaccine-preventable disease. Thus, the success of vaccination has led to increased public attention on health risks associated with vaccines.   Interesting, this link is no longer valid , looks like they re-worded this paragraph and took out the part about the 15,000 adverse events, guess they didn’t want to “scare” anyone out of vaccinating, but they sure have no qualms about scaring people INTO vaccinating. 


Decreases in Disease Risks

Today, vaccine-preventable diseases are at or near record lows. Many people no longer see reminders of the severity and potential life-threatening complications of these diseases. Recent outbreaks of vaccine–preventable diseases show that even vaccinated people are at risk for disease if there is not adequate vaccine coverage in the population. Parents and providers in the United States may be more likely to know someone who has experienced an adverse event following immunization than they are to know someone who has experienced a vaccine-preventable disease. The success of vaccination has led to increased public attention on potential health risks associated with vaccines.



In the United States, The National Childhood Vaccine Injury Act of 1986 established a Committee from the Institute of Medicine (IOM) to review the adverse consequences of childhood vaccines.

This group found severe limits in the knowledge and research capability on vaccine safety.

Of the 76 vaccine adverse events they reviewed for causal relation, 50 (66%) had no or inadequate research.

Specifically, the IOM Committees identified the following limitation’s:

1) Inadequate understanding of biologic mechanisms underlying adverse events;

2) Insufficient or inconsistent information from case reports and case series;

3) Inadequate size or length of follow-up of many population-based epidemiologic studies;

4) Limitations of existing surveillance systems to provide persuasive evidence of causation and

5) Few experimental studies published relative to the total number of epidemiologic studies published.13,14   link no longer valid


Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism.

J Biomed Sci. 2002 Jul-Aug;9(4):359-64.


Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism.

Copyright 2002 National Science Council, ROC and S. Karger AG, Basel

PMID:12145534  DOI:65007


7 years later and more laboratory findings continue to  support his hypothesis.


Phenotypic expression of autoimmune autistic disorder (AAD): a major

subset of autism.


Singh VK1.

Author information

  • 1Brain State International Research Center, Scottsdale, AZ 85260, USA.



Autism causes incapacitating neurologic problems in children that last a lifetime. The author of this article previously hypothesized that autism may be caused by autoimmunity to the brain, possibly triggered by a viral infection. This article is a summary of laboratory findings to date plus new data in support of an autoimmune pathogenesis for autism.


Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay.


Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)–salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants–a marker of systemic inflammation.


The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy. The author has advanced a speculative neuroautoimmune (NAI) model for autism, in which virus-induced autoimmunity is a key player. The latter should be targeted by immunotherapy to help children with autism.

PMID: 19758536


Dr. Halsey’s presentation at the National Vaccine Advisory Committee Workshop on Thimerosal and Vaccines held in Bethesda, Maryland on August 11-12, 1999.

Due to information disappearing and/or links that stop working will copy all the slide notes here.

Slide Notes:

The following summary is adapted from a presentation made by Dr. Halsey, Director of the Institute for Vaccine Safety (IVS), at a National Vaccine Advisory Committee Workshop on Thimerosal and Vaccines held in Bethesda, Maryland on August 11-12, 1999.

The Institute for Vaccine Safety was asked to provide a perspective on the transition from the current mercury-containing vaccines to vaccines containing little or no thimerosal.

The IVS perspective is no different than our position on all vaccines:

All children should be protected against vaccine preventable diseases using the safest possible vaccines.

The most important objective during the transition period is to minimize potential risks to children. In addition, we need to maintain public confidence in vaccines, federal agencies responsible for vaccine safety, and physicians who administer vaccines and provide advice patients and parents.

During the past few years, public concern about product safety had increased. As a society, we are more concerned than ever about chemical contamination in the environment and in food; we demand that our automobiles be as safe as possible including airbags and optimal seatbelt design; and almost daily, we see recalls of toys and other products for children. These are only a part of the overall concern to make the world as safe as possible for everyone, especially children. The increased focus on drug safety – including vaccine safety – is a logical part of this overall concern.

The quote is from the CEO of Novartis, the parent company of Gerber Foods, “We want a mother to buy our product and have no concern”.

IVS believes that vaccine manufacturers and professionals providing guidance on vaccines should adopt a similar philosophy so that the public has no worries when receiving vaccines.These are seven important points that need to be made during this presentation.

(FROM THE SLIDE 6 & 7 of 26)

  1. Mercury content in package label
  2. All children are not created equally with regard to the risk from exposure to thimerosal
  3. Hepatitis B vaccine unfairly targeted
  4. We need to inform physicians and parents about uncertainties and options
  5. Expedited review of products with reduced or no thimerosal
  6. Unit dosing should be encouraged
  7. Additional resources and scientists are needed at the FDA to address safety issues





The quantity of mercury in each vaccine should be listed on the package label. Currently, the package label lists a concentration either as a dilution (ie, 1:10,000) or as a percent (ie, 0.01%).

As Leslie Ball from the Food and Drug Administration outlined in an earlier presentation, one must go through a two or three step calculation processes and know the molecular weight of each of the components of thimerosal in order to know that it is 49.6% mercury by weight, in order to determine the mercury content in each dose of vaccine. Since mercury is the biologically active component in thimerosal, the amount should be listed on the package label.

(FROM THE SLIDE 9 or 26)

Factors associated with mercury toxicity

  • Dose
  • Form of mercury
  • Intermittent bolus?
  • Age
  • Weight
  • Other mercury exposures
  • Metabolism and excretion rates

There are numerous factors associated with mercury toxicity, as noted on the slide. All children are not created equal with regard to their risk from exposure to mercury. We cannot control many of these factors, but we can have some control over the age and weight of children at the time they are exposed to mercury in vaccines.

The smallest newborns can be less than half the weight of the largest newborns and this difference can continue until approximately 6 months of age. Guidelines should prevent potential harm from mercury exposure in this most vulnerable population, as pointed out by Kathryn R. Mahaffey, PhD, from the EPA. “If we take the weights of these children, and assume that they are receiving thimerosal-containing vaccines for each of the recommended vaccines by age, the following figure shows the dose of mercury in micrograms per kilogram that they would receive on the day vaccine is administered.”

Exposure to a fixed dose (e.g. 62.5 ug) of mercury at 2 months of age poses a greater potential risk than the same dose administered at 6 months of age because a child weighs more at 6 months and the target organ, the brain, is more vulnerable early in life.

Similarly, exposures at 9-12 months would carry much less theoretical risk than exposure to the same dose at 2 months of age.

The recent American Academy of Pediatrics/ Public Health Service recommendation to defer the first dose of hepatitis B vaccine for infants born to HBsAg negative mothers until 2-6 months of age has addressed the problem of exposure at birth, but the exposure to mercury at 2 months of age is much greater and we need to do more to reduce this potential exposure.

Which reference guideline for methyl mercury exposure should be used to evaluate ethyl mercury exposures from vaccines? WHO is the only organization that put a time period for exposure of more than one day, by giving a Provisional Weekly Tolerable Intake (PWTI). As noted by John Clements from WHO and Dr. Teely from the European Union, the WHO PWTI for pregnant women, nursing women, and infants would be one-fifth the PWTI for the general population. This makes the WHO guideline approximately the same as the EPA guideline. The Public Health Service has chosen the ATSDR guideline, which were based largely on the Seychelles data and allow for more liberal exposures.

Does that mean that we should ignore the data from the more recently generated studies in the Faroe Islands?

Dr. Lucier has summarized several possible explanations for the differences in the results of studies of children exposed in these two studies. In the Faroe Islands, there was evidence of harmful effects from maternal mercury exposures that were thought to be safe based on the Seychelles studies. In the Faroe Islands, exposure to mercury was primarily from intermittent bolus doses associated with consumption of pilot whales. Also, children in the Faroe Islands were examined at an older age than children in the Seychelles and more precise domain specific neurologic testing was performed. During the next two years, further follow-up data will become available from the Seychelles Islands using similar domain specific testing.

Testing in the Faroe Islands follow-up study required very sophisticated testing to detect very mild, subtle neurologic defects that would not be evident on routine examinations. The results provided many interesting observations, including the fact that the minor defects were noted primarily in boys. The biologic explanation for increased susceptibility to mercury of the male fetal brain has not been determined. There are other genetic factors associated with susceptibility to mercury toxicity which we may understand some day.

This figure shows the ATSDR guidelines selected by the Public Health Service superimposed on the daily exposures to ethyl mercury for children who receive all thimerosal-containing vaccines. At 2 months of age children of all weight categories receive more than 30 times the recommended daily maximum exposure and children of the smallest weight category receive almost three months worth of daily exposures on a single day.

If the EPA or WHO guidelines are used, the smallest children receive approximately 8 months of daily exposures in a single day. None of the guidelines provide us with the safety margin for these exposures or how single large exposures should be counted. Physicians administering vaccines and parents must make a decision at the time of immunization as to the safety of the dose of mercury delivered.

We need to tell physicians and parents about the options available for reducing mercury exposures. If only a single thimerosal-containing vaccine is administered such as Hib or DTaP at two, four and six months of age, then only the very smallest infants receive more than the total monthly mercury exposure allowed under the ATSDR guidelines.

Administering only hepatitis B vaccine gives one-half the mercury exposure and most children receive less than the weekly allowable dose after two months of age.

And it is possible to administer all of the recommended vaccines without using any thimerosal-containing vaccines.

There are many uncertainties that have been discussed with regard to the mercury that children receive from vaccines. We need to share these uncertainties with physicians and the general public by providing more information and more specific guidelines and options.

We have not talked about the possible effects of mercury on the immune system. There are several centers doing immunologic studies on the effects of mercury on the immune system. We can expect many new publications on this subject during the next two years.

One thing that has not been highlighted enough is the fact that the mercury exposures from vaccines are in addition to background exposures to methylmercury from fish consumption.

This chart is from the EPA report to congress and shows ranges of fish consumption in different populations within the United States. Most groups have low to moderate fish exposure, but there is great variability and there are numerous populations with very high levels of fish consumption in this country.

As noted by Kathryn R. Mahaffey, PhD, the EPA estimates that seven percent of women of childbearing age consume sufficient fish to have a mercury exposure of about 0.1 micrograms per kilogram per day, the upper level that EPA considers to be safe. The EPA also notes that about one percent of women of childbearing age are consuming 0.37 micrograms or more per kilogram of mercury per day, which is more than the ATSDR reference value.

Thus, some children are being born with mercury from their mother’s exposures that are above the guidelines provided by EPA, ATSDR, and WHO. Although safety factors have been built into these guidelines, we do not know what the effects of additional mercury will be on the developing brain.


Throughout the country there are warnings about mercury exposure from fish directed to pregnant women, nursing women, and in some cases for children as noted in this poster from Maine. Local populations, especially Native Americans, often ignore these guidelines.

Thimerosal is not a perfect preservative, as evidenced by numerous clusters of disease caused by DTP vials that had become contaminated with the group A streptococcus.

 Manufacturers should be encouraged to use unit dosing for vaccine delivery whenever possible. Not only does this preclude the need for preservatives such as thimerosal, but this can eliminate errors from improper reconstitution or mixing of vaccines. Although these errors occur infrequently, they can be harmful. There are drawbacks to unit dosing, including increased refrigerator space requirements, but newer developments may reduce space requirements. There are also increased costs associated with unit dose delivery, which will need to be addressed.

To maintain public confidence in vaccines, we should put the mercury content in the label. We also need to revise vaccine information statements to include specific information about mercury exposures. These forms are our primary tools for communicating potential risks to recipients of vaccines and parents.

We also need to provide physicians with more precise guidelines regarding maximum allowable exposures on a given day. Should we have separate specific recommendations for the highest risk populations? This has never been very practical, and I believe we need to have guidelines that are applicable to all of the population, including the most vulnerable.

Also, vaccines with little or no thimerosal should be preferred for use in infants as has been recommended by the European Union.

The last point is that we need to have good science used for decision making in the review of alternatives to thimerosal and the effects on the final product from reducing or removing thimerosal from vaccines. We expect scientists at the Food and Drug Administration to help manufacturers address these problems. Instead of increasing the budget to address increasing numbers of safety concerns in the past five years, the budget for research at CBER (Center for Biologics and Related Products) has decreased to one third of what it was in 1994. This trend must be reversed in order to maintain the tradition of good science at the FDA and protect children against disease with the safest possible vaccines.


What Is Coming
Through That Needle?
The Problem Of Pathogenic Vaccine Contamination

By Benjamin McRearden
In recent times mankind is experiencing a situation never previously encountered, that being the threat of release of pathogens intended to kill or disable large numbers of people. That danger has prompted certain health agencies to prepare for possible mass vaccination of the populace. The purpose of this report is to examine the existing scientific evidence of pathogenic contaminants in vaccines. This summary, while making no claim of being a complete review of the subject, will point out sufficient examples and illustrations of contamination with bacteria, viruses, and their components, so as to enable the reader to make a more informed decision regarding accepting a vaccination (or forcing others to receive one). It is presented in a format intended for the public, their physicians, and their agency or governmental representatives, and may be freely copied in its entirety. If you as an individual are too busy to read this brief summary in one sitting, please be aware there is ample evidence in the scientific literature that serious viruses, bacteria; or components and toxins therefrom; as well as foreign animal or cancer-related proteins and DNA are finding their way into the commercial vaccines intended for humans, pets, and agricultural animals. If you are interested in the short and long-term health of yourself and those you care about, or serve as a public servant or medic al advisor, you do owe it to yourself to be informed. In the production of viral vaccines on a commercial scale, the virus of concern must be reproduced in large quantities. Viruses cannot survive or reproduce without being introduced into cells that nourish them, which enables the viral reproductive activity. In that sense all viruses can be considered parasitic on other cells. Living cell types commonly used to reproduce viruses in the lab include monkey kidney cells, chicken embryos, as well as other animal and human cells. These cells must also be nourished with food, and are most often fed with a nutrient mix containing in large part, bovine (cow) calf serum (usually, serum extracted from fetal calf blood). This product can carry many types of bovine blood-borne viruses, and is one of the primary sources of vaccine contaminants. A journal article states, “a potential risk associated with the production and use of biological products is viral contamination. This contamination may be present in the source material, e.g. human blood, human or animal tissues, cell banks, or introduced in the manufacturing process through the use of animal sera…”(1) Bovine Viruses The viruses and other agents that can contaminate bovine calf serum are numerous. One of the most prominent is a pestivirus called bovine viral diarrhea virus (2). More specifically, we see in several scientific journal sources these types of statements: “contamination of a vaccine as a consequence of infection of fetal calf serum”(3); “many batches of commercially available serum are contaminated with viruses such as BVD” [bovine viral diarrhea] (4); “virus was isolated from 332 of 1,608 (20.6%) lots of raw fetal calf serum obtained specifically for the Center and 93 of 190 (49%) lots of commercially available fetal calf serum (5); “agents most frequently detected in CCL’s [continuous cell lines] have been bovine viral diarrhea virus and mycoplasma. Our laboratory has consistently found that the source of bovine viral diarrhea contamination of CCLs has been the use of contaminated fetal bovine cell culture enrichment serum”(6); and finally, “In conclusion, most commercially available bovine sera are contaminated with BVDV and, although there is no evidence that the virus is infectious, bovine sera should be screened for this virusfor the development or production of vaccine.”(7) Can this virus cause infection or disease in humans? New evidence shows this is possible, as researchers have found a new strain that was isolated from human cells, and it is very closely related to the bovine strains (8). One study finds that an alarming 75% of all laboratory cell lines examined were contaminated with pestivirus strains; of these, all of the bovine cell lines were contaminated with one of three possible BVDV strains; cell lines from other animal sources including primates, sometimes contained one of these BVDV strains (9). There is now heightened concern that this virus and others can cross species lines, creating new strains as they adapt to their new hosts, and this would include passage of the virus to and from humans. Whether the human strain of BVDV causes overt illness is uncertain, because physicians may be uninformed and not even be looking for this virus. It may be useful however, to compare the infection patterns in cattle. They can be persistently infected at a low level for their entire life with a non-pathogenic strain of the virus. Under these conditions, they consistently create and shed virus into the surrounding environment, which then infects other animals. The virus can nonetheless become lethal to the animal if it mutates, with the new form also causing “visible cell damage and death” in cultured conditions (10). The animal succumbs to gradual or acute deterioration of the gastrointestinal mucous lining, which produces diarrhea and its eventual demise. However, mutated virus is not always necessary to provoke debilitating illness and death, and ordinary virus can be isolated from the cow’s pancreas, adrenal glands, and pituitary glands (11); the virus has also been documented as causing serious pulmonary illness (12). A study describes an outbreak of disease among goats due to a vaccine contaminated with a bovine pestivirus; oddly, these animals experienced reproductive failure and lesions to the central nervous system (13). So, can these diseas symptoms in varied organs and tissues also occur in humans when they carry this virus short or longterm? A cursory examination of the literature indicates this may be occurring. One revealing study tells us “faeces from children under 2 years old who had gastroenteritis that could not be attributed to recognised enteric pathogens were examinedfor Pestivirus antigens. Such antigens were detected in 30 of 128 episodes of gastroenteritisThe diarrhoeal disease in children excreting Pestivirus antigens resembled that in other children except that it was more commonly associated with signs and symptoms of respiratory inflammation.”(14) There are also concerns regarding a pattern of pestivirus infection in infacts born with microcephaly, a condition wherein the head or cranial capacity is unusually small (15, 16). Scientists from the USDA National Veterinary Services Laboratory describe the situation quite clearly, and give an indication of the seriousness of the problem: “The high frequency of virus and antibody detection in individual animal or small pool samples suggests that any large pool of unscreened sera will be contaminated. Infection of cell cultures with BVDV can lead to interference with the growth of other viruses. Vaccine produced on contaminated cells may in turn be contaminated, leading to seroconversion or disease in the vaccine. The safety, purity, and efficacy of viral vaccines require BVDV testing of ingredients, cell substrates and final product.”(17) And here is a similar statement from a New York Blood Center: “Bovine viral diarrhea virus, whose small virion size does not allow 100% assurance of its removal by filtration, may potentially contaminate every lot of commercially produced fetal bovine serum.”(18) In reality though, how much of this particular viral contaminant has trickled into humans? Well, in spite of manufacturers and regulatory agencies claiming efficacy of their testing procedures, one 2001 study found 13% of human MMR, polio, or Streptococcus pneumoniae vaccines tested positive for pestivirus RNA (19). And another researcher observes, “serum antibodies against BVDV have been detected in approximately 30% of human population who had no contact with potentially infected animals.”(16) Also, “pestiviruses adapted to human cell cultures may be harmful because serious BVDV infections in humans have been frequently suggestedThe BVDV persistently infected in cell cultures used for vaccine productions have been shown to be a source of contamination in live virus vaccines. It is, therefore, prerequisite to examine pestivirus contamination in cell cultures to avoid secondary infections in humans as well as in animals.”(20) Continuous Immortal Cell Lines This same scientist brings up another important issue. Because many medical-use biological products (including vaccines) are now being cultured or produced on what is called “continuous” cell lines (i.e., these are cell cultures consisting of “immortal” or cancerous types of cells because they have no limits on how many times they can divide), there is concern that viral contamination of these cell lines with a pathogen like bovine viral diarrhea virus, could spread cancer-promoting material into the human recipient. How could this happen? Briefly, it works like this. The virus (which in this case has a single strand of RNA for its genome) is capable of incorporating RNA from the cells in which it has been cultured, into its own genome. If any contaminant RNA virus is present in a culture that contains immortal cancerous cells, this virus can easily mutate to include unwanted oncogenic material, which can then get passed into the biological product intended for human medical use (16). Were you aware that biological products, including some common vaccines (for instance, polio and rabies), are being produced on “continuous” immortal cell lines? Manufacturers, scientists, and agencies will often assure us that these cells themselves are not “tumorigenic”, i.e., they do not cause tumors per se. A closer look however, shows this is not always the case. While lab culturing may indicate that these types of cells are not immediately changing to overt tumor cells, it is now well known in the scientific community that after these cells have been repeatedly cultured a certain number of times, something causes them to convert to a cancerous state (21). This journal article summary addresses the issue in regards to Vero cells, which is a continuous cell line coming from the African green monkey, and is commonly used in vaccine production. It states, “One of the current criteria for evaluating the acceptability of cell lines for use in vaccine production is lack of tumorigenicity. Vero cells represent an example of a class of cells known as continuous cell lines. They were derived from African green monkey kidney, and their growth properties and culture characteristics have many advantages over other cell substrates for use in vaccine production. We have tested Vero cells for tumorigenicity in nude mice and in a human muscle organ culture system, and found a significant increase in their tumorigenic potential with increasing passage numbers. Cells at passage 232 and higher produced nodules in all nude mice inoculated.”(22) [The term “passage” in this context means the number of times a cell line has been cultured]. There is another very important issue reported in studies that is evidently being largely ignored as regards long-term vaccine effects and safety. There is obvious evidence that in the lab, continuous immortal cell lines react differently between one type of animal species and another (21, 23). As an example, tissue from one species will allow the immortal cell to induce a cancerous change more quickly, in comparison to tissue from a different species. These results then beg the following questions. How extensively have these continuous cell lines been tested on human tissues, and would the results vary from one type of tissue to another? And what happens over the long termif an immortal cell from a vaccine culture makes its way into the final vaccine product, does it keep dividing in the human body? Another scenario might suggest the tumor-promoting portion of its DNA inserting into a viral genome, which then gets injected into the bodywhat happens at that point? Furthermore, given the evidence that closely-related animal species (as an example, various species of monkeys) react differently to immortal cells, do we also need to consider that any one vaccine intended for all humans might ultimately react differently among the various races, ethnic groups, and sexes? And what are the effects of the vaccine contaminants on persons with immune depression, on the elderly, or on infants? A letter from the FDA to vaccine manufacturers dated as recently as March 2001 shows that this issue regarding immortal cell lines is still of concern. It states, “In general, CBER [Center for Biologics Evaluation and Research] currently views Vero cells as an acceptable substrate for viral vaccines, but has residual concernsCBER recommends that all products derived from Vero cells be free of residual intact Vero cells. If your manufacturing process does not include a validated filtration step or other validated procedure to clear residual intact Vero cells from the product, please incorporate such a procedure into your manufacturing process.”(24) It is now 16 years after the WHO gave a go-ahead (in 1986) to use continuous cell lines for vaccine production (25), and yet there are very basic safety questions not resolved by the manufacturers, agencies, and scientific community, much less the finer details (26, 27). One 1991 study reports: “Cell substrate DNA was shown to be an abundant contaminant in the clarified preparations of the Sabin type 1, 2 and 3 poliovaccines produced on a continuous cell line”(28). Another indicates that immortal cell lines showed 100-times greater number of DNA recombination events compared to normal cells (29). As one researcher states, “Using neoplastic cell lines as substrates for vaccine development could inadvertently result in viral-viral or viral-cellula r interactions whose biological consequences are unclearviral-viral and viral-cellular interactions can result in the generation of new retroviruses with pathological consequences.”(30). We note the term “neoplastic” means the quality of having an abnormal growth characteristic. There is an even stronger statement dating back to 1990. A scientist in the field writes, “The present concern is for safety of vaccines made using transformed or neoplastic mammalian cells that may contain endogenous contaminating viruses or integrated gene sequences from oncogenic viruses. There is also concern for use of plasmid vectors employing promoter elements from oncogenic viruses. The principal concern for safety lies with retention of residual DNA in the vaccine, especially since induction of cancer is a single -cell phenomenon, and a single functional unit of foreign DNA integrated into the host cell genome might serve to induce cell transformation as a single event or part of a series of multifactorial events. Current proposed standards for vaccines would permit contamination with up to 100 pg [picograms] of heterologous DNA per dose. This is equivalent to about 10(8) ‘functional lengths’ of DNA. Total safety would seem to require complete absence of DNA from the product.”(31) Please note that 10(8) means 10 to the power of 8, or 100,000,000 “functional lengths” of DNA are allowed per dose of vaccine . Is there something wrong with this picture? How long will the general public be subjected to these vaccine products that according to this information, are nowhere near safe? It has taken, for instance, approximately forty years for the scientific community to finally acknowledge that we have a serious problem as a result of the contaminatio n of polio vaccines with simian virus 40 (SV40) in the late 1950s-early 1960s. There has been previous evidence of some human brain and other tumors containing this virus (32, 33), but the medical community has been slow to acknowledge a definitive link between SV40 and cancer in humans. However, two independent research teams have recently found this virus present in 43% of cases of non-Hodgkins lymphoma (34, 35). Another study found it present in 36% of brain tumors, 16% of healthy blood cell samples, and 22% of healthy semen samples (36). And strangely, SV40 has now been found to infect children (37). Considering that children of this era, are not supposed to be receiving the virus via the vaccine contamination route, this would therefore imply that SV40 is being transmitted from one human to another, in ways not previously known. Other simian viruses may also be contaminating the (Vero) monkey cell lines used for vaccine production. One example from the literature cites the contamination presence of SV20, which is a oncogenic simian adenovirus (38). Simply put, are we in a state of denial that vaccines are ultimately transmitting viruses, DNA, and proteins into humans from foreign animal sources (and possibly unhealthy human sources), and that this may be strongly contributing to the incredible upsurge in cancers and serious chronic diseases? Are these foreign animal genes altering your DNA? Furthermore, given that viral presence can sometimes take years to manifest actual disease symptoms, and then considering the tendencies of health-related agencies and corporations towards short-term solutions and profits, will we ever truly know the long-term consequences until it is too late? Other Bovine Viruses Another contaminating virus found in the calf serum used for vaccine production is bovine polyomavirus (polyomaviruses are strongly associated with cancer); one pertinent article is titled “Bovine polyomavirus, a frequent contaminant of calf serum”(39). Other contaminants include a virus from the parvovirus family (40); another study cites “virus-like particles” and “mycoplasma-like agents” in 68% and 20% of the samples, respectively (41); and yet another mentions the presence of infectious bovine rhinotracheitis virus (aka bovine herpesvirus 1), and parainfluenza-3 virus in addition to the common BVDV (42). An interesting report from 1975 not only affirms the presence of these viruses in calf serum, and mentions the additional presence of bovine enterovirus-4, but also tells us that 25% of serum lots that were pre-tested by the suppliers and “considered to be free of known viral contaminants” were actually contaminated with bovine viruses (43). It should be obvious that any bovine blood-borne virus (including serious retroviruses such as bovine leukemia virus, bovine visna virus, and bovine immunodeficiency virus) could ultimately end up in human or animal vaccines via the use of calf serum in the manufacturing process. Contamination of calf serum with certain bovine herpesviruses, and the possible implication for human health, deserves a bit of scrutiny. It is known that bovine herpesvirus-1 replicates easily in a human embryo cell line called WI-38 (44). It is also known that bovine herpesvirus-4 is quite “persistent” in calf serum, and has a wide host range, including human cells (45). In fact, this particular virus strongly replicates in two human embryonic cell lines, WI-38 and MRC-5, enough so to prompt one author to give these details and a warning: “PCR [polymerase chain reaction] detected a 10,000-times-higher level of BHV-4 [bovine herpesvirus-4] DNA the supernatant indicated a 100-fold increase of infectious particles. Since this is the first bovine (human herpesvirus 8 and Epstein-Barr virus rela ted) herpesvirus which replicates on human cells in vitro, the danger of possible human BHV-4 infection should not be ignored.” (46) The clincher to this possible contamination, is that these same human cell lines WI-38 and MRC-5 are two of the most common human cell lines used to manufacture viral vaccines, (for example – rubella, chickenpox, smallpox) and these cell lines are of course, commonly nurtured with calf serum. Contaminants From Chicken Sources Some viral vaccines are produced by growing the virus in chicken eggs. Common human vaccines manufactured by this method include influenza, mumps, measles, yellow fever, and others. Like the vaccines that include bovine-source materials, those derived from chicken embryo culture are plagued with some very serious viral contamination problems. Avian leukosis virus (aka avian leukemia virus or ALV) is a retroviral pathogen that infects large segments of the modern poultry industry, is present in commercial chickens and eggs, and thus exposes humans on a consistent basis (47). An interesting virus in the sense that it can be considered a “parent”, it easily transforms into a dizzying array of related viruses by hijacking one of numerous cancer-related gene segments from its host, and inserting it into its own genome. Furthermore, it has the additional capability of inserting itself into the host (including human) genome, hiding out so to speak, and causing cancerous cell transformation from that location. There is now much scientific literature available that describes the various active mechanisms of this and other cancer-associated viruses (48). Viruses that originate from the “parent” avian leukosis virus, include the potent Rous sarcoma virus, Rous-associated viruses, avian myeloblastosis virus, avian myelocytoma virus, avian erythroblastosis virus, Fujinami sarcoma virus, etc. One group of researchers studying the mechanism of ALV writes, “Serial passaging of a retrovirus that does not carry an oncogene on such cultures leads with a high frequency to the emergence of new viruses that have transduced oncogenes”(49). In other words, given the right growth conditions, ALV can easily transform into other closely related viruses that are known to be cancer-related. Just how common is this avian leukosis virus in viral vaccines? The first evidence of contamination came to light in the 1960s when yellow fever vaccine was found to contain it (50). Since that time, it is common knowledge in the industry that this virus (or components thereof) still linger in human and animal vaccines (51). Indeed, the respected Fields Virology text (year 2001 edition) states, “At the present time, vaccines produced by some of the world’s 12 manufacturing institutes are contaminated with avian leukosis virus”(52). One point that researchers in this field do agree upon, are the presence of ALV, avian endogenous virus, avian reticuloendotheliosis virus (another poultry retrovirus), and also an enzyme called reverse transcriptase (a component of retroviruses) in final vaccine products intended for human use, especially the mumps, measles, yellow fever, and influenza vaccines (53, 54, 55). What they do not agree upon are the effects on humans in terms of transmission, infection, and possible subsequent disease. A recent study coming out of the U.S. CDC (Centers for Disease Control), which analyzed frozen blood serum samples from children that had received MMR vaccinations, reports no avian viral presence in these samples (56). And yet, we see reports from other researchers that make us question the results of that study. As is often the case with viruses, some strains will show particular affinities for certain types of tissues or growth conditions, and ALV is no exception (57). One researcher makes the effort to explain, “Because of the difficulty in infecting mammalian cells in vitro with these viruses, it is generally held that they do not infect humansOur results show that exposed poultry workers and subjects with no occupational exposure to these viruses have antibodies in their sera specifically directed against ALSV [Avian leucosis/sarcoma viruses] Further investigation into whether these findings mean that virus has been integrated into the human genome is needed, to assess the public health implications of these results.”(58). He also explains in another article, that given the known behavior of these viruses in mammalian cellular culture, a blood serum test will not always provide the correct evidence of viral presence in the human body (47).  In other words, does the virus (or viral antibodies) need to be actively present in the blood stream at the time of the blood draw? What if the viral particles have retreated into other tissues? Thus, the CDC study mentioned above may not have presented an accurate assessment of viral presence, or long-term effects from the numerous ALVassociated “offspring” viruses. Considering that ALV can for example, easily capture the human “erbB” oncogene (59), and that erbB as well as the oncogene called myc are strongly associated with common forms of human breast cancer, it seems that the issue of ALV vaccine contamination would deserve a high level of attention! (By the way, the general reader should not feel intimidated by the abbreviations associated with oncogeneserb refers to “erythroblastosis”, and myc refers to myelocytomatosis, which are the names of two ALV-associated offspring viruses). A well-known microbiology text reinforces these concepts by teaching, “Proto-oncogenes become incorporated into retroviral genomes with surprising ease.” (60) Toxin Contamination The unintentional presence of bacterial-source toxins (called “endotoxins” or “exotoxins”) in human and veterinary vaccines has been recognized for many years. Such toxins are originally present in source materials, or are produced as a result of bacterial infection during the manufacturing process (61, 62). The various methods used in attempts to eliminate viruses and bacteria from vaccines are simply not effective in the removal of these problematic toxic proteins (63). Several observers have expressed concern that the presence of endotoxin may be a source of severe adverse reactions seen in some individuals after receiving a vaccine (61, 64). Some vaccines, such as those for diphtheria and tetanus, are specifically created to induce a protective mechanism in the body against the bacterial toxin; however, vaccines prepared from bacteria can contain appreciable and potentially dangerous lingering amounts of toxin, despite the steps used during manufacture to decrease the toxic potency, as described in this comment: “Vaccines composed of gram-negative bacteria contain endotoxin in considerable amounts. This may result in adverse effects after vaccination of sensitive animals.” (65). It has also been reported that bacterial toxin contamination residing in calf serum, can cause breaks in the DNA of human cells (66). Bacterial Contamination – Nanobacteria Nanobacteria is a recently discovered pathogen that infects humans. Now considered to be the smallest existing bacterial form known to science, it escapes through common filtering processes, and can easily invade other cells and cause cell death. Nanobacteria also are classed as “pleomorphic”, that is, they have the ability the change physical form. A human variety of this pathogen has been found to cause or be associated with a host of disease conditions, only a few of which include atherosclerosis, coronary artery / heart disease, kidney stones and kidney disease, arthritis, MS, alzheimers, some cancers, and other conditions (67). Since this species of bacteria is specific to mammals, and must be lab-cultured in mammalian blood or serum, it is not surprising that this variety of nanobacterium has been isolated as a contaminant from bovine calf serum, other mammaliam bio-products, and vaccines. One study reports that 100% of serum of cattle in a US herd showed antigens to nanobacteria, and cites another report from Europe that, “more than 80% of commercial bovine serum lots contain Nanobacterium” (68). Obviously, any vaccines that must incorporate mammalian products during production (which would include cow, monkey, or human cells, blood or serum), will be prone to nanobacterial contamination. This was indeed verified when a group of researchers found that 2 out of 3 lots of inactivated polio vaccine, and 3 out of 6 lots of veterinary vaccines were contaminated with nanobacteria. They also point out that the bacteria could be coming from calf serum and contaminated culture cell lines (69). Any reasoning person with a basic knowledge of vaccine production can deduce that nanobacteria have undoubtedly been infecting humans in a fairly widespread manner via vaccination procedures. One might also wonder whether it has contributed to the current prevalence of atherosclerosis and generalized heart disease. Bacterial Contamination – Mycoplasmas And Related Forms If there is any one type of bacterial contamination in vaccines that warrants particular attention, it would be mycoplasmas. These small organisms have a structure not characteristic of most forms of bacteria, i.e., they usually contain a thin outer membrane as compared to the more complex walls of common bacterial forms. They are described as being capable of slipping through filtration procedures, and can transfer to other media through the air or via routine handling in the lab (70). One source states that “less than 10% of laboratories actually test for infectio n/contamination regularly”that mycoplasmas are “influencing almost every aspect of cell biology”and that labs “which do not test for mycoplasma probably harbour contaminated cell lines and may even have their entire stocks contaminated, as mycoplasma spreads readily along cell lines via regents and media, the operator and the work surface” (71). They are resistant to certain types of antibiotics used to kill other bacteria (70, 72), and are subject to changing form under varying physiological or biochemic al conditions (73). The journal and industry literature is filled with references to the problems of mycoplasma contamination in cell cultures and vaccines. Various studies cite corrupted cell lines ranging in occurrence from 5% to 87% (71, 72, 74, 75, 76), and as we now know, once this pathogen is in the cell culture being used to make the vaccine, it is liable to end up in the final product (77, 78, 79,80). One author states, “Mycoplasma contaminants can be considered important not only because of their role as pathogens but also because they may indicate that insufficient care has been taken during vaccine manufacture or quality control.” (81). Species of mycoplasmas that have polluted the cell cultures include Mycoplasma hominis, M. fermentans (implicated in Gulf War illness), M. arginini, M. hyorhinis, M. orale, M. pirum, M. pneumoniae, and Acholeplasma laidlawii (75, 76, 82). Any reputable company that sells tissue or cell culture material, also must test for and sell kits to detect mycoplasmas (72, 75, 76, 83, 84). Mycoplasmas and associated variant forms have long been associated with many disease processes, including cancer, chronic illnesses such as chronic fatigue syndrome, fibromyalgia, arthritis, Gulf War Illness, and many others (73, 85, 86). It would be impossible to cite all the pertinent references in this short report, on this vast arena of microbiology that is often ignored by much of the medical community, sometimes with tragic consequences. Mycoplasmas without question have the capability of altering cell membranes and their antigens, disrupting DNA, and altering cellular metabolism both in vitro and in vivo (70, 71, 72, 73, 86). Cross-Contamination Of Cell Lines As we recall that all viral vaccines can only be produced with the use of cells, the purity of the cell lines an important issue. The most famous example of many cell lines becoming contaminated from outside sources, occurred when the famous and extremely fastidious HeLa cancer cells started showing up in labs across the world in the 1960s. The phenomenon is well-documented (87, 88, 89, 90), and is even the subject of an entire book (91). One study from 1976 cited a litany of contamination in all primary and continuous cell lines that were examined – many viruses were found, as well as HeLa cells (92). As the years progress, the reports continue to come in: one from 1984, for instance, tells of inter- and intra-species cell cross-contamination, that 35% of all cell lines were corrupted, and that most of these lines were (originally) cells of human origin (93). Let’s fast-forward to 1999. A study in Germany finds that the problem is continuing, if not worsening. In a survey of human cell lines, the most common cross-contaminants came from “classic tumor cell lines”; that these polluted lines had been unknowingly used in “several hundred” projects which generated potentially false reports; and that they considered it a “grave and chronic problem demanding radical measures” (94). The situation is such that several scientists were prompted to write a letter to the respected journal “Nature” in January 2000, calling for immediate action to institute procedures that would verify the purity of cells used for research and production of biological products, ensure freedom from mycoplasma, and include biohazard information (95). (Did I hear that correctly – cells can be considered a biohazard)? Has anything changed since then to remedy the situation? There is another report from Jan. 2002, that two major cell lines used in research projects actually turned out to be HeLa cells (96). I ask the reader to now recall information from earlier in this report, that there are proposals being considered to produce vaccines and other biological products using distinctly cancerous cell lines, including HeLa (25). Does this seem reasonable, especially since the current lines are already dangerously tainted with HeLa and possibly other cancerous cells? Please remember the 100,000,000 allowable pieces of cell-source DNA allowed per dose of vaccine (and this does not include the viral contaminants). Anyone care for a small, under-the-skin serving of human cancer-cell-component soup? With maybe a few monkey cell fragments for garnish, and viruses for flavor? Additional Points To Consider There are several issues the public and medical community may want to be aware of concerning safe administration of vaccines. The human and animal body has normal barriers that help to protect against infiltration by foreign agents, among them are the skin, the respiratory and intestinal mucous linings, and the blood-brain barrier. The puncture of skin by a needle breaches that barrier. A group of researchers states, “Virus contamination of bioproducts such as vaccines, blood products or biological material used in surgery and for transplantations also is more hazardous because the application of contaminating virus usually occurs by circumvention of the natural barrier systems of the bodyvirus contamination of bioproducts should be considered as a hazard no matter which method has been used for its detection.” (97). Of even more concern, is the administration of vaccines nasally (through the nose), or accidental passage via that route (98). Fields Virology text (2001) says, “The olfactory tract has long been recognized as an alternative pathway to the CNS [central nervous system]olfactory neuronsare unprotected by the blood brain barrier.” While that writer particularly addresses the flavivirus family [i.e., “intranasal inoculation of flaviviruses may result in lethal encephalitis” (99)], this pattern of potential danger may deserve further attention than it currently receives, especially if there ever is consideration to use a method of nasal inoculation for mass vaccination of the public or military, and there may be contaminating viruses or toxins in a vaccine that have an affinity for nerve cells and tissues. Mass immunization programs often use jet injectors to save the time and inconvenience associated with needles and syringes. However, a study published in July 2001, found that the four injectors tested had the capability of transferring tiny amounts of fluid and blood (and thus, viruses such as hepatitis B and C, HIV, etc.) from one recipient to the next (100). Numerous other articles confirm the danger, and question the safety of these devices, including one study that reported an outbreak of hepatitis B associated with use of a jet injector (101, 102). Some of the newest types of vaccines are called “subunit” and “naked DNA” vaccines. Without going into the intricacies of their production, they involve techniques used in genetic engineering. Subunit vaccines generally will insert a viral or bacterial DNA section into the DNA from yeast, which is allowed to reproduce in large quantities. The protein intended for inclusion in the vaccine is then separated from the yeast cells. In the case of naked DNA vaccines, the viral or DNA gene is first reproduced, then spliced into a plasmid (which is essentially free DNA, widely used in recombinant technology), reproduced in bacteria or cells, and then separated from them for inclusion in the vaccine. Recombinant gene vaccines can also be produced via these methods – for instance, hepatitis B is now an exclusively recombinant vaccine (103, 104). One of the major concerns with these methods is the unpredictability and interaction of the final vaccine product with the proteins or DNA of the host. A document from the FDA states: “Genetic toxicity: Integration of the plasmid DNA vaccine into the genome of the vaccinated subjects is an important theoretical risk to consider in preclinical studies. The concern is that an integrated vaccine may result in insertional mutagenesis through the activation of oncogenes or inactivation of tumor suppressor genes. In addition, an integrated plasmid DNA vaccine may result in chromosomal instability through the induction of chromosomal breaks or rearrangements.” (105). Another group advises, “Research findings in gene therapy and vaccine development show that naked/free nucleic acids constructs are readily taken up by the cells of all species including human beings. These nucleic acid constructs can become integrated into the cell’s genome and such integration may result in harmful biological effects, including cancers.” (106). And to reiterate the danger of tumorigenic cell lines, a researcher says, “More recently, recombinant DNA technology has expanded beyond bacterial cells to mammalian cells, some of which may also be tumorigenic.” (107). It seems obvious that there needs to be a new and open dialog regarding vaccines among the regulatory agencies, manufacturers, research and medical community, and the public. Many have been ridiculed for refusing vaccination for themselves or their children, but considering the occurrences of short-term adverse events and questionable efficacy (108), possible long-term health damage, and now also facing the potential of wide-ranging loss of civil liberties (109), is it so surprising that many are questioning what the actual benefits are surrounding most vaccination protocols? Are the cases of damaged children, non-functional adults, the huge increases in cancer rates, immune and chronic diseases to be simply and blindly accepted by the public as “tolerable losses”? As a citizen with a right to good health, please be advised of the following issues. Vaccine quality in the U.S. relies for the most part, on manufacturers reporting to the FDA. Here is a relevant statement from the CDC: “Manufacturers are required to submit the results of their own tests for potency, safety, and purity for each vaccine lot to the FDA. They are also required to submit samples of each vaccine lot to FDA for testing. However, if the sponsor describes an alternative procedure which provides continued assurance of safety, purity and potency, CBER may determine that routine submission of lot release protocols (showing results of applicable tests) and samples is not necessary.” (110) Yes, this is the scope of the quality-control protocol that oversees a market worth billions of dollars, yet allowing all these contaminants into the vaccines. It may be helpful to have an idea of the scope of the operation to understand what we are dealing with here. We are advised that “Large-scale cell culture operations for biotechnology products use millions of litres of complex media and gases as well as huge quantities of organic and inorganic raw materials. These raw materials must always be assumed to contain contamination by adventitious agents” (111). And because there is a potentially large number of animal and human viruses (or viral segments) that could be entering into the final vaccine products, it would take a equally large bank of molecular probes, as well as frequent, wide-spread testing, to screen for presence of these contaminating agents. This would obviously add time and expense for the manufacturers. What needs to be decided is this – is the effort and cost involved in cleaning up these admittedly filthy medical products, worth the resultant benefit to the public health? And since certain animal products are necessary for the production of vaccines, it may also be necessary to clean house at several levels, including the agricultural sector. It is no secret for instance, that commercial chicken flocks raised for meat and eggs are often carrying infectious avian leucosis virus, mentioned earlier in this report (112, 113, 114) For the record, the smallpox vaccine ordered by the U.S. government from Aventis is being produced on two types of continuous cell lines, the human embryonic MRC-5 and the green monkey Vero cells (115). We might also be advised of one researcher’s thoughts, that “normal embryo and foreskin cells presumably represent a state in development which is genetically unstable, rendering them considerably more susceptible to malignant transformation.” (116). Are remnants of these types of cells something we want injected into our bodies? The decision you make in accepting or refusing a vaccination can be a very personal one, but whatever you decide, do try to be informed of the true benefits and risks. 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Nature 1968 Feb 24;217(5130):750-1. PMID 5641128. 88. Lavappa KS. Survey of ATCC stocks of human cell lines for HeLa contamination. In Vitro 1978 May;14(5):469-75. PMID 566722. 89. Nelson-Rees WA, Daniels DW, Flandermeyer RR. Cross-contamination of cells in culture. Science 1981 Apr 24;212(4493):446-52. PMID 6451928. 90. Gold M. The cells that would not die. Science 81 1981 April; 29-35. 91. Gold M, 1986. A Conspiracy of Cells: One Woman’s Immortal Legacy and the Medical Scandal It Caused. State University of New York Press. 92. Demidova SA, Tsareva AA, Mikhailova GR, Perekrest VV, Gushchin BV. Several methodologic problems in the control of cell cultures. Vopr Virusol 1976 May-Jun;(3):371-9. PMID 983006. 93. Hukku B, Halton DM, Mally M, Peterson WD Jr. Cell characterization by use of multiple genetic markers. Adv Exp Med Biol 1984;172:13-31. PMID 6328905. 94. MacLeod RA, Dirks WG, Matsuo Y, Kaufmann M, Milch H, Drexler HG. Widespread intraspecies crosscontamination of human tumor cell lines arising at source. Int J Cancer 1999 Nov 12;83(4):555-63. PMID 10508494. 95. Stacey GN. Cell contamination leads to inaccurate data: we must take action now. Nature 2000 Jan 27;403(6768):356. PMID 10667765. 96. Kniss DA, Xie Y, Li Y, Kumar S, Linton EA, Cohen P, Fan-Havard P, Redman CW, Sargent IL. ED(27) Trophoblast-like Cells Isolated from First-trimester Chorionic Villi are Genetically Identical to HeLa Cells Yet Exhibit a Distinct Phenotype. Placenta 2002 Jan;23(1):32-43. PMID 11869090. 97. Buttner M, Oehmig A, Weiland F, Rziha HJ, Pfaff E. Detection of virus or virus specific nucleic acid in foodstuff or bioproducts–hazards and risk assessment. Arch Virol Suppl 1997;13:57-66. PMID 9413526. 98. Monath TP, Cropp CB, Harrison AK. Mode of entry of a neurotropic arbovirus into the central nervous system. Reinvestigation of an old controversy. Lab Invest 1983 Apr;48(4):399-410. PMID 6300550. 99. Burke DS, Monath TP, “Flaviviruses”, in Knipe DM et al (ed.), 2001. Fields Virology (4th ed), Vol. I, chapter 33, p.1057. Lippincott. 100. Hoffman PN, Abuknesha RA, Andrews NJ, Samuel D, Lloyd JS. A model to assess the infection potential of jet injectors used in mass immunisation. Vaccine 2001 Jul 16;19(28-29):4020-7. PMID 11427278. 101. Canter J, Mackey K, Good LS, Roberto RR, Chin J, Bond WW, Alter MJ, Horan JM. An outbreak of hepatitis B associated with jet injections in a weight reduction clinic. Arch Intern Med 1990 Sep;150(9):1923-7. PMID 2393323. 102. Brink PR, van Loon AM, Trommelen JC, Gribnau FW, Smale-Novakova IR. Virus transmission by subcutaneous jet injection. J Med Microbiol 1985 Dec;20(3):393-7. PMID 4068027. 103. McAleer WJ, Buynak EB, Maigetter RZ, Wampler DE, Miller WJ, Hilleman MR. Human hepatitis B vaccine from recombinant yeast. Nature 1984 Jan 12-18;307(5947):178-80. PMID 6318124. 104. Hilleman MR. Yeast recombinant hepatitis B vaccine. Infection 1987 Jan-Feb;15(1):3-7. PMID 2437037. 105. Points to Consider on Plasmid DNA Vaccines for Preventive Infectious Disease Indications. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Vaccine Research and Review, December 1996. Full article available at 106. Ho M, Ryan A, Cummins J, Traavik T. Slipping through the regulatory net: ‘Naked’ and ‘free’ nucleic acids. TWN Biotechnology and Biosafety Series No. 5, 2001. Available at 107. Petricciani JC. Safety issues relating to the use of mammalian cells as hosts. Dev Biol Stand 1985;59:149-53. PMID 3891461. 108. Phillips A. Dispelling vaccination myths: an internationally published, referenced report. 1998. Report available at For statistics regarding adverse events, see the link at 109. See a discussion of issues surrounding proposed forced smallpox vaccination at: Fisher, BL. Smallpox and forced vaccination: what every American needs to know. The Vaccine Reaction, Winter 2002. Article available at The entire text of the Model State Emergency Health Powers Act, currently being considered by the various U.S. state governments is available at 110. National Vaccine Program Office, Vaccine Fact Sheets: Vaccine Product Approval Process. Article available at 111. Garnick RL. Raw materials as a source of contamination in large-scale cell culture. Dev Biol Stand 1998;93:21-9. PMID 9737373. 112. Fadly AM, Smith EJ. Isolation and some characteristics of a subgroup J-like avian leukosis virus associated with myeloid leukosis in meat-type chickens in the United States. Avian Dis 1999 Jul- Sep;43(3):391-400. PMID 10494407. 113. Grunder AA, Benkel BF, Chambers JR, Sabour MP, Gavora JS, Dickie JW. Characterization of four endogenous viral genes in semi -congenic lines of meat chickens. Poult Sci 1999 Jun;78(6):873-7. PMID 10438132. 114. Pham TD, Spencer JL, Johnson ES. Detection of avian leukosis virus in albumen of chicken eggs using reverse transcription polymerase chain reaction. J Virol Methods 1999 Mar;78(1-2):1-11. PMID 10204692. 115. 116. Kopelovich L. Are all normal diploid human cell strains alike? Relevance to carcinogenic mechanisms in vitro. Exp Cell Biol 1982;50(5):266-70. PMID 7141068.

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MedImmune RSV drug meets trial goals

24th August 2007

By Sarah Routledge

MedImmune said that in a Phase III study its investigational drug motavizumab reduced hospitalizations due to respiratory syncytial virus by 83% as compared to placebo, meeting the trial’s primary endpoint.

In addition, the trial showed a 71% reduction in the incidence of RSV-specific lower respiratory infections (LRIs) requiring outpatient management (9.5% in placebo group and 2.8 percent in the motavizumab group), which was a secondary endpoint.

Motavizumab is an investigational monoclonal antibody (MAb) being evaluated for its potential to prevent serious disease caused by respiratory syncytial virus (RSV) in high-risk pediatric patients. This phase III trial involved 1,410 full-term infants less than six months of age in two Native American populations. In previous medical studies these populations were shown to have high rates of hospitalization due to RSV.

The randomized, double-blind study was designed to compare monthly intramuscular injections of motavizumab against placebo. After an interim analysis conducted by an independent data safety monitoring committee, the study was unblinded early due to statistical evidence demonstrating that motavizumab reduced RSV hospitalizations and LRIs requiring outpatient medical management within this population.

Motavizumab was well tolerated in these Native American infants, with an overall incidence and severity of adverse events that were similar between the motavizumab and the placebo groups. The mortality rates were not statistically different between groups and were not considered to be related to the study drug. As was suggested in the pivotal phase III trial conducted in high-risk, preterm infants, rates of hypersensitivity related skin rashes within two days of dosing were seen in about 1% of treated children in the motavizumab group.



Personal Health


Published: December 28, 1994

BY the age of 3, virtually every American child has had at least one respiratory infection caused by a virus that few people have heard of and fewer still take seriously. It is respiratory syncytial virus, or R.S.V., which was first discovered in chimpanzees in 1956 but was soon recognized as a nearly universal cause of a cold-like illness in people.

Regardless of its relative obscurity and usually benign nature, R.S.V. is not an organism to be taken lightly. An R.S.V. infection can result in serious, even fatal, respiratory illness when it infects very young infants or any children with medical conditions like congenital heart or lung disease or respiratory damage after premature birth.

R.S.V., a highly contagious virus, is the leading cause in young children of severe lower respiratory illness — bronchiolitis and pneumonia — which often requires hospital treatment. Each year, 90,000 children are hospitalized with R.S.V., and the virus is responsible for an estimated 4,500 childhood deaths. It can be a very expensive illness, costing more than $5,000 a day to treat infants who need respiratory assistance and a total of $77,600 for a two-week hospital stay. In addition, after recovering from R.S.V., some children develop an asthmatic condition that can persist throughout childhood and occasionally into adulthood.

Adults too sometimes become very ill with an R.S.V. infection. In most adults, the virus causes a mild respiratory infection that is clinically indistinguishable from any other common cold. But British researchers reported last year that in elderly people R.S.V. might be as important as influenza viruses in causing serious and even fatal respiratory illness. The virus’s symptoms in the elderly often mimic those of influenza, Dr. D. M. Fleming and Dr. K. W. Cross of the Birmingham Research Unit in England reported in The Lancet, a medical journal published in Britain. In fact, the researchers suggested that R.S.V. infections might be one reason flu vaccine appears to be less effective in older people; such people may think they have the flu but actually have R.S.V.

The "season" for R.S.V. infections in the temperate zone starts in December, peaks in January and February and peters out in April. There is no better time than now to learn how best to protect very young and high-risk children and how to recognize and deal with a serious R.S.V. infection should it occur. Is It R.S.V.?

Dr. Susan Brugman, a pediatric pulmonologist at the National Jewish Center for Immunology and Respiratory Medicine in Denver, said R.S.V. typically started like any cold: in the upper respiratory tract, causing a runny nose, slight fever and fussiness. But the infection can then move into the lower respiratory tract — the bronchioles and lungs. She explained that although "the majority of babies are not at risk of developing severe R.S.V., infants under 6 months of age have much smaller airways that are more likely to become plugged up, making breathing difficult."

Dr. William C. Gruber, a specialist in pediatric infectious diseases at Vanderbilt University in Nashville, said the virus spread to the lower respiratory tract in about 20 percent of infected children. Signs of such spread include wheezing, a sinking of the chest between the ribs when the child inhales, rapid breathing and halted breathing for periods of time.

Dr. Brugman cautions parents to be on the alert for a serious infection. "The infection has become severe if the baby begins to breathe faster, has difficulty breathing, wheezes and coughs and stops drinking fluids," she said. "That’s the time to see a physician right away. And especially if the baby was born prematurely, has congenital heart disease or cystic fibrosis, the sooner the baby gets to the doctor the better."

Babies with such respiratory symptoms should always have their blood checked to see if they are getting enough oxygen. Even if the baby does not look blue, more oxygen may be needed, Dr. Brugman said. Although a 20-minute antibody test for the viral infection can be performed in a doctor’s office, the test is complex and the diagnosis of R.S.V. is more often made in a hospital laboratory, Dr. Gruber said.

Reinfection is common, but the severity of the illness nearly always diminishes with age. Other less serious complications of R.S.V. infection in young children include tracheobronchitis, middle ear infection and reactive airway disease, a tendency to wheeze when exposed to any respiratory irritant. Most children outgrow wheezing by the time they are 3 to 5 years old, but some develop persistent asthma. Dr. Brugman said those at high risk of developing asthma included babies with a family history of asthma, those who already had allergies and babies exposed to cigarette smoke or other environmental irritants at home. How It Spreads

There may be no virus more efficient at finding hosts than R.S.V. The organism can live on surfaces and clothing for hours, sometimes days, Dr. Brugman said. "Good, frequent hand washing is the single most important thing to do to curb the spread of this disease," she noted. "You can easily infect yourself after touching a contaminated surface and then touching your nose or eyes."

Likewise, an adult whose hands become contaminated by a child’s virus-laden secretions can readily spread the infection to other children. Dr. Brugman noted, for example, that "almost 100 percent of children in a day care center will get R.S.V. if one child does." The infection often becomes epidemic in hospital settings, presumably spread by health professionals from child to child. Dr. Brugman said the risk of R.S.V. was the primary reason for avoiding elective pediatric surgery at this time of year.

About the only effective treatment for infection by the virus is the antiviral agent ribavirin (Virazole). When administered as an aerosol to hospitalized children, it can reduce the severity of lower respiratory infections.

Although antibodies to the virus form after an R.S.V. infection, they are not very protective, and no lasting immunity develops. A previous attempt to develop a vaccine against R.S.V. ended in disaster, with vaccinated children developing very serious and even fatal disease.

Researchers have also experimented with passively immunizing babies at high risk of severe R.S.V. infection by giving them intravenous injections of antibodies extracted from the blood of people, like pediatric nurses, who have high antibody levels.

Dr. Gruber and Dr. Kathy Neuzil, an infectious disease specialist, are exploring the value of extra doses of vitamin A in reducing the severity of infections from the virus. He explained that levels of vitamin A in the blood dropped after an R.S.V. infection, and that this might interfere with the repair of respiratory lining cells damaged by the infection, leading to more severe disease.


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FDA MedWatch: Synagis (palivizumab) label revised to clarify risk of anaphylaxis, hypersensitivity reaction. Nov 27 2002. []


Sample Contracts

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This Settlement Agreement and Amendment to RSV License Agreement (the "Settlement Agreement") is entered into this 16th day of December 2002 (the "Effective Date") by and between MedImmune, Inc. ("MedImmune" or "Licensee"), and the Massachusetts Biologic Laboratories of the University of Massachusetts ("MBL" or "Licensor") (collectively the "Parties");

WHEREAS, reference is made to the RSV License Agreement dated August 1, 1989 by and between the Massachusetts Health Research Institute, Inc. ("MHRI"), Pediatric Pharmaceuticals, Inc. ("PPI") and Molecular Vaccines, Inc. ("MVI"), as amended on September 30, 1998 (the "RSV License Agreement"). As successor-in-interest to MHRI with respect to the RSV License Agreement, MBL is presently the sole Licensor thereunder. As successor-in-interest to PPI and MVI with respect to the License Agreement, MedImmune is presently the sole Licensee thereunder;

WHEREAS, MedImmune has developed and may hereafter develop monoclonal antibody(ies) that are Royalty Bearing Product (as defined in the RSV License Agreement); and

WHEREAS, a dispute has arisen between MBL and MedImmune over MedImmune’s compliance with its obligations under Section 2.5 of the RSV License Agreement to transfer information and to provide technical assistance with regard to MedImmune’s monoclonal antibody(ies) that are Royalty Bearing Product ("Dispute 1"); and

WHEREAS, a further dispute has arisen between MBL and MedImmune over whether a Distribution Agreement ("Distribution Agreement"), dated December 1, 1997, between MedImmune and Abbott International, Ltd. ("Abbott"), which designates Abbott as the exclusive distributor of Synagis® overseas, constitutes a sub-license under the RSV License Agreement ("Dispute 2"); and

WHEREAS, in connection with Dispute 1 and Dispute 2, MedImmune claimed that MBL acted in bad faith under the RSV License Agreement ("Dispute 3"); and

WHEREAS, MBL and MedImmune have agreed to delete Section 2.5 of the RSV License Agreement covering the grant by MedImmune to MBL of a royalty free right and license to make, have made, use and sell or have sold on its behalf any monoclonal antibody(ies) developed by MedImmune useful in the Field (as defined in the RSV License Agreement) for use within the Commonwealth of Massachusetts and the State of Maine in consideration of an increased royalty for sales of such monoclonal antibodies in the Commonwealth of Massachusetts and the State of Maine, as set forth below; and

WHEREAS, MBL and MedImmune have mediated the above referenced disputes (the "Mediation"), have previously reached an agreement in principle resolving said disputes, and now wish formally to memorialize the resolution of their differences and move forward with their cooperative efforts;

NOW, THEREFORE, in consideration of the mutual benefits to be derived from this Settlement Agreement and the representations, conditions and promises hereinafter contained, the Parties hereby agree as follows:

1. Amendments to the RSV License Agreement


The RSV License Agreement is hereby amended as follows:


Section 1.7 of the RSV License Agreement is hereby amended to read as follows:


"Licensed Territory" shall mean all countries of the World except, within the United States, the Commonwealth of Massachusetts and the State of Maine, provided, however, with respect to Licensee’s monoclonal antibody(ies) that are Royalty

Bearing Product, including, but not limited to, Synagis®, "Licensed Territory" shall also include both the Commonwealth of Massachusetts and the State of Maine.


A new Section 1.14 is added to the RSV License Agreement as follows:


"Massachusetts and Maine Net Sales" shall mean with respect to any period prior to July 1, 2010, an amount equal to (CONFIDENTIAL TREATMENT REQUESTED) ("Applicable Percentage") of Net Sales during such period of Licensee’s monoclonal antibody(ies) that are Royalty Bearing Product, including, but not limited to, Synagis® in the United States. On July 1, 2010, Licensor and Licensee will reset the Applicable Percentage by taking the actual Net Sales by month of Licensee’s monoclonal antibody(ies) that are Royalty Bearing Product including, but not limited to, Synagis® sold for use within the Commonwealth of Massachusetts and the State of Maine during the twelve (12) month period immediately proceeding such date (MedImmune to schedule its actual sales of Synagis® in good faith), and dividing by the actual Net Sales of Licensee’s monoclonal antibody(ies) that are Royalty Bearing Product including, but not limited to, Synagis® within the United States during the same twelve (12) month period. Such reset procedure will be repeated at the conclusion of each six-year period thereafter.


Section 2.5 of the RSV License Agreement is hereby deleted.


Section 2.7 of the RSV License Agreement is hereby amended to read as follows:

Licensee agrees to take all reasonable steps to ensure that any products including but not limited to Licensed Product sold by Licensee for use in the Field as permitted by this Agreement will not be sold for and used in the Commonwealth of Massachusetts and Maine. As a result, Licensee agrees to cease sales to any person or entity who uses such products or resells such products within the State of Maine and Massachusetts. This section, however, does not restrict or apply in any way to the marketing and sale of Licensee’s monoclonal antibody(ies) that are Royalty Bearing Product, including, but not limited to, Synagis®.


Section 3.1(a) is hereby amended and replaced in its entirety to read as follows:


(a)(i) Subject to the provisions of Section 3.2, Licensee agrees to pay Licensor a royalty of (CONFIDENTIAL TREATMENT REQUESTED of Net Sales of any Royalty Bearing Product which is sold by Licensee or its Affiliates, including uses outside of the Field.


(a)(ii) Beginning July 1, 2004, and with respect to Licensee’s monoclonal antibody(ies) that are Royalty Bearing Product, including, but not limited to Synagis®, in addition to royalties under Section 3.1(a)(i), Licensee agrees to pay Licensor a royalty of (CONFIDENTIAL TREATMENT REQUESTED) of Massachusetts and Maine Net Sales, as defined by paragraph 1.14.


A new Section 3.5 is added to the RSV License Agreement as follows:


Licensee, in the manner in which it does so presently, shall track actual sales of its monoclonal antibody(ies) that are Royalty Bearing Product (including but not limited to, Synagis®), within the Commonwealth of Massachusetts and the State of Maine and within the United States. No later than thirty days before resetting the Applicable Percentage as contemplated by Section 1.14, Licensee shall compile the data concerning actual sales of its monoclonal antibody(ies) that are Royalty Bearing Product (including, but not limited to, Synagis®, (i) within the Commonwealth of Massachusetts and the State of Maine and (ii) within the United States, for the


preceding twelve (12) month period for the purpose of calculating the reset figure. Upon resetting the Applicable Percentage, Licensee, upon request, shall provide reasonably necessary data to Licensor so that Licensor may verify Licensee’s calculations and reset figure. The provisions of section 3.4 shall apply in their entirety to the obligations set forth in this paragraph.


Section 6.4 is hereby amended to read as follows:


Licensor and Licensee agree to provide each other on a quarterly basis with all relevant information concerning Licensed Product, Licensed Process and Royalty Bearing Product including but not limited to adverse drug reaction reports, except such obligation does not apply to information concerning Licensee’s monoclonal antibody(ies) that are Royalty Bearing Product, including, but not limited to, Synagis®.


In all other respects, Licensor and Licensee hereby ratify and affirm the RSV License Agreement.

2. Payments


By no later than December 31, 2002, MedImmune will pay MBL a non-refundable fee of the sum of five million dollars (US$5,000,000) in settlement of Dispute 1 and Dispute 2.


MBL acknowledges that, under Section 4(a) of this Settlement Agreement, it has released any and all claims that the Distribution Agreement, as it exists on the date of this Settlement Agreement, constitutes a sub-license under the RSV License Agreement. Based upon its review of the Distribution Agreement, MBL agrees that with respect to revenues received by MedImmune under the Distribution Agreement, as it exists on the date of this Settlement Agreement, MedImmune’s royalty obligation to the Licensor shall be governed only by Section 3.1(a)(i) of the RSV License Agreement. Exempted from this provision are the $60 million in milestone payments, portions of which MedImmune has received and portions of which MedImmune has yet to receive, from Abbott under paragraph 7 of the Distribution Agreement ("Milestone Payments"). In consideration of the settlement set forth in this Settlement Agreement, MBL agrees that MedImmune has no financial obligations to the Licensor whatsoever with respect to any and all Milestone Payments that have been previously paid by Abbott to MedImmune, that are now owed by Abbott to MedImmune, or that might be owed in the future by Abbott to MedImmune, it being understood that MBL’s agreement in this regard applies only to the amount of those Milestone Payments ($60 million) as set forth in the Distribution Agreement as of the date of MBL’s review of such Distribution Agreement, and that MBL’s agreement in this regard applies to no other past or future payments under the Distribution Agreement.


MedImmune agrees that the RSV License Agreement remains in full force and effect and that the term "Royalty Bearing Product" (paragraph 1.10 of the RSV License Agreement) covers, subject to paragraph 2(d) herein, future "Royalty Bearing Product" as such term is defined in paragraph 1.10 of the RSV License Agreement.


Further to Section 6(a) and 6(b), and except for the Release (paragraph 4(a)) and the substance of paragraph 2(b), neither MedImmune nor MBL releases or waives any claims or defenses, or concedes any point whatsoever with respect to the scope and meaning of the term "sublicense" in the RSV License Agreement, including, but not limited to, whether the term "sublicense" as it is used in the RSV License Agreement applies to any monoclonal antibody(ies) useful in the Field (as defined in the RSV License Agreement) developed by MedImmune. By way of clarifying example and not by way of limitation, MedImmune agrees


that MBL does not release or waive, and expressly reserves, the right to claim that an agreement which duplicates the Distribution Agreement in all material respects constitutes a "sublicense" for purposes of the RSV License Agreement. By way of a further clarifying example, MBL agrees that MedImmune’s acknowledgement in paragraph 2(c) herein that the term "Royalty Bearing Product" (paragraph 1.10 of the RSV License Agreement) covers future "Royalty Bearing Product" in no way is to be read or interpreted as an acknowledgement or admission by MedImmune that the term "sublicense," as such term is used in the RSV License Agreement, applies to any present or future monoclonal antibody(ies) developed by MedImmune that might constitute "Royalty Bearing Product" under the RSV License Agreement or a waiver or release of MedImmune’s position thereon.

3. Return Of MedImmune’s Proprietary Information


Within thirty (30) days of the execution of this Settlement Agreement, MBL will return to MedImmune any and all proprietary materials and documentary information previously provided to MBL by MedImmune pursuant to Section 2.5 of the RSV License Agreement that remain in the possession, custody or control of MBL or MBL shall destroy such materials, and certify to MedImmune in writing that such materials have been destroyed. If such materials and documentary information do not remain in the possession, custody or control of MBL, MBL agrees immediately to take all necessary steps to retrieve such materials and information and return such to MedImmune (or destroy such materials). It is agreed and understood that the obligations of this Section 3(a) do not apply to routine e-mail communications and other routine communications among the parties, provided MBL complies with its Section 3(b) obligations with respect to such communications.


MBL agrees and covenants not to use any and all proprietary materials and information, whether orally transmitted or transmitted in documentary form, previously provided by MedImmune to MBL pursuant to Section 2.5 of the RSV License Agreement for any purpose whatsoever and further agrees to keep confidential such materials and information under the provisions of Section 5.3 of the RSV License Agreement. It is agreed and understood that this Section 3(b) shall not apply to standard assays and other standard techniques concerning monoclonal antibodies.

4. Release


MBL will immediately execute a Release, a copy of which is attached as Exhibit A, which releases MedImmune from any and all claims which MBL and/or MHRI has raised or may raise in connection with Dispute 1 and/or Dispute 2.


MedImmune will immediately execute a Release, a copy of which is attached as Exhibit B, which releases MBL from any and all claims which MedImmune has raised or may raise in connection with Dispute 3.

5. Warranties and Representations


MBL represents and warrants that (i) it is the successor-in-interest to MHRI under the RSV License Agreement; (ii) MBL has full and complete authority to enter into this Settlement Agreement and attached Release on behalf of MBL and on behalf of MHRI to the extent that MHRI continues to possess any rights or interests in the RSV License Agreement; and (iii) MBL is in fact executing this Settlement Agreement and the attached Release on behalf of MBL and MHRI to the extent that MHRI continues to possess any rights or interests in the RSV License Agreement. MBL acknowledges that MedImmune is expressly relying upon the foregoing warranties and representations in executing this Settlement Agreement.


6. General Provisions

a. This Settlement Agreement does not constitute an admission by either of the Parties as to the merit or lack of merit of the claims asserted or of the claims or defenses that would be asserted in any possible resolution of this dispute in a court of law.

b. This Settlement Agreement may not be used by or against the Parties in any proceedings for any purpose, except in any proceeding in which the validity or effect of this agreement is at issue.

c. This Settlement Agreement sets forth the entire agreement and understanding of the Parties with respect to this dispute.

d. This Settlement Agreement may be amended or modified only by a written instrument executed by the Parties hereto or by their successors and assigns.

e. If a dispute arises out of or relates to this Settlement Agreement, and if said dispute cannot be settled through negotiation, the Parties agree first to try in good faith to settle the dispute by mediation before resorting to arbitration, litigation or some other dispute resolution procedure.

f. This Settlement Agreement and its terms are confidential. Neither of the Parties will make any public statements with respect to this dispute or this Settlement Agreement unless required by law or government regulation. Notwithstanding the above, MBL shall be entitled to state that, by agreement, it is not manufacturing Synagis® for the State of Maine and the Commonwealth of Massachusetts, and shall be entitled to issue a mutually agreeable press release to that effect.

g. This Settlement Agreement shall be construed and enforced in accordance with the laws of the Commonwealth of Massachusetts without reference to its choice of law principles.

h. This Settlement Agreement may be executed in counterparts and, as executed, shall constitute one agreement.

MedImmune, Inc. MBL


Title: Chief Executive Officer Title: Deputy Chancellor, Finance and Administration
Date: December 16, 2002 Date: December 16, 2002


"We disagree with the preliminary guidelines of the American Academy
of Pediatrics that recommend palivizumab be considered in infants younger than 2 years of age with chronic lung disease (CLD) who have required medical therapy for their CLD within 6 months before the anticipated RSV season or in infants born at 32 weeks’ gestation or earlier."

"Although the admission rate to the intensive care unit was lower in
the palivizumab group (1.3% vs 3.0% in the placebo group), more
infants were ventilated in the palivizumab than in the placebo

Furthermore, we calculated a mean hospital stay of 7.6 days in the palivizumab group versus 5.9 days in the placebo group.

The mean days with a lower respiratory tract infection score $3 was 6.3 days in the palivizumab group versus 4.8 days in
the placebo group.

The mean days of increased oxygen requirement were 6.2 days in the palivizumab group versus 4.5 days in the placebo group. Therefore, although palivizumab clearly can prevent RSV hospitalization, it does not decrease the severity of RSV in hospitalized patients.

Unfortunately, the efficacy of palivizumab was lowest in the groups with the highest RSV hospitalization rates (infants born before 32 weeks gestation or with BPD).

It is therefore difficult to select a group of patients who should receive prophylaxis."


From same paper below…………………………………………………….

"Although the admission rate to the intensive care unit was lower in
the palivizumab group (1.3% vs 3.0% in the placebo group), more
infants were ventilated in the palivizumab than in the placebo

Furthermore, we calculated a mean hospital stay of 7.6 days in the palivizumab group versus 5.9 days in the placebo group.

The mean days with a lower respiratory tract infection score $3 was 6.3 days in the palivizumab group versus 4.8 days in
the placebo group.

The mean days of increased oxygen requirement were 6.2 days in the palivizumab group versus 4.5 days in the placebo group. Therefore, although palivizumab clearly can prevent RSV hospitalization, it does not decrease the severity of RSV in hospitalized patients.

Unfortunately, the efficacy of palivizumab was lowest in the groups with the highest RSV hospitalization rates (infants born before 32 weeks gestation or with BPD).

It is therefore difficult to select a group of patients who should receive prophylaxis."



Edited for posting:

Proper name: Palivizumab
Tradename: Synagis
Manufacturer: MedImmune, Inc, Gaithersburg, MD, License #1252
Indication for Use: Prophylaxis of serious lower respiratory tract disease, caused by respiratory syncytial virus, in pediatric patients at high risk of RSV disease
Approval Date: 6/19/98
Type of submission: Biologics license application

"We disagree with the preliminary guidelines of the American Academy
of Pediatrics that recommend palivizumab be considered in infants younger than 2 years of age with chronic lung disease (CLD) who have required medical therapy for their CLD within 6 months before the anticipated RSV season or in infants born at 32 weeks’ gestation or earlier."

"Although the admission rate to the intensive care unit was lower in
the palivizumab group (1.3% vs 3.0% in the placebo group), more
infants were ventilated in the palivizumab than in the placebo
group. "

"Unfortunately, the efficacy of palivizumab was lowest in the groups with the highest RSV hospitalization rates (infants born before 32 weeks gestation or with BPD)."



In a letter to health care professionals, MedImmune, the manufacturer of Synagis, reports that two cases of anaphylaxis have occurred after re-exposure to the product during surveillance in 400,000 individuals receiving 2 million doses. Both individuals recovered completely. In addition, some individuals have experienced acute, severe hypersensitivity reactions after initial exposure or re-exposures to Synagis. The signs and symptoms of reactions have included dyspnea, cyanosis, respiratory failure, urticaria, pruritis, angioedema, hypotonia, and unresponsiveness.
????? The Warnings and Postmarketing Experience sections of the Synagis label have therefore been revised to alert professionals of these potential risks. The new labeling advises professionals to administer epinephrine and other appropriate treatment to patients who experience severe allergic reactions or anaphylaxis after receiving this agent. Furthermore, it advises professionals not to give additional doses of Synagis to patients who experience a severe reaction, and to use caution when giving additional doses to patients who have had milder hypersensitivity reactions.

Both the letter to health care professionals and the revised Synagis labeling are online, at

and , respectively.

The top 10 list of drugs suspected as a cause of serious and deadly
reactions when administered directly to children included treatments for
respiratory syncytial virus, antibiotics and over-the-counter analgesics, such as acetaminophen and ibuprofen.




laisdell and her colleagues culled through more than 7,100 reports to the FDA of adverse reactions to drug and biologic therapies between November 1997 and December 2000. Analyzing the cases, they found an average of 243 deaths a year linked to the substances, and a far higher number of serious but nonfatal complications. About 40 percent of the deaths occurred in the first month of life and 84 percent happened before the baby’s first birthday.

Leading the group of the most commonly reported drugs was palivizumab, prescribed to prevent severe respiratory infections. It was implicated in nearly 28 percent of cases. "This is a drug used for prevention, not for treatment of an illness once it is started," Blaisdell says.

This was recommended for my infant who was born with heart and lung defects, his heart was repaired at 6 weeks of age and his right lung was removed. I felt he had been through and declined the shots. Instead, I kept sick people away from him, made anyone who held him wash their hands/hand sanitizer first, kept him out of daycare and breastfed for as long as possible. He is now 7.5 yrs old and doing well.


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Synagis is a "humanized" monoclonal antibody manufactured by recombinant DNA technology. Synagis is a new medication that is used to prevent respiratory syncytial virus (RSV) infections.


Pressure to prescribe RSV shots:

Sun Nov 01, 1998 01:48:01 PM Julius:let us finish by discussing synergis since this is so hot
and expensive and we are getting a lot of pressure
Sun Nov 01, 1998 01:49:32 PM mabrown:Synagis – a very difficult topic. Its efficacy is
somewhat limited, and its expense high. We are taking a very restrained approach to its use, even
more restrained than the AAP guidelines.

Sun Nov 01, 1998 01:50:08 PM Julius:boy is the sales force pressuring us

Sun Nov 01, 1998 01:50:25 PM miki:what about racemic vs. simple epi?
Sun Nov 01, 1998 01:50:32 PM mabrown:Basically we plan to treat any infant leass than 6 months
old at the start of the season who was born at less than 32 weeks gestation. Infants with BPD who
are less than 2 years and treated for BPD in the last 6 months also get it.
Sun Nov 01, 1998 01:50:38 PM willy:Thanks Julius
Sun Nov 01, 1998 01:50:50 PM mabrown:There is indeed a ferocious sales effort for this product.
Sun Nov 01, 1998 01:51:19 PM Vladimiro:pasive immunity with synergis, what about respigam?
Sun Nov 01, 1998 01:51:20 PM miki:???
Sun Nov 01, 1998 01:51:35 PM Julius:because of pressure from managed care and sales force the
pressure stinks


Study Ties 250 Baby Deaths Yearly to Drug Reactions

Researchers say they should be tested on the young first


By Adam Marcus
HealthScoutNews Reporter

MONDAY, Nov. 4 (HealthScoutNews) — Nearly 250 infants and toddlers may die every year from bad reactions to drugs and treatments that no longer have to be tested in the youngest patients.

A new study appearing in the November issue of Pediatrics found that only 17 drugs and other therapies accounted for 54 percent of all serious and deadly adverse reaction reports to the U.S. Food and Drug Administration (FDA).

However, a federal court recently overturned a 1998 FDA requirement that companies test products in children if they are often given to them. The U.S. District Court in Washington ruled the FDA didn’t have the authority to impose the so-called "pediatric rule."

That court decision worries many pediatricians.

Dr. Carol J. Blaisdell, a University of Maryland pediatrician and a study co-author, says: "We pediatricians are very concerned about that and will hope that the Congress supports FDA authority" to force drug makers to test their products in children. "We do need to be looking at kids specifically, and we can’t assume that drug is safe and effective" in a child simply because it works in adults. The absence of a pediatric rule "leaves doctors without a lot of ability to know if what we’re doing is safe."

Blaisdell adds the reports in the study aren’t proof that medication was responsible for the deaths.

"What we don’t know from this analysis is all the clinical issues that went into those children’s care," such as whether they were very ill, had multiple medical problems, or didn’t receive an appropriate dose of the drug. Even so, Blaisdell says, the study relied on voluntarily reported events and likely far underestimates the risks of medications to young children.

Blaisdell and her colleagues culled through more than 7,100 reports to the FDA of adverse reactions to drug and biologic therapies between November 1997 and December 2000. Analyzing the cases, they found an average of 243 deaths a year linked to the substances, and a far higher number of serious but nonfatal complications. About 40 percent of the deaths occurred in the first month of life and 84 percent happened before the baby’s first birthday.

Leading the group of the most commonly reported drugs was palivizumab, prescribed to prevent severe respiratory infections. It was implicated in nearly 28 percent of cases. "This is a drug used for prevention, not for treatment of an illness once it is started," Blaisdell says.

Second on the list was cisapride, a heartburn drug sold as Propulsid that was pulled from the market in 2000 after being tied to heart rhythm anomalies.

Ibuprofen, the active ingredient in painkillers such as Motrin and Advil, accounted for 33 reports of reactions, or 1.3 percent of the total.

A quarter of side effects were linked to mothers who exposed the baby to the substance during late pregnancy, delivery or through breast-feeding.

Susan Cruzan, an FDA spokeswoman, says the agency was "disappointed" in the court’s decision to overturn the pediatric rule. "We still believe it’s vitally important that drugs be studied in children," she says.

Some drug makers elect to study their products in children, and Cruzan says "about 40" now have warning labels with pediatric information. The FDA has also encouraged pharmaceutical firms to study their products in children by offering them a six-month patent extension for their trouble. The 2002 Best Pharmaceuticals for Children Act renewed that provision.

Thomas J. Moore, a health policy analyst at George Washington University in Washington, D.C., says it’s too soon to tell if this year’s law will improve drug safety in children. However, he says marrying studies to patents could result in only the most profitable drugs undergoing pediatric testing.

"The pediatric rule provided the ability for the FDA to identify those [substances] for which proper information about the drug in children was most needed," he says.

What To Do

For more information about drug safety in children, try the U.S. "; or the ";.

SOURCES: Carol J. Blaisdell, M.D., associate professor and chief, pediatric pulmonology and allergy, University of Maryland School of Medicine, Baltimore; Thomas J. Moore, health policy analyst, George Washington University School of Public Health and Health Services, Washington, D.C.; Susan Cruzan, spokeswoman, U.S. Food and Drug Administration, Rockville, Md.; November 2002 Pediatrics

Copyright © 2002 ScoutNews, LLC. All rights reserved.


Proper name: Palivizumab
Tradename: Synagis
Manufacturer: MedImmune, Inc, Gaithersburg, MD, License #1252
Indication for Use: Prophylaxis of serious lower respiratory tract disease, caused by respiratory syncytial virus, in pediatric patients at high risk of RSV disease
Approval Date: 6/19/98
Type of submission: Biologics license application


“Admissions to the intensive care unit were required by 1.3% of the palivizumab recipients compared with 3% of the placebo patients (P=0.026) (5). The duration of stay in the intensive care unit, the need for mechanical ventilation and the duration of mechanical ventilation were not statistically different between the palivizumab and placebo groups (Table 1). No differences were observed between the two groups for non-RSV-related hospitalizations and the development of otitis media during the study period (5). Four children (0.4%) in the palivizumab group and five children (1%) in the placebo group died during the study. The deaths were not attributed to the study drug.”


1. Given the limited clinical benefits of palivizumab and RSV-IGIV in the prevention
of RSV infection in high risk patients, other preventive measures remain important.
They are: emphasizing hand-washing
when siblings or adult contacts have respiratory infections, eliminating exposure
to tobacco smoke, and limiting exposure
to contagious settings such as childcare
centres (6).”


Drug Side Effects Can Be Deadly in Children Under 2


By Natalie Engler
NEW YORK (Reuters Health) – Medications used to treat either a mother or
child played a role in nearly 6,000 serious side effects, including 769
deaths, in children under 2 years of age in the US between 1997 and 2000, according to an analysis of cases reported to the Food and Drug
Medications given to pregnant or breast-feeding women may have caused a
large proportion of adverse events, and just four drugs were the principal suspect in more than one third of all the reported deaths.
"The results of this study underscore the need for additional testing in the youngest pediatric patients and for greater vigilance in the use of higher risk drugs and in medication for pregnant and lactating women," the researchers report in the November issue of the journal Pediatrics. However, they note that the reports do not prove that the medication was the actual cause of the side effect or death.

Overall, the investigators identified 1,902 drugs, chemicals, biological
products, vaccines, over-the-counter medications, vitamins, minerals,
dietary supplements and other substances in the reports, but just 17 drugs were indicated in more than half of the serious side effects or deaths in children given medication directly.
The vast majority of deaths (84%) happened before the infant’s first
birthday. In the study, Thomas J. Moore of George Washington University in Washington DC and his colleagues analyzed over 7,000 reports of adverse drug reactions in children under age 2 received by the US Food and Drug Administration from November 1997 through December 2000. Overall, 5,976 reports were new and unique cases that had not been reported previously.

They found that in 1,432 cases, or 24%, the drug or product had been given to the mother either during pregnancy, labor or while breast-feeding. The most common adverse effects in these cases were birth defects or disability in the child.

The top 10 list of drugs suspected as a cause of serious and deadly
reactions when administered directly to children included treatments for
respiratory syncytial virus, antibiotics and over-the-counter analgesics, such as acetaminophen and ibuprofen. Infection with RSV is common, and most people are infected by age 2 and experience cold-like symptoms that eventually improve without treatment. But in some infants and in adults with weakened immune systems or lung disease, the virus can cause pneumonia and other potentially life-threatening complications. RSV infection is the leading cause of hospital admissions in young children.

"Drugs have many important benefits. But this should make parents aware that all drugs–even familiar ones such as acetaminophen and ibuprofen–can sometimes have serious adverse effects," Moore said in an interview with Reuters Health.

This is the first time such data has been made available to pediatricians, said Moore. Moore cautioned that the findings do not mean infants should stop receiving drugs when necessary. "The information in this study contributes to a much larger balance of risks and benefits that must be weighed in the decision whether to use a particular drug in a particular patient," he said. He added that, while he has no data that compares the number of adverse reactions to the total number of infants given each medication, "serious adverse reactions to acetaminophen are rare." Acetaminophen was suspect in just 1.6% of all serious adverse reactions to drugs administered directly.
Moore stressed that "these reports do not prove that the suspect drug
directly caused the reported adverse event. Instead they should be
considered a warning flag to encourage us to examine those drugs more

He added that they also underscore the need for more pediatric testing to more accurately measure drugs’ risks and benefits.
SOURCE: Pediatrics 2002;110:e53.


Clinical Studies

RSV Prophylaxis Study

A Study of the Safety, Tolerance and Efficacy of Palivizumab (Synagisҍ ) for Prophylaxis of Respiratory Syncytial Virus in Children with Congenital Heart Disease

Penn State Hershey Medical Center is part of a multi-center study of the safety, tolerance and efficacy of Palivizumab (Synagis ). Synagis is a "humanized" monoclonal antibody manufactured by recombinant DNA technology. Synagis is a new medication that is used to prevent respiratory syncytial virus (RSV) infections. The study period will be from October 2000 until approximately May 2001. (note by 2002, the label was changed to add a warning)

Synagis has been studied in children with prematurity and bronchopulmonary dysplasia (BPD) and has been shown to be safe and effective to decrease the incidence of RSV infection and hospitalizations. Based on this study, Synagis was approved by the FDA. However, children with congenital heart disease (CHD) were not evaluated in the study. The past two years Hershey Medical Center has been actively involved with this study. The study will continue this winter and likely one more year thereafter.

Past experience with other medicines used to prevent RSV infections:

Respigam is a polyclonal antibody preparation that was studied in 416 children with CHD. This study demonstrated increased cyanotic episodes in cyanotic infants (shunt malfunction, increased cyanosis and death). Proposed mechanisms for these increased adverse events with Respigam include: (1) the large volume and dose (750mg intravenously) required and (2) the protein load of the polyclonal antibody product. In addition, Respigam interfered with timing of routine immunizations.

During this study, the following is required:


Five monthly intramuscular (IM) injections and one visit one month after the final

injection (six visits total).


Blood sample for SynagisҠblood levels at the first, second and fifth visits.


If surgery is performed during the study period, blood levels of SynagisҠwill be

obtained before and after surgery.


If there are any signs or symptoms of upper respiratory infection or RSV infection,

an RSV nasal washing test will be obtained.


Close follow up with the study coordinator and principle investigator regarding any

"adverse events."


The study is randomized, placebo controlled and double blinded. This means that there is a 50-50 chance (like flipping a coin) of receiving Synagis or an inactive substance (placebo). The parents, doctors, nurses and pharmacists involved in the study will not know which child is receiving Synagis or the placebo. This is necessary to fairly study the drug and remove all possible bias in reporting the results.



24 months of age or younger.


Documented hemodynamically significant cyanotic and acyanotic CHD (simple, small ASDs, VSDs and PDAs are not eligible).

Example: VSD requiring medical therapy for CHF is eligible.


Unoperated or partially corrected CHD. Example: Hypoplastic left heart after 1st or 2nd staged operation.




Unstable or severe disease that survival is unexpected or heart transplant is planned.


Hospitalization (unless discharge is expected within 21 days).


Cardiac surgery planned within two weeks.


Mechanical ventilation or other support.


Associated non-cardiac anomalies or end-organ dysfunction such that survival is < 6 months.


Known HIV positive.


Presence of acute RSV or other acute infection or illness. (Must have NEG RSV test if symptomatic).


Previous administration of SynagisҠor other monoclonal antibody.


Use of other investigational agents within the last 3 months.


Current participation in other investigational protocols.


IVIG use within 3 months, or anticipated use of IVIG or SynagisҠduring the study period.


Please direct questions regarding this study to:

Kerry L. Rosen, MD Principle Investigator 717-531-6847

Sarah A. Sturgis, RN, CRNP Study Coordinator 717-531-7762 *********************************************************************

Revised Synagis labeling warns of potential for hypersensitivity reactions and anaphylaxis

NEW YORK, Dec 2, 2002? The monoclonal antibody Synagis (palivizumab) may cause severe hypersensitivity reactions and anaphylaxis in some individuals, according to a safety alert from the Food and Drug Administration (FDA). The alert notifies health care professionals that the product labeling has been revised to warn of these potential adverse effects, which were identified during postmarketing surveillance.
????? In a letter to health care professionals, MedImmune, the manufacturer of Synagis, reports that two cases of anaphylaxis have occurred after re-exposure to the product during surveillance in 400,000 individuals receiving 2 million doses. Both individuals recovered completely. In addition, some individuals have experienced acute, severe hypersensitivity reactions after initial exposure or re-exposures to Synagis. The signs and symptoms of reactions have included dyspnea, cyanosis, respiratory failure, urticaria, pruritis, angioedema, hypotonia, and unresponsiveness.
????? The Warnings and Postmarketing Experience sections of the Synagis label have therefore been revised to alert professionals of these potential risks. The new labeling advises professionals to administer epinephrine and other appropriate treatment to patients who experience severe allergic reactions or anaphylaxis after receiving this agent. Furthermore, it advises professionals not to give additional doses of Synagis to patients who experience a severe reaction, and to use caution when giving additional doses to patients who have had milder hypersensitivity reactions.
????? The Postmarketing Experience section of the product labeling has also been revised based on the availability of new data pertaining to overdosage. The labeling now indicates that patients receiving six or more doses of Synagis during a single respiratory syncytial virus season have a similar frequency and nature of adverse events as patients receiving the initial five doses.
????? In the letter to health care professionals, MedImmune asks that they report any adverse events associated with administration of Synagis to the company or to the FDA MedWatch program.
????? Both the letter to health care professionals and the revised Synagis labeling are online, at and, respectively.

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