Public Comments: Dr. William J. Bicknell, Professor of International Health, Boston University

Dear Dr. Ball:

I am submitting these comments in reference to the announcement published in the Federal Register, Vol. 67, No. 211, Thursday, October 31, 2002 regarding the Solicitation of Public Review and Comment on Research Protocol: A Multicenter, Randomized Dose Response Study of the Safety, Clinical and Immune Response of Dryvax Administered to Children 2 to 5 Years of Age.

These comments have been submitted electronically on December 1 and again on December 2, 2002 to http://www.fda.gov/dockets/ecomments. A copy was also emailed to you at on December 1, 2002.

OVERVIEW

This study proposes to test the immunogenicity of undiluted and a 1:5 dilution of Dryvax in pre-school children between the ages of 2 and 5. I believe the study is seriously flawed. There is nothing to suggest that the immune response of children is different now than it was 30 years ago. All children in the study would be exposed to a very small but finite risk of death or severe permanent disability from Post-Vaccinal Encephalitis (PVE), a vaccine side effect with no known treatment. And, given the supply of other vaccines and the likely uses of existing stocks of Dryvax, there is no compelling need to know if the 1:5 dilution is immunogenic. Notwithstanding the approvals of other IRBs, I find the risks exceed the benefits. The study should not be approved by the Department of Health and Human Services.

QUALIFICATIONS

I am a member of the Boston Medical Center Institutional Review Board, a former Commissioner of Public Health in Massachusetts and a faculty member at the Schools of Medicine and Public Health at Boston University. I am very familiar with the published literature regarding smallpox vaccine and its complications. Although I am opposed to approval of this protocol, I am not at all opposed to selective pre-exposure, voluntary vaccination of adults or, in a post-exposure scenario, of children.

RELEVANT CONTEXT & MAJOR CONCERNS

I will not review the protocol or the informed consent form in detail. Rather I will limit my remarks to those few points which I feel are of vital importance in considering whether or not to approve this protocol.

A. We know Dryvax is potent in adults from the recent studies published in the New England Journal of Medicine (NEJM) April 25, 2002.

B. We also know from the protocol that the vaccine has been tested in children in the 60s and 70s. Further, I have seen nothing to question the immunogenicity of Dryvax administered to children prior to 1972.

C. We know from the 1968 data published in the NEJM in 1969 that a very small number of children under ten will develop Post Vaccinal Encephalitis (PVE). PVE has an overall mortality rate of 30% for which there is NO KNOWN TREATMENT. 5 of 16 cases of PVE reported in the 1968 data were in children between the ages of 2 and 5 with the following outcomes: possible seizure disorder, possible psychiatric disturbance, quadriplegia, recovery and death. (Lane JM, Ruben FL, Neff JM, Millar JD, Complications of smallpox, national surveillance in the United States 1968. N Engl J Med, 1969; 281, 1201-1208, November 27.)

D. To the best of my knowledge there is nothing to suggest that the immune response of children between 2 and 5 has changed since the 1960s and 1970s.

E. The only remaining possible justification centers around learning more about the immunogenicity of a 1:5 dilution of Dryvax in children. We know that the responses to 1:5 and 1:10 dilutions in adults are not significantly different from undiluted vaccine (Frey SE, Couch RB, Tacket CO, et al. Clinical response to undiluted and diluted smallpox vaccine. N Engl J Med 2002;346, April 25, 2002). The protocol points out that 1:10 dilutions in tests carried out in children in the 60s and 70s resulted in takes of between 74% and 90%. Thus, there is some uncertainty about the effectiveness of a 1:5 dilution. Does this uncertainty justify the proposed research? The question is only relevant if we are likely to dilute Dryvax.

What is the current situation? The justification for testing the 1:5 dilution is based on the limited availability of vaccine and the requirement to dilute existing stocks in the case of an attack. It appears the nation is on a course to vaccinate many in the military and according to press reports (not yet officially confirmed by the Government) up to 10 million first responders with existing stocks of Dryvax. Therefore, with planned military and possible/probable civilian first responders use of from 6 million to up to 11 million doses of undiluted Dryvax, no amount of dilution will be sufficient to protect children or adults in case of an attack. If there is an attack and a dilute vaccine is required it will have to be the 70 to 90 million doses of the Aventis Pasteur vaccine that came to light earlier this year. Far more likely, existing stocks of the new Acambis vaccine, still in clinical trials but reported to be on a fast track for licensure, will be used instead. In any case this protocol is NOT proposing to test the old Aventis Pasteur product or the Acambis product. With every passing day the availability of substantial stocks of Dryvax for the general population and the need to dilute Dryvax decreases. Thus, there is no meaningful dilution argument in support of the proposed research.

Conclusion:

The protocol proposes to put 40 children, including 20 controls, at a very small but finite risk of death or permanent major disability from a known vaccine complication (PVE) for which there is no known treatment. As it is not plausible that the immune response of children has changed in the past several decades, we can reasonably expect no significant new knowledge from this research while exposing children to the risk of death and permanent severe disability. Further, the stated need to determine the efficacy of the 1:5 dilution in children, if it ever existed, no longer exists. Modifications to the consent form cannot be sufficient to justify or allow the research as the benefits, essentially none, cannot outweigh the remote but real risks of death and permanent severe disability. In brief, the risks outweigh the benefits and the protocol should be DISAPPROVED.

THE CONSENT FORM

The consent form, in part, states:

“More serious reactions may also occur, but they are rare and occur most often in small infants, people with eczema and people who take medicines, such as steroids, or have problems with their immune system. More serious reactions may include signs and symptoms of brain and nervous system infection such as 1) convulsions or seizures, 2) muscle weakness, 3) paralysis, and/or 4) stiff neck."

and later

“The risk of death from smallpox vaccination for children in this age group was estimated to be 2 for every 1,000,000 first vaccinations. Complications occurred less often in children who received a second vaccine (revaccination). In rare cases, vaccinia immune globulin (a substance which provides antibodies or substances that fight infection against vaccinia) is needed to prevent or treat complications."

THE CONSENT FORM NEVER STATES THE CHILD IS AT RISK OF DEATH OR SERIOUS DISABILITY FOR WHICH THERE IS NO KNOWN TREATMENT.

Other reviewers have commented on other deficiencies in the consent form.

COMMENTS ON THE RATIONALE

Please see my comments within parentheses (in bold face type)

The following is from section 2.3 Rationale for the current study:

Given the limited amount of smallpox vaccine currently available, (The vaccine supply is no longer limited) there is a public health need to specify an optimal minimal dose and optimal vaccination strategy to protect the maximum number of people in the event of a terrorist release of the smallpox virus. The current adult trials summarized above have focused on the immunogenicity and take rate of Dryvax vaccine in varying dilutions. However, in a pediatric population, the safety assessment is particularly important. (Two groups of 20 can hardly assess or predict safety) Even though Dryvax was a licensed vaccine with prior widespread use in millions of children, the Food and Drug Administration (FDA) currently regards it as an investigational new drug (IND). (It is my understanding that the IND status either has been removed or is about to be removed) The US population is no longer immune to smallpox (substantially non-immune would be more accurate but this is not relevant to the issue) and there are other reasons (such as?) for concern about the use of this stockpiled vaccine.

This is a non-sterile bovine product proposed for use at a time when standards of vaccine safety are much more stringent than they were 30 years ago. (Relevance to argument?) Our population must now be considered essentially non-immune (to vaccinia?) and there is (may be is probably more accurate) greater potential for secondary transmission of virus to susceptible children and adults, and to those with immunologic deficiency states who have greater potential for serious complications (Relevance to argument?). There is little information available concerning the risk of secondary transmission of vaccinia in a largely nonimmune population. (This protocol with two groups of 20 each using the specified dressing will not be able to address this question) Control of possible autoinoculation and transmission from vaccinees to contacts is more problematic for infants or young children than adults (correct). The effectiveness of placing a semi-occlusive dressing over the vaccination site, to minimize risk of transmission has never been adequately studied (Would it not be far safer and easier to do this in adults who have far fewer risks of vaccination and will we not be able to do this almost automatically as we move to vaccinating 500,000 or many more in the next few months?)

Finally, fewer intra-dermal punctures (3-5 punctures) have been used to administer the vaccine to children than in adults (10-15 punctures). (And what does this have to do with the argument?)

MINOR CONSIDERATIONS

The number of punctures proposed by the protocol is 5. The protocol suggests that this is less than usual and needs to be validated. However, the Dryvax product brochure suggests 2 to 3 punctures with the bifurcated needle in primary vaccinees without regard to age. Thus, depending on whether the baseline is two or three, the proposed research more or less doubles the manufacturers suggested dose, in effect increasing the amount of virus inoculated and reducing the effect of dilution.

The protocol is slightly inconsistent with regard to whether or not the semi-occlusive dressing will be used on the dilution group. For example, section 3.5.1, page 19, has group 2 with no mention of the dressing while the in section 3.5.3 on page 21 the box describing Stage 1 specifies using the semi-occlusive dressing.

SUMMARY

The proposal to vaccinate 40 children with dilute and full-strength Dryvax should not be approved. Modifications of the consent form cannot be sufficient to allow approval as, even if parents are fully informed of the risks, the risks outweigh the benefits.

I appreciate the opportunity to comment on this protocol and compliment your office and the Department for soliciting wide public comment.

Please feel free to contact me if you have any questions..

With best regards,

Bill Bicknell
William J. Bicknell, MD, MPH
Professor of International Health, Socio-Medical Sciences, and Community Medicine
Department of International Health
Boston University School of Public Health
715 Albany Street, T4W
Boston, MA 02118-2526 USA

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Comments by Dr. William J. Bicknell, Professor of International Health, Boston University
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