November 2000
In the Sept. 13 issue of the Journal of the American Medical Association, here was a report on the postlicensure surveillance of varicella vaccine. The vaccine was found to be quite safe given the relatively low frequency of reactions and particularly serious reactions. The events following immunization, some of which were not due to the vaccine at all, were much less frequent than the complications which might have occurred if no immunization was given. None of these reactions occurred more often than problems that can occur when a patient has chickenpox. One of the things we can appreciate from the latter is the complexity in evaluating reports of adverse reactions that occur following immunization.
The results of the analysis are based on reports we are all required to submit to the Vaccine Adverse Events Reporting System (VAERS) when vaccinees have unexpected events following immunization. It is assumed that not all of these events are reported, and thus, these data provide us with some underestimation of risk. The hazard is calculated based on the number of doses of vaccine sold during the period of surveillance. As not all the doses that are sold are used, this tends also to underestimate the risk. One must also appreciate that 12% received other vaccines at the same time and so it may be difficult to assign causality to any one vaccine.
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It has been apparent in all previous analyses that some of these temporally associated "events" are not reactions to vaccine but intercurrent events. One of the cases of meningitis in this report was found to be caused by Borrelia burgdorferi and another by Neisseria meningitidis. Although these vaccinees developed meningitis following receipt of vaccine, meningitis was not due to varicella virus. Two other cases of meningitis were found to be caused by wild type, and not vaccine, virus. It is essential to collect vesicular fluid, cerebrospinal fluid and even scrapings of skin lesions to determine whether the offending virus is vaccine or wild type.
As long as varicella is still present in the community, there always will be a risk of exposure to and infection with wild virus. In our initial vaccine trials started in 1978, we found it necessary to distinguish whether the vaccine or an unidentified exposure to varicella caused rashes in vaccine recipients. At that time, we identified a restriction enzyme, which would differentiate the two (Pediatrics. 1987;79:922-27). Subsequently the group at Columbia expanded these observations and developed a PCR, that does not require the isolation of virus but can be done directly on specimens such as skin scrapings, which often do not contain live virus. This has been invaluable in determining the cause of rashes in vaccinees. Wild virus has been found to be the cause a median of one week after exposure while vaccine virus has been found a median of four weeks following immunization.
Four of the injection site rashes appeared to be zoster appearing two to 16 weeks post immunization. In the 26 of 251 cases of zoster that have occurred in vaccinees that could be tested, approximately half were wild type occurring a median of three weeks post immunization. The remainder were due to vaccine virus, which occurred a median of 19 weeks post immunization.
We had reported a child who contracted varicella due to vaccine strain from his brother who had vaccine-induced zoster (Pediatrics. 2000;106[e28]). Thus, one must be aware these vaccinees are capable of spreading vaccine virus to contacts, although there appears to be few reports of transmission from vaccinees to contacts. One transmission from a child to his pregnant mother reminds us that we must remain concerned about possible transmission of vaccine virus to contacts who are at increased risk. Thus far, there have been 87 women who have been reported to have received that vaccine around the time of conception or during pregnancy. The infants of these women have all been reported to be without stigmata of intrauterine infection, however, most of these women probably were immune despite the fact that they had a negative history of varicella (Infect Control and Hosp Epidemiol. 1999;50(5):355-357).
Some of the exposures in pregnancy were among women who had mistakenly been given varicella vaccine instead of varicella zoster immune globulin for an exposure. There also are a few cases in the report of immunocompromised recipients who had very severe reactions including a death.
There are a group of immune-mediated reactions, which might be attributable to immunization: anaphylaxis very likely; erythema multiforme and arth ropathy likely; thrombocytopenia quite possibly; vasculitides and aplastic anemia some. These events were uncommon following immunization and do occur in the unimmunized. Thrombocytopenia and vasculitis are known complications of varicella and are of some concern. The rate of the former, however, is far less than one would have expected from varicella, so even if they are related, we are better off with than without the vaccine on this score. Unfortunately, some of these events were reproduced by the second dose of varicella vaccine, which does provide convincing proof of etiological association.
In summary, the vaccine appears to get good marks on safety. None of the associated reactions, even if they were proven to be due to the vaccine rather than wild virus exposure or intercurrent events, appear to occur in greater frequency than is produced by varicella.
We need to continue to report and be alert to possible events related to varicella vaccine. There will be some revision of vaccine labeling to reflect the reports or adverse events following licensure. Finally, we must be cognizant of the cautions associated with the use of the vaccine.
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