- EZ =
- Edmonston-Zagreb (vaccine strain) •
- SW =
- Schwarz (vaccine)
The high-titered (doses >4.7 log10 infectious units1) measles vaccine era was curtailed abruptly by safety concerns in 1992.2 No new safety issues relevant to measles vaccines have surfaced in the interim, but misunderstandings about the overall safety of one of the vaccines involved in these events, the Edmonston-Zagreb (EZ) strain, appear to us to have persisted and become sufficiently widespread to merit an attempt at clarification. A brief historical review of events may help to disclose the likely origins of this problem.
The high-titer measles vaccine trials involved mainly EZ and Schwarz (SW) vaccines given to young infants. Both SW and EZ are derived from the original Edmonston strain, and differ only in their passage levels and cell substrate—chick embryo fibroblasts and WI-38, respectively.3 EZ was rather consistently and significantly more immunogenic than SW in infants with maternal antibodies, and produced seroconversions in high frequencies. Consequently, on review of the immunogenicity data in 1990, the World Health Organization recommended only high-titer EZ vaccine for routine use at 6 months of age in developing countries where risk of measles deaths made it unwise to wait until later ages to vaccinate.4
As follow-up data from the high-titer trials became available, concerns about increased mortality began to arise. To make a long and complex story short and simple, in 4 studies conducted in areas with high baseline infant mortality, mortality in infant girls receiving high-titer vaccines, both EZ and SW, consistently exceeded that of infant girls given standard doses of vaccine at 9 to 10 months of age.2 Girls given high-titer vaccines also had higher mortality than boys who received high-titer vaccines in 3 of the 4 studies. When evaluated, the high-titer vaccine recipients did not have increased mortality relative to unvaccinated children who had received placebo.5 Mortality differences between vaccine groups disappeared within a few years after vaccination.6Similar studies of high-titer vaccines in both the United States and developing countries with relatively low baseline infant mortality failed to reveal any such disparity in morbidity or mortality. Despite epidemiologic, clinical, and laboratory studies, a plausible and satisfactory biological explanation for these findings has yet to surface.
As these observations were being disclosed, the World Health Organization prudently decided to rescind its earlier recommendation for routine use of high-titer EZ at 6 months of age, although the recommendation was never implemented widely in routine programs for a variety of reasons.2 Because high-titer SW had never been recommended in the first place, EZ became the main and sometimes the sole target of safety concerns. Indeed, an article by a noted science reporter failed to mention that high-titer SW was also involved,7 as did a subsequent commentary by a researcher prominently involved in the high-titered vaccine trials.8Other less obvious influences may also have played a role. Consequently, what was in reality a high-titer measles vaccine problem became commonly but improperly viewed as an EZ problem. Also, the critical importance of dosage was often ignored, especially among those less familiar with the research.
Hundreds of millions of standard titer doses of EZ and SW have been given over the last decade to children with no reported harmful effects on mortality. These vaccines are currently distributed interchangeably for routine vaccination in developing countries, according to annual tendering procedures. EZ is produced by several manufacturers, and is routinely used in Switzerland, Mexico, and India.
Because of its greater immunogenicity in the presence of maternal antibody,9 EZ may have advantages when used in standard titer at 10 months of age or younger in developing countries.10–13 It seems plausible that EZ will also have superior immunogenicity in persons with vaccine-induced antibodies, and if so may perhaps have advantages for use in mass “catch-up” campaigns14 where most of the children will have received one or more previous doses of measles vaccine. SW vaccine tends to induce higher antibody titers than EZ in children with little or no maternal antibodies,12 and thus may have advantages over EZ for routine use at 15 months of age in areas with low measles incidence. Further exploitation of these usefully different properties of vaccine strains is warranted.
This attempt to set the record straight will hopefully help to allay unwarranted concerns about the safety of an efficacious and beneficial vaccine, when used in customary doses, that has been victimized by an unfortunate sequence of events.
- Received January 19, 1999.
- Accepted March 25, 1999.
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- Expanded Programme on Immunization
- ↵Expanded Programme on Immunization: Global Advisory Group. Wkly Epidemiol Rec. 1992;67:357–364
- ↵Markowitz L, Katz S. Measles vaccine. In: Plotkin S, Orenstein W eds. Vaccines. Philadelphia, PA: WB Saunders; 1999:231–232
- ↵Expanded Programme on Immunization: Global Advisory Group. Wkly Epidemiol Rec. 1990;65:5–11
- Weiss R
- Garenne M
- Copyright © 1999 American Academy of Pediatrics