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PEDIATRICS Vol. 104 No. 5 November 1999, pp. 1123
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 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.6 Similar 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.8
Other 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.
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
Department of Epidemiology
Rollins School of Public Health
Emory University
Atlanta, GA 30322
Infectious Disease Epidemiology Unit
London School of Hygiene and Tropical Medicine
London, United Kingdom WC1 E7HT
Department of Pediatrics
Duke University Medical Center
Durham, NC 27710
FOOTNOTES
Received for publication Jan 19, 1999; accepted Mar 25, 1999.
Reprint requests to (J.V.B.) Room 470, Rollins School of Public Health, 1518 Clifton Road NE, Atlanta, GA 30322. E-mail: bennettj{at}compuserve.com
ABBREVIATIONS
EZ, Edmonston-Zagreb (vaccine strain); SW, Schwarz (vaccine).
REFERENCES
evolving strategies.
JAMA.
1996;
275:224-229 [Abstract]
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