INTRODUCTION
The use of combined vaccines or the simultaneous administration of
multiple vaccines permits a number of desirable outcomes (1). Most importantly, the number
of health care provider visits can be reduced while vaccine coverage can be increased.
This permits better protection against more diseases earlier in life, and in the case of
combined vaccines, reduced number of injections and the associated morbidity. These
efficient and positive outcomes need to be carefully weighed, however, against the
possibility that without careful evaluation, the sum may be less than the parts with
respect to immunogenicity or efficacy. In terms of adverse reactions or safety, there is
the opposite concern, that the sum may be greater than the parts, the combining of
vaccines may increase the frequency of existing serious reactions or lead to new
reactions. Sorting out which reaction is due to which vaccine may be quite difficult,
however. Finally, with respect to economics, combining vaccines may increase the
complexity of vaccine production for manufacturers, and may lead to the creation of a
monopoly (2).
Before adopting a policy of simultaneous administration of multiple
vaccines or licensing a combined vaccine, randomized clinical trials with careful
follow-up of the patients are usually conducted (3). These trials are usually limited in
sample size and duration of follow-up, and may be conducted in populations not fully
representative of the general population, however.
The recommendation for simultaneous administration of
measles-mumps-rubella (MMR) vaccine with diphtheria-tetanus-pertussis (DTP) and oral polio
vaccines (OPV) at 15 months of age, for example, was based on a comparison of
approximately 250 to 400 children in each group (4). The recent recommendation for the use
of HbOC (haemophilus influenzae type b, Hib) conjugate vaccine during infancy was
based on a larger study. Approximately 500 to 4000 infants in each arm of the trial
(HbOC
alone, HbOC + diphtheria-tetanus-pertussis [DTP], and DTP alone) were interviewed by
telephone within 72 hours of vaccination for local and systemic reactions. About 30,000
vaccinees were also followed for emergency room visits, hospitalization, and sudden death
(5). Even with this larger sample size, detection and evaluation of rare or delayed
adverse events require surveillance postlicensure or postadoption of new recommendations.
While such surveillance is important, methodologically, it is quite difficult to do well.
Classically, such postmarketing surveillance has been passive in nature,
relying on spontaneous reporting system (SRS) of adverse events. These reports are
frequently difficult to assess for attribution of causality to vaccine because such
attribution requires either a specific laboratory finding, for example, the isolation of
vaccine virus from a normally sterile site, as in isolation of mumps vaccine virus from
the cerebrospinal fluid of patients with aseptic meningitis (6); a unique clinical
syndrome, for example, acute flaccid paralysis in an OPV recipient in the absence of
circulation of wild poliovirus; or an epidemiologic study that shows that the risk of the
adverse event is greater among vaccinated than among the unvaccinated persons. SRS data
are usually inadequate for epidemiologic assessment, however, for several reasons.
Any epidemiologic assessment requires data necessary to complete a
two-by-two table of exposures and outcomes (table 1). In this case exposures are
vaccinations, and outcomes are adverse events. However, SRS reports represent at best only
one cell, cell "a", of such a table -- those who are vaccinated and have the
outcome of interest. Usually, because of selective or biased reporting, SRS reports are
only an unrepresentative sample of cell a. The remaining three cells of the two-by-two
table, b, c, and d are usually not reported to the SRS. Finally, in a postlicensure
setting allocation to vaccinated and nonvaccinated is no longer random; the data necessary
to control for potential confounding is also usually not reported to SRS. Because most SRS
reports do not contain laboratory or clinical findings that can be specifically attributed
to vaccination, it is clear then that SRS are quite limited in assessing causality of
reported adverse events.
Recognizing these weaknesses of the SRS, the Centers for Disease Control
and Prevention (CDC) began in 1991 to organize a large-linked database study of about
500,000 children zero to 6 years of age in four HMOs (7). Information on all four cells of
a two-by-two table plus potential confounders are being collected to permit controlled
epidemiologic assessment of vaccine safety concerns, including those raised by this
workshop.
Despite the shortcomings described, SRS can still provide a modicum of
useful postlicensure data on the safety of simultaneous administration of vaccines. If
prior to the introduction of the new procedure or new combined vaccine baseline SRS
experience with at least one of the antigens is available and the reporting behavior to
the SRS remains otherwise unchanged, a crude ecologic analysis can be done to see if there
is any change in the profile of reported adverse events from the baseline. If no change is
observed, this can be interpreted to be generally reassuring that there is no augmentation
of adverse reactions with simultaneous or combined vaccinations. On the other hand, if a
change is observed, a controlled study is still needed to validate this ecologic
observation. A more refined ecologic analysis is possible if denominator data is available
on how often and in which combination vaccines are administered. In which case, estimated
rates of adverse events can be compared rather than numerator analysis alone.
To illustrate the utility of SRS for this purpose using the two types of
ecologic analyses, we focused on the following case studies of simultaneous
administration: 1) the recommendation to permit the simultaneous administration of MMR,
DTP, and OPV vaccines at 15 month of age; (8) and 2) the recommendation for administration
of various types of Hib vaccines, initially at 24 months, (9) then 18 months, (10) and
more recently for infants; (11) these vaccinations are usually administered with DTP and
OPV.
METHODS
The data sources used for this ecologic evaluation are the Monitoring
System for Adverse Events Following Immunization (MSAEFI), operated by the CDC from 1979
to October 31, 1990 (12). Persons who received a publicly purchased vaccine also received
an Important Information Statement, which encouraged vaccinees to report any adverse event
which resulted in a health care visit within 30 days (4 weeks) of vaccination. The MSAEFI
form was a basically "closed" report form with check-off boxes for specific
adverse events. A number of improvements were made to MSAEFI in 1985, so the following
analyses are based on MSAEFI data between 1985 and 1990.
On November 1, 1990, the Vaccine Adverse Event Reporting System (VAERS)
became fully operational as a single unified system for the United States (13) . VAERS is
jointly supervised by the CDC and the FDA. Reports are submitted using an
"open-ended" report form. The reports are then assigned standard codes by using
Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) (similar in principle
to assignment of International Classification of Diseases or ICD codes). The VAERS
analyses are based on data collected between November 1, 1990 and July 15, 1993.
Estimates of doses of vaccine administered were derived from two sources.
The 1991 National Health Interview Survey, a cross-sectional interview of approximately
50,000 households and 135,000 persons annually based on a multistage area probability
sampling design (14), and routine administrative data on doses administered submitted
quarterly to the National Immunization Program from recipients of public sector
immunization grants.
RESULTS
The age of vaccination on reports to MSAEFI in 1985 for children 12-23
months of age are shown on figure 1. As might be expected, reports of adverse events for
which MMR was the only vaccine received peaked shortly after 15 months of age, and reports
for which only DTP or DTP and OPV were administered peaked shortly after 18 months of age.
There were few reports in which DTP, OPV, and MMR were administered simultaneously. In
contrast by 1990, most of the reports in this age group were for DTP, OPV, and MMR
vaccines administered simultaneously, and many fewer reports for the vaccines administered
separately (figure 2). This change in schedule then permits us to examine for major
changes in profiles of adverse event reports.
Examining a fairly specific adverse event first, febrile convulsions,
table 2 shows the total number of reports to MSAEFI for children 15-23 months of age after
different DTP, OPV, and MMR vaccine combinations, and the proportion of reports with
febrile convulsions. We see that this proportion did not change significantly with the
successive addition of OPV and MMR to DTP vaccine. While we do not know the exact
denominator for each of these categories, we know that they are only the order of millions
of persons. The results of this very crude ecologic analysis of postadoption surveillance
data are in general agreement with preadoption clinical trials.
Serious neurologic adverse events are by themselves difficult to evaluate
due to their rarity and the crudeness of SRS. But grouped together and performing a
similar analysis, the data is generally reassuring again (table 2). The successive
addition of OPV and MMR to DTP vaccines does not change the baseline proportion of reports
which contain >1 neurologic event. In this instance, it actually suggests that
simultaneous administration may be safer; 23% of reports with DTP-OPV-MMR vaccines
reported at least one neurologic event compared to 30% of reports with DTP alone (p =
0.02). Due to the many potential biases and confounding in SRS data, however, one would
need to validate this finding in a controlled study before reaching a definite conclusion.
Table 3 examines the overall safety profile more broadly in terms of DTP
and MMR, administered either alone or in combination with other vaccines at 15-23 months
of age in MSAEFI. Overall, we again see a general constancy in profile irrespective of
simultaneous vaccination. The only exceptions are in settings like local reaction after
MMR, which was more frequent with simultaneous administration (23%) than when given alone
(8%) (p<0.01), but no higher than DTP given alone (48%).
Hib or Hib conjugate vaccination at age 18 to 36 months of age will now be
considered. Because of the small numbers and the similarity in adverse event profile of
Hib vaccine alone and Hib conjugate vaccine (HbCV) alone, these vaccines are grouped in
these analyses. With accurate documentation of vaccinations and lot numbers that will be
possible under the proposed National Vaccine Registry, product-specific evaluation using
SRS data will be even easier. We see again that there is no significant increase in
febrile convulsions as a percentage of total reports when these are given with successive
combinations with DTP and OPV (table 4). Similarly for neurologic events reported after
various DTP, OPV and Hib combinations, there are no significant changes in the proportion
of neurologic events with the administration of additional antigens. Again with the
exception of reports of more frequent local reactions with simultaneous administration,
there were no major differences in the broader safety profile of Hib given alone or
administered simultaneously with other vaccines (table 5).
When denominator data are available, a more refined type of ecologic
analyses of SRS data is possible. In late 1990, Hib conjugate vaccine began to be
administered to infants at 2, 4, and 6 months of age. From vaccine coverage data collected
by the National Health Interview Survey, the percent of DTP vaccine simultaneously
administered with Hib increased rapidly, from less than 10% in 1990 to 60% in 1991.
The switch from MSAEFI to VAERS in the public sector occurred on November
1, 1990. Because there were major differences in reporting forms between the two systems,
comparing ecologic trends over time for most adverse events is difficult. However,
hospitalization and deaths are two very specific outcomes that were captured by both
MSAEFI and VAERS; therefore, each of these outcomes can be analyzed for changes over a
time frame that spans both SRSs. For consistency, we examined only reports after vaccines
received in the public sector. Because doses-administered data by specific vaccine are
reported in the public sector also, we could examine the estimated rates of
hospitalization and death reported per million doses of DTP vaccine administered. The
relative stability of these rates in 1991 and 1992 despite the large increase in
simultaneous administration of Hib vaccine suggests that this change in schedule did not
result in significant increase in hospitalization or deaths(figure 3).
Any death reported after vaccination understandably raises concern. One
might even ask why should there be any baseline rate of death reported after DTP or any
other vaccine. Because vaccinations are recommended during the first year of life and
sudden infant death syndrome (SIDS) also occurs during the first year of life, one would
expect some SIDS to occur shortly after vaccination by chance alone. If the SRS is
working, one would ,in fact, expect these deaths to be reported. The difficult question is
whether one can determine which of these deaths are coincidental and which might be
causally related to vaccination. Our FDA colleagues examine reports of deaths to VAERS for
consistent patterns in clinical presentation; we have done some analyses for epidemiologic
patterns.
Figure 4 shows the age distribution of all deaths among infants within 30
days after DTP vaccination reported to VAERS compared to the age distribution of 1) SIDS
cases in the 1983 to 1987 birth cohorts from the national mortality statistics, and 2) DTP
vaccinations from the National Health Interview Survey 1986-90. Drawing a line across the
peak of the VAERS deaths matches the shape of the SIDS curve extremely well, but not the
distribution of DTP vaccinations. The small hills correspond to when vaccinations are
administered and when temporal clustering of reports are expected. Figure 5 shows the
similar data for MSAEFI 1985 to 1990. With more years of data these hills smooth out, so
that the two curves now coincide even more closely.
Figure 6 plots the seasonality of all infant deaths reported to VAERS
within 30 days after DTP vaccination. This line appears similar to the shape of the
seasonality of SIDS, and dissimilar from the seasonality of DTP administration as reported
by the public sector. From the age distribution and seasonality figures, we conclude that
most of the infant deaths after DTP vaccination reported to MSAEFI or VAERS are probably
due to coincidence. A 1991 Institute of Medicine review of this issue arrived at a similar
conclusion (15).
CONCLUSION
In summary, the benefits of simultaneous administration have generally
been shown to outweigh the risks in prelicensure/adoption trials (1). Ecologic analyses of
data from two postlicensure surveillance systems for adverse events were used to confirm
that simultaneous administration of DTP, OPV, and MMR at 15 months of age and DTP,
OPV,
and Hib vaccines at various ages probably have not resulted in an increase of serious
adverse events. If baseline SRS experience is available, similar ecologic analyses of SRS
surveillance data can be used in the future to crudely assess the safety of new
combinations of vaccine antigens. Due to the intrinsic methodologic deficiencies of SRS,
however, controlled studies will be needed to confirm or refute signals generated by these
relatively crude ecologic analyses of SRS data. CDC has embarked on a large linked
database study to provide a ready setting with sufficient power for such validation
studies (7).