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Adverse Events Following Immunization

Identification of adverse events caused by vaccine occurs both before and after licensure. Before licensure, candidate vaccines undergo clinical trials to evaluate safety and efficacy. These trials typically involve several thousand individuals and are able to identify relatively frequent events causally associated with vaccination. However, rare adverse events may not be detected in prelicensure testing and can only be detected by postmarketing surveillance as the vaccine becomes widely used. Postmarketing surveillance is complicated by the fact that events that follow vaccination are not necessarily caused by the vaccine. Establishing that an adverse event after immunization was caused by a particular vaccine requires careful weighing of clinical, laboratory, and epidemiologic evidence. Epidemiologically, a cause-and-effect association is greatly strengthened by a determination that the rate of a given illness following immunization is significantly higher than the rate of that illness in the absence of vaccination. Ascertaining this may require detailed study. In addition, issues of reporting and design bias, reproducibility of findings, consistency with other data, and biologic plausibility must be weighed to infer causality when epidemiologic association exists. Consequently, considerable caution must be used in interpreting reports of adverse events temporally associated with immunization before inferring causality.

At present, there are two complementary national postmarketing surveillance systems for vaccines in the United States. The U.S. Food and Drug Administration receives reports from manufacturers, pharmacists, physicians, and the military services of adverse events following immunization. Almost all reports to this system come from the private sector. In late 1978, CDC established the Monitoring System for Adverse Events Following Immunization (MSAEFI) to collect reports from the public sector concerning adverse events following immunization. Each parent or guardian of a child who receives publicly funded vaccines is requested to report any illness that occurs within 30 days of receiving vaccine and that is severe enough to require a visit to a doctor, clinic, or hospital. Approximately half of all childhood vaccines administered are provided with public funds.

In the 4-year period 1979-1982, 4,503 reports were submitted to MSAEFI; 3,708 (83%) of these came from the public sector. The remainder came from private physicians, the military services, or other sources. Only analyses of public-sector reports are included in this article. Since the system was first implemented, the number of reports has increased each year. During the 4 years, it has increased 40%. Table 3 presents rates of reports for different types of vaccines administered during 1979-1982. Oral polio vaccine (OPV) is not listed separately in this table, since virtually all OPV-associated events reported to this system occurred among individuals who also received diphtheria-tetanus-pertussis (DTP), diphtheria-tetanus (DT), or tetanus-diphtheria (Td) vaccines, and the events reported seemed more likely to be due to these vaccines. Twenty-four reports were received regarding events following receipt of OPV alone.

The reporting rate was highest for events following measles-, mumps-, and rubella-containing vaccines, with 74.8 to 83.8 reports per million doses administered (Table 3). Since the majority of measles, mumps, and rubella is administered as combined vaccine (measles-mumps-rubella (MMR)), adverse events to individual vaccine antigens cannot be dissociated. This is a limitation of the surveillance system. All reports of events associated with MMR vaccine are attributed to each of the vaccine antigens, making the rates of reported events for measles, mumps, and rubella antigens appear approximately the same. When arthralgia and arthritis associated with single-antigen rubella vaccine are added to those events that are attributed to MMR vaccine, rubella antigen has the highest reported rate of adverse events (Table 4).

Rates of adverse events associated with DTP were somewhat lower, with 70.8 reports received per million doses administered (Table 3). More doses of DTP are administered per child than measles, mumps, and rubella vaccines (five doses of DTP are routinely recommended, compared to one dose of measles-, mumps-, and rubella-containing vaccines). Therefore, although rates per dose may be similar, the actual number of children with adverse events after DTP is higher than the number after measles-, mumps-, and rubella-containing vaccines. The rate for DTP was about twice that of Td or DT. Rates of reporting increased progressively throughout the 4-year period for all these vaccines except Td.

Reported rates of encephalitis and/or encephalopathy are low and similar for all vaccines (Table 4). Rates of febrile convulsions are similar for DTP and for measles-, mumps-, and rubella-containing vaccines.

The increases in reporting were principally due to increased reporting of local reactions, fever, or rash (Table 5). Seventy-four percent of all persons reported to MSAEFI had experienced only these minor events. By contrast, except for febrile convulsions, there was no increase in reporting for other, potentially more serious, events. Between 1979 and 1982, the total number of vaccine doses administered did not increase.

Seventy-eight deaths were reported among vaccine recipients during the 4-year period; 45 (58%) of these were classified as sudden infant death syndrome (SIDS). Except for a single SIDS death, which was temporally associated with the administration of inactivated polio vaccine (IPV) in 1982, all SIDS deaths were reported in temporal association with DTP or DTP and OPV vaccine administration. This temporal association might be expected, since, by definition, SIDS occurs only in infants under 1 year of age, a period during which the only vaccines recommended for routine use are DTP and OPV. The National Institutes of Health has recently completed a case-control study that found no evidence of causal relationship between administration of DTP or OPV and subsequent sudden infant death (1). These results have been supported by a smaller case-control study in the United Kingdom (2). Of the 33 non-SIDS deaths reported to MSAEFI, 18 (55%) had a defined cause clearly not related to vaccine, such as severe congenital birth defects, sepsis, or meningitis. Of the remaining 15 deaths, nine were temporally associated with DTP and OPV; two, with DTP, OPV, and MMR; two, with MMR; and two, with measles vaccine. Specific causes of death could not be found, nor could vaccine causation be proved. No deaths were reported following administration of Td, DT, measles-rubella (MR), single-antigen mumps, or single-antigen rubella vaccines.

MSAEFI data have assisted in identifying risk factors that may predispose to adverse events. As an example, a comparison of personal history of convulsions in those who had convulsions following receipt of DTP was compared with those who had other (nonneurologic) adverse events following receipt of DTP (Table 6). Persons who had convulsions following DTP vaccination were significantly more likely to have had convulsions previously than persons who had other adverse events following DTP vaccination. The risk of convulsions following DTP vaccination was 8.1 times higher for persons with histories of convulsions than for persons without such histories (95% confidence limits, 5.0-13.0). Reported by Surveillance, Investigations, and Research Br, Div of Immunization, Center for Prevention Svcs, CDC.

Editorial Note

Editorial Note: MSAEFI collects data on adverse events temporally associated with vaccine administration. The system probably receives only a proportion of potential case reports, since it relies on parents or guardians to retain the phone number and instructions for reporting events, recognize that the event occurred within 30 days of vaccination, and initiate the report. Events occurring 1 week or more after vaccination are probably less likely to be reported than those occurring soon after vaccination. It is also probable that less serious events are not as likely to be reported as are more serious events. It is not possible at this time to estimate the degree of underreporting. As a result of the incompleteness of reporting, rates derived from MSAEFI data must be viewed only as an approximation of the true rates. Moreover, since reporting may be influenced by the type of reaction, the timing of the occurrence of the reaction, patient age, and other factors, comparison of rates by antigen should be interpreted with caution.

The increases in reported rates of adverse events during the 4-year period are probably due to improved reporting, as would be expected during the first years of implementation of the surveillance system. The greatest increase occurred in 1982, a year in which national attention was focused on adverse events associated with vaccines. The data are presented as rates, and, therefore, the increases cannot be attributed to greater utilization of vaccines. Also, these increases cannot be attributed to any documented changes in vaccine quality. Although the reported rate of febrile convulsions was greater in 1982 than in the preceding 3 years, the other more

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