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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality
The initial method of prevention depended on postexposure prophylaxis with immune gamma globulin (Stokes et al., 1944). This method, although quite effective, was marred by several difficulties. It required vigilance with respect to exposure and almost immediate action, because if gamma globulin was given more than 4 days after the exposure, it was no longer effective at preventing disease, although it did attenuate it. Moreover, the prevention it afforded was short-lived, because the injected antibodies tended to disappear within about 2 months. An effort to allow the infection to take place, but in an attenuated form, by injecting less immune globulin was usually successful. The consequence of this was a milder case of clinical measles and a resulting lifelong immunity. However, the titration was not always perfect, and in some children the disease was inadvertently prevented, and therefore, they were soon susceptible again, whereas other children developed nearly full-blown measles, with all the risks of serious morbidity and complications.
The next step in prevention efforts was the development of a killed vaccine. The killed vaccine was derived from the Edmonston strain, which was originally isolated in 1954 (Enders and Peebles, 1954). The component antigen was the virus inactivated by formalin and precipitated by alum. Although this vaccine was in use for nearly 4 years (1963 to 1967), it was abandoned when analysis indicated that it provided only short-lived immunity and it was found that formerly vaccinated children developed severe reactions called ''atypical measles'' after their immunity waned and they became infected with the wild-type measles virus (Centers for Disease Control, 1967).
Development of a live attenuated measles vaccine began a new era in the prevention of this disease. The initial vaccine was derived from the Edmonston strain, which was attenuated by serial passage in various tissue cultures and ultimately grown in chicken embryo cells. The resulting variant was named the Edmonston B strain. It was quite immunogenic, but it was not free of side effects. One-third of the recipients developed high fever, and half of the recipients had a rash. Nevertheless, none of the recipients acted ill. Administration of the vaccine with immune globulin of the proper titer attenuated the reaction without interfering with the induction of permanent immunity.
In the meantime, two vaccines derived from the Edmonston B strain were developed by additional serial passage in chicken embryo cells that were maintained at a lower than optimal temperature. The resulting more-attenuated Enders strain (Hilleman et al., 1968a,b) was the product of an additional 40 passages of the Edmonston B strain; the Schwarz strain was the product of an additional 85 passages of the Edmonston B strain (Schwarz, 1964). Each vaccine induced immunity, and the side effects from these further attenuated vaccines were substantially reduced. The more-attenu-