Lessons Learned from Clinical Trials in 1976 and 1977 of Vaccines for the Newly Emerged Swine and Russian Influenza A/H1N1 Viruses

Abstract

An explosive local outbreak of respiratory disease in the US in 1976 with a swine influenza A/H1N1-like virus [A/New Jersey/76 (H1N1)] and the appearance of another A/H1N1 virus [A/USSR/77 (H1N1)] in the subsequent year led to extensive clinical trials of vaccines as preparations for public use. Two whole virus (WV) and two subunit (SV) vaccines of each virus were evaluated in all age groups for safety and immunogenicity. A/NJ WV vaccines were more reactogenic and more immunogenic than SV vaccines, particularly in children. Increase in the dosage led to increase in reactogenicity, which was significant for one WV vaccine that contained more antigen, but reactogenicity was best associated with the presence of WV particles of varied morphology. Although this result led to the concept that WV vaccines were not acceptable for children, WV A/USSR vaccines were not reactogenic in adults as were the A/NJ vaccines.

Patterns of antibody response by age, dosage, and number of doses were similar for both A/NJ and A/USSR vaccines. Increasing dosage increased the frequency and magnitude of responses and μg of HA related better to this finding than CCA units used initially for dosage of A/NJ vaccines. “Primed” persons (exposed to A/H1N1 viruses circulating before 1957) responded to single doses of vaccine. One dose of WV vaccine induced acceptable antibody responses among most unprimed persons but SV vaccines required two doses. For WV vaccine, one dose of high dosage vaccine (60–118 μg HA) was as immunogenic as two doses of lower dosage among adults; two doses as low as 2.5 μg HA were immunogenic in children. For “primed” persons, doses of 15–20 μg HA induced adequate responses. These principles of dosage, morphology and priming as major determinants of reactogenicity and immune responses have been replicated since 1976–1977 and seem likely to be replicated again in the current vaccine trials with the 2009 swine-like A/H1N1 virus.