Revisiting the 1976 Swine Flu Vaccine Clinical Trials: Cross-reactive Hemagglutinin and Neuraminidase Antibodies and Their Role in Protection Against the 2009 H1N1 Pandemic Virus in Mice

Background. The 2009 H1N1 pandemic viruses are genetically similar to A/New Jersey/76 H1N1 virus (NJ/76), the strain selected for the 1976 swine flu vaccines. Approximately 45 million people in the United States were vaccinated against NJ/76 30 years ago, but the impact of this nationwide immunization on the current pandemic is largely unknown. Methods. Archived human serum samples collected during the 1976 swine flu vaccine trials were assessed for cross-reactive antibody responses to the 2009 H1N1 pandemic viruses. Results. Administration of an NJ/76 monovalent vaccine or the combination of a bivalent vaccine (NJ/76 H1N1 and A/Victoria/75 H3N2) plus a B/Hong Kong/72 monovalent vaccine increased hemagglutinin inhibition (HAI) and neuraminidase inhibition (NAI) antibodies cross-reacting with the 2009 H1N1 pandemic viruses. We showed that cross-reactive human HAI antibodies elicited by the 1976 swine flu vaccination played a dominant role in protecting recipient mice against the wild-type A/California/04/2009. Cross-reactive human NAI antibodies were also protective in recipient mice after a lethal challenge with a hemagglutinin mismatched virus bearing the A/California/04/2009 neuraminidase gene. Transfer of human serum samples with an original HAI titer of 43 or an original NAI titer of 472 was estimated to protect 50% of recipient mice from a lethal infection under the experimental conditions described. Conclusions. The 1976 swine flu vaccination induced cross-reactive HAI and NAI antibodies that were functionally protective in mice, suggesting that this vaccination campaign might have had a positive impact on older adults (>= 50 years) in the United States during the 2009 H1N1 pandemic.