Perspectives on pandemics: a research agenda.

During the 20th century, indisputable pandemics of influenza occurred in 1918, 1957, and 1968. The pandemics of 1957 (A/H2N2) and 1968 (A/H3N2) were associated with major antigenic changes in the virus, probably reflecting introduction by recombination of animal virus genes. The 1918 epidemic is beyond the reach of modern virology but, based on seroarcheology, appears to have been caused by a virus very similar to present swine (A/H1N1) influenza viruses. Changes in both principal antigens of the A/H1N1 subtype in 1947 resulted in total vaccine failure and pandemic spread of virus. On the basis of three periods of prevalence in the 20th century, A/H1N1 may be the "default" human virus, although the 39-year persistence of A/H3N2 to the present challenges this view. Only H1, H2, and H3 and N1 and N2 antigens have been found in human influenza viruses, but virologic history is too brief to preclude the contribution of other antigens to future pandemics.