Influenza Immunity: New Insights from Old Studies

All viruses mutate, but influenza remains highly unusual among infectious diseases in the rapid evolutionary rate of its causative viruses. The defensive response of the human immune system to repeated viral attacks is both the driving selective force in the evolution of new viral variants and, indirectly, the determinant of the subsequent compromised ability of the immune system to protect against the new variants. As a consequence, new vaccines are needed almost every year if an optimal match of vaccine and new (immunoselected) challenge virus is to be achieved If the ABCs of influenza are simple—influenza A, influenza B, and influenza C (ranked in decreasing order of importance)—the immunity and epidemiologic patterns are not. Restricting our discussion to the influenza A viruses—and these are the most prevalent and the most important—there are 16 antigenically defined hemagglutinin (HA) subtypes in mammals and birds and 9 neuraminidase (NA) antigens, both of primary importance in the induction of protective immunity. The 2 viral genes coding for these surface glycoproteins and the 6 other viral genes reassort freely with those of other influenza A viruses of the same or other subtypes, to produce almost any possible HA-NA combination (H2N2, H3N2, etc.). Thus, the immunity and epidemiologic patterns of influenza are those of the individual influenza A virus genes as much as they are of the individual viruses. To date, at least in the 20th century, only 3 influenza subtypes are known to have produced pandemic disease in humans: H1N1, H2N2, and H3N2. In 1957, the H1N1 subtype, linked retrospectively to human disease since 1918, was replaced by H2N2, the Asian influenza virus, which produced the first of the pandemics during the era of modern virology. Morbidity rates were high and mortality exceeded that of the regional epidemics of the post-1918 period, but they were considerably lower than the toll taken in 1918. The global spread of the virus and the reappearance of fatal viral pneumonia was explained by the virtual absence of demonstrable antibody against H2N2 in acute-phase serum from infected patients. Now, in this issue of the Journal of Infectious Diseases Epstein presents evidence suggesting that, in family groups intensively exposed to H2N2, adults were more frequently spared of influenza than were children [1]. She suggests that the protective factor in adults was prior infection and, therefore, immunity induced by natural infection with earlier strains that could not have been of the H2N2 subtype. In other words, some protection against the new subtype had been conferred as heterosubtypic (cross-subtype) immunity Immunity to infection with influenza virus is complex. Focusing here solely on the humoral antibody response, only HA, as the major glycoprotein antigen, evokes a neutralizing antibody response that is capable of true binding and neutralization of the virus and, thus, of preventing infection. Response to the NA glycoprotein sialidase antigen is effective in damping virus release from the infected cell, thereby reducing the endogenous spread of newly formed virus and, thus, of total virus production, often to levels below that required to produce manifest disease. Other viral proteins—including the nucleoprotein and M2, the third (and minor) surface glycoprotein—also evoke antibody responses but have not yet been unequivocally shown to be involved in protection. Therefore, by implication, any heterosubtypic protection of adults probably requires shared epitopes of the HA and/or NA antigens. Epstein proposes that we take advantage of this heterosubtypic protection by utilizing the vaccines that we have available in the face of a pandemic. She also cautions that “these historical data alone cannot prove cross-protection in humans or establish its mechanism” but notes that the findings are sufficiently suggestive to “call for further investigation” (p. 52). The author of this editorial commentary concurs. I myself have stressed that so-called barricade vaccines should be thrown into the breach until definitive matching vaccines can be made from the pandemic virus itself [2]. However, I have proposed that a provisional barricade vaccine can be made in advance for each of the 16 known HA subtypes and that, even if the one that has been made and stored proves not to match exactly the emerging pandemic strain, as long as it is of the same subtype it should be sufficiently protective to be welcome during the initial stages of a pandemic [2] The principal importance of Epstein’s study is its intelligent revisitation and analysis of archived clinical specimens and data from a new and fresh perspective. We owe a large debt to those investigators, including Dr. William S. Jordan (with whom Epstein conferred), who conducted the careful prospective surveillance of the Cleveland Family Study and left a legacy of invaluable archived specimens and data [3] We are just beginning to appreciate the importance of archived materials in studies of infectious diseases. With respect to influenza alone, the literal resurrection via modern technology of the 1918 virus from formalin-fixed human lungs by Taubenberger et al. is providing new insights not only into the genesis of pandemics, but into history itself [4]. Perhaps because there is no standard “influenza A virus,” since it has mutated and reassorted itself over the years, representative earlier strains have been preserved in laboratories as workhorses for studies, molecular and otherwise, of the virus’s structure, replication, and genetics. As older laboratories close, some investigators, including myself, have catalogued and preserved mutants, reassortant virus strains, and samples of antiserum of possible future interest and have contributed them to government archives, especially those of the National Institutes of Health. Certain of these viruses could serve as sources for future pandemic vaccines Perhaps most interesting is the growing science of viral paleontology [5], in which fossils are not imprinted in stone but are carried in the DNA of all of us as human endogenous retrovirus pieces, which have been used as markers of primate evolution [6]. Yes, it pays to save. Data that appear unexciting today may prove to be exceedingly valuable in the future, as new technologies and new insights develop