Abstract
Despite the availability of yearly vaccinations, influenza continues to cause seasonal, and pandemic rises in illness and death. An error prone replication mechanism results in antigenic drift and viral escape from immune pressure, and recombination results in antigenic shift that can rapidly move through populations that lack immunity to newly emergent strains. The development of a “universal” vaccine is a high priority and many strategies have been proposed, but our current understanding of influenza immunity is incomplete making the development of better influenza vaccines challenging. Influenza immunity has traditionally been measured by neutralization of virions and hemagglutination inhibition, but in recent years there has been a growing appreciation of other responses that can contribute to protection such as antibody-dependent cellular cytotoxicity (ADCC) that can kill influenza-infected cells. ADCC has been shown to provide cross-strain protection and to assist in viral clearance, making it an attractive target for “universal” vaccine designs. Here we provide a brief overview of the current state of influenza research that leverages “the other end of the antibody.”
Highlights
Influenza causes 3–5 million cases of severe illness and 290,000–650,000 deaths annually [1]
Antibodies against both NP and the internal RNA-binding and structural matrix 1 (M1) protein did not mediate antibody-dependent cellular cytotoxicity (ADCC) against target cells expressing those specific antigens, but immune complexes of those proteins primed natural killer (NK) cells to secrete cytokines [60] (Figure 1C); the authors suggested such activity could contribute to an anti-viral environment
Experimental infection models have been used to test swine for protection against challenge following vaccination [72] and as a model of enhanced influenza disease [73]. Studies in this latter model have suggested that a lack of neutralizing activity against the challenge strain combined with ADCC-mediating antibodies can produce enhanced disease in swine [73, 74], suggesting that caution may be appropriate in the development of vaccines that do not elicit traditional correlates of influenza protection [75]
Summary
Influenza causes 3–5 million cases of severe illness and 290,000–650,000 deaths annually [1]. The influenza virion has three virally-encoded surface antigens (Figure 1A): a trimeric glycoprotein hemagglutinin (HA) that binds to sialic acid on cell surface receptors promoting virion endocytosis followed by fusion of viral and host cell membranes, a tetrameric neuraminidase (NA) that cleaves sialic acid to release virions from infected cells, and enhance passage through respiratory mucins, and a proton channel (M2 matrix) that helps the release of the viral genome after acidification in endocytic vacuoles These proteins are present in most split-virus vaccine products [24], but the exact contribution of each of these, or of other influenza proteins that are not surface expressed, to vaccine efficacy is unclear
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