H3N2 influenza viruses in humans: Viral mechanisms, evolution, and evaluation

Abstract

Annual seasonal influenza vaccines are composed of two influenza A strains representing the H1N1 and H3N2 subtypes, and two influenza B strains representing the Victoria and Yamagata lineages. Strains from these Influenza A and Influenza B viruses currently co-circulate in humans. Of these, strains associated with the H3N2 subtype are affiliated with severe influenza seasons. H3N2 influenza viruses pre-dominated during 3 of the last 5 quite severe influenza seasons. During the 2016/2017 flu season, the H3N2 component of the influenza vaccine exhibited a poor protective efficacy (∼28-42%) against preventing infection of co-circulating strains. Since their introduction to the human population in 1968, H3N2 Influenza viruses have rapidly evolved both genetically and antigenically in an attempt to escape host immune pressures. As a result, these viruses have added numerous N-linked glycans to the viral hemagglutinin (HA), increased the overall net charge of the HA molecule, changed their preferences in receptor binding, and altered the ability of neuraminidase (NA) to agglutinate red blood cells prior to host entry. Over time, these adaptations have made characterizing these viruses increasingly difficult. This review investigates these recent changes in modern H3N2 influenza viruses and explores the methods that researchers are currently developing in order to study these viruses.

Keywords: H3N2; Influenza; focal reduction assay; glycosylation; hemagglutination inhibition assay; micro-neutralization assay; molecular virology; oseltamivir carboxylate.

Figure 1.

An overview of H3N2 IAV clade diversity from 2013–2018. During the 2013/14 season clades 3c.2 and 3c.3 represented the majority of H3N2 strains in human circulation. In the 2014/15 season, 2 new clades began to emerge, 3c.2a, which is characterized by F159Y and K160T mutations, that lead to a potential gain of a glycosylation site, and 3c.3a, from which the vaccine strain A/Switzerland/9715293/2013 emerged. By the 2015/16 season 3c.3a viruses began to wane from circulation resulting in another vaccine strain change to A/Hong Kong/4801/2014 (HK/14), which belongs to clade 3c.2a. In the 2016/17 season clade 3c.2a began diverging into two new clades, 3c.2a1, possessing the characteristic amino acid changes T135K, N171K, and D122N, which resulted in the loss of a glycosylation site, and 3c.2a2, which possess the mutations N121K and S144K. In the 2017/18 season clade 3c.2a2 began to split into cluster I, which is defined by the I58V and S219K mutations, and cluster II, which contains N122D and S262N mutations, with the N122D mutation representing the potential loss of a glycosylation site. Clades 3c.2a1 of which A/Singapore/INFIMH-16–0019/2016 (Sing/16) belongs, and 3c.3a were also still in circulation during the 2017/18 season.