Immune history shapes specificity of pandemic H1N1 influenza antibody responses

Abstract

The specificity of H1N1 antibody responses can be shifted to epitopes near the HA receptor–binding domain after sequential infections with viral strains that share homology in this region.

Focused antibody response to influenza linked to antigenic drift

“…The results of our detailed clonal analysis extend two recent serological studies of the human antibody response to the H1N1pdm09 virus (14,37). Li et al have shown that human individuals born between 1983 and 1996 (after donor H), who were exposed in early life to former seasonal H1 viruses that retained K130, narrowly focused their antibody response on this region on exposure to H1N1pdm09 (37).…”

“…Mice were weighed and scored according to previously described criteria (65), and mice with 20% weight loss or morbid clinical scores were humanely killed. (14,37). The importance of this distinction lies in the fact that the 2013-2014 H1N1 viruses, which were not detected as drifted in the standard analysis with ferret sera, have been associated with severe infections in middle-aged and elderly humans previously shown to be relatively protected (63).…”

“…The high frequency of somatic mutations in the 4 sets of monoclonal antibodies from donor H that recognize K163 suggested that they may have been selected from the memory B cell pool (33). It is well known that the first exposure to influenza virus induces a repertoire of B cells that remain for life, from which subsequent exposures to influenza can select, if cross-reactive (34)(35)(36)(37). The H1N1 viruses related to A/USSR/90/1977 reappeared in humans in 1977 after being absent since 1957.…”

“…Li et al have shown that human individuals born between 1983 and 1996 (after donor H), who were exposed in early life to former seasonal H1 viruses that retained K130, narrowly focused their antibody response on this region on exposure to H1N1pdm09 (37). This is similar to the site defined by our antibody, 2-12C, derived from a control individual, which selected for the K130E substitution, and we also detected 2 sera after vaccination with reduced neutralization of viruses carrying the K130 substitution ( Figure 6A Linderman et al noted that severe influenza infection was occurring with higher frequency in middle-aged individuals in the 2013-2014 season that was related to the appearance of clade 6B H1N1pdm09 viruses and showed that, in the cohort born between 1965 and 1979 (which would have included our donor), 42% of serum samples had reduced titer in HAI and MN assays on viruses with K166E/Q substitutions (K163 in our HA numbering) (14).…”

Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation

“…The haemagglutination inhibition (HI) titre is associated with the level of protection [3,4] against a given strain. However, as influenza epidemiological studies adopt a 'life course view' to the immune response, it has become apparent that interpretation of HI titre should be done within the context of the timing, order, and antigenic similarity of the viral strains to which an individual is exposed [5][6][7][8].…”