Potential antigenic explanation for atypical H1N1 infections among middle-aged adults during the 2013–2014 influenza season

Abstract

Influenza viruses typically cause the most severe disease in children and elderly individuals. However, H1N1 viruses disproportionately affected middle-aged adults during the 2013-2014 influenza season. Although H1N1 viruses recently acquired several mutations in the hemagglutinin (HA) glycoprotein, classic serological tests used by surveillance laboratories indicate that these mutations do not change antigenic properties of the virus. Here, we show that one of these mutations is located in a region of HA targeted by antibodies elicited in many middle-aged adults. We find that over 42% of individuals born between 1965 and 1979 possess antibodies that recognize this region of HA. Our findings offer a possible antigenic explanation of why middle-aged adults were highly susceptible to H1N1 viruses during the 2013-2014 influenza season. Our data further suggest that a drifted H1N1 strain should be included in future influenza vaccines to potentially reduce morbidity and mortality in this age group. influenza | antigenic drift | hemagglutinin | antibody | vaccine

Focused antibody response to influenza linked to antigenic drift

“…Of the 41 sera samples screened after vaccination (MN titer >1:40), we found a second example in which the sera lost the ability to neutralize H1N1 viruses with K163 substitutions (Figure 6). These findings with sera are consistent with those of the survey of Linderman et al (14), who found up to 42% of sera from donors born before 1979 showed reduced reactivity with clade 6B H1N1pdm09 isolates. Both our sera were from donors born before 1982 (2 of 28).…”

“…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).…”

“…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). Our paper extends these results by showing that multiple monoclonal antibodies from such individuals can select substitutions at this same site, which suggests that selection is occurring in nature.…”

“…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).…”

“…Early evidence for this came from finding reduced neutralization of viruses with single-point mutations (8)(9)(10)(11)(12) and selective inhibition by sera of binding by characterized hemagglutinin-specific monoclonal antibody Fab fragments (13). A recent paper has identified a single amino acid substitution (K163Q in our numbering) to be responsible for reduced serologic reactivity with 2013-2014 H1N1pdm09 viruses in up to 42% of middle-aged adults born between 1965 and 1979, who would have been exposed to the H1N1 viruses that reemerged in 1977 (14).…”