Influenza immune escape under heterogeneous host immune histories

Abstract

In a pattern called immune imprinting, individuals gain the strongest immune protection against the influenza strains encountered earliest in life. In many recent examples, differences in early infection history can explain birth year-associated differences in susceptibility (cohort effects). Susceptibility shapes strain fitness, but without a clear conceptual model linking host susceptibility to the identity and order of past infections general conclusions on the evolutionary and epidemic implications of cohort effects are not possible. Failure to differentiate between cohort effects caused by differences in the set, rather than the order (path), of past infections is a current source of confusion. We review and refine hypotheses for path-dependent cohort effects, which include imprinting. We highlight strategies to measure their underlying causes and emergent consequences.

Keywords: antigenic evolution; cohort effects; immune escape; immune imprinting; influenza; original antigenic sin.

Figure 1:. Mechanisms for preferential immune memory against strains encountered in childhood.

(A) Influenza viruses evolve antigenically over time. (B) A hypothetical example of an antibody landscape that reconciles two observed patterns: on average, infection causes the largest boost to the current strain (arrow) [32], but absolute titers remain highest to childhood strains due to back-boosting, wherein titers rise simultaneously to current and past strains, which have some antigenic homology [32,45,48,62]. Dashed line represents a hypothetical 50% protective titer. (C) Repeated recall of cross-reactive memory leads to a pattern in which titers are, on average, highest to the strains that circulated in childhood [45,62]. (D) OAS can cause path-dependent immune repertoire development. When hosts with different immune histories are subsequently infected with strain x, existing immune memory reduces the total size (response blunting) and shapes the epitope specificity (epitope bias) of the subsequent response (dashed outline separates the new response from the standing repertoire). The following year, strain y has one epitope in common with strain x, but the strength of cross-immunity hosts gain against strain y from a past infection with strain x depends on immune history (Adapted from [49]). (E) Set-dependent immunity implies that differences in the development of the immune repertoire depend on the identity of the antigens experienced in the past, but not on the order in which they were experienced. Here, immunity accumulates additively, so all hosts gain the same cross-protection against y from a past infection with x, regardless of their immune history. (F) Measuring response blunting: current evidence shows a linear decrease in log boost with log titer to specific influenza epitopes [23,24,77] or strains [24] (solid line) [77], but evidence for this quantitative relationship is limited and it could differ in other contexts (dashed lines). (G) Measuring epitope bias involves tracking how the fraction of antibodies or antibody secreting cells specific to a given epitope changes as a function of pre-existing titer to that epitope. The exact functional relationship and the degree of epitope masking is predicted to depend on factors including antigen dose and the degree of steric interference between epitopes [–24]. (H) Illustration of epitope masking, in which pre-existing antibodies to the blue epitope occlude binding of cognate B cells, whereas B cells to the pink, novel epitope are more able to bind and replicate.

Figure 2:. Set-dependent versus path-dependent cohort effects.

(A) Cohorts can differ in susceptibility due to differences in the order or identity of past infections. (B-D) An example of imprinting: (B) Adult cohorts have lived through decades of co-circulation of influenza A strains whose hemagglutinin antigens fall on two distant branches of the phylogenetic tree. (Seasonal strains from hemagglutinin group 1, H1N1 and H2N2 are shown in blue, and strains from group 2, H3N2, are shown in red). If immunity accumulated in a strictly set-dependent manner, adult cohorts would show equally strong protection against both groups, given repeated infections and immunizations (D), but instead cohorts show stronger protection against the group that circulated in childhood, consistent with imprinting (C) (Box 1). (E-F) An example of non-imprinting cohort effects: (E) Immune memory of a cross-reactive epitope present in past H1N1 strains (light blue dot), which circulated most recently in the late 1970s, provided cross-protection against the 2009 H1N1 pandemic strain. However, this epitope was shielded by a glycan and inaccessible from 1983–2009 [2,58]. (F) Younger cohorts born after this cross-reactive epitope became inaccessible were immunologically naive to the 2009 pandemic strain, whereas older cohorts had some cross-protective immunity. However, this set-dependent cohort effect did not persist. Younger cohorts quickly built new immune memory on infection or vaccination with the 2009 strain (arrow).

Key figure

Mechanisms for preferential immune memory against strains encountered in childhood