H1 Hemagglutinin Priming Provides Long-Lasting Heterosubtypic Immunity against H5N1 Challenge in the Mouse Model

Abstract

Influenza virus infections leave a signature of immune memory that influences future responses to infections with antigenically related strains. It has been hypothesized that the first exposure in life to H1N1 influenza virus imprints the host immune system, potentially resulting in protection from severe infection with H5N1 later in life through hemagglutinin (HA) stalk-specific antibodies. To study the specific role of the HA on protection against infection without interference of cellular immunity or humoral antineuraminidase immunity, we primed mice with influenza B viruses that express an H1 HA (group 1; B-H1), H3 HA (group 2; B-H3), or wild-type influenza B virus and subsequently challenged them at different time points with an H5N1 virus. Weight loss and survival monitoring showed that the B-H1-primed mice exhibited better protection against H5N1 compared to the control mice. Analysis of H5-specific serum IgG, before and 21 days after H5N1 challenge, evidenced the presence of anti-stalk H5 cross-reactive antibodies in the BH-1 group that were boosted by H5N1 infection. The increased immune responses and protection induced by priming with the B-H1 viruses lasted at least up to 1 year. Hence, a single HA priming based on natural infection induces long-lasting protective immunity against heterosubtypic strains from the same phylogenetic HA group in mice. This study gives mechanistic support to the earlier finding in humans that imprinting by H1 HA protects against H5N1 infections and that highly conserved regions on the HA, like the stalk, are involved in this phenomenon.IMPORTANCE Current studies point out that an HA-mediated immunological imprint is established early in life during the first exposure to influenza viruses, which critically shapes and biases future immune responses. However, studies in animal models are limited and the precise mechanisms of this phenomenon are under investigation. Studies that explore the effect of HA-specific immunity induced during natural infection on future exposures to heterosubtypic influenza strains are needed.

Lineage-specific protection and immune imprinting shape the age distributions of influenza B cases

“…The major antigens HA and NA evolve more slowly within the influenza B lineages than within influenza A subtypes (Bedford et al, 2014, 2015; Vijaykrishna et al, 2015), and the amino acid sequence divergences are much lower between B/Victoria and B/Yamagata (≈ 14%, 2% and 7% in 2019 for the HA head, the HA stalk, and NA, respectively) than between H1N1 and H3N2 (≈ 66%, 50% and 60%, respectively) (Figure S23). Still, epitopes conserved within the lineages but variable between them (or between the lineages and their ancestor) might be the basis for imprinting protection against B/Yamagata (and potentially B/Victoria), as has been hypothesized for influenza A subtypes (Gostic et al, 2019; Arevalo et al, 2020a,b; Carreño et al, 2020).…”

“…It is unclear if people have increased protection against their first infecting influenza B lineage. One hypothesized mechanism for immune imprinting in influenza A is antibodies to conserved epitopes (Gostic et al, 2016, 2019; Arevalo et al, 2020a,b; Carreño et al, 2020). Since B/Victoria and B/Yamagata diverged from each other more recently (Rota et al, 1990; Chen and Holmes, 2008; Dudas et al, 2015) and evolve antigenically much more slowly than the influenza A subtypes (Bedford et al, 2014, 2015; Vijaykrishna et al, 2015), conserved epitopes within a lineage might also be conserved between lineages, leading to strong cross-lineage protection by antibodies targeting those epitopes, regardless of which lineage was encountered first.…”

Influenza immune escape under heterogeneous host immune histories

“…However, there is growing interest in antibody, B, and T cell responses that target conserved influenza epitopes, which can provide broader cross-subtype protection, and provide a potential basis for universal influenza vaccination [71,72]. The proliferation of serological techniques to measure antibodies to conserved epitopes has revealed that, contrary to the classical within-subtype paradigm, OAS can also shape the quality and specificity of broadly protective, cross-subtype immunity [25,73]. Similarly, the breadth of cross-protection from imprinting and other cohort effects is context-dependent and depends on which epitopes are the dominant immune targets and how conserved those epitopes are.…”

“…For example, epitopes that are conserved between influenza subtypes that have and have not previously circulated in humans are, by definition, the only recognizable immune targets present on novel, avian subtypes, such as H5N1 and H7N9. Imprinting protection against zoonotic H5N1 and H7N9 infections involves memory of these conserved epitopes and provides broad cross-subtype protection [25,37,73]. On the other hand, memory responses against familiar seasonal strains are more likely to target variable, immunodominant epitopes, and in this context imprinting acts narrowly within a subtype [38,39].…”

ELISA–on-Chip: High throughput antibody profiling using antigen microarrays

“…Previous work has reported that antibodies developed following H1N1 infection or vaccination can cross-react with HA proteins of H5N1 strains (e.g. [16][17][18][19][20]).…”