Heterosubtypic cross-reactivity of HA1 antibodies to influenza A, with emphasis on nonhuman subtypes (H5N1, H7N7, H9N2).

Dennis E Te Beest,Michiel Van Boven,Marion Koopmans,Sandra Imholz,Erwin De Bruin,Sang-Moo Kang

doi:10.1371/journal.pone.0181093

Abstract

Epidemics of influenza A vary greatly in size and age distribution of cases, and this variation is attributed to varying levels of pre-existing immunity. Recent studies have shown that antibody-mediated immune responses are more cross-reactive than previously believed, and shape patterns of humoral immunity to influenza A viruses over long periods. Here we quantify antibody responses to the hemagglutinin subunit 1 (HA1) across a range of subtypes using protein microarray analysis of cross-sectional serological surveys carried out in the Netherlands before and after the A/2009 (H1N1) pandemic. We find significant associations of responses, both within and between subtypes. Interestingly, substantial overall reactivity is observed to HA1 of avian H7N7 and H9N2 viruses. Seroprevalence of H7N7 correlates with antibody titers to A/1968 (H3N2), and is highest in persons born between 1954 and 1969. Seroprevalence of H9N2 is high across all ages, and correlates strongly with A/1957 (H2N2). This correlation is most pronounced in A/2009 (H1N1) infected persons born after 1968 who have never encountered A/1957 (H2N2)-like viruses. We conclude that heterosubtypic antibody cross-reactivity, both between human subtypes and between human and nonhuman subtypes, is common in the human population.

Highlights

Epidemics of influenza A in temperate regions are notoriously variable in duration, size, and age distribution of cases [1,2,3,4,5]
We focus on correlations that must be caused by cross-reactive responses and cannot be caused by associations in infection histories, e.g., responses to avian influenza viruses, and responses against hemagglutinin subunit 1 (HA1) of A/1957 (H2N2) virus in persons born after 1968, i.e. who are too young to have been infected naturally
Correlations in the antibody responses to different influenza viruses may arise by cross-reactivity of responses after infection by one virus, or by associations in infection histories

Summary

Introduction

Epidemics of influenza A in temperate regions are notoriously variable in duration, size, and age distribution of cases [1,2,3,4,5]. This appears to be true for influenza pandemics caused by novel or reappearing subtypes as well [3, 5,6,7,8,9,10]. Show that antibody-mediated immune responses, especially those directed against the stalk of the hemagglutinin protein (HA), are more cross-reactive than previously believed [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]

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Results

Conclusion