Nasal IgA Provides Protection against Human Influenza Challenge in Volunteers with Low Serum Influenza Antibody Titre

Abstract

In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines.

The protective potential of Fc‐mediated antibody functions against influenza virus and other viral pathogens

“…Owing to its presence in the respiratory tract and its polyvalency, IgA has significant protective potential against influenza virus . Indeed, high levels of nasal IgA correlated with protection in a human influenza challenge study . The Fc domain of mucosal IgG also interacts weakly with mucins.…”

Meeting report and review: Immunological assays and correlates of protection for next‐generation influenza vaccines

“…Single radial hemolysis assay 11,12 Nasal IgA Enzyme-linked immunosorbent assay (ELISA) 13 Serum virus neutralization antibody titer…”

“…1 Since then, several other immune markers have been reported to correlate with protection, several of them independently of the serum HI antibody titer. These include interferon γ secreting cells, CD8 and CD4 T cells in peripheral blood, [4][5][6][7][8] neuraminidase (NA) inhibition (NI) antibody titers 9,10 antibodies measured by single radial hemolysis (SRH), 11,12 nasal IgA 13 and, more recently, antibodies that target the hemagglutinin (HA) stalk domain. 14 In contrast to HI antibodies, which lead to narrow, strain specific protection, these potential new "correlates of protection" are often based on conserved viral epitopes that are also targeted by next-generation influenza virus vaccines.…”

T-bet+ Memory B Cells Link to Local Cross-Reactive IgG upon Human Rhinovirus Infection

“…However, knowledge of antibodies against influenza, another common respiratory viral pathogen, could yield clues. In this context, IgA is more crossreactive and more neutralizing than IgG, primarily as a result of its more efficient secretion into the airways, and its divalence, which enhances avidity and complex formation with virus (Gould et al, 2017;Muramatsu et al, 2014;Taylor and Dimmock, 1985). Interestingly, whereas IgA outperforms IgG in neutralizing influenza in the upper airways, the reverse may be true in the lower airways during acute infection (Renegar et al, 2004).…”