Cross‐reactive antibody‐dependent cellular cytotoxicity antibodies are increased by recent infection in a household study of influenza transmission

Abstract

Objectives Influenza causes a spectrum of disease from asymptomatic infection to fatal outcome, and pre‐existing immunity can alter susceptibility and disease severity. In a household transmission study, we recruited outpatients with confirmed influenza virus infection and prospectively identified secondary infections in their household contacts, therefore identifying infection cases with baseline samples for determining immune‐mediated protection from influenza infection. Methods We examined baseline broadly reactive immune correlates of relevance to universal vaccine development, specifically antibody‐dependent cytotoxic (ADCC) antibodies and T‐cell responses in functional assays. Antibodies were assessed in a cell‐based NK cell degranulation assay by flow cytometry, and T‐cell responses were assessed by IFN‐γ intracellular cytokine staining flow cytometry assay. Results The magnitude of antibody responses and ADCC function for multiple influenza‐specific proteins was lower in participants who became infected, consolidating the role of pre‐existing antibodies in protection from seasonal influenza virus infection. Among H1N1‐infected contacts, we found that higher levels of pre‐existing H1‐haemagglutinin ADCC responses correlated with reduced symptom severity. Recent infection boosted the titre and magnitude of haemagglutinin‐, neuraminidase‐ and nucleoprotein‐specific ADCC antibodies. Limited T‐cell samples precluded conclusions on the role of pre‐existing T‐cell responses. Conclusions Overall, ADCC responses are a protective correlate against influenza virus infection that should be considered in future vaccine development and evaluation. Influenza‐specific ADCC responses are elevated in uninfected subjects, associated with reduced symptoms and boosted by recent infection, whilst HA stem and NA IgG are also elevated in uninfected participants irrespective of ADCC function.

Vaccination with ADCC activating HA peptide epitopes provides partial protection from influenza infection

“…1D ). To further assess ADCC responses at baseline before infection, we used pre H1N1 infection samples (Positive) from a household study and compared responses to household members who did not become infected (Negative) [ 3 ]. We did not find a difference in the profile of H1-HA targeted peptides between uninfected (Negative) and H1N1 infected (Positive) household contacts at baseline to account for acquisition of infection ( Fig.…”

“…Vaccination of mice with ADCC activating peptides provided moderate protection, in terms of survival, viral loads and lung inflammation from homologous influenza virus challenge. Whilst peptide vaccination did not achieve the level of protection afforded by full H1-HA protein vaccination, it did demonstrate the protective potential of ADCC responses which has also been evident in human studies [ 1 , 3 ]. A limitation of our study is the reductionist approach of using linear peptides to identify antibody epitopes, as conformational epitopes may also play a role in influenza-ADCC responses.…”

“…ADCC responses have shown a high level of cross-reactivity between seasonal and avian influenza viruses in the absence of virus neutralization [ 2 ], and increased responses correlate with reduced viral shedding during infection [ 1 ] and symptom severity [ 3 ]. Importantly, in adults cross-reactive ADCC antibodies are already present before the development of neutralizing antibody responses [ 4 ], reflecting their protective roles in the early phase of influenza infection.…”

“…Importantly, in adults cross-reactive ADCC antibodies are already present before the development of neutralizing antibody responses [ 4 ], reflecting their protective roles in the early phase of influenza infection. Influenza-specific ADCC responses are increased by a recent infection [ 3 , 5 ], but are not boosted by current inactivated influenza vaccines [ 6 ]. Therefore, new strategies need to be devised and assessed to stimulate the production of cross-reactive ADCC antibodies against influenza.…”

Behavioral strategies to prevent and mitigate COVID-19 infection

“… 51 Regarding the latter, a recent longitudinal study showed that increased levels of antibodies capable of facilitating ADCC decreases susceptibility to influenza infection. 52 There is optimism that the same might hold true during infection with SARS-CoV-2 53 . Moreover, Bongen et al.…”