Objectives Enhanced inactivated influenza vaccines (eIIV) aim to increase immunogenicity and protection compared with the widely used standard IIV (S‐IIV). Methods We tested four vaccines in parallel, FluZone high dose, FluBlok and FluAd versus S‐IIV in a randomised controlled trial of older adults and in a mouse infection model to assess immunogenicity, protection from lethal challenge and mechanisms of action. Results In older adults, FluAd vaccination stimulated a superior antibody profile, including H3‐HA antibodies that were elevated for up to 1 year after vaccination, higher avidity H3HA IgG and larger HA stem IgG responses. In a mouse model, FluAd also elicited an earlier and larger induction of HA stem antibodies with increased germinal centre responses and upregulation and long‐term expression of B‐cell switch transcription factors. Long‐term cross‐reactive memory responses were sustained by FluAd following lethal heterosubtypic influenza challenge, with reduced lung damage and viral loads, coinciding with increased T‐ and B‐cell recall. Advantages were also noted for the high‐dose FluZone vaccine in both humans and mice. Conclusion The early, broadly reactive and long‐lived antibody response of FluAd indicates a potential advantage of this vaccine, particularly in years when there is a mismatch between the vaccine strain and the circulating strain of influenza viruses.

SARS-CoV-2 infection of children leads to a mild illness and the immunological differences with adults remains unclear. We quantified the SARS-CoV-2 specific T cell responses in adults and children (<13 years of age) with RT-PCR confirmed asymptomatic and symptomatic infection for long-term memory, phenotype and polyfunctional cytokines. Acute and memory CD4+ T cell responses to structural SARS-CoV-2 proteins significantly increased with age, whilst CD8+ T cell responses increased with time post infection. Infected children had significantly lower CD4+ and CD8+ T cell responses to SARS-CoV-2 structural and ORF1ab proteins compared to infected adults. SARS-CoV-2-specific CD8+ T cell responses were comparable in magnitude to uninfected negative adult controls. In infected adults CD4+ T cell specificity was skewed towards structural peptides, whilst children had increased contribution of ORF1ab responses. This may reflect differing T cell compartmentalisation for antigen processing during antigen exposure or lower recruitment of memory populations. T cell polyfunctional cytokine production was comparable between children and adults, but children had a lower proportion of SARS-CoV-2 CD4+ T cell effector memory. Compared to adults, children had significantly lower levels of antibodies to b-coronaviruses, indicating differing baseline immunity. Total T follicular helper responses was increased in children during acute infection indicating rapid co-ordination of the T and B cell responses. However total monocyte responses were reduced in children which may be reflective of differing levels of inflammation between children and adults. Therefore, reduced prior b-coronavirus immunity and reduced activation and recruitment of de novo responses in children may drive milder COVID-19 pathogenesis.

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.