Early vaccine-mediated strain-specific cytokine imbalance induces mild immunopathology during influenza infection.

Influenza A viruses (IAVs) exist as distinct serological subtypes, with limited antibody cross reactivity compared with T-cell responses, leading to universal vaccines that elicit robust T-cell responses entering clinical trials to combat pandemic and zoonotic outbreaks. Previously we have extensively characterized the viral-vectored universal vaccine, Wyeth/IL-15/5flu, a group 1 hemagglutinin, H5N1-based vaccine using a vaccinia backbone with interleukin (IL)-15. The vaccine elicits robust T-cell responses to provide heterosubtypic protection from lethal infection; however, we have also observed short-term morbidity of vaccinated mice with a disparity between the effects of sublethal infection with group 1 and 2 IAV strains. At day 3 of H3N2 (group 2 IAV) infection, there was a heavily skewed T helper type 1 response in vaccinated infected mice with overproduction of cytokines and reduced chemokines, whereas H1N1 (group 1 IAV) infection had increased innate cellular responses. These findings suggest that increased and early immune activation by T-cell activating vaccines may induce mild immunopathology when there is a mismatch between non-neutralizing antibody and cross-reactive memory T-cell responses leading to exuberant cytokine production. Therefore, to avoid overstimulating proinflammatory immune responses upon infection, universal influenza vaccines that elicit strong T-cell immunity will need a robust cross-reactive antibody response.

SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection.

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 ß-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 ß-coronavirus immunity and reduced activation and recruitment of de novo responses in children may drive milder COVID-19 pathogenesis.