The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life Graphical abstract Highlights d Analysis of aged mice exposed to antibiotics in the preweaning period d Microbiota community type following antibiotics affects host health in later life d PAM II mice have increased insulin resistance, inflammaging, and reduced lifespan

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Highlights d Antibiotic-treated and germ-free mice are protected from IAA-induced toxicity d Antibiotic treatment does not impair IAA + anti-PD1 antitumor efficacy d Gut microbiota modulates IAA-induced immune responses in liver d MyD88 mediates IAA-induced CRS and anti-CD137-induced liver damage

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Despite promising pre-clinical and clinical data demonstrating that immune agonist antibody immunotherapies (IAAs) such as OX40 induce strong anti-tumor immune responses, clinical translation has been significantly hampered by the propensity of some IAAs to induce doselimiting and sometimes life-threatening immunotoxicities such as cytokine release syndrome and hepatoxicity. For example, in a recent study OX40 was shown to induce significant liver damage in mice by inducing the pyroptosis of liver natural killer T cells (NKT) cells. Surprisingly however, given these previous reports, OX40 treatment in our hands did not induce NKT cell pyroptosis or liver damage. We investigated numerous potential confounding factors including age, sex, tumour burden, dosing strategy and the gut microbiota, which could have explained this discrepancy with the previous study. In none of these experiments did we find that OX40 induced any more than very mild inflammation in the liver. Our study therefore suggests that, preclinically, OX40 is a safe and effective immunotherapy and further studies into the clinical benefit of OX40 are warranted.

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We longitudinally profiled immune responses in 102 adults who received BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (Oxford-AstraZeneca) as their primary vaccinations. Bloods were collected pre-vaccination, 1-7 days after the 1st, 2nd and 3rd doses (BNT162b2 or mRNA-1273) to assess innate and early adaptive responses, and ~28 days after the 2nd and 3rd doses to assess immunogenicity. Using a multi-omics approach including RNAseq, cytokine multiplex assay, proteomics, lipidomics, and flow cytometry we identified key differences in the immune responses induced by the ChAdOx1-S and BNT162b2 vaccines that were correlated with subsequent antigen-specific antibody and T cell responses or vaccine reactogenicity. We observed that vaccination with ChAdOx1-S but not BNT162b2 induced a memory-like response after the first dose, which was correlated with the expression of several proteins involved in complement and coagulation. The COVID-19 Vaccine Immune Responses Study (COVIRS) thus represents a major resource to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.