Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines-an exploratory sub-study of the BRACE trial.

BACKGROUND: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. METHODS: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. FINDINGS: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. INTERPRETATION: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

Diet at birth is critical for healthy growth, independent of effects on the gut microbiota.

BACKGROUND: Colostrum is the first milk for a newborn. Its high content in microbiota shaping compounds and its intake at the time of gut microbiota seeding suggests colostrum may be critical in the establishment of a healthy microbiota. There is also accumulating evidence on the importance of the gut microbiota for healthy growth. Here, we aimed to investigate the contribution of colostrum, and colostrum-induced microbiota to growth promotion. Addressing this question is highly significant because (1) globally, less than half of the newborns are fully colostrum fed (2) the evidence for the importance of the microbiota for the prevention of undernutrition has only been demonstrated in juvenile or adult pre-clinical models while stunting already starts before weaning. RESULTS: To address the importance of diet at birth in growth failure, we developed a unique mouse model in which neonates are breastfed by mothers at an advanced stage of lactation who no longer provide colostrum. Feeding newborn mice with mature milk instead of colostrum resulted in significant growth retardation associated with the biological features of chronic undernutrition, such as low leptin levels, dyslipidemia, systemic inflammation, and growth hormone resistance. We next investigated the role of colostrum in microbiota shaping. At the end of the lactation period, we found a major difference in gut microbiota alpha diversity, beta diversity, and taxa distribution in control and colostrum-deprived mice. To determine the causal relationship between changes in microbiota and growth trajectories, we repeated our experiment in germ-free mice. The beneficial effect of colostrum on growth remained in the absence of microbiota. CONCLUSION: Our data suggest that colostrum may play an important role in the prevention of growth failure. They highlight that the interplay between neonatal gut microbiome assembly and diet may not be as crucial for growth control in the developing newborn as described in young adults. This opens a paradigm shift that will foster research for colostrum's bioactives that may exert a similar effect to microbiota-derived ligands in promoting growth and lead to new avenues of translational research for newborn-tailored prevention of stunting. Video Abstract.