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ABSTRACT Objective Class III obesity (body mass index [BMI] ≥ 40 kg m−2) significantly impairs the immune response to SARS‐CoV‐2 vaccination. However, the effect of an elevated BMI (≥ 25 kg m−2) on humoral immunity to SARS‐CoV‐2 infection and COVID‐19 vaccination remains unclear. Methods We collected blood samples from people who recovered from SARS‐CoV‐2 infection approximately 3 and 13 months of post‐infection (noting that these individuals were not exposed to SARS‐CoV‐2 or vaccinated in the interim). We also collected blood samples from people approximately 5 months of post‐second dose COVID‐19 vaccination (the majority of whom did not have a prior SARS‐CoV‐2 infection). We measured their humoral responses to SARS‐CoV‐2, grouping individuals based on a BMI greater or less than 25 kg m−2. Results Here, we show that an increased BMI (≥ 25 kg m−2), when accounting for age and sex differences, is associated with reduced antibody responses after SARS‐CoV‐2 infection. At 3 months of post‐infection, an elevated BMI was associated with reduced antibody titres. At 13 months of post‐infection, an elevated BMI was associated with reduced antibody avidity and a reduced percentage of spike‐positive B cells. In contrast, no significant association was noted between a BMI ≥ 25 kg m−2 and humoral immunity to SARS‐CoV‐2 at 5 months of post‐secondary vaccination. Conclusions Taken together, these data showed that elevated BMI is associated with an impaired humoral immune response to SARS‐CoV‐2 infection. The impairment of infection‐induced immunity in individuals with a BMI ≥ 25 kg m−2 suggests an added impetus for vaccination rather than relying on infection‐induced immunity.

Abstract Objectives Thrombotic and microvascular complications are frequently seen in deceased COVID‐19 patients. However, whether this is caused by direct viral infection of the endothelium or inflammation‐induced endothelial activation remains highly contentious. Methods Here, we use patient autopsy samples, primary human endothelial cells and an in vitro model of the pulmonary epithelial–endothelial cell barrier. Results We show that primary human endothelial cells express very low levels of the SARS‐CoV‐2 receptor ACE2 and the protease TMPRSS2, which blocks their capacity for productive viral infection, and limits their capacity to produce infectious virus. Accordingly, endothelial cells can only be infected when they overexpress ACE2, or are exposed to very high concentrations of SARS‐CoV‐2. We also show that SARS‐CoV‐2 does not infect endothelial cells in 3D vessels under flow conditions. We further demonstrate that in a co‐culture model endothelial cells are not infected with SARS‐CoV‐2. Endothelial cells do however sense and respond to infection in the adjacent epithelial cells, increasing ICAM‐1 expression and releasing pro‐inflammatory cytokines. Conclusions Taken together, these data suggest that in vivo, endothelial cells are unlikely to be infected with SARS‐CoV‐2 and that infection may only occur if the adjacent pulmonary epithelium is denuded (basolateral infection) or a high viral load is present in the blood (apical infection). In such a scenario, whilst SARS‐CoV‐2 infection of the endothelium can occur, it does not contribute to viral amplification. However, endothelial cells may still play a key role in SARS‐CoV‐2 pathogenesis by sensing adjacent infection and mounting a pro‐inflammatory response to SARS‐CoV‐2.