LAUSR

Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in 20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques. Description Ad26.COV2.S vaccination generated durable immune responses that were enhanced by homologous or beta variant boosters in rhesus macaques. The value of variant boosters Ad26.COV2.S is an approved vaccine for SARS-CoV-2 and has been shown to elicit protective and durable immune responses. However, as boosters are now considered part of a full immunization regimen, the response to homologous boosting with Ad26.COV2.S merits study. Here, He et al. evaluated humoral and cellular immune responses in nonhuman primates vaccinated and boosted with Ad26.COV2.S, showing that boosting increased both responses. Further, boosting with a modified Ad26.COV2.S.351, which uses the spike protein from the SARS-CoV-2 beta variant, elicited increased immune responses that were cross-reactive, including against the omicron variant. Together, these data provide evidence that homologous or variant-specific booster immunizations may further potentiate the effectiveness of Ad26.COV2.S.