COVID-19 vaccine (NVX-CoV2373 and NVX-CoV2540) doses and virus strain match impact sex- and age-specific immunity and protection in mice.

Sex and age impact immune responses to diverse vaccines. Using a preclinical mouse model, we investigated immune responses to a COVID-19 spike (S) protein-based vaccine and booster doses in adult (25 weeks) and aged (64 weeks) male and female C57BL/6 mice. Mice were intramuscularly vaccinated with either two doses of NVX-CoV2373 (Ancestral Wuhan-Hu-1) or two doses of NVX-CoV2373 followed by a booster of NVX-CoV2540 (Omicron BA.5) in 3-week intervals. Steroid concentrations, antibody titers, and immune cell frequencies in draining lymph nodes were quantified. Three weeks post-boost, subsets of mice were challenged with SARS-CoV-2 (Mu variant B.1.621) to measure cross-protection against an antigenically distinct strain. After two ancestral vaccine doses, adult females had greater binding antibody titers than either adult males or aged females, that were positively correlated with circulating estradiol concentrations. Adult females also had greater cross-neutralizing antibodies and had lower viral titers in respiratory tissues following live virus challenge than adult males. Aged mice, particularly males, had lower antibody titers and frequencies of B and follicular helper T cells than adult mice that were not cross-protective against B.1.621 challenge. Immunization with the BA.5 booster improved antibody responses and B and T cell frequencies in both adults and aged mice, eliminating sex and age differences in immunity and protection from SARS-CoV-2 challenge. These data highlight that there are limits to cross-protective immunity, particularly among males and aged individuals, that can be improved through booster doses that more closely match the challenge SARS-CoV-2 virus.