The authors sought to evaluate the efficacy of the NVX-CoV2373 nanoparticle COVID-19 vaccine (Novavax vaccine) in response to the emergence of the B.1.351 SARS-CoV-2 variant. 4387 participants from South Africa were enrolled from August 17,2020 through November 25, 2020. The participants were either healthy adults from the ages of 18 to 84 years who were HIV-negative (2684 participants), or they were HIV-positive with a medically stable condition. Participants were randomly assigned to receive either the NVX-CoV2373 vaccine or a placebo injection. Of the 4387 participants who received injections, only 4332 received both injections. Among all patients who were seronegative at baseline, 44 cases of symptomatic (mild-to-moderate) COVID-19 were observed with 15 participants from the vaccine group and 29 from the placebo group, corresponding to a vaccine efficacy of 49.4%. Among the HIV negative participants who were seronegative at baseline, symptomatic COVID-19 was observed in 11 participants from the vaccine group and 27 participants form the placebo group, corresponding to a vaccine efficacy of 60.1%. 92.7% of the sequenced isolates were the B.1.351 variant and in a post hoc analysis; the vaccine efficacy against the variant was 51.0% among the HIV-negative participants and 43.0% in the entire participant sample. These findings suggest high NVX-CoV2373 vaccine efficacy against the B.1.351 variant.