NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. The authors of this article initiated a randomised, placebo-controlled, phase 1–2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-μg and 25-μg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti–spike protein response (in enzyme-linked immunosorbent assay [ELISA] units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralisation (microneutralisation assay), and T-cell responses (cytokine staining). IgG and microneutralisation assay results were compared with 32 (IgG) and 29 (neutralisation) convalescent serum samples from patients with COVID-19, most of whom were symptomatic. A primary analysis was performed at day 35. After randomisation, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose–sparing, and induced a T helper 1 (Th1) response. The two-dose 5-μg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralisation (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic COVID-19 patients (8344 and 983, respectively). The authors concluded that, at 35 days, NVX-CoV2373 appeared safe, and elicited immune responses that exceeded levels in COVID-19 convalescent serum. Matrix-M1 adjuvant induced CD4+ T-cell responses were biased toward a Th1 phenotype.