RESUMO
BackgroundThe emergence of SARS-CoV-2 variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5{micro}g SARS-CoV-2 rS + 50{micro}g Matrix-M adjuvant) was evaluated to determine induction of cross-reactive antibodies to variants of concern. MethodsA phase 2 randomized study assessed a fourth dose of NVX-CoV2373 in adults 18-84 years of age (2-dose primary series followed by third and fourth doses at 6-month intervals). Local/systemic reactogenicity was assessed the day of vaccination and for 6 days thereafter. Unsolicited adverse events (AEs) were reported. Immunogenicity was measured before, and 14 days after, fourth dose administration using anti-spike neutralization assays against the ancestral SARS-CoV-2 strain and Omicron sublineages. Antigenic cartography assessed antigenic distances between ancestral and variant strains. ResultsAmong 1283 enrolled participants, 258 were randomized to receive the 2-dose primary series, of whom 104 received a third dose, and 45 received a fourth dose of NVX-CoV2373. The incidence of local/systemic reactogenicity events increased after the first three doses of NVX-CoV2373, and leveled off after dose four. Unsolicited AEs were reported in 9% of participants after dose 4 (none severe or serious). Neutralization antibody titers increased following booster doses. Antigenic cartography demonstrated reductions in antigenic distance between ancestral and variant SARS-CoV-2 strains with increased number of NVX-CoV2373 doses. ConclusionsA fourth dose of NVX-CoV2373 enhanced immunogenicity without increasing reactogenicity. Antigenic cartography demonstrated a more universal-like response against SARS-CoV-2 variants after a fourth dose of NVX-CoV2373, indicating that updates to the vaccine composition may not be warranted. Trial registration numberNCT04368988
RESUMO
BackgroundCovid-19 vaccines are urgently needed, especially against emerging variants. NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 rS) nanoparticle vaccine containing trimeric full-length SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant. MethodsA phase 3, randomized, observer-blinded, placebo-controlled trial was conducted in adults 18-84 years old who received two intramuscular 5-{micro}g doses, 21 days apart, of NVX-CoV2373 or placebo (1:1) across 33 sites in the United Kingdom. The primary efficacy endpoint was virologically confirmed symptomatic Covid-19 with onset 7 days after second vaccination in serologically negative participants. ResultsA total of 15,187 participants were randomized, of whom 7569 received NVX-CoV2373 and 7570 received placebo; 27.2% were 65 years or older, 44.7% had comorbidities and 4.2% had baseline serological evidence of SARS-CoV-2. There were 10 cases of Covid-19 among NVX-CoV2373 recipients and 96 cases among placebo recipients, with symptom onset at least 7 days after second vaccination; NVX-CoV2373 was 89.7% (95% confidence interval, 80.2 to 94.6) effective in preventing Covid-19, with no hospitalizations or deaths reported. There were five cases of severe Covid-19, all in the placebo group. Post hoc analysis revealed efficacies of 96.4% (73.8 to 99.5) and 86.3% (71.3 to 93.5) against the prototype strain and B.1.1.7 variant, respectively. Vaccine efficacy was similar across subgroups, including participants with comorbidities and those [≥]65 years old. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. ConclusionA two-dose regimen of NVX-CoV2373 conferred 89.7% protection against a blend of prototype and variant Covid-19, demonstrated high efficacy against the B.1.1.7 variant, and had a reassuring safety profile. (Funded by Novavax, Inc. EudraCT number, 2020-004123-16).