Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico

Abstract

Background: NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America.

Methods: We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed.

Results: Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose.

Conclusions: NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.).

Figure 1. Screening, Randomization, and Follow-up.

The full analysis population included all participants who underwent randomization and received at least one dose of vaccine or placebo, regardless of protocol violations or missing data; participants in the full analysis population are included in the analysis according to the group to which they were randomly assigned. The safety analysis population included all participants who received at least one dose of vaccine or placebo. The per-protocol efficacy analysis population included all participants who underwent randomization and received both doses as assigned, were seronegative for anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein and had a SARS-CoV-2 RNA reverse-transcriptase–polymerase-chain-reaction (RT-PCR)–negative nasal swab at baseline, and did not have a censoring event at any time before 7 days after the second injection. Data from participants at two sites (193 assigned to receive NVX-CoV2373 and 93 assigned to receive placebo) were excluded from analyses because of Good Clinical Practice quality concerns. The window for the first dose of vaccine or placebo was December 20, 2020, to February 18, 2021.

Figure 2. Overall Efficacy of NVX-CoV2373 against Covid-19.

Shown is the cumulative incidence of symptomatic (mild, moderate, or severe) coronavirus disease 2019 (Covid-19). Panel A shows all participants in the full analysis population during the period of surveillance that started at the first dose of NVX-CoV2373 or placebo. Panel B shows all participants in the per-protocol efficacy analysis population during the period of surveillance starting 7 days after the second dose (i.e., up to 28 days after the first dose) through approximately 3 months of follow-up, until unblinding, or until receipt of a vaccine under emergency use authorization. Panel C shows all participants in the full analysis population during the period of surveillance that started 7 days after the second dose. Panel D shows all participants in the per-protocol efficacy analysis population with cases of Covid-19 due to variants that are not considered variants of concern (VOC) or variants of interest (VOI). Panel E shows all participants in the per-protocol efficacy analysis population with cases of Covid-19 due to VOC or VOI.

Figure 3. Vaccine Efficacy of NVX-CoV2373 in Specific Subgroups (Per-Protocol Efficacy Analysis Population).

Vaccine efficacy was defined as 1 minus the relative risk (NVX-CoV2373 minus placebo). Non-White race included end-point cases in participants from all other races to ensure that these subgroups would be large enough for meaningful analyses. The assessment of coexisting conditions is based on the Centers for Disease Control and Prevention definitions of persons at risk for complications of Covid-19. Participants at overall high risk for Covid-19 included those 65 years of age or older and those of any age with chronic health conditions or an increased risk for Covid-19 because of work or living conditions.

Figure 4. Solicited Local and Systemic Adverse Events (Safety Analysis Population).

The percentage of participants in each group with solicited local and systemic adverse events during the 7 days after each dose is plotted according to Food and Drug Administration toxicity grade, either as any grade (mild, moderate, severe, or potentially life-threatening) or as grade 3 or higher (severe or potentially life-threatening). An expanded x axis is used for events of grade 3 or higher to highlight differences between small percentages.