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.
Of the 31,588 participants who were screened, 29,949 underwent randomization between December 27, 2020, and February 18, 2021 (Figure 1). Among the 29,582 participants who received at least one dose of NVX-CoV2373 (19,714 participants) or placebo (9868 participants) and were included in the full analysis population (median age, 47 years; 12.6% ≥65 years of age), 25,452 participants (17,312 NVX-CoV2373 recipients and 8140 placebo recipients) were included in the per-protocol efficacy analysis population. The main reasons for exclusion from the per-protocol efficacy analysis population included baseline positivity for anti–SARS-CoV-2 nucleoprotein or SARS-CoV-2 RNA on RT-PCR testing, failure to receive both doses as prescribed, unblinding, or other censoring event (Table S18). At baseline, 6.3% of the NVX-CoV2373 recipients and 6.9% of the placebo recipients in the safety analysis population were seropositive or RT-PCR–positive for SARS-CoV-2 (Table S4).
The demographic characteristics of the participants in the per-protocol efficacy analysis population were well balanced between the treatment groups; 48.2% identified as female, 75.9% as White, 11.0% as Black or African American, 6.2% as Native American or Alaska Native (including American Indians and Native Mexicans), and 21.5% as Hispanic or Latino. One or more coexisting conditions18 were reported by 47.3% of the participants. The median age was 47 years, and 11.8% of the participants were 65 years of age or older (Table 1).
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.
In the full analysis population, the incidence of Covid-19 was 21.2 cases per 1000 person-years (95% confidence interval [CI], 16.2 to 27.7) in the NVX-CoV2373 group and 51.9 cases per 1000 person-years (95% CI, 40.9 to 66.0) in the placebo group when the observation period started after dose 1. The cumulative incidence curves separated between days 14 and 21 (Figure 2A).
Among the 25,452 participants in the per-protocol efficacy analysis population who were followed through April 19, 2021 (median follow-up for efficacy, approximately 3 months), 77 central laboratory–confirmed Covid-19 cases occurred: 14 cases in NVX-CoV2373 recipients and 63 in placebo recipients (incidence, 3.3 cases per 1000 person-years [95% CI, 1.6 to 6.9] and 34.0 cases per 1000 person-years [95% CI, 20.7 to 55.9], respectively). These results yielded a vaccine efficacy of 90.4% (95% CI, 82.9 to 94.6; P<0.001) (Figure 2B and Table S5). The rate of new Covid-19 cases among NVX-CoV2373 recipients was higher during the first 42 days of follow-up than during the remainder of the accrual period covered in this report. Subsequently, the incidence of new cases declined among vaccine recipients and increased among placebo recipients (Figure 2B).
Similar results for vaccine efficacy were obtained in the full analysis population when the observation period started 7 days after the second dose: 85 Covid-19 cases occurred (16 in NVX-CoV2373 recipients and 69 in placebo recipients; incidence, 3.7 cases per 1000 person-years [95% CI, 1.8 to 7.4] and 34.6 cases per 1000 person-years [95% CI, 22.3 to 53.6], respectively). These results yielded a vaccine efficacy of 89.3% (95% CI, 81.6 to 93.8) (Figure 2C and Table S17).
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 definitions18 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.
All the cases reported in NVX-CoV2373 recipients were mild in severity, whereas 14 moderate-to-severe cases (10 moderate and 4 severe) occurred in the placebo group, yielding a vaccine efficacy against moderate-to-severe Covid-19 of 100% (95% CI, 87.0 to 100) (Table S7). Vaccine efficacy against severe Covid-19 alone (4 cases) was 100% (95% CI, 34.6 to 100 in a post hoc analysis). Vaccine efficacy against confirmed Covid-19 meeting the definition of the primary end point among participants who were at high risk for acquisition or complications of Covid-19 was 91.0% (95% CI, 83.6 to 95.0) (Figure 3). Vaccine efficacy in several prespecified demographic subgroups was in most cases found to be similarly high. Among Black participants, vaccine efficacy was 100% (95% CI, 67.9 to 100) (Figure 3). Hispanic or Latino participants were the only demographic group in which vaccine efficacy was lower than in other subgroups (67.3%; 95% CI, 18.7 to 86.8) (Figure 3).
Nasal swabs from 61 of 77 participants (79%) with RT-PCR–confirmed Covid-19 yielded sequences by whole-genome sequencing. Sequences from 48 of these 61 specimens were identified as variants of concern or interest, and 13 were identified as other variants (Fig. S1); vaccine efficacy against the latter variants was 100% (95% CI, 85.8 to 100) (Figure 2D). The alpha variant accounted for most specimens with sequences that were identified as variants of concern (31 of 35, 89%); vaccine efficacy against the alpha variant was 93.6% (95% CI, 81.7 to 97.8 in a post hoc analysis), and vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7) (Figure 2E). An assessment of vaccine efficacy for cases that yielded no sequence information (16 of 77, 21%) was not conducted.
Solicited local and systemic adverse events were predominantly mild to moderate and transient. These events occurred more frequently among NVX-CoV2373 recipients than among placebo recipients (any local adverse event, 58.0% and 21.1%, respectively, after dose 1 and 78.9% and 21.7% after dose 2; any systemic adverse event, 47.7% and 40.0%, respectively, after dose 1 and 69.5% and 35.9% after dose 2).
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).19 An expanded x axis is used for events of grade 3 or higher to highlight differences between small percentages.
After each dose, the most frequently reported solicited local adverse events were tenderness and injection-site pain. The median duration of these events was 2 days or less (Table S11). Severe (grade ≥3) local reactions were infrequent overall but were more common among NVX-CoV2373 recipients than among placebo recipients, particularly after dose 2 (1.1% of NVX-CoV2373 recipients and <1% of placebo recipients after dose 1 and 6.7% and <1%, respectively, after dose 2) (Figure 4 and Table S10).
The most common solicited systemic adverse events were headache, myalgia, fatigue, and malaise, which were detected more frequently among NVX-CoV2373 recipients and after the second injection and lasted for a median duration of 1 day or less (Table S13). Fever of any severity was rare (<1%) and was similarly distributed in the vaccine and placebo groups after each dose. Severe systemic reactions were more common among NVX-CoV2373 recipients, particularly after dose 2 (2.4% of NVX-CoV2373 recipients and 2.1% of placebo recipients after dose 1 and 12.1% and 2.1%, respectively, after dose 2) (Figure 4 and Table S12), but they were less frequent than has been reported for other Covid-19 vaccines.2
In this preliminary safety “snapshot,” unsolicited adverse events were slightly more frequent among NVX-CoV2373 recipients than among placebo recipients (16.3% and 14.8%, respectively), although the imbalance appeared to include duplicate reporting by investigators of reactogenicity that had also been derived from participant-reported outcomes. The frequencies of medically attended adverse events, serious adverse events, severe adverse events, adverse events of special interest related to Covid-19, and potential immune-mediated medical conditions were balanced between the two groups (Table S9). No episodes of anaphylaxis, no evidence of vaccine-associated enhanced Covid-19, and no events that triggered prespecified pause rules were observed. No episodes of the Guillain–Barré syndrome20 and no imbalance in myocarditis or pericarditis21 or in vaccine-induced immune thrombosis with thrombocytopenia22 were observed during the relatively short safety follow-up period reported here (Tables S14 through S16). All-cause mortality was balanced: nine deaths occurred among NVX-CoV2373 recipients (0.5%), and five occurred among placebo recipients (0.5%).