Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine | NEJM - nejm.org

Participants

Figure 1. Figure 1. Enrollment and Outcomes.

The full analysis set (safety population) included all the participants who had undergone randomization and received at least one dose of the NVX-CoV2373 vaccine or placebo, regardless of protocol violations or missing data. The primary end point was analyzed in the per-protocol population, which included participants who were seronegative at baseline, had received both doses of trial vaccine or placebo, had no major protocol deviations affecting the primary end point, and had no confirmed cases of symptomatic coronavirus disease 2019 (Covid-19) during the period from the first dose until 6 days after the second dose.

Of the 16,645 participants who were screened, 15,187 underwent randomization (Figure 1). A total of 15,139 participants received at least one dose of NVX-CoV2373 (7569 participants) or placebo (7570 participants); 14,039 participants (7020 in the vaccine group and 7019 in the placebo group) met the criteria for the per-protocol efficacy population.

Table 1. Table 1. Demographic and Clinical Characteristics of the Participants at Baseline (Per-Protocol Efficacy Population).

The demographic and clinical characteristics of the participants at baseline were well balanced between the groups in the per-protocol efficacy population, in which 48.4% were women; 94.5% were White, 2.9% were Asian, and 0.4% were Black. A total of 44.6% of the participants had at least one coexisting condition that had been defined by the Centers for Disease Control and Prevention as a risk factor for severe Covid-19. These conditions included chronic respiratory, cardiac, renal, neurologic, hepatic, and immunocompromising conditions as well as obesity.¹⁴ The median age was 56 years, and 27.9% of the participants were 65 years of age or older (Table 1).

Safety

Figure 2. Figure 2. Solicited Local and Systemic Adverse Events.

The percentage of participants who had solicited local and systemic adverse events during the 7 days after each injection of the NVX-CoV2373 vaccine or placebo is plotted according to the maximum toxicity grade (mild, moderate, severe, or potentially life-threatening). Data are not included for the 400 trial participants who were also enrolled in the seasonal influenza vaccine substudy.

A total of 2310 participants were included in the subgroup in which adverse events were solicited. Solicited local adverse events were reported more frequently in the vaccine group than in the placebo group after both the first dose (57.6% vs. 17.9%) and the second dose (79.6% vs. 16.4%) (Figure 2). Among the vaccine recipients, the most commonly reported local adverse events were injection-site tenderness or pain after both the first dose (with 53.3% reporting tenderness and 29.3% reporting pain) and the second dose (76.4% and 51.2%, respectively), with most events being grade 1 (mild) or 2 (moderate) in severity and of a short mean duration (2.3 days of tenderness and 1.7 days of pain after the first dose and 2.8 and 2.2 days, respectively, after the second dose). Solicited local adverse events were reported more frequently among younger vaccine recipients (18 to 64 years of age) than among older recipients (≥65 years).

Solicited systemic adverse events were reportedly more frequently in the vaccine group than in the placebo group after both the first dose (45.7% vs. 36.3%) and the second dose (64.0% vs. 30.0%) (Figure 2). Among the vaccine recipients, the most commonly reported systemic adverse events were headache, muscle pain, and fatigue after both the first dose (24.5%, 21.4%, and 19.4%, respectively) and the second dose (40.0%, 40.3%, and 40.3%, respectively), with most events being grade 1 or 2 in severity and of a short mean duration (1.6, 1.6, and 1.8 days, respectively, after the first dose and 2.0, 1.8, and 1.9 days, respectively, after the second dose). Grade 4 systemic adverse events were reported in 3 vaccine recipients. Two participants reported a grade 4 fever (>40 °C), one after the first dose and the other after the second dose. A third participant was found to have had positive results for SARS-CoV-2 on PCR assay at baseline. Five days after dose 1, this participant was hospitalized for Covid-19 symptoms and subsequently had six grade 4 events: nausea, headache, fatigue, myalgia, malaise, and joint pain. Systemic adverse events were reported more often by younger vaccine recipients than by older vaccine recipients and more often after the second dose than after the first dose. Among the vaccine recipients, fever (temperature, ≥38°C) was reported in 2.0% after the first dose and in 4.8% after the second dose. Grade 3 fever (39°C to 40°C) was reported in 0.4% after the first dose and in 0.6% after the second dose; grade 4 fever (>40°C) was reported in 2 participants, with one event after the first dose and one after the second dose.

All 15,139 participants who had received at least one dose of vaccine or placebo through the data cutoff date of the final efficacy analysis were assessed for unsolicited adverse events. The frequency of unsolicited adverse events was higher among vaccine recipients than among placebo recipients (25.3% vs. 20.5%), with similar frequencies of severe adverse events (1.0% vs. 0.8%), serious adverse events (0.5% vs. 0.5%), medically attended adverse events (3.8% vs. 3.9%), adverse events leading to discontinuation of dosing (0.3% vs. 0.3%) or participation in the trial (0.2% vs. 0.2%), potential immune-mediated medical conditions (<0.1% vs. <0.1%), and adverse events of special interest relevant to Covid-19 (0.1% vs. 0.3%). One related serious adverse event (myocarditis) was reported in a vaccine recipient, which occurred 3 days after the second dose and was considered to be a potentially immune-mediated condition; an independent safety monitoring committee considered the event most likely to be viral myocarditis. The participant had a full recovery after 2 days of hospitalization. No episodes of anaphylaxis or vaccine-associated enhanced Covid-19 were reported.

Two deaths related to Covid-19 were reported, one in the vaccine group and one in the placebo group. The death in the vaccine group occurred in a 53-year-old man in whom Covid-19 symptoms developed 7 days after the first dose; he was subsequently admitted to the ICU for treatment of respiratory failure from Covid-19 pneumonia and died 15 days after vaccine administration. The death in the placebo group occurred in a 61-year-old man who was hospitalized 24 days after the first dose; the participant died 4 weeks later after complications from Covid-19 pneumonia and sepsis.

Efficacy

Figure 3. Figure 3. Kaplan–Meier Plots of Efficacy of the NVX-CoV2373 Vaccine against Symptomatic Covid-19.

Shown is the cumulative incidence of symptomatic Covid-19 in the per-protocol population (Panel A), the intention-to-treat population (Panel B), and the per-protocol population with the B.1.1.7 variant (Panel C). The timing of surveillance for symptomatic Covid-19 began after the first dose in the intention-to-treat population and at least 7 days after the administration of the second dose in the per-protocol population (i.e., on day 28) through approximately the first 3 months of follow-up.

Figure 4. Figure 4. Vaccine Efficacy of NVX-CoV2373 in Specific Subgroups.

Shown is the efficacy of the NVX-CoV2373 vaccine in preventing Covid-19 in various subgroups within the per-protocol population. Vaccine efficacy and 95% confidence intervals were derived with the use of Poisson regression with robust error variance. In the intention-to-treat population, vaccine efficacy was assessed after the administration of the first dose of vaccine or placebo. Participants who identified themselves as being non-White or belonging to multiple races were pooled in a category of “other” race to ensure that the subpopulations would be large enough for meaningful analyses. Data regarding coexisting conditions were based on the definition used by the Centers for Disease Control and Prevention for persons who are at increased risk for Covid-19.

Among the 14,039 participants in the per-protocol efficacy population, cases of virologically confirmed, symptomatic mild, moderate, or severe Covid-19 with an onset at least 7 days after the second dose occurred in 10 vaccine recipients (6.53 per 1000 person-years; 95% confidence interval [CI], 3.32 to 12.85) and in 96 placebo recipients (63.43 per 1000 person-years; 95% CI, 45.19 to 89.03), for a vaccine efficacy of 89.7% (95% CI, 80.2 to 94.6) (Figure 3). Of the 10 vaccine breakthrough cases, 8 were caused by the B.1.1.7 variant, 1 was caused by a non-B.1.1.7 variant, and 1 viral strain could not be identified. Ten cases of mild, moderate, or severe Covid-19 (1 in the vaccine group and 9 in the placebo group) were reported in participants who were 65 years of age or older (Figure 4). Severe Covid-19 occurred in 5 participants, all in the placebo group. Among these cases, 1 patient was hospitalized and 3 visited the emergency department; a fifth participant was cared for at home. All 5 patients met additional criteria regarding abnormal vital signs, use of supplemental oxygen, and Covid-19 complications that were used to define severity (Table S1). No hospitalizations or deaths from Covid-19 occurred among the vaccine recipients in the per-protocol efficacy analysis.

Additional efficacy analyses in subgroups (defined according to age, race, and presence or absence of coexisting conditions) are detailed in Figure 4. Among the participants who were 65 years of age or older, overall vaccine efficacy was 88.9% (95% CI, 12.8 to 98.6); efficacy among all the participants starting 14 days after the first dose was 83.4% (95% CI, 73.6 to 89.5). A post hoc analysis of the primary end point identified the B.1.1.7 variant in 66 participants and a non-B.1.1.7 variant in 29 participants; in 11 participants, PCR testing had been performed at a local hospital laboratory in which the variant had not been identified. Vaccine efficacy was 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 variant and 96.4% (95% CI, 73.8 to 99.4) against non-B.1.1.7 strains. Too few non-White participants were enrolled in the trial to draw meaningful conclusions about variations in efficacy on the basis of race or ethnic group.

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Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine | NEJM - nejm.org
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