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

We conducted this phase 3, randomized, observer-blinded, placebo-controlled trial at 113 clinical sites in the United States and 6 in Mexico to evaluate the efficacy and safety of NVX-CoV2373. Adults 18 years of age or older who were healthy or who had stable chronic medical conditions, including chronic pulmonary, renal, or cardiovascular disease, diabetes mellitus type 2, or well-controlled human immunodeficiency virus (HIV) infection, were eligible for participation. Key exclusion criteria included known previous laboratory-confirmed SARS-CoV-2 infection or known immunosuppression. In accordance with the Food and Drug Administration (FDA) and funding agency guidance,^1,15 enrollment targets were specified for the inclusion of racial and ethnic minorities, and site selection prioritized accessibility to participants at high risk for acquisition or complications of Covid-19. Participants received initial injections between December 27, 2020, and February 18, 2021, and were followed through April 19, 2021. During this period, the predominant viral variants detected in the United States and Mexico were alpha, beta, gamma, epsilon, and iota.¹⁴ Additional details regarding trial design, conduct, oversight, and analyses are provided in the Supplementary Appendix and in the protocol and statistical analysis plan, available with the full text of this article at NEJM.org.

Participants provided written informed consent before enrollment, were stratified according to age (18 to 64 years or ≥65 years), and were randomly assigned with the use of a Web-based interactive response system in a 2:1 ratio to receive two 0.5-ml intramuscular injections of either NVX-CoV2373 (5 μg of SARS-CoV-2 recombinant spike protein adjuvanted with 50 μg of Matrix-M) or saline placebo 21 days apart. Site personnel who were aware of the randomization assignments managed the logistics of the injections and the preparation of the vaccine and placebo but had no other role in trial conduct. Novavax was the trial sponsor and was responsible for the trial design and for the development and manufacture of the NVX-CoV2373 clinical trial material. The trial was part of the U.S. Government–funded harmonized trial program. Site selection, monitoring of clinical data, data collection and analysis, and preparation of the manuscript (the first draft of which was written by authors who are employees of Novavax) were conducted in collaboration with the Biomedical Advanced Research and Development Authority, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, the Covid-19 Prevention Network, and the trial cochairs.¹⁶ Trial data were available to all the authors, who vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The trial is continuing after the time of this analysis, and investigators and Novavax clinical team remain unaware of the participant-level randomization assignments. The protocol, amendments, and overall oversight were provided by institutional review boards and ethics committees according to local regulations. Safety oversight was provided by an NIAID-sponsored protocol safety review team, and safety, efficacy, and potential vaccine-induced harm were monitored through regular review of unblinded data by the NIAID-sponsored data and safety monitoring board.¹⁷

The aim of the trial was to estimate, as the primary end point, the efficacy of NVX-CoV2373 for the prevention of a first occurrence of reverse-transcriptase–polymerase-chain-reaction (RT-PCR)–confirmed symptomatic mild, moderate, or severe Covid-19 (defined with the use of FDA criteria¹⁵) (Table S3 in the Supplementary Appendix) with onset at least 7 days after the second dose. The primary end point was assessed in the per-protocol efficacy analysis population, which included participants who underwent randomization and received both doses as assigned, were seronegative for anti–SARS-CoV-2 nucleoprotein and had a SARS-CoV-2 RNA RT-PCR–negative nasal swab at baseline, and did not have a censoring event at any time before 7 days after the second injection. Symptoms of suspected Covid-19 (Table S2) were reported daily by participants using an electronic diary. When specified symptoms were reported for 2 or more consecutive days, participants were instructed to obtain three nasal swab specimens themselves daily and to undergo in-clinic medical evaluation, including collection of a nasal swab specimen for SARS-CoV-2 testing at a central laboratory. Covid-19 cases for end-point assessment were considered to be confirmed when at least one of four nasal swab specimens tested positive for SARS-CoV-2 RNA by RT-PCR at the central laboratory. Whole-genome sequencing and clade and lineage assignment were performed on RT-PCR–positive samples with sufficient viral RNA loads (see the Supplementary Appendix).

The key secondary objective was to determine the vaccine efficacy of NVX-CoV2373 for the prevention of RT-PCR–confirmed Covid-19 cases caused by SARS-CoV-2 that was neither a variant of concern nor a variant of interest (i.e., virus that did not have mutations associated with variants of concern or interest), which could be considered to most closely resemble the ancestral Wuhan-Hu-1 strain. Conversely, vaccine efficacy against RT-PCR–confirmed Covid-19 caused by variants of concern or variants of interest, as defined by the Centers for Disease Control and Prevention (CDC) at the time of end-point case accrual,⁶ was estimated as an exploratory end point.

We also estimated vaccine efficacy against moderate and severe Covid-19 as secondary end points, with moderate Covid-19 defined as high fever and objective evidence of lower respiratory tract infection and severe Covid-19 defined as the presence of clinically significant tachypnea, tachycardia, or hypoxia; receipt of intensive respiratory support; major dysfunction of one or more organ systems; admission to an intensive care unit; or death. Additional analyses of vaccine efficacy, although they were not statistically powered, were performed in relevant subgroups (based on race, ethnic group, age, and coexisting conditions associated with an increased risk of severe Covid-19 complications according to CDC criteria,¹⁸ as well as on the risk of exposure related to occupation or living conditions).

Covid-19 severity as an end point was assessed by investigators and trial physicians; severe cases were confirmed by an external independent end-point review committee. All evaluations were blinded to randomization assignments.

Data on solicited local and systemic adverse events were collected with the use of a participant-recorded electronic diary for 7 days after each injection. Data on unsolicited adverse events were collected from the first dose through 28 days after the second dose; data on serious adverse events, adverse events of special interest, and medically attended adverse events were collected from the first dose through data cutoff (secondary end points).

Data on solicited local and systemic adverse events were assessed for severity (according to FDA criteria¹⁹) and duration after each injection. Unsolicited adverse events were coded according to preferred term and system organ class with the use of the Medical Dictionary for Regulatory Activities, version 23.1, and were summarized according to severity and relationship to vaccine or placebo.

Vaccine efficacy was assessed in both the full analysis population (i.e., all participants who underwent randomization and received at least one dose of vaccine or placebo) and the per-protocol efficacy analysis population (defined above in “Efficacy Assessments”). In analyses involving the full analysis population, two observation periods were used — one starting at dose 1 and the other starting 7 days after dose 2. In analyses involving the per-protocol efficacy population, only the observation period that started 7 days after dose 2 was used.

The primary efficacy analysis was based on the per-protocol efficacy analysis population. Vaccine efficacy was defined as (1−RR)×100, where RR is the relative risk of the end point of interest based on the incidence in the NVX-CoV2373 group as compared with that in the placebo group. The estimated relative risk and two-sided 95% confidence interval were derived with the use of a Poisson regression with robust error variance. The prespecified criteria for success in the primary efficacy analysis were a lower bound of the two-sided 95% confidence interval for vaccine efficacy of greater than 30% and a point estimate for vaccine efficacy of 50% or greater.¹⁵

The trial was designed to evaluate efficacy on the basis of the number of events expected to be required in order to achieve significance with respect to the primary end point, originally estimated to be 144 cases meeting the definition of the primary end point. However, to maintain the viability of the trial and retain participants in the face of nationwide availability of vaccines under emergency use authorization, a blinded crossover (i.e., participants who had originally been randomly assigned to receive placebo were administered NVX-CoV2373 and vice versa) was implemented. This coincided with the accumulation of a median of 2 months of safety follow-up and ensured that all participants received active vaccine at the earliest possible time without compromising FDA-required placebo-controlled safety follow-up. The final analysis of the placebo-controlled portion of the trial, which was approved by the data and safety monitoring board before general access to unblinded data and is reported here, includes the number of confirmed cases of Covid-19 fulfilling the definition of the primary end point that occurred before the crossover. As a result of the blinded crossover, the two initially planned formal interim analyses of efficacy and futility were replaced with a single analysis of efficacy in which the full two-sided type I error of 5% was used for the primary end point.

The safety analysis population included all participants who received at least one dose of vaccine or placebo. Data on safety were summarized descriptively.

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).

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).

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).

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%).