The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1–2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission.
In this phase 2a–b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)–negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection.
Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, −0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups.
The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399. opens in new tab.)
The coronavirus disease 2019 (Covid-19) pandemic, caused by the emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had resulted in more than 144 million documented cases and 3 million deaths worldwide as of April 23, 2021.1,2 Vaccination remains a cornerstone of control strategies. Current vaccines primarily target the SARS-CoV-2 spike protein on the basis of the prototype Wuhan strain.3 The messenger RNA (mRNA) vaccines (BNT162b2 and mRNA-1273) have shown vaccine efficacy of 94 to 95%4,5 against Covid-19 of any severity, and corresponding vaccine efficacy for vector-based vaccines has been reported to be 70% for ChAdOx1 nCoV-19, 92% for Gam-COVID-Vac, and 67% for Ad26.COV2.S, with the Ad26.COV2.S vaccine measured against moderate-to-severe Covid-19.6-8
Among the Covid-19 vaccines under development is a recombinant SARS-CoV-2 nanoparticle vaccine (NVX-CoV2373, Novavax). The vaccine is produced by engineering a baculovirus that contains a gene encoding full-length SARS-CoV-2 spike glycoprotein (prototype Wuhan-Hu-1 sequence) stabilized in the prefusion conformation. Cultures of cells obtained from the Spodoptera frugiperda moth are infected with recombinant baculovirus to express SARS-CoV-2 spike protein trimers, which are then extracted and chromatographically purified. When formulated with polysorbate 80 (PS 80), the purified trimers assemble into protein nanoparticles consisting of rosettes of spike trimers held together by hydrophobic interactions with a PS 80 micellar core. The nanoparticles are then further coformulated with the saponin-based adjuvant Matrix-M1.9,10 In an ongoing randomized, placebo-controlled, phase 1–2 trial involving healthy adults, the NVX-CoV2373 vaccine, administered in a two-dose regimen 21 days apart, had an acceptable safety profile and was associated with a strong antigen-specific polyfunctional CD4+ T-cell response and induced a neutralizing-antibody level that was four times the level in convalescent serum obtained from patients with predominantly moderate-to-severe Covid-19.11
Recent reports from the United Kingdom, Brazil, and South Africa on the emergence of the B.1.1.7, P1, and B.1.351 (N501Y.V2) variants, respectively, confirm the acquisition of mutations in key antigenic sites in the receptor-binding domain and N-terminal domain of the spike protein.12-17 These antigenic changes may render naturally acquired or vaccine-derived immunity to prototype-like virus less effective against subsequent infection with variant viruses.13,17-19 Here, we describe early findings on the primary efficacy end point and preliminary safety of a randomized, observer-blinded, placebo-controlled, phase 2a–b trial of NVX-CoV2373 in South Africa during a period of predominant circulation of the B.1.351 variant virus.
TRIAL DESIGN AND PARTICIPANTS
From August 17, 2020, through November 25, 2020, we enrolled participants at 16 sites in South Africa. The trial was designed to provide a preliminary evaluation of vaccine safety and efficacy during ongoing pandemic transmission of SARS-CoV-2. Participants were healthy adults between the ages of 18 and 84 years without human immunodeficiency virus (HIV) infection or a subgroup of adults between the ages of 18 and 64 years with HIV infection whose condition was medically stable. Baseline IgG antibodies against the spike protein (anti-spike IgG antibodies) were measured at study entry to help determine baseline SARS-CoV-2 serostatus for the analysis of vaccine efficacy. As a safety measure, enrollment was staggered into stage 1 (defined by the first third of targeted enrollment) and stage 2 (the remainder of enrollment) for both HIV-negative and HIV-positive participants. Progression from stage 1 to stage 2 in each group required a favorable review of safety data through day 7 from the previous stage against prespecified rules that would trigger a pause in vaccine administration. (Details regarding the participants in each stage are provided in Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.)
Key exclusion criteria were pregnancy, long-term receipt of immunosuppressive therapy, autoimmune or immunodeficiency disease except for medically stable HIV infection, a history of confirmed or suspected Covid-19, and SARS-CoV-2 infection as confirmed on a nucleic acid amplification test (NAAT) performed as part of screening within 5 days before anticipated initial administration of the vaccine or placebo. All the participants provided written informed consent before enrollment. Additional details regarding the trial design, conduct, oversight, and analyses are provided in the Supplementary Appendix and the protocol (which includes the statistical analysis plan), available at NEJM.org.
The NVX-CoV2373 vaccine was developed by Novavax, which sponsored the trial and was responsible for the overall design (with input from the lead investigator), site selection, monitoring, and analysis. Trial investigators were responsible for data collection. The protocol was approved by the South African Health Products Regulatory Authority and by the institutional review board at each trial center. Oversight of safety, which included monitoring for specific vaccination-pause rules, was performed by an independent safety monitoring committee.
The first author wrote the first draft of the manuscript with assistance from a medical writer who is an author and an employee of Novavax. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.
Participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections, 21 days apart, of either NVX-CoV2373 (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or saline placebo (injection volume, 0.5 ml), administered by staff members who were aware of trial-group assignments but were not otherwise involved with other trial procedures or data collection. All other staff members and trial participants remained unaware of trial-group assignments. Participants were scheduled for in-person follow-up visits on days 7, 21, and 35 and at 3 months and 6 months to collect vital signs, review any adverse events, discuss changes in concomitant medications, and obtain blood samples for immunogenicity analyses. A follow-up telephone visit was scheduled for 12 months after vaccination.
The primary safety end points were the occurrence of all unsolicited adverse events, including those that were medically attended, serious, or of special interest, through day 35 (Tables S2 and S3) and solicited local and systemic adverse events that were evaluated by means of a reactogenicity diary for 7 days after each vaccination (Tables S4 and S5). Safety follow-up was ongoing through month 12.
The primary efficacy end point was confirmed symptomatic Covid-19 that was categorized as mild, moderate, or severe (hereafter called symptomatic Covid-19) and that occurred within 7 days after receipt of the second injection (i.e., after day 28) (Table S6). Starting on day 8 and continuing through 12 months, we performed active surveillance (telephone calls every 2 weeks from trial sites to participants) and passive surveillance (telephone contact at any time from participants to trial sites) for symptoms of suspected Covid-19 (Table S7 and Fig. S1). A new onset of suspected symptoms of Covid-19 triggered initial in-person and follow-up surveillance visits to perform clinical assessments (vital signs, including pulse oximetry, and a lung examination) and for collection of nasal swabs (Fig. S2). In addition, suspected Covid-19 symptoms were also assessed and nasal swabs collected at all scheduled trial visits. Nasal-swab samples were tested for the presence of SARS-CoV-2 by NAAT with the use of the BD MAX system (Becton Dickinson). We used the InFLUenza Patient-Reported Outcome (FLU-PRO) questionnaire to comprehensively assess symptoms for the first 10 days of a suspected episode of Covid-19.
In a blinded fashion, we performed post hoc whole-genome sequencing of nasal samples obtained from all the participants who had symptomatic Covid-19. Details regarding the whole-genome sequencing methods and phylogenetic analysis are provided in Fig. S3.
The safety analysis population included all the participants who had received at least one injection of NVX-CoV2373 or placebo; regardless of group assignment, participants were evaluated according to the intervention they had actually received. Safety analyses were presented as numbers and percentages of participants who had solicited local and systemic adverse events through day 7 after each vaccination and who had unsolicited adverse events through day 35.
We performed a per-protocol efficacy analysis in the population of participants who had been seronegative for SARS-CoV-2 at baseline and who had received both injections of NVX-CoV2373 or placebo as assigned, had no evidence of SARS-CoV-2 infection (by NAAT or anti-spike IgG analysis) within 7 days after the second injection (i.e., before day 28), and had no major protocol deviations affecting the primary efficacy outcome. A second per-protocol efficacy analysis population was defined in a similar fashion except that participants who were seropositive for SARS-CoV-2 at baseline could be included.
Vaccine efficacy (calculated as a percentage) was defined as (1–RR)×100, where RR is the relative risk of Covid-19 illness in the vaccine group as compared with the placebo group. The official, event-driven efficacy analysis targeted a minimum number of 23 end points (range, 23 to 50) to provide approximately 90% power to detect vaccine efficacy of 80% on the basis of an incidence of symptomatic Covid-19 of 2 to 6% in the placebo group. This analysis was performed at an overall one-sided type I error rate of 0.025 for the single primary efficacy end point. The relative risk and its confidence interval were estimated with the use of Poisson regression with robust error variance. Hypothesis testing of the primary efficacy end point was performed against the null hypothesis of vaccine efficacy of 0%. The success criterion required rejection of the null hypothesis to show a statistically significant vaccine efficacy.