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Preliminary Findings of Covid-19 Vaccine Safety in Pregnant People

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Many pregnant persons in the United States are receiving coronavirus disease 2019 (Covid-19) vaccines, but data are limited on their safety in pregnancy. From December 14, 2020, to February 28, 2021, we used data from the “v-safe after vaccination health checker” surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA Covid-19 vaccines in pregnant persons.

RESULTS

A total of 35,691 v-safe participants 16 to 54 years of age identified as pregnant. Injection-site pain was reported more frequently among pregnant persons than among nonpregnant women, whereas headache, myalgia, chills, and fever were reported less frequently. Among 3958 participants enrolled in the v-safe pregnancy registry, 827 had a completed pregnancy, of which 115 (13.9%) resulted in a pregnancy loss and 712 (86.1%) resulted in a live birth (mostly among participants with vaccination in the third trimester). Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported. Although not directly comparable, calculated proportions of adverse pregnancy and neonatal outcomes in persons vaccinated against Covid-19 who had a completed pregnancy were similar to incidences reported in studies involving pregnant women that were conducted before the Covid-19 pandemic. Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases).

CONCLUSIONS

Preliminary findings did not show obvious safety signals among pregnant persons who received mRNA Covid-19 vaccines. However, more longitudinal follow-up, including follow-up of large numbers of women vaccinated earlier in pregnancy, is necessary to inform maternal, pregnancy, and infant outcomes.

The first coronavirus disease 2019 (Covid-19) vaccines available in the United States were messenger RNA (mRNA) vaccines: BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna). In December 2020, the vaccines were granted Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) as a two-dose series, 3 weeks apart for Pfizer–BioNTech and 1 month apart for Moderna, and were recommended for use by the Advisory Committee on Immunization Practices (ACIP).1-4 Pregnant persons were excluded from preauthorization clinical trials, and only limited human data on safety during pregnancy were available at the time of authorization. However, pregnant persons with Covid-19 are at increased risk for severe illness (e.g., resulting in admission to an intensive care unit, extracorporeal membrane oxygenation, or mechanical ventilation) and death, as compared with nonpregnant persons of reproductive age.5 Furthermore, pregnant persons with Covid-19 might be at increased risk for adverse pregnancy outcomes, such as preterm birth, as compared with pregnant persons without Covid-19.6 The Centers for Disease Control and Prevention (CDC) and ACIP, in collaboration with the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics, have issued guidance indicating that Covid-19 vaccines should not be withheld from pregnant persons.7-9

Postauthorization monitoring in pregnant persons is necessary to characterize the safety of these new Covid-19 vaccines, which use mRNA, lipid nanoparticles, and state-of-the-art manufacturing processes. Furthermore, establishing their safety profiles is critical to inform recommendations on maternal vaccination against Covid-19. We report preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons from three U.S. vaccine safety monitoring systems: the “v-safe after vaccination health checker” surveillance system,10 the v-safe pregnancy registry,11 and the Vaccine Adverse Event Reporting System (VAERS).12

MONITORING SYSTEMS AND COVERED POPULATIONS

V-safe Surveillance System and Pregnancy Registry

V-safe is a new CDC smartphone-based active-surveillance system developed for the Covid-19 vaccination program; enrollment is voluntary. V-safe sends text messages to participants with weblinks to online surveys that assess for adverse reactions and health status during a postvaccination follow-up period. Follow-up continues 12 months after the final dose of a Covid-19 vaccine. During the first week after vaccination with any dose of a Covid-19 vaccine, participants are prompted to report local and systemic signs and symptoms during daily surveys and rank them as mild, moderate, or severe; surveys at all time points assess for events of adverse health effects. If participants indicate that they required medical care at any time point, they are asked to complete a report to the VAERS through active telephone outreach.

To identify persons who received one or both Covid-19 vaccine doses while pregnant or who became pregnant after Covid-19 vaccination, v-safe surveys include pregnancy questions for persons who do not report their sex as male. Persons who identify as pregnant are then contacted by telephone and, if they meet inclusion criteria, are offered enrollment in the v-safe pregnancy registry. Eligible persons are those who received vaccination during pregnancy or in the periconception period (30 days before the last menstrual period through 14 days after) and are 18 years of age or older. For persons who choose to enroll, the pregnancy registry telephone-based survey collects detailed information about the participant, including medical and obstetric history, pregnancy complications, birth outcomes, and contact information for obstetric and pediatric health care providers to obtain medical records; infants are followed through the first 3 months of life. Details about v-safe and v-safe pregnancy registry methods have been published previously.10,11

OUTCOMES

V-safe outcomes included participant-reported local and systemic reactogenicity to the BNT162b2 (Pfizer–BioNTech) vaccine and the mRNA-1273 (Moderna) vaccine on the day after vaccination among all pregnant persons 16 to 54 years of age and among nonpregnant women 16 to 54 years of age as a comparator. For analysis of pregnancy outcomes in the v-safe pregnancy registry, data were restricted to completed pregnancies (i.e., live-born infant, spontaneous abortion, induced abortion, or stillbirth). Participant-reported pregnancy outcomes included pregnancy loss (spontaneous abortion and stillbirth) and neonatal outcomes (preterm birth, congenital anomalies, small size for gestational age, and neonatal death) (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). In the VAERS, outcomes included non–pregnancy-specific adverse events and pregnancy- and neonatal-specific adverse events.

STATISTICAL ANALYSIS

Demographic information and pregnancy characteristics are described for both v-safe and VAERS participants. Descriptive analyses were performed with the use of v-safe survey data for persons who identified as pregnant through February 28, 2021 (35,691 persons); persons enrolled in the v-safe pregnancy registry who were vaccinated through February 28, 2021 (3958 persons); and VAERS reports involving pregnant women received through February 28, 2021 (221 persons). Local and systemic reactogenicity was compared between persons who identified as pregnant and nonpregnant women. Descriptive analyses were conducted with the use of SAS software, version 9.4 (SAS Institute). All activities were reviewed by the CDC and were conducted in accordance with applicable federal law and CDC policy.

V-SAFE SURVEILLANCE: LOCAL AND SYSTEMIC REACTOGENICITY IN PREGNANT PERSONS

From December 14, 2020, to February 28, 2021, a total of 35,691 v-safe participants identified as pregnant. Age distributions were similar among the participants who received the Pfizer–BioNTech vaccine and those who received the Moderna vaccine, with the majority of the participants being 25 to 34 years of age (61.9% and 60.6% for each vaccine, respectively) and non-Hispanic White (76.2% and 75.4%, respectively); most participants (85.8% and 87.4%, respectively) reported being pregnant at the time of vaccination (Table 1). Solicited reports of injection-site pain, fatigue, headache, and myalgia were the most frequent local and systemic reactions after either dose for both vaccines (Table 2) and were reported more frequently after dose 2 for both vaccines. Participant-measured temperature at or above 38°C was reported by less than 1% of the participants on day 1 after dose 1 and by 8.0% after dose 2 for both vaccines.

Most Frequent Local and Systemic Reactions Reported in the V-safe Surveillance System on the Day after mRNA Covid-19 Vaccination.

These patterns of reporting, with respect to both most frequently reported solicited reactions and the higher reporting of reactogenicity after dose 2, were similar to patterns observed among nonpregnant women (Figure 1). Small differences in reporting frequency between pregnant persons and nonpregnant women were observed for specific reactions (injection-site pain was reported more frequently among pregnant persons, and other systemic reactions were reported more frequently among nonpregnant women), but the overall reactogenicity profile was similar. Pregnant persons did not report having severe reactions more frequently than nonpregnant women, except for nausea and vomiting, which were reported slightly more frequently only after dose 2 (Table S3).

Preparing for the Future — Nanobodies for Covid-19?

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Many had hoped that monoclonal antibody drugs would provide an important stopgap to the coronavirus disease 2019 (Covid-19) pandemic by limiting severe disease and thus the number of hospitalizations until safe and effective vaccines could be approved.1 Despite the emergency use authorization issued by the Food and Drug Administration (FDA) for antibody drugs on the basis of their ability to reduce viremia in mildly and moderately ill patients with Covid-19, only a small proportion of the nation’s supply has been used.

Myriad challenges include the therapeutic window (these drugs are more effective when administered during the first 4 to 7 days in the course of illness), the sheer number of patients during a pandemic surge and the relative paucity of infusion centers and medical staff professionals, and the emergence of mutations that affect the spike protein, which could lead to increased transmissibility and the potential for resistance to neutralization by antibodies.2 Therefore, new therapies that are effective against variants and offer an alternative to intravenously administered antibody drugs are highly desired.

A study by Koenig and colleagues3 on camelid-derived, single-domain antibodies (or nanobodies) is therefore timely. The researchers immunized alpacas and llamas with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and identified nanobodies that specifically bind to the receptor-binding domain of the virus. They characterized four neutralizing nanobodies (labeled E, U, V, and W) structurally and functionally with multiple in vitro assays. Three of the nanobodies (U, V, and W) recognize a common epitope located near the threefold axis of the prefusion trimeric spike, whereas nanobody E recognizes the extended loop (residues R466 through P491) overlapping the receptor-binding domain (Figure 1C).

The nanobodies bound the receptor-binding domain of the virus with an equilibrium dissociation constant of between 2 and 22 nmol and neutralized SARS-CoV-2 infection by 50% in a plaque-reduction assay at concentrations ranging from 48 to 185 nmol, results similar to those achieved with monoclonal antibodies.5 In contrast to the V nanobody, nanobodies E, U, and W have the potential to prevent SARS-CoV-2 from binding angiotensin-converting enzyme 2 (ACE2) on host cells, in agreement with the location of the epitopes to which they bind and their mode of engagement with the receptor-binding domain. The nanobodies neutralize the virus by inducing a premature structural transition from a prefusion conformation to an irreversible postfusion conformation, the latter of which is incapable of binding ACE2 and thus incapable of triggering membrane fusion.

The authors then made biparatopic nanobodies (i.e., nanobodies that have two antigen-binding sites in one molecule) by fusing nanobodies that targeted distinct epitope regions (e.g., E+V, V+E, E+W, and W+E). Using cryoelectron microscopy, they showed that the most potent biparatopic nanobody (V+E) binds to all three spike proteins of the trimer (nanobody-to-trimer, 1:3 stoichiometry) with all the receptor-binding domains in the “up” conformation, indicating that the binding of nanobodies stabilizes the receptor-binding domain and prevents up–down motion, most likely contributing to proteolytic cleavage of the spike and premature transition to an irreversible postfusion conformation. The V+E biparatopic nanobody neutralized SARS-CoV-2 infection at a dilution 62 times greater than that achieved by the individual nanobodies, possibly because of the improved avidity to the spike protein (an affinity that is at least 22 times greater than that of individual nanobodies).4

While passaging a chimeric virus in Vero E6 cells in the presence of nanobodies E, U, V, and W, but not in the presence of the biparatopic (V+E or E+V) nanobodies, the authors found escape variants that had mutations within the epitope regions. This observation highlights the advantage of simultaneously targeting more than one vulnerable epitope. Of note, the footprint of the V nanobody does not include amino acids 417, 484, and 501 of the spike protein (Figure 1C), which are changed in the strains recently identified in Britain, South Africa, and Brazil, suggesting that the biparatope antibody V+E (or E+V) would be effective against these antigenic variants. The epitope recognized by nanobody V is relatively more constrained than the E epitope (which includes residues E484 and N501), meaning it is less likely to tolerate changes caused by mutation. Therefore, mutations that arise in the part of the S gene that encodes this region (i.e., the region of the spike to which the V nanobody binds) are less likely to survive selection. JJJ

Koenig et al. have contributed to the growing number of studies that have isolated nanobodies against SARS-CoV-2. Owing to the relatively small size of nanobodies, they have favorable biophysical properties and are cheaper to produce than standard monoclonal antibodies. Their small size and their long, heavy-chain complementarity-determining regions enable them to target concave epitopes such as the receptor-binding site of the spike protein.

Nanobodies can be made with the use of prokaryotic or eukaryotic expression systems because they lack the glycan-harboring Fc domain, making them easier to manufacture than standard monoclonal antibodies. The absence of an Fc region eliminates the risk of antibody-dependent enhancement of infection, but it also shortens the half-life, which could plausibly be addressed through attachment to or amalgamation with polyethylene glycol or human serum albumin. Moreover, nanobodies can be nebulized and delivered straight to the lungs of a patient with Covid-19 with an inhaler, thus presenting a better logistic alternative to intravenously administered antibodies. Aerosol formulation of nanobodies has shown promising nonclinical results.

Although nanobodies are under clinical investigation for use in a wide range of diseases from cancer to infectious diseases, it was the approval of caplacizumab (an anti–von Willebrand factor bivalent nanobody) by the European Medicines Agency and the FDA for the treatment of thrombotic thrombocytopenic purpura and thrombosis that marked the foray of nanobodies into clinical medicine. The format of the biparatopic nanobody V+E engineered by Koenig et al., although distinct from that of a conventional nanobody, is similar to that of the FDA-approved single-chain, variable fragment–based bispecific antibody blinatumomab (Figure 2).

All things considered, the available structural and clinical data suggest that the biparatopic antibody could potentially offer a better alternative to conventional monoclonal antibodies for the treatment of Covid-19. Recently, experts representing various organizations including regulatory bodies, academia, and pharmaceutical and biotechnology companies have made a call to develop small-molecule drugs that inhibit the machinery that the virus uses to replicate. Such agents are convenient to administer and insensitive to viral mutations. The biparatopic antibody, when formulated for aerosol or subcutaneous administration, will lend those benefits just as effectively.

Infection Rates Among Vaccinated Nursing Home Residents Are Better Than Unvaccinated

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Since the deployment of the messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2 in nursing homes nationwide starting in mid-December 2020, aggregate public data have shown decreases in the incidence of cases of SARS-CoV-2 infection and related deaths.3 However, there have been minimal individual-level data available for understanding vaccine effectiveness in nursing home residents, who were absent from the clinical trials and who often have reduced immune responses.4 Using electronic health record data from Genesis HealthCare, a large long-term care provider in the United States, we report the incidence of SARS-CoV-2 infection among vaccinated residents and unvaccinated residents of 280 nursing homes across 21 states.

From immunization records, we identified residents who had received at least one dose of mRNA vaccine as of February 15, 2021; those who had received both doses by February 15, 2021; and those who were present at their facility on the day of the first vaccination clinic but who were not vaccinated as of March 31, 2021. We identified incident SARS-CoV-2 infections through March 31, 2021, on the basis of polymerase-chain-reaction assay and antigen-test records.

Residents were tested every 3 to 7 days when there were confirmed cases in their facility and were tested if they had any new symptoms or potential exposure. Residents who had been infected in the 90 days before the study window were excluded. We counted incident infections after receipt of each dose among vaccinated residents and after the date of the first vaccination clinic among unvaccinated residents.

Nurses assessed residents daily and documented new symptoms in structured change-in-condition notes. From these notes, we deemed residents to be symptomatic if SARS-CoV-2–related symptoms developed during the period from 5 days before to 14 days after a positive test. Detailed methods are described in the Supplementary Appendix, available with the full text of this letter at NEJM.org.

The sample included 18,242 residents who received at least one dose of mRNA vaccine; 14,669 residents (80.4%) received the Pfizer–BioNTech vaccine, and 3573 (19.6%) received the Moderna vaccine. Of these 18,242 residents, 13,048 also received the second dose of vaccine. A total of 3990 residents were unvaccinated. Table S1 in the Supplementary Appendix summarizes the characteristics of the residents.

The incidence of infection decreased over time among both vaccinated residents and unvaccinated residents (Table 1). After receipt of the first vaccine dose, there were 822 incident cases (4.5% of vaccinated residents) within 0 to 14 days and 250 cases (1.4%) at 15 to 28 days. Among the 13,048 residents who received both doses of vaccine, there were 130 incident cases (1.0% of vaccinated residents) within 0 to 14 days after receipt of the second dose and 38 cases (0.3%) after 14 days (which included 19 cases occurring 15 to 21 days after receipt of the second dose) (Fig. S1). Among unvaccinated residents, incident cases decreased from 173 cases (4.3% of unvaccinated residents) within 0 to 14 days after the first vaccination clinic to 12 cases (0.3%) at more than 42 days after the clinic.

Across all the study groups, most infections were asymptomatic, and the incidence of both asymptomatic and symptomatic infections decreased. Nursing homes that were located in counties with the highest incidence of SARS-CoV-2 infection had the most incident cases but still had large decreases (Table S2). We observed inconsistent patterns in the incidence of infection among residents relative to rates of vaccination among staff members (Table S3).

These findings show the real-world effectiveness of the mRNA vaccines in reducing the incidence of asymptomatic and symptomatic SARS-CoV-2 infections in a vulnerable nursing home population. Our observation of a reduced incidence of infection among unvaccinated residents suggests that robust vaccine coverage among residents and staff, together with the continued use of face masks and other infection-control measures, is likely to afford protection for small numbers of unvaccinated residents in congregate settings. Still, the continued observation of incident cases after vaccination highlights the critical need for ongoing vaccination programs and surveillance testing in nursing homes to mitigate future outbreaks.

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant

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BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Methods

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.

OVERSIGHT

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.

TRIAL PROCEDURES

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.

SAFETY ASSESSMENTS

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.

EFFICACY ASSESSMENTS

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.

WHOLE-GENOME SEQUENCING

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.

STATISTICAL ANALYSIS

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.