Trial Design and Contributors
From August 17, 2020, by way of November 25, 2020, we enrolled members at 16 websites in South Africa. The trial was designed to offer a preliminary analysis of vaccine security and efficacy throughout ongoing pandemic transmission of SARS-CoV-2. Contributors had been wholesome adults between the ages of 18 and 84 years with out human immunodeficiency virus (HIV) an infection or a subgroup of adults between the ages of 18 and 64 years with HIV an infection whose situation was medically steady. Baseline IgG antibodies towards the spike protein (anti-spike IgG antibodies) had been measured at research entry to assist decide baseline SARS-CoV-2 serostatus for the evaluation of vaccine efficacy. As a security measure, enrollment was staggered into stage 1 (outlined by the primary third of focused enrollment) and stage 2 (the rest of enrollment) for each HIV-negative and HIV-positive members. Development from stage 1 to stage 2 in every group required a good assessment of security information by way of day 7 from the earlier stage towards prespecified guidelines that will set off a pause in vaccine administration. (Particulars relating to the members in every stage are offered in Desk S1 within the Supplementary Appendix, obtainable with the complete textual content of this text at NEJM.org.)
Key exclusion standards had been being pregnant, long-term receipt of immunosuppressive remedy, autoimmune or immunodeficiency illness apart from medically steady HIV an infection, a historical past of confirmed or suspected Covid-19, and SARS-CoV-2 an infection as confirmed on a nucleic acid amplification check (NAAT) carried out as a part of screening inside 5 days earlier than anticipated preliminary administration of the vaccine or placebo. All of the members offered written knowledgeable consent earlier than enrollment. Further particulars relating to the trial design, conduct, oversight, and analyses are offered within the Supplementary Appendix and the protocol (which incorporates the statistical evaluation plan), obtainable at NEJM.org.
The NVX-CoV2373 vaccine was developed by Novavax, which sponsored the trial and was chargeable for the general design (with enter from the lead investigator), website choice, monitoring, and evaluation. Trial investigators had been chargeable for information assortment. The protocol was accepted by the South African Well being Merchandise Regulatory Authority and by the institutional assessment board at every trial middle. Oversight of security, which included monitoring for particular vaccination-pause guidelines, was carried out by an impartial security monitoring committee.
The primary creator wrote the primary draft of the manuscript with help from a medical author who’s an creator and an worker of Novavax. All of the authors made the choice to submit the manuscript for publication and vouch for the accuracy and completeness of the information and for the constancy of the trial to the protocol.
Contributors had been randomly assigned in a 1:1 ratio to obtain two intramuscular injections, 21 days aside, of both NVX-CoV2373 (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or saline placebo (injection quantity, 0.5 ml), administered by workers members who had been conscious of trial-group assignments however weren’t in any other case concerned with different trial procedures or information assortment. All different workers members and trial members remained unaware of trial-group assignments. Contributors had been scheduled for in-person follow-up visits on days 7, 21, and 35 and at 3 months and 6 months to gather very important indicators, assessment any adversarial occasions, focus on modifications in concomitant medicines, and procure blood samples for immunogenicity analyses. A follow-up phone go to was scheduled for 12 months after vaccination.
The first security finish factors had been the prevalence of all unsolicited adversarial occasions, together with people who had been medically attended, critical, or of particular curiosity, by way of day 35 (Tables S2 and S3) and solicited native and systemic adversarial occasions that had been evaluated via a reactogenicity diary for 7 days after every vaccination (Tables S4 and S5). Security follow-up was ongoing by way of month 12.
The first efficacy finish level was confirmed symptomatic Covid-19 that was categorized as gentle, average, or extreme (hereafter referred to as symptomatic Covid-19) and that occurred inside 7 days after receipt of the second injection (i.e., after day 28) (Desk S6). Beginning on day 8 and persevering with by way of 12 months, we carried out lively surveillance (phone calls each 2 weeks from trial websites to members) and passive surveillance (phone contact at any time from members to trial websites) for signs of suspected Covid-19 (Desk S7 and Fig. S1). A brand new onset of suspected signs of Covid-19 triggered preliminary in-person and follow-up surveillance visits to carry out medical assessments (very important indicators, together with pulse oximetry, and a lung examination) and for assortment of nasal swabs (Fig. S2). As well as, suspected Covid-19 signs had been additionally assessed and nasal swabs collected in any respect scheduled trial visits. Nasal-swab samples had been examined for the presence of SARS-CoV-2 by NAAT with the usage of the BD MAX system (Becton Dickinson). We used the InFLUenza Affected person-Reported Consequence (FLU-PRO) questionnaire to comprehensively assess signs for the primary 10 days of a suspected episode of Covid-19.
In a blinded trend, we carried out put up hoc whole-genome sequencing of nasal samples obtained from all of the members who had symptomatic Covid-19. Particulars relating to the whole-genome sequencing strategies and phylogenetic evaluation are offered in Fig. S3.
The security evaluation inhabitants included all of the members who had obtained not less than one injection of NVX-CoV2373 or placebo; no matter group task, members had been evaluated based on the intervention they’d truly obtained. Security analyses had been offered as numbers and percentages of members who had solicited native and systemic adversarial occasions by way of day 7 after every vaccination and who had unsolicited adversarial occasions by way of day 35.
We carried out a per-protocol efficacy evaluation within the inhabitants of members who had been seronegative for SARS-CoV-2 at baseline and who had obtained each injections of NVX-CoV2373 or placebo as assigned, had no proof of SARS-CoV-2 an infection (by NAAT or anti-spike IgG evaluation) inside 7 days after the second injection (i.e., earlier than day 28), and had no main protocol deviations affecting the first efficacy end result. A second per-protocol efficacy evaluation inhabitants was outlined similarly besides that members who had been seropositive for SARS-CoV-2 at baseline may very well be included.
Vaccine efficacy (calculated as a share) was outlined as (1–RR)×100, the place RR is the relative threat of Covid-19 sickness within the vaccine group as in contrast with the placebo group. The official, event-driven efficacy evaluation focused a minimal variety of 23 finish factors (vary, 23 to 50) to offer roughly 90% energy to detect vaccine efficacy of 80% on the idea of an incidence of symptomatic Covid-19 of two to six% within the placebo group. This evaluation was carried out at an total one-sided sort I error fee of 0.025 for the one major efficacy finish level. The relative threat and its confidence interval had been estimated with the usage of Poisson regression with sturdy error variance. Speculation testing of the first efficacy finish level was carried out towards the null speculation of vaccine efficacy of 0%. The success criterion required rejection of the null speculation to indicate a statistically vital vaccine efficacy.