Trial objectives, participants and supervision
In this multisite, double-blind, randomized, placebo-controlled trial conducted in South Africa, we assessed the safety and efficacy of two standard doses of the ChAdOx1 nCoV-19 vaccine, administered 21 to 35 days apart, in comparison with saline (0.9% sodium chloride) placebo. Adults aged 18 to less than 65 years of age, without chronic medical conditions, or well controlled, were eligible for participation. Among the participants were 70 HIV-negative people enrolled in group 1, in which intensive safety and immunogenicity studies were planned. Main exclusion criteria were positive human immunodeficiency virus (HIV) during screening (for the efficacy group), previous or current laboratory-confirmed Covid-19, a history of anaphylaxis associated with vaccination, and morbid obesity (body mass index) [BMI, the weight in kilograms divided by the square of the height in meters], ≥40). Detailed criteria for inclusion and exclusion are provided in the supplementary appendix, available in full text of this article at NEJM.org. The ChAdOx1 nCoV-19 vaccine was developed at Oxford University, which was responsible for conducting and supervising the trial (see supplementary appendix).
The authors had full access to the trial data, confirmed the accuracy and completeness of the data reported, and agreed to the fidelity of the trial to the protocol (available at NEJM.org). An independent data and safety monitoring committee reviewed the effectiveness and unblinded safety data. A local probation physician checked all serious side effects as they occurred. The trial was monitored by an external clinical research organization that ensured compliance with the protocol.
The trial was approved before the trial by the South African Regulatory Authority for Health Products and by the ethics committees of the University of the Witwatersrand, Cape Town, Stellenbosch and OxTREC. All participants were fully informed of the trial procedures and the possible risks, and all written informed consent documents were signed before they were entered for the trial.
Trial Procedures
Trial participants were randomly assigned to either a dose of 0.33 to 0.5 ml (depending on the amount) of the ChAdOx1 nCoV-19 vaccine or placebo on intramuscular injection on the day of randomization and a second injection. 21 to 35 days later. Injections were administered into the deltoid muscle of the non-dominant arm, and the participants were observed for acute reactions 30 minutes after the injection. Injections were prepared and administered by staff members who were aware of the instructions of the participants in the trial group, but who were not involved in any other trial procedures. Trial participants and all other trial staff remain unaware of trial group assignments. Details of the trial procedures are given in the minutes (pages 68–73). Follow-up is underway.
Safety
The safety analysis evaluated the occurrence of required local and systemic reactogenicity within the first 7 days after injection, undesirable side effects within 28 days after injection, changes from baseline in safety laboratory measures and serious adverse events. Further details of the methods used to evaluate safety and reactogenicity are given in the supplementary annex. Adverse events up to 15 January 2021 have been included in this report.
SARS-CoV-2 testing, whole genome sequencing and genome assembly
The use of a nucleic acid amplification test for SARS-CoV-2 infection includes sampling during routine scheduled visits (set out in the protocol) and during non-routine visits when participants have any symptoms indicative of Covid-19 disease. Participants were advised at the time of randomization about what clinical symptoms should cause a visit to investigate possible SARS-CoV-2 infection (Table S1 in the supplementary appendix). In addition, short messages were sent to the participants every 2 weeks to present a reminder if they had symptoms. Details of nucleic acid amplification testing, genome sequencing, and phylogenetic analysis are described in the supplementary appendix.
Neutralization provisions
SARS-CoV-2 serostatus at randomization was evaluated using an IgG test of the nucleoprotein (N), as described elsewhere.8 For antibody neutralization studies, pseudovirus neutralization tests were performed (see section Methods in the Supplementary Appendix) at Monogram Biosciences, to obtain virus prototype on serum samples obtained 2 weeks after the second dose of vaccine in 107 randomly selected ChAdOx1 nCoV-19 vaccine recipients. which was seronegative for IgG N proteins at entry.
To assess the neutralizing activity of vaccine antibodies against B.1.351, serum samples from group 1 participants who had negative SARS-CoV-2 serostatus at enrollment and different pseudovirus neutralization assay titers to the original D614G ear virus at 14 days after the second injection was tested with pseudovirus and live virus neutralization assays for activity against the B.1.351 variant.14.21 The testing of the neutralizing antibody activity against the original virus and the B.1.351 variant was undertaken before the experimental group assignments were blinded. The pseudovirus tests for neutralization activity against the original D614G peak, an RBD triple mutant (containing only K417N, E484K and N501Y), and the B.1.351 peak are at the National Institute for Communicable Diseases (South Africa) exported.14 Tests for live virus neutralization tests were performed by a microphone neutralization focus-forming test in Vero E6 cells at the African Health Research Institute, South Africa.14.21 Details of the pseudovirus and live virus neutralization provisions have been published and are briefly described in the supplementary annex.14.21
Efficiency goals
The primary endpoint was efficacy against nucleic acid amplification test – the symptomatic Covid-19 was confirmed starting more than 14 days after the second injection in participants who were seronegative at random. Confirmed symptomatic Covid-19 and the grading of mild, moderate and severe diseases are prescribed and are described in Tables S1 and S2. Covid-19 cases were evaluated by at least two physicians who were independent of the trial and were not aware of the assignments of the trial group. Indiscriminate assessments were discussed between the two judges. Vaccination of the vaccine against the B.1.351 variant was a pre-specified secondary objective.
Other secondary efficacy objectives include efficacy against Covid-19 in the general population (including participants who were seropositive at random), efficacy specific for the baseline seropositive group, and efficacy against Covid-19 starting more than 14 or more than 21 days after the first dosage. Further details of secondary efficacy analyzes are included in the supplementary appendix. Furthermore, a post hoc analysis was performed for the overall and seronegative populations to evaluate the efficacy of the vaccine against diseases occurring more than 14 days after the first injection, with endpoint cases limited to 31 October 2020, as a proxy for non -B .1.351 variant Covid-19. The B.1.351 variant was first identified in the areas where the test sites (Johannesburg and Tshwane in Gauteng and the Cape metro in the Western Cape) were based from mid-November 2020 (Fig. S1).15
Statistical analysis
Participants who received at least one dose of ChAdOx1 nCoV-19 vaccine or placebo, and who returned diary tickets completed by day 7 after the first injection, were included in the safety reactogenicity analysis. The occurrence of each required local and systemic reactogenicity sign and symptom for 7 days after vaccination, adverse events and serious side effects until 15 January 2021, is presented according to the experimental group.
The primary efficacy analysis was endpoint-driven for the composition of mild, moderate, or severe Covid-19 and required 42 cases to detect a vaccine efficacy of at least 60% (with a lower limit of 0% for the 95% confidence interval). , with 80% power. The effectiveness of the vaccine is calculated as 1 minus the relative risk, and 95% confidence intervals are calculated according to the Clopper – Pearson method. Only participants in the per-protocol population (all participants who received two doses of vaccine or placebo and were grouped according to the injection they received, regardless of their planned group assignment) who were seronegative for SARS-CoV-2 at enrollment. the primary effectiveness analysis. A sensitivity analysis was performed that included seronegative participants in the modified population intended for treatment (all participants who received two doses and were grouped according to their planned assignment, regardless of the injection they received). Confidence intervals reported in this article have not been adjusted for multiple comparisons.