Trial objectives, participants and observation
In this multisite, double-blind, randomized, placebo-controlled trial in South Africa, we evaluated the safety and efficacy of two standard doses of the CHAdOx1 nCoV-19 vaccine, compared to salt, within 21 to 35 days. % Sodium chloride) placebo. Adults between the ages of 18 and 65 were eligible for participation, with no or well-controlled chronic medical conditions. Participants included 70 HIV-negative individuals registered as group 1, in which intensive safety and immunogenicity studies were conducted. The main exclusion criteria for screening were human immunodeficiency virus (HIV) positivity (for efficacy group), previous or current laboratory-confirmed covid-19, history of anaphylaxis in relation to vaccination, and morbid obesity (body). [BMI, the weight in kilograms divided by the square of the height in meters], ≥40). Detailed inclusion and exclusion criteria are provided in the supplementary appendix available with the full text of this article on NEJM.org. The CHAdOx1 nCoV-19 vaccine was developed at Oxford University, which was responsible for the conduct and supervision of the trial (see Supplementary Appendix).
The authors had full access to the trial data, confirming the accuracy and completeness of the reported data and guaranteeing the fidelity of the trial to Protocol (available on NEJM.org). The Independent Data and Safety Monitoring Committee reviewed the effectiveness and unblinded safety data. The local trial-safety physician reviewed all serious adverse events. The trial was monitored by an external clinical research institute, which ensured adherence to the protocol.
The trial was reviewed by the South African Health Products Regulatory Authority and was preceded by ethical committees from the University of Witwatersrand, Cape Town, Stalenobos and Ox Kstrassi. All participants were given full information about the trial proceedings and potential risks, and all signed informed informed consent documents prior to registration at the hearing.
Trial proceedings
Trial participants were randomly assigned to receive the CHAdOx1 nCoV-19 vaccine or placebo with a 0.33 to-0.5-mL dose (depending on lots) by intramuscular injection on the day of randomization and another injection 21 to 35 days later. Injections were given into the deltoid muscle of the nondominant arm, and participants were observed for 30 min after injection for acute reactions. The injections were prepared and administered by site staff who were familiar with the trial-group assignments of participants but were not involved in any other trial procedures. Trial participants and all other trial staff are unaware of trial-group assignments. Details of the trial procedure are provided in the Protocol (pp. 68–73). Follow-up on.
Safety
The safety analysis assessed the incidence of local and systemic reactogenicity within the first days after injection, adverse events within 28 days after injection, baseline changes in safety laboratory measures, and serious adverse events. Further details of the methods used to assess safety and reactivity are provided in the Supplementary Appendix. This report includes event data as opposed to January 15, 2021.
SARS-Cavi-2 testing, full-genome sequencing and genome assembly
Nucleic acid amplification testing for SARS-CoV-2 infection was used to include samples in routine scheduled visits (detailed in protocol) and in non-routine visits when participants had no symptom indicator of Covid-19 illness. Participants were advised at the time of randomization to begin an interview to diagnose possible SARS-CoV-2 infection (Table S1 in Supplementary Appendix). In addition, participants were sent 2 weeks of short messages as a reminder to submit for investigation if there were symptoms. The supplemental appendix details nucleic acid amplification testing, full-genome sequencing, and phylogenetic analysis.
Neutralization Essays
Evaluation of SARS-Cavi-2 serostatus during randomization was performed using IgG asina of nucleoprotein (N) as described above.8 For the antibody-neutralization study, pseudovirus neutralization assays (see the methods section in the supplementary appendix) were performed in monogram bioscience, for prototype viruses on serum samples, randomly selected ChAdOx1 nCoV-2 vaccines after 10 weeks in 107 vaccine recipients. IgG was seronegative to N protein.
To assess the neutral activity of vaccinated antibodies against B..3.551, serum samples of group 1 participants with negative SARS-Co-2 serostats at the time of registration for the original D614G spike virus 1 ser days after the second injection B.1.351 Was tested with pseudovirus and live-virus neutralization asso for activity against variants.Is 14.21 A trial of neutralizing antibody activity against the original virus and the B.1.351 variant was conducted prior to binding of trial-group assignments. Original D614G spike, an RBD triple mutant (contains only K417N, E484K, and N501Y), and B1.351 pseudovirus aces for neutralization activity against the spike, performed at the National Institute for Communicable Diseases (South Africa).14 Live-virus neutralization was adequately tested by micronutrient Focus-Forming Ace in Vero E6 cells in the African Health Research Institute, South Africa.Is 14.21 Details of pseudovirus and live-virus neutralization essays have been published and will be described shortly in the Supplementary Appendix.Is 14.21
Effectiveness Objectives
The primary endpoint was the efficacy against the nucleic acid amplification test – a typical covid-19 confirmed onset more than 14 days after the second injection in participants who were seronegative at randomization. The grading of confirmed typical covid-19 and mild, moderate, and severe disease was predetermined and defined in Tables S1 and S2. The Covid-19 case was evaluated by at least two physicians who were independent of the hearing and unaware of the trial-group assignments. Disagreeable assessment was discussed between the two reviewers. Vaccine efficacy against B.1.351 variant was a predetermined secondary objective.
Other secondary efficacy objectives include efficacy against Covid-19 in the overall population (including participants at randomization), efficacy pertaining to the baseline seropositive group, and efficacy against Covid-19 after 14 to 21 days or more with onset. First dose. Further details of the secondary efficacy analysis are included in the Supplementary Appendix. In addition, to evaluate the effectiveness of the vaccine against illness for more than 14 days after the first injection, over-point cases were prohibited until October 31, 2020, as a proxy for non-B, post-analysis for the overall and seronegative population. .1.351 variable covid-19. The B.1.351 variable began to be identified only in places where the trial sites (Johannesburg and Tswane in Gauteng, and the Cape Metro in the western Cape Province) were based in mid-November 2020 (Fig. S1).15
Statistical analysis
Participants who received at least one dose of the ChAdOx1 nCoV-19 vaccine or placebo and who returned diary cards completed 7 days after the first injection were included in the safety reactogenicity analysis. Indications and symptoms of each requested local and systemic reactogenicity up to 7 days after vaccination, adverse events, and severe adverse events until January 15, 2021, are presented according to the trial group.
The primary efficacy analysis was the final point – running for a combination of mild, moderate or severe Covid-19 and requiring at least 42 cases to detect at least 60% vaccine efficacy (with a low bound of 0% for 95% confidence). , With 80% power. Vaccine efficacy was calculated as 1 less than the relative risk, and 95% confidence intervals were calculated using the Klopper-Pearson method accurately. Only participants in the counter-protocol population (all participants who received two doses of vaccine or placebo and were grouped according to the injections they received, regardless of their planned group assignment) who were seronegative for SARS-COVI-2 at enrollment Were primary efficacy analysis. A sensitivity analysis was conducted that included the surrogate participants in a modified purpose-to-treatment population (all participants who received two doses and were grouped by their planned assignment, regardless of the injection they took). The confidence intervals recorded in this article have not been adjusted for multiple comparisons.
