Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine

Abstract

Background: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known.

Methods: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru.

Results: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose.

Conclusions: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).

Figure 1. Screening, Randomization, and Analyses.

Of the 34,301 persons initially screened, 184 were screened twice and counted twice. A total of 34,117 unique participants were screened for the trial; 181 persons failed screening twice and were counted twice, and 1661 unique participants failed screening, which does not include 4 persons who were screened and did not undergo randomization but are not included in the number of failed screenings. Of the total 32,451 participants who underwent randomization, 1 participant was enrolled at two separate sites under two subject identification numbers, underwent randomization at both sites, and received both doses of assigned vaccine or placebo. This participant is included once in the all-participants analysis population but is excluded from all other analysis populations. Three participants underwent randomization twice in error. The safety analysis population for each group reflects treatment actually received. The number of participants in each group who received the second dose are those included as of data cutoff. Participants could be excluded from the fully vaccinated analysis population for more than one reason, including for not receiving two doses, and may therefore be counted for exclusion twice. Group assignment was unblinded for 7635 participants (35.3%) in the AZD1222 group and 4157 participants (38.4%) in the placebo group after the second dose. Covid-19 denotes coronavirus disease 2019, RT-PCR reverse transcriptase–polymerase chain reaction, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.

Figure 2. Local and Systemic Solicited Adverse Events after First and Second Dose, by Age Group.

Erythema and induration were classified by size as mild (2.5 to 5 cm), moderate (5.1 to 6 cm), or moderate-to-severe (>6 cm). Fevers were graded by temperature as none (≤37.8°C), mild (37.9 to 38.4°C), moderate (38.5 to 38.9°C), severe (39.0 to 40.0°C), or life threatening (≥40.1°C). The most common solicited adverse events that occurred in at least 5% of participants within 7 days after any dose in either group were tenderness (68.4% in the AZD1222 group and 19.0% in the placebo group) and pain (58.3% and 15.7%), both local adverse events; the most common systemic adverse events were headache (50.2% in the AZD1222 group and 35.5% in the placebo group), fatigue (49.7% and 31.2%), muscle pain (41.9% and 19.5%), malaise (35.0% and 17.0%), chills (28.2% and 9.5%), nausea (15.3% and 12.1%), and temperature higher than 37.8°C (7.0% and 0.6%). The All Ages group included 1013 participants for dose 1, placebo; 968 for dose 2, placebo; 2037 for dose 1, AZD1222; and 1962 for dose 2, AZD1222. The age 18 to 64 group included 663 participants for dose 1, placebo; 629 for dose 2, placebo; 1339 for dose 1, AZD1222; and 1288 for dose 2, AZD1222. The age 65 and older group included 350 participants for dose 1, placebo; 339 for dose 2, placebo; 698 for dose 1, AZD1222; and 674 for dose 2, AZD1222.

Figure 3. Estimated Vaccine Efficacy ≥15 Days after the Second Dose (Fully Vaccinated Analysis Population).

Values shown for no. of events/total no. are the number of events that occurred among the participants within each group and do not account for censoring due to unblinding of group assignment or loss to follow-up. The primary efficacy end point is the first case of SARS-CoV-2 RT-PCR–positive symptomatic illness occurring 15 days or more after the second dose of AZD1222 or placebo among participants with negative serostatus at baseline. Vaccine efficacy is shown with 95% confidence intervals (CIs), except for vaccine efficacy values for the primary efficacy end point according to SARS-CoV-2 baseline serostatus, the secondary end point of severe or critical symptomatic Covid-19, and the exploratory end point of Covid-19–related intensive care unit (ICU) admissions, which are based on a one-sided 97.5% CI calculated with the exact Poisson model, owing to nonconvergence of the Poisson regression with robust variance. Race and ethnic group were reported by the participant. Other denotes participants who provided a race or ethnic group identification other than White, Black, or American Indian or Alaska Native. Key secondary end points were incidence of symptomatic illness (at 15 days or more after the second dose of AZD1222 or placebo) regardless of evidence of previous SARS-CoV-2 infection at baseline, severe or critical symptomatic Covid-19 (at 15 days or more after the second dose of AZD1222 or placebo), Covid-19–related emergency department visits, symptomatic Covid-19 as defined by Centers for Disease Control and Prevention (CDC) criteria, and first response (change from negative serostatus for SARS-CoV-2 nucleocapsid antibodies at baseline to positive serostatus after receiving AZD1222 or placebo). P values are reported for the primary and key secondary outcomes; analyses followed prespecified plan to adjust for multiple comparisons. I bars indicate confidence intervals; arrows indicate truncated values, with actual values shown in the accompanying column; the dashed vertical line represents the upper limit (i.e., 100% vaccine efficacy); and the solid vertical line represents the nominally statistically significant criterion of a lower confidence interval greater than 30% applicable to the primary end point and is shown for reference. NA denotes not available, and NE could not be estimated.

Figure 4. Time to First SARS-CoV-2 RT-PCR–Positive Symptomatic Illness Occurring 15 Days or More after the Second Dose (Fully Vaccinated Analysis Population).

The time to the first event was relative to the time of the actual second dose administration, calculated as (date of SARS-CoV-2–positive test) – (date of second dose of AZD1222 or placebo + 14 days) + 1. For participants whose data were censored, the censoring time was from the date of the second dose of AZD1222 or placebo + 14 days to the last time observed before data cutoff (March 5, 2021). The cumulative incidence of Covid-19 was estimated with the Kaplan–Meier method. Vaccine efficacy, estimated on the basis of the supportive analysis of the time to primary efficacy end point with the use of the Cox proportional-hazards model, with the randomization and age groups at the time of informed consent as covariates, was 73.9% (95% CI, 65.3 to 80.5). Tick marks indicate censored data.