Randomized Controlled Trial
Study population and setting
This paper describes a randomized, placebo-controlled, phase 3 clinical trial that took place across 88 sites in the United States, Chile, and Peru between August 28, 2020 and January 15, 2021. The trial aimed to study safety, efficacy, and immunogenicity of the ChAdOx1 n-CoV-19 vaccine (Oxford/AstraZeneca) in these countries. There were 32,451 participants, who were randomized in a 2:1 ratio to either receive two doses of vaccine (5^10 viral particles) administered four weeks apart (21,635 participants) or two doses of a saline placebo four weeks apart (10,816 participants). Participants were aged 18 or older, and the group randomization was stratified by age group (18-64 or 64 years+). Safety analysis was performed on all participants who received at least one dose of vaccine or placebo. Unsolicited adverse events were recorded for 28 days following each dose, while serious adverse events were recorded throughout the duration of the study. A sub-study to assess reactogenicity and immunogenicity was conducted, with reactogenicity being studied for 7 days following each dose. Immunogenicity was analyzed by measuring antibodies against the SARS-CoV-2 spike protein and neutralizing antibodies found in serum samples from sub-study participants. The primary efficacy endpoint was to see how well the vaccine could prevent the onset of symptomatic and severe RT-PCR confirmed COVID-19 infection 15 or more days following the second dose compared to second dose of placebo. Patients in efficacy analysis were seronegative at baseline.
Summary of Main Findings
The safety analysis found that the most common adverse events were generalized pain, headache, injection-site pain, and fatigue, at a rate of at least 5% in either vaccine and/or placebo groups. A similar and very small percentage (around 0.5%) of participants in both groups had a serious adverse event within 28 days after any dose. Zero vaccine or placebo related deaths occurred during the trial, and no COVID-19 related deaths were noted, either. Importantly, incidences of deep-vein thrombosis, pulmonary embolism, thrombocytopenia, and immune thrombocytopenia was very low and similar in both groups (generally < 0.1%). The sub-study on reactogenicity found that more participants in the vaccine group experienced local and systemic adverse events compared to the placebo group. Most (about 92%) of these adverse events were mild or moderate in degree and resolved 1-2 days after onset. There were fewer adverse events following the second dose in both the vaccine and placebo group. Overall vaccine efficacy (VE) was estimated to be 74% (95% CI, 65.3-80.5; P < 0.0001). Due to the clinical trial being put on hold, some patients received their second dose outside of the normal 28-day window, but VE was calculated to be similar in this group 78.1%, 95% CI, 49.2-90.6). When using the CDC’s definition of COVID-19, which can include mild disease, overall VE was estimated to be 70%. VE in participants ages 65 and older was estimated to be 83.5% (95% CI, 54.2-94.1). No severe or critical symptomatic cases of COVID-19 were observed in fully vaccinated participants, while 8 cases were noted in the placebo group. Then efficacy of the vaccine in preventing infection, assessed by measuring antibodies in patient serum, was 64.3% (95% CI, 56.1-71.0; P < 0.001). As for the exploratory endpoint measuring the vaccine’s efficacy in prevention against COVID-19 hospitalizations, VE was estimated to be 94.2% (95% CI, 53.2-99.3). Neutralizing antibodies against the COVID-19 spike protein were observed to increase after the first dose of vaccine and even more so when measured 28 days after second dose of vaccine, while levels remained low throughout the trial in the placebo group.
This trial aimed to include a diverse population, studying the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine in three new countries across a wide age range. Participants also included those with coexisting conditions, as well as some participants with well-controlled HIV.
While trying to include a diverse population, 79% of participants were still white. Due to small COVID-19 case numbers in Chile and Peru sites, vaccine efficacy could not be estimated for those locations. The level of neutralizing antibodies that correlates with protection is still unknown. Early unblinding of group assignment for more than one third of participants occurred in order to allow patients a choice in deciding whether they would like to become vaccinated after other vaccines received emergency use approval. Finally, the results included in this report encompass only a short duration of follow up.
This report describes the safety and efficacy of the Oxford/AstraZeneca vaccine in United States, Chile, and Peru.