Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant

Abstract

Background: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa.

Methods: We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×10¹⁰ viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose.

Results: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups.

Conclusions: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).

Figure 1. Enrollment of Participants, Randomization, Vaccine or Placebo Administration, and Follow-up.

NAAT denotes nucleic acid amplification test.

Figure 2. Pseudovirus and Live-Virus Neutralization Assay Findings.

Panel A depicts the results of pseudovirus assay to assess neutralization of the original SARS-CoV-2 virus in ChAdOx1 nCoV-19 vaccine recipients from the United Kingdom, Brazil, and South Africa. Vaccine serum samples from 107 participants in South Africa who were 18 to 64 years old and seronegative at baseline and were assigned to receive two standard doses were evaluated in a validated pseudovirus neutralization assay at a centralized facility at baseline, at 28 days after the first dose, and at 28 days after the second dose. Results for 226 vaccine recipients enrolled in ChAdOx1 nCoV-19 studies in Brazil and 326 in the United Kingdom have not been published previously but are included for comparative purposes. Boxes show medians and interquartile ranges. In trial participants in the United Kingdom, Brazil, and South Africa, median titers at 28 days after the first dose were 41.35, 46.69, and 131.57, respectively, and 200.44, 154.40, and 276.61 at 28 days after the second dose. The ChAdOx1 nCoV-19 vaccine recipients included in the analysis were randomly selected participants from the efficacy trial who contributed to the pooled vaccine efficacy and safety results reported from those studies. Panel B shows the results of the pseudovirus assay to assess neutralization of the original virus, the RBD triple mutant, and the B.1.351 variant. Serum samples obtained from 13 ChAdOx1 nCoV-19 vaccine recipients without SARS-CoV-2 infection through 41 days after vaccination (left) and 6 placebo recipients who had natural infection-induced antibody (right) were assessed with the pseudovirus assay to assess neutralization activity against the original D614G lineage, an RBD-only chimeric virus containing the K417N, E484K, and N501Y substitutions, and the B.1.351 variant. Background colors indicate dilutional titers, and pie charts summarize the proportions according to dilutional titer. Geometric mean titers against each virus are shown below the graphs. Panel C shows the results of live-virus neutralization assay against the original virus and the B.1.351 variant in 13 vaccine recipients (left) and 6 placebo recipients who had natural infection–induced antibody (right) of B.1.1.117 (the sublineage [GISAID accession EPI_ISL_602622] of B.1.1 used in the assay) and B.1.351 variants. Participants were as for the pseudovirus neutralization assay. Neutralization is represented by the 50% plaque reduction neutralization titer (PRNT₅₀), the reciprocal of the 50% inhibitory dilution per participant. Participants with no detectable neutralization (defined as PRNT₅₀<1) are shaded in red. Bars and associated numbers represent geometric means (using the limit of detection of PRNT₅₀ = 1 for undetectable participants), and boxes 95% confidence intervals.

Figure 3. Kaplan–Meyer Plot of ChAdOx1 nCoV-19 Vaccine Efficacy against Symptomatic Covid-19 Illness of Mild or Moderate Severity after Two Doses, as Compared with Placebo.

The shading represents 95% confidence intervals. The tick marks indicate data censored at the time of one of the following events: a Covid-19 infection that did not meet the trial criteria for symptomatic Covid-19 illness, withdrawal from the trial, or death. The inset shows the same data on an expanded y axis.