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

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, as compared with saline (0.9% sodium chloride) placebo. Adults 18 to less than 65 years of age, with no or well-controlled chronic medical conditions, were eligible for participation. Included among the participants were 70 HIV-negative persons enrolled as group 1, in whom intensive safety and immunogenicity studies were planned. Key exclusion criteria were human immunodeficiency virus (HIV) positivity at screening (for the efficacy cohort), previous or current laboratory-confirmed Covid-19, a history of anaphylaxis in relation to vaccination, and morbid obesity (body-mass index [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 at NEJM.org. The ChAdOx1 nCoV-19 vaccine was developed at the University of Oxford, which was responsible for the conduct and oversight of the trial (see the Supplementary Appendix).

≥40). Detailed inclusion and exclusion criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. The ChAdOx1 nCoV-19 vaccine was developed at the University of Oxford, which was responsible for the conduct and oversight of the trial (see the Supplementary Appendix). The authors had full access to the trial data, confirm the accuracy and completeness of the data reported, and vouch for the fidelity of the trial to the protocol (available at NEJM.org). An independent data and safety monitoring committee reviewed efficacy and unblinded safety data. A local trial-safety physician reviewed all serious adverse events as they occurred. The trial was monitored by an external clinical research organization, which ensured adherence to the protocol. The trial was reviewed and approved by the South African Health Products Regulatory Authority and by the ethics committees of the University of the Witwatersrand, Cape Town, Stellenbosch, and OxTREC before trial initiation. All participants were fully informed about the trial procedures and the possible risks, and all signed written informed consent documents before enrollment in the trial.

Regulatory Authority and by the ethics committees of the University of the Witwatersrand, Cape Town, Stellenbosch, and OxTREC before trial initiation. All participants were fully informed about the trial procedures and the possible risks, and all signed written informed consent documents before enrollment in the trial. Trial participants were randomly assigned to receive either a 0.33-to-0.5-ml dose (depending on the lot) of the ChAdOx1 nCoV-19 vaccine or placebo by 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 nondominant arm, and participants were observed for 30 minutes after the injection for acute reactions. Injections were prepared and administered by site staff who were aware of participants’ trial-group assignments but 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 provided in the protocol (pages 68–73). Follow-up is ongoing. The safety analysis evaluated the occurrence of solicited local and systemic reactogenicity within the first 7 days after an injection, unsolicited adverse events within 28 days after an injection, changes from baseline in safety laboratory measures, and serious adverse events. Further details of methods used to evaluate safety and reactogenicity are provided in the Supplementary Appendix. Adverse event data through January 15, 2021, are included in this report.

d adverse events within 28 days after an injection, changes from baseline in safety laboratory measures, and serious adverse events. Further details of methods used to evaluate safety and reactogenicity are provided in the Supplementary Appendix. Adverse event data through January 15, 2021, are included in this report. Use of a nucleic acid amplification test for SARS-CoV-2 infection included sampling at routine scheduled visits (detailed in the protocol) and at nonroutine visits when participants had any symptom suggestive of Covid-19 illness. Participants were advised at the time of randomization as to which clinical symptoms should trigger a visit for investigation of possible SARS-CoV-2 infection (Table S1 in the Supplementary Appendix). In addition, short messages were sent to participants every 2 weeks as a reminder to present for investigation if they had symptoms. Details of nucleic acid amplification testing, whole-genome sequencing, and phylogenetic analysis are described in Supplementary Appendix. SARS-CoV-2 serostatus at randomization was evaluated with the use of an IgG assay of the nucleoprotein (N), as described elsewhere.8 For antibody-neutralization studies, pseudovirus neutralization assays (see the Methods section in the Supplementary Appendix) were performed at Monogram Biosciences, to prototype virus on serum samples obtained 2 weeks after the second dose of vaccine in 107 randomly selected ChAdOx1 nCoV-19 vaccine recipients who were seronegative for IgG N protein at enrollment.

s neutralization assays (see the Methods section in the Supplementary Appendix) were performed at Monogram Biosciences, to prototype virus on serum samples obtained 2 weeks after the second dose of vaccine in 107 randomly selected ChAdOx1 nCoV-19 vaccine recipients who were seronegative for IgG N protein at enrollment. To assess neutralization activity of vaccine-elicited antibodies against B.1.351, serum samples from group 1 participants who had negative SARS-CoV-2 serostatus at enrollment and varying pseudovirus neutralization assay titers to the original D614G spike virus at 14 days after the second injection were tested with pseudovirus and live-virus neutralization assays for activity against the B.1.351 variant.14,21 Testing of neutralizing antibody activity against the original virus and the B.1.351 variant was undertaken before unblinding of trial-group assignments. The pseudovirus assays for neutralization activity against the original D614G spike, an RBD triple mutant (containing only K417N, E484K, and N501Y), and the B.1.351 spike were performed at the National Institute for Communicable Diseases (South Africa).14 Live-virus neutralization assay testing was performed by a microneutralization focus-forming assay in Vero E6 cells at the African Health Research Institute, South Africa.14,21 Details of the pseudovirus and live-virus neutralization assays have been published and are described briefly in the Supplementary Appendix.14,21

ve-virus neutralization assay testing was performed by a microneutralization focus-forming assay in Vero E6 cells at the African Health Research Institute, South Africa.14,21 Details of the pseudovirus and live-virus neutralization assays have been published and are described briefly in the Supplementary Appendix.14,21 The primary end point was efficacy against nucleic acid amplification test–confirmed symptomatic Covid-19 with onset more than 14 days after the second injection in participants who were seronegative at randomization. Confirmed symptomatic Covid-19 and the grading of mild, moderate, and severe disease were prespecified and are defined in Tables S1 and S2. Covid-19 cases were evaluated by at least two physicians who were independent of the trial and were unaware of trial-group assignments. Discordant assessments were discussed between the two reviewers. Vaccine efficacy against the B.1.351 variant was a prespecified secondary objective.

d are defined in Tables S1 and S2. Covid-19 cases were evaluated by at least two physicians who were independent of the trial and were unaware of trial-group assignments. Discordant assessments were discussed between the two reviewers. Vaccine efficacy against the B.1.351 variant was a prespecified secondary objective. Other secondary efficacy objectives included efficacy against Covid-19 in the overall population (including participants who were seropositive at randomization), efficacy specific to the baseline seropositive group, and efficacy against Covid-19 with onset more than 14 or more than 21 days after the first dose. Further details of secondary efficacy analyses are included in the Supplementary Appendix. Furthermore, a post hoc analysis was performed for the overall and seronegative populations, to evaluate vaccine efficacy against illness occurring more than 14 days after the first injection, with end-point cases restricted until October 31, 2020, as a proxy for non–B.1.351 variant Covid-19. The B.1.351 variant only began to be identified in the areas where the trial sites (Johannesburg and Tshwane in Gauteng, and Cape Metro in Western Cape Province) were based from mid-November 2020 onward (Fig. S1).15

on, with end-point cases restricted until October 31, 2020, as a proxy for non–B.1.351 variant Covid-19. The B.1.351 variant only began to be identified in the areas where the trial sites (Johannesburg and Tshwane in Gauteng, and Cape Metro in Western Cape Province) were based from mid-November 2020 onward (Fig. S1).15 Participants who received at least one dose of the ChAdOx1 nCoV-19 vaccine or placebo and who returned diary cards completed until day 7 after the first injection were included in the safety reactogenicity analysis. The occurrence of each solicited local and systemic reactogenicity sign and symptom for 7 days after vaccination, adverse events, and serious adverse events through January 15, 2021, are presented according to trial group.

pleted until day 7 after the first injection were included in the safety reactogenicity analysis. The occurrence of each solicited local and systemic reactogenicity sign and symptom for 7 days after vaccination, adverse events, and serious adverse events through January 15, 2021, are presented according to trial group. The primary efficacy analysis was end-point–driven for the composite of mild, moderate, or severe Covid-19 and required 42 cases to detect a vaccine efficacy of at least 60% (with a lower bound of 0% for the 95% confidence interval), with 80% power. Vaccine efficacy was calculated as 1 minus the relative risk, and 95% confidence intervals calculated with the Clopper–Pearson exact method are reported. 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 were included in the primary efficacy analysis. A sensitivity analysis was conducted that included seronegative participants in the modified intention-to-treat population (all participants who received two doses and were grouped by their planned assignment, irrespective of the injection they received). Confidence intervals reported in this article have not been adjusted for multiple comparisons.

Trial participants were randomly assigned to receive either a 0.33-to-0.5-ml dose (depending on the lot) of the ChAdOx1 nCoV-19 vaccine or placebo by 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 nondominant arm, and participants were observed for 30 minutes after the injection for acute reactions. Injections were prepared and administered by site staff who were aware of participants’ trial-group assignments but 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 provided in the protocol (pages 68–73). Follow-up is ongoing.

The safety analysis evaluated the occurrence of solicited local and systemic reactogenicity within the first 7 days after an injection, unsolicited adverse events within 28 days after an injection, changes from baseline in safety laboratory measures, and serious adverse events. Further details of methods used to evaluate safety and reactogenicity are provided in the Supplementary Appendix. Adverse event data through January 15, 2021, are included in this report.

Use of a nucleic acid amplification test for SARS-CoV-2 infection included sampling at routine scheduled visits (detailed in the protocol) and at nonroutine visits when participants had any symptom suggestive of Covid-19 illness. Participants were advised at the time of randomization as to which clinical symptoms should trigger a visit for investigation of possible SARS-CoV-2 infection (Table S1 in the Supplementary Appendix). In addition, short messages were sent to participants every 2 weeks as a reminder to present for investigation if they had symptoms. Details of nucleic acid amplification testing, whole-genome sequencing, and phylogenetic analysis are described in Supplementary Appendix.

SARS-CoV-2 serostatus at randomization was evaluated with the use of an IgG assay of the nucleoprotein (N), as described elsewhere.8 For antibody-neutralization studies, pseudovirus neutralization assays (see the Methods section in the Supplementary Appendix) were performed at Monogram Biosciences, to prototype virus on serum samples obtained 2 weeks after the second dose of vaccine in 107 randomly selected ChAdOx1 nCoV-19 vaccine recipients who were seronegative for IgG N protein at enrollment.

The primary end point was efficacy against nucleic acid amplification test–confirmed symptomatic Covid-19 with onset more than 14 days after the second injection in participants who were seronegative at randomization. Confirmed symptomatic Covid-19 and the grading of mild, moderate, and severe disease were prespecified and are defined in Tables S1 and S2. Covid-19 cases were evaluated by at least two physicians who were independent of the trial and were unaware of trial-group assignments. Discordant assessments were discussed between the two reviewers. Vaccine efficacy against the B.1.351 variant was a prespecified secondary objective. Other secondary efficacy objectives included efficacy against Covid-19 in the overall population (including participants who were seropositive at randomization), efficacy specific to the baseline seropositive group, and efficacy against Covid-19 with onset more than 14 or more than 21 days after the first dose. Further details of secondary efficacy analyses are included in the Supplementary Appendix. Furthermore, a post hoc analysis was performed for the overall and seronegative populations, to evaluate vaccine efficacy against illness occurring more than 14 days after the first injection, with end-point cases restricted until October 31, 2020, as a proxy for non–B.1.351 variant Covid-19. The B.1.351 variant only began to be identified in the areas where the trial sites (Johannesburg and Tshwane in Gauteng, and Cape Metro in Western Cape Province) were based from mid-November 2020 onward (Fig. S1).15

Participants who received at least one dose of the ChAdOx1 nCoV-19 vaccine or placebo and who returned diary cards completed until day 7 after the first injection were included in the safety reactogenicity analysis. The occurrence of each solicited local and systemic reactogenicity sign and symptom for 7 days after vaccination, adverse events, and serious adverse events through January 15, 2021, are presented according to trial group. The primary efficacy analysis was end-point–driven for the composite of mild, moderate, or severe Covid-19 and required 42 cases to detect a vaccine efficacy of at least 60% (with a lower bound of 0% for the 95% confidence interval), with 80% power. Vaccine efficacy was calculated as 1 minus the relative risk, and 95% confidence intervals calculated with the Clopper–Pearson exact method are reported. 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 were included in the primary efficacy analysis. A sensitivity analysis was conducted that included seronegative participants in the modified intention-to-treat population (all participants who received two doses and were grouped by their planned assignment, irrespective of the injection they received). Confidence intervals reported in this article have not been adjusted for multiple comparisons.

We screened 3022 persons across seven sites and enrolled 2026 HIV-negative persons in the trial between June 24 and November 9, 2020. All participants except 5 who did not receive vaccine or placebo were included in the safety analysis. The initiation of enrollment coincided with the peak of the first Covid-19 wave in South Africa (Fig. S2). Overall, 1010 participants received the vaccine and 1011 received the placebo (Figure 1). A total of 1467 seronegative participants (750 assigned to the vaccine and 717 to placebo) were eligible for the primary efficacy analysis; reasons for exclusion are listed in Figure 1. The median age of the participants was 30 years, 56.5% identified as male, and the racial distribution included 70.5% Black Africans, 12.8% Whites, and 14.9% identifying as mixed race. Nineteen percent of participants were obese (BMI, 30 to 39.9), 42.0% were smokers, 2.8% had underlying hypertension, and 3.1% had chronic respiratory conditions. The median time between doses was 28 days, and the median duration of follow-up from enrollment and from 14 days after the second dose of vaccine or placebo was 156 and 121 days, respectively (as of January 15, 2021). Demographic characteristics of the baseline seronegative population were similar to those of the overall population (Table 1).

doses was 28 days, and the median duration of follow-up from enrollment and from 14 days after the second dose of vaccine or placebo was 156 and 121 days, respectively (as of January 15, 2021). Demographic characteristics of the baseline seronegative population were similar to those of the overall population (Table 1). Local and systemic reactogenicity data are presented in Figures S3 and S4. The incidence of adverse events and serious adverse events was similar among vaccine and placebo recipients (Tables S3 and S4). The only serious adverse event attributed to the ChAdOx1 nCoV-19 vaccine was a body temperature above 40°C after the first dose; the fever subsided within 24 hours, and no reactogenicity was observed after the second dose. All other events were considered unrelated or unlikely to be related to the injection received. Humoral response to the ChAdOx1 nCoV-19 vaccine induced strong neutralizing antibodies at 28 days after the first dose (geometric mean titer, 132; interquartile range, 20 to 404), which rose further after a second dose (geometric mean titer, 277; interquartile range, 124 to 526) (Figure 2A and Table S5).

Local and systemic reactogenicity data are presented in Figures S3 and S4. The incidence of adverse events and serious adverse events was similar among vaccine and placebo recipients (Tables S3 and S4). The only serious adverse event attributed to the ChAdOx1 nCoV-19 vaccine was a body temperature above 40°C after the first dose; the fever subsided within 24 hours, and no reactogenicity was observed after the second dose. All other events were considered unrelated or unlikely to be related to the injection received. Humoral response to the ChAdOx1 nCoV-19 vaccine induced strong neutralizing antibodies at 28 days after the first dose (geometric mean titer, 132; interquartile range, 20 to 404), which rose further after a second dose (geometric mean titer, 277; interquartile range, 124 to 526) (Figure 2A and Table S5). There were 25 participants in group 1 (the group of 70 participants who also had laboratory measures evaluated as part of their safety analysis) who were SARS-CoV-2 seronegative at enrollment and had neutralizing antibody activity against the original D614G virus on the pseudovirus neutralization assay at 14 days after the second dose. The serum samples from these participants, obtained 14 days after the second dose, were further tested with pseudovirus and live-virus assays for neutralizing activity against the B.1.351 variant. After unblinding of the data, 6 of the 25 serum samples were identified as having been obtained from placebo recipients likely to have been infected with the original SARS-CoV-2 (which predated the emergence of the B.1.351 variant in South Africa) during the follow-up period. Furthermore, nucleic acid amplification testing showed that 6 of the vaccine recipients were also infected with SARS-CoV-2 by 14 days after the second dose. Six of 13 vaccine recipients (46%) without evidence of previous SARS-CoV-2 infection showed no neutralization activity against an RBD triple-mutant pseudovirus (containing K417N, E484K, and N501Y variants), and 11 of the 13 (85%) had no neutralization activity against B.1.351 pseudovirus (Figure 2B).

r the second dose. Six of 13 vaccine recipients (46%) without evidence of previous SARS-CoV-2 infection showed no neutralization activity against an RBD triple-mutant pseudovirus (containing K417N, E484K, and N501Y variants), and 11 of the 13 (85%) had no neutralization activity against B.1.351 pseudovirus (Figure 2B). Geometric mean titers dropped from 297 against the original virus to 85 against the RBD-only mutant and 74 against the B.1.351 variant. Vaccine recipients with nucleic acid amplification test–confirmed illness (before the emergence of B.1.351) showed results similar to those among participants with no confirmed illness (Fig. S6). Samples from the SARS-CoV-2–infected placebo recipients showed similarly low neutralizing activity, with residual titers of less than 100 (or undetectable) against the RBD triple-mutant pseudovirus and the B.1.351 variant (Figure 2B).

owed results similar to those among participants with no confirmed illness (Fig. S6). Samples from the SARS-CoV-2–infected placebo recipients showed similarly low neutralizing activity, with residual titers of less than 100 (or undetectable) against the RBD triple-mutant pseudovirus and the B.1.351 variant (Figure 2B). Live-virus assay showed lower neutralization overall, relative to pseudovirus assay (Figure 2C). Of the 13 vaccine recipients without evidence of previous SARS-CoV-2 infection before or during follow-up, one had undetectable neutralization activity against B.1.1 and B.1.351. Seven of the 12 participants (58%) with neutralization activity against B.1.1 had undetectable neutralization activity against the B.1.351 variant, and the remaining 5 showed neutralization that was lower by a factor of 4.1 to 31.5 (Figure 2C). As with the pseudovirus neutralization assay, six vaccine recipients with nucleic acid amplification test–confirmed illness showed results similar to those among participants with no confirmed illness (Fig. S6B, light gray points). Among the six placebo recipients recently infected with SARS-CoV-2, all had detectable neutralization of the B.1.1 variant, whereas neutralization activity against the B.1.351 variant was undetectable in two cases, lower neutralization by a factor of 6.0 to 9.5 was noted in three cases, and no change was seen in one case (Figure 2C).

lacebo recipients recently infected with SARS-CoV-2, all had detectable neutralization of the B.1.1 variant, whereas neutralization activity against the B.1.351 variant was undetectable in two cases, lower neutralization by a factor of 6.0 to 9.5 was noted in three cases, and no change was seen in one case (Figure 2C). Given the potential importance of T cells in protection from severe disease,26 we include data on 17 recipients of the ChAdOx1 nCoV-19 vaccine from the United Kingdom, who were evaluated with T-cell–receptor variable beta-chain sequencing for expansion of spike-specific T cells (see the Supplementary Appendix). The ChAdOx1 nCoV-19 vaccine caused expansion of CD4+ and CD8+ T lymphocytes to specific epitopes of the spike protein. Of 87 spike-specific antigens identified by the sequencing, 75 remained unaffected by the B.1.351 mutations. Of note, the D215G mutation found in the B.1.351 variant is within a region that had prevalent T-cell antigen responses (Fig. S7).

ansion of CD4+ and CD8+ T lymphocytes to specific epitopes of the spike protein. Of 87 spike-specific antigens identified by the sequencing, 75 remained unaffected by the B.1.351 mutations. Of note, the D215G mutation found in the B.1.351 variant is within a region that had prevalent T-cell antigen responses (Fig. S7). All 42 cases of Covid-19 were graded as mild (15 vaccine recipients and 17 placebo recipients) or moderate (4 vaccine recipients and 6 placebo recipients); there were no cases of severe disease or hospitalization in either group. The incidence of confirmed mild-to-moderate Covid-19 more than 14 days after the second dose among previously seronegative participants was 93.6 per 1000 person-years in the placebo group and 73.1 per 1000 person-years in the vaccine group; vaccine efficacy was 21.9% (95% CI, −49.9 to 59.8) (Table 2 and Figure 3). Similarly, among seropositive participants who had had a nonreactive nucleic acid amplification test before or at randomization, the incidence of mild-to-moderate Covid-19 more than 14 days after the second injection did not differ between placebo (81.9 per 1000 person-years) and vaccine (73.2 per 1000 person-years) recipients; vaccine efficacy was 10.6% (95% CI, −66.4 to 52.2) (Table S6).

leic acid amplification test before or at randomization, the incidence of mild-to-moderate Covid-19 more than 14 days after the second injection did not differ between placebo (81.9 per 1000 person-years) and vaccine (73.2 per 1000 person-years) recipients; vaccine efficacy was 10.6% (95% CI, −66.4 to 52.2) (Table S6). Forty-one of the 42 nasal swab samples (97.6%) were successfully sequenced and classified; 39 (95.1%) cases were caused by the B.1.351 variant and 2 (4.9%; both in the placebo group) by the B.1.1.1 and B.1.144 lineages (Fig. S8). Further details of phylogenetic characterization are provided in the Supplementary Appendix. In a secondary-outcome analysis, efficacy against B.1.351 was not evident (vaccine efficacy, 10.4%; 95% CI, −76.8 to 54.8) (Table 2). Results of analyses of other secondary and exploratory efficacy end points are detailed in Table S6. Overall vaccine efficacy for Covid-19 of any degree of severity more than 14 days after the first dose was 33.5% (95% CI, −13.4 to 61.7). Also presented in Table S6 are efficacy estimates for any symptomatic illness or asymptomatic SARS-CoV-2 infection after the first and second injections; differences in efficacy estimates were nonsignificant and were similar to those for mild-to-moderate Covid-19 estimates.

first dose was 33.5% (95% CI, −13.4 to 61.7). Also presented in Table S6 are efficacy estimates for any symptomatic illness or asymptomatic SARS-CoV-2 infection after the first and second injections; differences in efficacy estimates were nonsignificant and were similar to those for mild-to-moderate Covid-19 estimates. In a post hoc analysis of vaccine efficacy at more than 14 days after a single injection through October 31, 2020, as a proxy for infection by a non–B.1.351 variant (Fig. S1),15,27 the overall attack rate of mild-to-moderate Covid-19 at least 14 days after the first injection was 1.3% in placebo recipients and 0.3% in vaccine recipients; vaccine efficacy was 75.4% (95% CI, 8.7 to 95.5) (Table S8). Similar efficacy estimates were observed in other post hoc analyses for end points occurring through October 31, 2020.

Local and systemic reactogenicity data are presented in Figures S3 and S4. The incidence of adverse events and serious adverse events was similar among vaccine and placebo recipients (Tables S3 and S4). The only serious adverse event attributed to the ChAdOx1 nCoV-19 vaccine was a body temperature above 40°C after the first dose; the fever subsided within 24 hours, and no reactogenicity was observed after the second dose. All other events were considered unrelated or unlikely to be related to the injection received.

Humoral response to the ChAdOx1 nCoV-19 vaccine induced strong neutralizing antibodies at 28 days after the first dose (geometric mean titer, 132; interquartile range, 20 to 404), which rose further after a second dose (geometric mean titer, 277; interquartile range, 124 to 526) (Figure 2A and Table S5). There were 25 participants in group 1 (the group of 70 participants who also had laboratory measures evaluated as part of their safety analysis) who were SARS-CoV-2 seronegative at enrollment and had neutralizing antibody activity against the original D614G virus on the pseudovirus neutralization assay at 14 days after the second dose. The serum samples from these participants, obtained 14 days after the second dose, were further tested with pseudovirus and live-virus assays for neutralizing activity against the B.1.351 variant. After unblinding of the data, 6 of the 25 serum samples were identified as having been obtained from placebo recipients likely to have been infected with the original SARS-CoV-2 (which predated the emergence of the B.1.351 variant in South Africa) during the follow-up period. Furthermore, nucleic acid amplification testing showed that 6 of the vaccine recipients were also infected with SARS-CoV-2 by 14 days after the second dose. Six of 13 vaccine recipients (46%) without evidence of previous SARS-CoV-2 infection showed no neutralization activity against an RBD triple-mutant pseudovirus (containing K417N, E484K, and N501Y variants), and 11 of the 13 (85%) had no neutralization activity against B.1.351 pseudovirus (Figure 2B).

All 42 cases of Covid-19 were graded as mild (15 vaccine recipients and 17 placebo recipients) or moderate (4 vaccine recipients and 6 placebo recipients); there were no cases of severe disease or hospitalization in either group. The incidence of confirmed mild-to-moderate Covid-19 more than 14 days after the second dose among previously seronegative participants was 93.6 per 1000 person-years in the placebo group and 73.1 per 1000 person-years in the vaccine group; vaccine efficacy was 21.9% (95% CI, −49.9 to 59.8) (Table 2 and Figure 3). Similarly, among seropositive participants who had had a nonreactive nucleic acid amplification test before or at randomization, the incidence of mild-to-moderate Covid-19 more than 14 days after the second injection did not differ between placebo (81.9 per 1000 person-years) and vaccine (73.2 per 1000 person-years) recipients; vaccine efficacy was 10.6% (95% CI, −66.4 to 52.2) (Table S6). Forty-one of the 42 nasal swab samples (97.6%) were successfully sequenced and classified; 39 (95.1%) cases were caused by the B.1.351 variant and 2 (4.9%; both in the placebo group) by the B.1.1.1 and B.1.144 lineages (Fig. S8). Further details of phylogenetic characterization are provided in the Supplementary Appendix. In a secondary-outcome analysis, efficacy against B.1.351 was not evident (vaccine efficacy, 10.4%; 95% CI, −76.8 to 54.8) (Table 2).

ariant and 2 (4.9%; both in the placebo group) by the B.1.1.1 and B.1.144 lineages (Fig. S8). Further details of phylogenetic characterization are provided in the Supplementary Appendix. In a secondary-outcome analysis, efficacy against B.1.351 was not evident (vaccine efficacy, 10.4%; 95% CI, −76.8 to 54.8) (Table 2). Results of analyses of other secondary and exploratory efficacy end points are detailed in Table S6. Overall vaccine efficacy for Covid-19 of any degree of severity more than 14 days after the first dose was 33.5% (95% CI, −13.4 to 61.7). Also presented in Table S6 are efficacy estimates for any symptomatic illness or asymptomatic SARS-CoV-2 infection after the first and second injections; differences in efficacy estimates were nonsignificant and were similar to those for mild-to-moderate Covid-19 estimates. In a post hoc analysis of vaccine efficacy at more than 14 days after a single injection through October 31, 2020, as a proxy for infection by a non–B.1.351 variant (Fig. S1),15,27 the overall attack rate of mild-to-moderate Covid-19 at least 14 days after the first injection was 1.3% in placebo recipients and 0.3% in vaccine recipients; vaccine efficacy was 75.4% (95% CI, 8.7 to 95.5) (Table S8). Similar efficacy estimates were observed in other post hoc analyses for end points occurring through October 31, 2020.

In this trial, we found that two doses of the ChAdOx1 nCoV-19 vaccine had no efficacy against the B.1.351 variant in preventing mild-to-moderate Covid-19. There were no cases of hospitalization for severe Covid-19 observed in the study. The lack of efficacy against the B.1.351 variant should be considered in the context of the 75% efficacy (95% CI, 8.7 to 95.5) in preventing mild-to-moderate Covid-19 with onset at least 14 days after even a single dose of ChAdOx1 nCov-19 vaccine that was observed before the B.1.351 variant emerged in South Africa. Of note, the vaccine efficacy in preventing Covid-19 due to the B.1.351 variant was estimated in a secondary analysis; the trial was powered for the primary objective of a vaccine efficacy of at least 60% in preventing Covid-19 of any severity, irrespective of variants. In addition, the demographic and clinical profile of the enrolled participants contributed to the absence of severe Covid-19 cases; hence, the trial findings are inconclusive with respect to whether the ChAdOx1 nCov-19 vaccine may protect against severe Covid-19 caused by infection with the B.1.351 variant.

f variants. In addition, the demographic and clinical profile of the enrolled participants contributed to the absence of severe Covid-19 cases; hence, the trial findings are inconclusive with respect to whether the ChAdOx1 nCov-19 vaccine may protect against severe Covid-19 caused by infection with the B.1.351 variant. The pseudovirus and live-virus neutralization assay experiments, however, provide evidence of reduced or abrogated vaccine-induced antibody neutralization against the B.1.351 variant. Although the degree of attenuation that compromises an effective neutralizing antibody response in vivo is unknown, the highest degree of neutralization achieved against B.1.351 in a vaccinated participant as determined with the live-virus neutralization assay was a 1:20 dilution, and the highest remaining titer against B.1.351 was less than 1:200 with the pseudovirus neutralization assay. Comparison of the RBD triple mutant and the B.1.351 variant in the pseudovirus neutralization assay suggests that much, though not all, of the vaccine-elicited neutralization is directed to the RBD. A similar loss of neutralizing activity against the B.1.351 variant in antibodies induced by natural infection after the first wave of the Covid-19 outbreak has been reported.14

ant in the pseudovirus neutralization assay suggests that much, though not all, of the vaccine-elicited neutralization is directed to the RBD. A similar loss of neutralizing activity against the B.1.351 variant in antibodies induced by natural infection after the first wave of the Covid-19 outbreak has been reported.14 The responses to the original SARS-CoV-2 virus as determined by pseudovirus neutralization assays in recipients of the ChAdOx1 nCoV-19 vaccine in our trial were similar to the responses in vaccinated participants in the studies conducted in the United Kingdom and Brazil (Figure 2A and Table S5). The extent to which the effectiveness of other Covid-19 vaccines may be affected by variants with mutations similar to those of B.1.351 (and P.1) could depend on the magnitude of neutralizing antibody induced by vaccination. Whether an enhanced antibody response resulting from a longer interval between the first and second doses of the ChAdOx1 nCov-19 vaccine, as described elsewhere,17,24 might confer better residual neutralizing activity against the B.1.351 variant than that observed in our trial is not known.

body induced by vaccination. Whether an enhanced antibody response resulting from a longer interval between the first and second doses of the ChAdOx1 nCov-19 vaccine, as described elsewhere,17,24 might confer better residual neutralizing activity against the B.1.351 variant than that observed in our trial is not known. Although the mRNA Covid-19 vaccines have modest neutralizing antibody activity after the first dose, they produce a greater increase in neutralizing activity after the second dose than that produced by the ChAdOx1 nCoV-19 and heterologous Sputnik V (adenovirus-26 followed by adenovirus-5 vector) Covid-19 vaccines.5,6,9 Neutralizing activity of the two mRNA vaccines against the B.1.351 variant has also been observed to be lower, by a factor of 8.6 (mRNA-1273 vaccine [Moderna]) or 6.5 (BNT-162b2 vaccine [Pfizer]) on pseudovirus neutralization assay, than activity against the D614G virus, whereas no difference was evident against the N510Y.V1 (B.1.1.7)–like mutant.19,28,29 Results of a recent interim analysis of the NVX-CoV2373 nanoparticle spike protein Covid-19 vaccine (Novavax), described in a press release, have not yet been published. However, reports suggest that the vaccine may have lower efficacy against the B.1.351 variant than against the original virus or the B.1.1.7 variant.12 In the absence of established correlates of protection against Covid-19 caused by the original virus or by B.1.351 or other variants, clinical evidence of the effectiveness of other Covid-19 vaccines against mild-to-moderate Covid-19 illness is needed.

1 variant than against the original virus or the B.1.1.7 variant.12 In the absence of established correlates of protection against Covid-19 caused by the original virus or by B.1.351 or other variants, clinical evidence of the effectiveness of other Covid-19 vaccines against mild-to-moderate Covid-19 illness is needed. Another recent multinational study that included South Africa evaluated the efficacy of a single dose of the Ad26.COV2.S nonreplicating adenovirus type 26 vaccine (Janssen). Interim results from South Africa reported a vaccine efficacy of 57% against moderate-to-severe Covid-19 and 89% against severe Covid-19 mainly due to the B.1.351 variant.13 The Ad26.COV2.S vaccine study, however, submitted for end-point adjudication only cases confirmed by nucleic acid amplification test in patients who had at least three symptoms30; consequently, the vaccine-efficacy analyses were likely to have excluded the majority of cases of mild Covid-19 in the study. Of note, the immunogenicity of the Ad26.COV2.S vaccine is similar to that of the ChAdOx1 nCoV-19 vaccine after the first and second doses have been administered.13,31 The neutralizing antibody response induced by the Ad26.COV2.S vaccine against the B.1.351 variant has not yet been reported.

mild Covid-19 in the study. Of note, the immunogenicity of the Ad26.COV2.S vaccine is similar to that of the ChAdOx1 nCoV-19 vaccine after the first and second doses have been administered.13,31 The neutralizing antibody response induced by the Ad26.COV2.S vaccine against the B.1.351 variant has not yet been reported. Although the correlation between antibody response and vaccine efficacy is high, which suggests that the neutralizing antibody response is important, T-cell responses may contribute to protection from Covid-19 even in the presence of lower neutralizing antibody titers.32 In a post hoc analysis reported here, we found that in spike-specific T cells that expanded after vaccination with ChAdOx1 nCoV-19, the majority of antigens and epitopes remained intact in recognition of the B.1.351 variant.

ibute to protection from Covid-19 even in the presence of lower neutralizing antibody titers.32 In a post hoc analysis reported here, we found that in spike-specific T cells that expanded after vaccination with ChAdOx1 nCoV-19, the majority of antigens and epitopes remained intact in recognition of the B.1.351 variant. Although efforts to develop second-generation Covid-19 vaccines targeted against B.1.351 and P1-like variants are under way, the only Covid-19 vaccines likely to be available for most of 2021 have been formulated against the original virus. ChAdOx1 nCoV-19 is likely to be one of the most accessible of all the currently authorized Covid-19 vaccines,33,34 with expected manufacture of approximately 3 billion doses during 2021, and the least costly.35 Relative resistance to human neutralizing antibody responses is expected to be a feature of the pandemic coronavirus in the years ahead, as a result of pressure on the virus to select for variants that can transmit despite immunity after natural infection or vaccination. Deliberations on the utility of the ChAdOx1 nCoV-19 vaccine also need to be made in the context of ongoing global spread and community transmission of the B.1.351 variant36 and the evolution of other SARS-CoV-2 lineages that include similar mutations.