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

This is an ongoing phase 3, double-blind, placebo-controlled trial conducted at 88 sites in the United States, Chile, and Peru in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines. The trial protocol (available with the full text of this article at NEJM.org) and six amendments were approved by the ethics committee or institutional review board at each center, and all participants provided written informed consent before enrollment. Safety is reviewed on a continual basis. Data were gathered by the trial site investigators in collaboration with a contract research organization (IQVIA) and AstraZeneca and analyzed by IQVIA and AstraZeneca. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. All authors contributed to the writing and editing of the manuscript and reviewed and approved the manuscript for submission. Medical writing assistance was funded by AstraZeneca. Agreements requiring authors to maintain data confidentiality were in place between the sponsor and the authors.

the trial to the protocol. All authors contributed to the writing and editing of the manuscript and reviewed and approved the manuscript for submission. Medical writing assistance was funded by AstraZeneca. Agreements requiring authors to maintain data confidentiality were in place between the sponsor and the authors. The trial was designed by AstraZeneca in collaboration with the Department of Health and Human Services and the National Institutes of Health and the trial cochairs.5,6 The objectives of the trial were to assess the safety, efficacy, and immunogenicity of AZD1222 as compared with placebo for the prevention of symptomatic Covid-19 in participants 18 years of age or older whose conditions were medically stable and who were at increased risk for SARS-CoV-2 infection, including high risk for symptomatic and severe Covid-19. Key inclusion and exclusion criteria along with definitions and descriptions of testing protocols are provided in the Supplementary Appendix, available at NEJM.org.

er whose conditions were medically stable and who were at increased risk for SARS-CoV-2 infection, including high risk for symptomatic and severe Covid-19. Key inclusion and exclusion criteria along with definitions and descriptions of testing protocols are provided in the Supplementary Appendix, available at NEJM.org. Participants received two intramuscular injections of either AZD1222 (5×1010 viral particles) or saline placebo administered 4 weeks apart on days 1 and 29 (−3 to +7 days). Random assignment was in a 2:1 ratio to increase the number of participants who received AZD1222. Randomization was stratified according to age (≥18 to 64 years and ≥65 years), with a target of 25% or more of the participants 65 years of age or older. The safety analysis population was defined as all participants who received at least one dose of AZD1222 or placebo, with participants grouped according to the actual vaccine or placebo received. The fully vaccinated analysis population included all participants who were SARS-CoV-2 seronegative at baseline, who received two doses of vaccine or placebo, and who remained in the trial for 15 days or more after their second dose and did not have a previous confirmed SARS-CoV-2 RT-PCR–positive infection.

o received. The fully vaccinated analysis population included all participants who were SARS-CoV-2 seronegative at baseline, who received two doses of vaccine or placebo, and who remained in the trial for 15 days or more after their second dose and did not have a previous confirmed SARS-CoV-2 RT-PCR–positive infection. Participants were reminded weekly to monitor for Covid-19 symptoms. Participants who had one or more qualifying symptoms of Covid-19 underwent illness evaluations and SARS-CoV-2 testing. All trial participants were scheduled to have serum collected for SARS-CoV-2 antibody testing to assess the efficacy of the vaccine, regardless of the presence or severity of symptoms. All participants will remain in the study for 2 years (730 days) after receipt of the first dose of AZD1222 or placebo for safety follow-up and assessment of durability of immune response. A substudy to further assess reactogenicity and immunogenicity of AZD1222 included the first participants who underwent randomization in each age group in the United States (1500 participants 18 to 55 years of age, 750 participants 56 to 69 years of age, and 750 participants 70 years of age or older). These participants completed symptom diaries after vaccination and had additional blood samples obtained on days 15 and 43.

who underwent randomization in each age group in the United States (1500 participants 18 to 55 years of age, 750 participants 56 to 69 years of age, and 750 participants 70 years of age or older). These participants completed symptom diaries after vaccination and had additional blood samples obtained on days 15 and 43. Unsolicited adverse events were recorded for all participants for 28 days after each dose of AZD1222 or placebo, and serious adverse events will be recorded from the time of signed informed consent through day 730. Medically attended adverse events and adverse events of special interest will be recorded from day 1 after the first dose through day 730. Reactogenicity was evaluated in the substudy group to investigate the incidence of solicited local and systemic adverse events for 7 days after each dose of AZD1222 or placebo. The primary efficacy end point was the first occurrence of SARS-CoV-2 symptomatic illness, confirmed by positive results on RT-PCR testing, with onset 15 days or more after the second dose of vaccine or placebo among participants who were seronegative for Covid-19 at baseline (descriptions of end points and analyses are provided in the Supplementary Appendix). Estimated vaccine efficacy was analyzed according to demographic subgroups of interest.

testing, with onset 15 days or more after the second dose of vaccine or placebo among participants who were seronegative for Covid-19 at baseline (descriptions of end points and analyses are provided in the Supplementary Appendix). Estimated vaccine efficacy was analyzed according to demographic subgroups of interest. Key secondary end points included the incidence of symptomatic illness (at 15 days or more after the second dose) regardless of evidence of previous SARS-CoV-2 infection at baseline, severe or critical symptomatic Covid-19, Covid-19–related emergency department visits, symptomatic Covid-19 as defined by Centers for Disease Control and Prevention (CDC) criteria, and SARS-CoV-2 infection regardless of symptoms or severity, measured as a post-treatment serologic response (negative at baseline and positive after baseline) for SARS-CoV-2 nucleocapsid antibodies. Estimated vaccine efficacy was analyzed for exploratory end points, including the incidence of Covid-19–related hospitalizations and intensive care unit (ICU) admissions. As prespecified, immunogenicity analyses, which included analysis of antibodies to spike proteins and nucleocapsid proteins and neutralizing antibodies, were performed on serum samples obtained from participants in the substudy group during the trial to assess antibody titers and responses to SARS-CoV-2 antigens. Saliva specimens were collected at clinical sites or provided by trial participants at illness visits. Specimens positive for SARS-CoV-2 on RT-PCR testing were available for next-generation sequencing.

om participants in the substudy group during the trial to assess antibody titers and responses to SARS-CoV-2 antigens. Saliva specimens were collected at clinical sites or provided by trial participants at illness visits. Specimens positive for SARS-CoV-2 on RT-PCR testing were available for next-generation sequencing. The required number of symptomatic Covid-19 events for the primary analysis was approximately 150 and was reached after independent determination that the interim analysis criteria had been met. The cutoff date for the primary analysis was March 5, 2021. Adjudication of 14 outstanding potential cases that occurred before the cutoff date was conducted in parallel with the initial primary analysis. Once all events that occurred before the data cutoff had been fully adjudicated, the data analysis was refreshed and reflects the final data presented here. Data from participants whose treatment assignment was unmasked or from participants who received a Covid-19 vaccine administered under an emergency use authorization (EUA) were censored at the date of unblinding to the group assignment or EUA vaccine administration, whichever was earlier. All other participant data were censored at the date of the last trial contact. All deaths that were adjudicated as related to Covid-19 were included as a primary efficacy end-point event. Deaths that were adjudicated as not related to Covid-19 were treated as intercurrent events and therefore censored at the date of death.

ther participant data were censored at the date of the last trial contact. All deaths that were adjudicated as related to Covid-19 were included as a primary efficacy end-point event. Deaths that were adjudicated as not related to Covid-19 were treated as intercurrent events and therefore censored at the date of death. The primary efficacy end point was a binary response, whereby a participant’s status was classified as symptomatic Covid-19 or not, before the end of the follow-up period. We used a Poisson regression model with robust variance7 adjusted for follow-up time as the primary efficacy analysis model to estimate the relative risk of the incidence of symptomatic infection in the AZD1222 group as compared with the placebo group. We calculated vaccine efficacy as 1 minus the relative risk, with the result expressed as a percentage. The success criterion for the primary efficacy end point was statistical significance with an observed vaccine efficacy point estimate of at least 50%. A sensitivity analysis was performed with the use of a multiple imputation approach to evaluate the robustness of the analysis of the primary end point to missing data after censoring. Additional details on the statistical analyses are provided in the Supplementary Appendix.

The trial was designed by AstraZeneca in collaboration with the Department of Health and Human Services and the National Institutes of Health and the trial cochairs.5,6 The objectives of the trial were to assess the safety, efficacy, and immunogenicity of AZD1222 as compared with placebo for the prevention of symptomatic Covid-19 in participants 18 years of age or older whose conditions were medically stable and who were at increased risk for SARS-CoV-2 infection, including high risk for symptomatic and severe Covid-19. Key inclusion and exclusion criteria along with definitions and descriptions of testing protocols are provided in the Supplementary Appendix, available at NEJM.org.

Unsolicited adverse events were recorded for all participants for 28 days after each dose of AZD1222 or placebo, and serious adverse events will be recorded from the time of signed informed consent through day 730. Medically attended adverse events and adverse events of special interest will be recorded from day 1 after the first dose through day 730. Reactogenicity was evaluated in the substudy group to investigate the incidence of solicited local and systemic adverse events for 7 days after each dose of AZD1222 or placebo.

The primary efficacy end point was the first occurrence of SARS-CoV-2 symptomatic illness, confirmed by positive results on RT-PCR testing, with onset 15 days or more after the second dose of vaccine or placebo among participants who were seronegative for Covid-19 at baseline (descriptions of end points and analyses are provided in the Supplementary Appendix). Estimated vaccine efficacy was analyzed according to demographic subgroups of interest. Key secondary end points included the incidence of symptomatic illness (at 15 days or more after the second dose) regardless of evidence of previous SARS-CoV-2 infection at baseline, severe or critical symptomatic Covid-19, Covid-19–related emergency department visits, symptomatic Covid-19 as defined by Centers for Disease Control and Prevention (CDC) criteria, and SARS-CoV-2 infection regardless of symptoms or severity, measured as a post-treatment serologic response (negative at baseline and positive after baseline) for SARS-CoV-2 nucleocapsid antibodies. Estimated vaccine efficacy was analyzed for exploratory end points, including the incidence of Covid-19–related hospitalizations and intensive care unit (ICU) admissions.

As prespecified, immunogenicity analyses, which included analysis of antibodies to spike proteins and nucleocapsid proteins and neutralizing antibodies, were performed on serum samples obtained from participants in the substudy group during the trial to assess antibody titers and responses to SARS-CoV-2 antigens. Saliva specimens were collected at clinical sites or provided by trial participants at illness visits. Specimens positive for SARS-CoV-2 on RT-PCR testing were available for next-generation sequencing.

The required number of symptomatic Covid-19 events for the primary analysis was approximately 150 and was reached after independent determination that the interim analysis criteria had been met. The cutoff date for the primary analysis was March 5, 2021. Adjudication of 14 outstanding potential cases that occurred before the cutoff date was conducted in parallel with the initial primary analysis. Once all events that occurred before the data cutoff had been fully adjudicated, the data analysis was refreshed and reflects the final data presented here. Data from participants whose treatment assignment was unmasked or from participants who received a Covid-19 vaccine administered under an emergency use authorization (EUA) were censored at the date of unblinding to the group assignment or EUA vaccine administration, whichever was earlier. All other participant data were censored at the date of the last trial contact. All deaths that were adjudicated as related to Covid-19 were included as a primary efficacy end-point event. Deaths that were adjudicated as not related to Covid-19 were treated as intercurrent events and therefore censored at the date of death.

Between August 28, 2020, and January 15, 2021, a total of 34,117 unique participants were screened, 32,451 of whom met eligibility criteria and underwent randomization to receive the AZD1222 vaccine (21,635 participants) or placebo (10,816 participants) (Figure 1). The majority of participants were men (55.6%) and had at least one coexisting condition (59.2%); the mean (±SD) age was 50.2±15.9 years (Table 1). Overall, 79.0% of the participants were White, 8.3% were Black, 4.4% were Asian, 4.0% were American Indian or Alaska Native, 2.4% were of multiple races or ethnic groups, 0.3% were Native Hawaiian or other Pacific Islander, and the remainder were of unknown or unreported race or ethnic group. Across both groups, 22.3% of participants were Hispanic or Latinx. Baseline demographic and clinical characteristics were balanced between the trial groups in both the safety analysis population (Table 1) and the fully vaccinated analysis population (Table S1 in the Supplementary Appendix). A total of 347 participants (1.6%) in the AZD1222 group and 169 (1.6%) in the placebo group were living with well-controlled human immunodeficiency virus infection.

en the trial groups in both the safety analysis population (Table 1) and the fully vaccinated analysis population (Table S1 in the Supplementary Appendix). A total of 347 participants (1.6%) in the AZD1222 group and 169 (1.6%) in the placebo group were living with well-controlled human immunodeficiency virus infection. The incidence of adverse events is shown in Table S2. A total of 11,972 participants (37.0%) — 8771 (40.6%) in the AZD1222 group and 3201 (29.7%) in the placebo group — reported 23,538 adverse events. The most common adverse events, occurring in at least 5% of participants within 28 days after any dose in either group, were general pain (8.2% in the AZD1222 group and 2.3% in the placebo group), headache (6.2% and 4.6%, respectively), injection-site pain (6.8% and 2.0%), and fatigue (5.1% and 3.5%). A similar percentage of participants in each group had a serious adverse event within 28 days after any dose: 119 serious adverse events occurred among 101 participants (0.5%) in the AZD1222 group and 59 events among 53 participants (0.5%) in the placebo group. During the entire trial period, a total of 7 adverse events leading to death occurred in 7 participants in the AZD1222 group, and 9 adverse events leading to 7 deaths occurred in the placebo group. These deaths are described in Table S2. No deaths were considered by investigators to be related to the vaccine or placebo. No deaths related to Covid-19 occurred in the AZD1222 group, and two deaths related to Covid-19 occurred in the placebo group.

d 9 adverse events leading to 7 deaths occurred in the placebo group. These deaths are described in Table S2. No deaths were considered by investigators to be related to the vaccine or placebo. No deaths related to Covid-19 occurred in the AZD1222 group, and two deaths related to Covid-19 occurred in the placebo group. Medically attended adverse events and adverse events of special interest within 28 days after a dose also occurred in similar proportions in the two groups (Table S2). The incidences of individual adverse events related to the vaccine or placebo during the entire trial period are shown in Tables S3 through S5. The incidence of potential immune-mediated conditions was similar in the two groups (1.8% in the AZD1222 group and 3.4% in the placebo group), as were the incidences of adverse events of special interest: neurologic (0.5% in the AZD1222 group and 0.4% in the placebo group), vascular (0.1% in the AZD1222 group and <0.1% in the placebo group), and hematologic (<0.1% in both groups). Specifically, the incidences of deep-vein thrombosis (<0.1% in both groups), pulmonary embolism (<0.1% in both groups), thrombocytopenia (<0.1% in the AZD1222 group and none in the placebo group), and immune thrombocytopenia (none in the AZD1222 group and <0.1% in the placebo group) were low and similar in the groups. There were no cases in either group of thrombosis with thrombocytopenia, cerebral venous sinus thrombosis, or venous thrombosis in unusual locations.

e AZD1222 group and none in the placebo group), and immune thrombocytopenia (none in the AZD1222 group and <0.1% in the placebo group) were low and similar in the groups. There were no cases in either group of thrombosis with thrombocytopenia, cerebral venous sinus thrombosis, or venous thrombosis in unusual locations. In the substudy population, more participants in the AZD1222 group than in the placebo group had local solicited adverse events (74.1% in the AZD1222 group vs. 24.4% in the placebo group) and systemic solicited adverse events (71.6% vs. 53.0%) (Figure 2). The majority of solicited adverse events (92.6%) across both groups were mild or moderate in intensity. Events occurred less frequently after the second dose than after the first dose in both age groups, a difference that was more marked in participants 18 to 64 years of age. The majority of local and systemic solicited adverse events resolved within 1 to 2 days after onset.

oth groups were mild or moderate in intensity. Events occurred less frequently after the second dose than after the first dose in both age groups, a difference that was more marked in participants 18 to 64 years of age. The majority of local and systemic solicited adverse events resolved within 1 to 2 days after onset. Once adjudication of all events that occurred before the data cutoff was complete, 203 symptomatic Covid-19 events met the case definition of the primary end point and were included in the updated primary analysis for the fully vaccinated analysis population (17,662 participants in the AZD1222 group and 8550 in the placebo group) (Figure 1). The efficacy analyses presented here are based on the updated primary analysis of the group whose data were censored as of the cutoff date. In the full analysis population, the median follow-up duration from the second dose to the data cutoff date, regardless of unblinding of group assignments, was 61.0 days (range, 1 to 129) in both groups (Table 1). Overall, 73 events (0.4%) occurred in the AZD1222 group and 130 (1.5%) occurred in the placebo group (Figure 3). For the primary efficacy end point, the success criterion was met in the fully vaccinated analysis population on the basis of an overall vaccine efficacy estimate of 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001). Results regarding the cumulative incidence of the first SARS-CoV-2 RT-PCR–positive symptomatic illness after the second dose of AZD1222 (Figure 4) showed that the effect of AZD1222 began soon after the second dose. Vaccine efficacy was consistent in the analyses in which follow-up data were not censored at unblinding of the treatment assignment or EUA vaccination (74.3%; 95% CI, 66.0 to 80.6) and also when multiple imputation was used (73.3%; 95% CI, 64.6 to 79.9).

owed that the effect of AZD1222 began soon after the second dose. Vaccine efficacy was consistent in the analyses in which follow-up data were not censored at unblinding of the treatment assignment or EUA vaccination (74.3%; 95% CI, 66.0 to 80.6) and also when multiple imputation was used (73.3%; 95% CI, 64.6 to 79.9). On September 9, 2020, the trial was placed on clinical hold owing to an event of transverse myelitis reported in a different AZD1222 clinical study.2 After a review of the event and all available safety data, the Food and Drug Administration lifted the clinical hold on October 23, 2020, and the trial resumed on October 28, 2020. A total of 775 participants (2.4%) in the safety analysis population were affected by the clinical hold and received their second dose outside the planned 28-day window. Vaccine efficacy in this subgroup of participants who received their second dose at an extended dosing interval was consistent with that in the overall group (78.1%; 95% CI, 49.2 to 90.6).

the safety analysis population were affected by the clinical hold and received their second dose outside the planned 28-day window. Vaccine efficacy in this subgroup of participants who received their second dose at an extended dosing interval was consistent with that in the overall group (78.1%; 95% CI, 49.2 to 90.6). Vaccine efficacy estimates according to subgroup are shown in Figure 3, although small case numbers hindered confidence in some subgroup estimates, such as those for ICU admissions and those based on data from participants in Chile and Peru. Estimated vaccine efficacy was high against symptomatic illness in participants 18 to 64 years of age (72.8%; 95% CI, 63.4 to 79.9) and those 65 years of age or older (83.5%; 95% CI, 54.2 to 94.1) and was consistent across participants of different races and ethnic groups, status with respect to coexisting conditions, baseline SARS-CoV-2 serostatus, and sex. In Chile, 4 cases of symptomatic illness were noted among 1360 participants in the AZD1222 group as compared with 2 cases among 672 participants in the placebo group. In Peru, 11 cases among 867 participants in the AZD1222 group and 9 cases among 435 participants in the placebo group were observed. Estimated vaccine efficacy against symptomatic Covid-19 regardless of evidence of previous SARS-CoV-2 infection (a secondary end point) was 73.7% (95% CI, 65.1 to 80.1; P<0.001).

o group. In Peru, 11 cases among 867 participants in the AZD1222 group and 9 cases among 435 participants in the placebo group were observed. Estimated vaccine efficacy against symptomatic Covid-19 regardless of evidence of previous SARS-CoV-2 infection (a secondary end point) was 73.7% (95% CI, 65.1 to 80.1; P<0.001). The vaccine was significantly effective against all other key secondary efficacy end points (Figure 3). In the fully vaccinated analysis population, no cases of severe or critical symptomatic Covid-19 were observed among the 17,662 participants in the AZD1222 group, as compared with 8 cases (<0.1%) among the 8550 participants in the placebo group. Estimated vaccine efficacy of AZD1222 for the prevention of Covid-19 (as defined by CDC criteria) was high (69.7%; 95% CI, 60.7 to 76.6; P<0.001), as was efficacy against emergency department visits attributed to Covid-19 (94.8%; 95% CI, 59.0 to 99.3; P=0.005), with 1 (<0.1%) emergency department visit in the AZD1222 group and 9 (0.1%) in the placebo group. Estimated vaccine efficacy against Covid-19–related hospitalizations (an exploratory end point) was 94.2% (95% CI, 53.3 to 99.3) (Figure 3). One participant in the AZD1222 group who had a Covid-19–related emergency department visit had an allergic reaction to a monoclonal antibody treatment and was hospitalized. This hospitalization did not meet the criteria for severe or critical Covid-19.

exploratory end point) was 94.2% (95% CI, 53.3 to 99.3) (Figure 3). One participant in the AZD1222 group who had a Covid-19–related emergency department visit had an allergic reaction to a monoclonal antibody treatment and was hospitalized. This hospitalization did not meet the criteria for severe or critical Covid-19. The estimated vaccine efficacy for incidences of first SARS-CoV-2 RT-PCR–positive symptomatic illness occurring after the first dose of AZD1222 or placebo is described in Figure S1. AZD1222 was efficacious at preventing infection with SARS-CoV-2, as measured by nucleocapsid antibody seroconversion 15 days or more after the second dose; this included all participants who tested positive for SARS-CoV-2 nucleocapsid antibodies regardless of symptoms or severity (64.3%; 95% CI, 56.1 to 71.0; P<0.001). Additional details of the efficacy analyses are provided in the Supplementary Appendix. Participants who received AZD1222 and were seronegative at baseline showed strong vaccine-induced serum IgG responses to the spike protein (Fig. S2). Levels of neutralizing antibodies were higher than baseline at all time points in the AZD1222 group, increasing further after a second dose, but remained low throughout the trial in the placebo group (Fig. S3).

re seronegative at baseline showed strong vaccine-induced serum IgG responses to the spike protein (Fig. S2). Levels of neutralizing antibodies were higher than baseline at all time points in the AZD1222 group, increasing further after a second dose, but remained low throughout the trial in the placebo group (Fig. S3). Among participants in the full analysis population (the 30,889 participants who were seronegative at baseline), whole-genome sequencing of saliva samples obtained from 176 participants in the AZD1222 group and 183 participants in the placebo group attending illness visits, regardless of qualifying symptoms, yielded four cases of variants of concern, including alpha and beta variants (one putative B.1.351 case was determined by clade). Of the variants of interest observed, epsilon was the most common (B.1.429 in 14 participants and B.1.427 in 3 participants) followed by iota (B.1.526 in 1 participant) (Table S6).

The incidence of adverse events is shown in Table S2. A total of 11,972 participants (37.0%) — 8771 (40.6%) in the AZD1222 group and 3201 (29.7%) in the placebo group — reported 23,538 adverse events. The most common adverse events, occurring in at least 5% of participants within 28 days after any dose in either group, were general pain (8.2% in the AZD1222 group and 2.3% in the placebo group), headache (6.2% and 4.6%, respectively), injection-site pain (6.8% and 2.0%), and fatigue (5.1% and 3.5%). A similar percentage of participants in each group had a serious adverse event within 28 days after any dose: 119 serious adverse events occurred among 101 participants (0.5%) in the AZD1222 group and 59 events among 53 participants (0.5%) in the placebo group. During the entire trial period, a total of 7 adverse events leading to death occurred in 7 participants in the AZD1222 group, and 9 adverse events leading to 7 deaths occurred in the placebo group. These deaths are described in Table S2. No deaths were considered by investigators to be related to the vaccine or placebo. No deaths related to Covid-19 occurred in the AZD1222 group, and two deaths related to Covid-19 occurred in the placebo group.

In the substudy population, more participants in the AZD1222 group than in the placebo group had local solicited adverse events (74.1% in the AZD1222 group vs. 24.4% in the placebo group) and systemic solicited adverse events (71.6% vs. 53.0%) (Figure 2). The majority of solicited adverse events (92.6%) across both groups were mild or moderate in intensity. Events occurred less frequently after the second dose than after the first dose in both age groups, a difference that was more marked in participants 18 to 64 years of age. The majority of local and systemic solicited adverse events resolved within 1 to 2 days after onset.

Once adjudication of all events that occurred before the data cutoff was complete, 203 symptomatic Covid-19 events met the case definition of the primary end point and were included in the updated primary analysis for the fully vaccinated analysis population (17,662 participants in the AZD1222 group and 8550 in the placebo group) (Figure 1). The efficacy analyses presented here are based on the updated primary analysis of the group whose data were censored as of the cutoff date. In the full analysis population, the median follow-up duration from the second dose to the data cutoff date, regardless of unblinding of group assignments, was 61.0 days (range, 1 to 129) in both groups (Table 1). Overall, 73 events (0.4%) occurred in the AZD1222 group and 130 (1.5%) occurred in the placebo group (Figure 3). For the primary efficacy end point, the success criterion was met in the fully vaccinated analysis population on the basis of an overall vaccine efficacy estimate of 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001). Results regarding the cumulative incidence of the first SARS-CoV-2 RT-PCR–positive symptomatic illness after the second dose of AZD1222 (Figure 4) showed that the effect of AZD1222 began soon after the second dose. Vaccine efficacy was consistent in the analyses in which follow-up data were not censored at unblinding of the treatment assignment or EUA vaccination (74.3%; 95% CI, 66.0 to 80.6) and also when multiple imputation was used (73.3%; 95% CI, 64.6 to 79.9).

exploratory end point) was 94.2% (95% CI, 53.3 to 99.3) (Figure 3). One participant in the AZD1222 group who had a Covid-19–related emergency department visit had an allergic reaction to a monoclonal antibody treatment and was hospitalized. This hospitalization did not meet the criteria for severe or critical Covid-19. The estimated vaccine efficacy for incidences of first SARS-CoV-2 RT-PCR–positive symptomatic illness occurring after the first dose of AZD1222 or placebo is described in Figure S1. AZD1222 was efficacious at preventing infection with SARS-CoV-2, as measured by nucleocapsid antibody seroconversion 15 days or more after the second dose; this included all participants who tested positive for SARS-CoV-2 nucleocapsid antibodies regardless of symptoms or severity (64.3%; 95% CI, 56.1 to 71.0; P<0.001). Additional details of the efficacy analyses are provided in the Supplementary Appendix.

Participants who received AZD1222 and were seronegative at baseline showed strong vaccine-induced serum IgG responses to the spike protein (Fig. S2). Levels of neutralizing antibodies were higher than baseline at all time points in the AZD1222 group, increasing further after a second dose, but remained low throughout the trial in the placebo group (Fig. S3).

Among participants in the full analysis population (the 30,889 participants who were seronegative at baseline), whole-genome sequencing of saliva samples obtained from 176 participants in the AZD1222 group and 183 participants in the placebo group attending illness visits, regardless of qualifying symptoms, yielded four cases of variants of concern, including alpha and beta variants (one putative B.1.351 case was determined by clade). Of the variants of interest observed, epsilon was the most common (B.1.429 in 14 participants and B.1.427 in 3 participants) followed by iota (B.1.526 in 1 participant) (Table S6).

AZD1222 is a safe and efficacious vaccine for the prevention of symptomatic Covid-19. In a diverse adult population of more than 32,000 participants, two doses of AZD1222 administered 4 weeks apart were 74% efficacious overall at preventing symptomatic illness 15 days or more after the second dose. Success criteria for AZD1222 were met on the basis of the measured primary and secondary end points. When measured according to the CDC definition of Covid-19, which can include mild disease, AZD1222 had 70% efficacy. Furthermore, although event rates were low, participants who received AZD1222 had no cases of severe or critical symptomatic Covid-19 and had significantly fewer Covid-19–related emergency department visits, hospitalizations, and ICU admissions than participants who received placebo. A key strength of this trial is that it showed the efficacy of AZD1222 across all age groups, including in adults 65 years of age or older. This finding is further supported by emerging real-world data from the United Kingdom that show high vaccine effectiveness for prevention of Covid-19, including severe disease and hospitalization in older adults, after the first AZD1222 dose.8-10 Because of small case numbers in Chile and Peru, we were unable to precisely estimate vaccine efficacy in those groups. This trial was not designed to assess vaccine efficacy according to enrollment country or in smaller subpopulations.

A key strength of this trial is that it showed the efficacy of AZD1222 across all age groups, including in adults 65 years of age or older. This finding is further supported by emerging real-world data from the United Kingdom that show high vaccine effectiveness for prevention of Covid-19, including severe disease and hospitalization in older adults, after the first AZD1222 dose.8-10 Because of small case numbers in Chile and Peru, we were unable to precisely estimate vaccine efficacy in those groups. This trial was not designed to assess vaccine efficacy according to enrollment country or in smaller subpopulations. Although the level of SARS-CoV-2 neutralizing antibodies that correlates with protection is not yet known, the role of these antibodies as an important contributor to protective immunity is widely accepted.11 In our trial, both SARS-CoV-2 spike protein binding and neutralizing antibodies increased in all age groups after the first dose of AZD1222 and further increased from baseline when measured 28 days after the second dose,1 a finding consistent with results from previous trials.12 No new vaccine-related safety signals were identified, and solicited adverse events were mostly mild or moderate and were fewer in number after the second dose of AZD1222 than after the first. Results from this trial showed no evidence of increased overall risk of neurologic events, specifically demyelinating disease or acute transverse myelitis, with AZD1222 as compared with placebo and showed no instances of enhanced respiratory disease.

ewer in number after the second dose of AZD1222 than after the first. Results from this trial showed no evidence of increased overall risk of neurologic events, specifically demyelinating disease or acute transverse myelitis, with AZD1222 as compared with placebo and showed no instances of enhanced respiratory disease. In multiple countries, rare instances of thrombotic events with thrombocytopenia have been reported after Covid-19 vaccinations,13-15 including among persons who received AZD1222.16-21 Although no evidence of increased overall risk of thrombosis or thrombosis with thrombocytopenia was noted among participants who received AZD1222 in this trial, thrombosis with thrombocytopenia syndrome (also known as vaccine-induced immune thrombotic thrombocytopenia) is rare. Independent safety reviews by regulatory authorities of available clinical and real-world evidence2,3,8,9,22,23 have concluded that the benefits of AZD1222 outweigh the potential risks, with protection from the serious consequences of Covid-19 increasing with age and SARS-CoV-2 infection rate.17,24,25

topenia) is rare. Independent safety reviews by regulatory authorities of available clinical and real-world evidence2,3,8,9,22,23 have concluded that the benefits of AZD1222 outweigh the potential risks, with protection from the serious consequences of Covid-19 increasing with age and SARS-CoV-2 infection rate.17,24,25 A comparison of data from different trials, including trials that evaluated the same vaccine, is challenging owing to numerous variables, such as difference in trial participants, symptomatic illness criteria, and circulating viruses.26 With dosing intervals ranging from 4 weeks, as reported here, to 12 weeks, as reported previously, AZD1222 has shown similar safety, side-effect profile, efficacy, and immunogenicity in adults in a pooled analysis of trials across different geographic locations,1,2 albeit with lower efficacy observed against mild-to-moderate disease in South Africa associated with the beta (B.1.351) variant.27

s reported previously, AZD1222 has shown similar safety, side-effect profile, efficacy, and immunogenicity in adults in a pooled analysis of trials across different geographic locations,1,2 albeit with lower efficacy observed against mild-to-moderate disease in South Africa associated with the beta (B.1.351) variant.27 A limitation of this trial is the early unblinding of group assignment for more than one third of participants, whose data were censored for most analyses. Unblinding occurred because other Covid-19 vaccines became authorized for use during the trial, allowing participants to make individual vaccination decisions. Other limitations include the small number of variants of concern owing to the timing of the trial within the pandemic and the short duration of follow-up, which also precludes evaluations of the duration of the efficacy and long-term safety of AZD1222. Analysis of the efficacy of the vaccine over time is ongoing. These data support AZD1222 as a safe and efficacious vaccine that prevents symptomatic and severe Covid-19 across diverse adult populations.