Of 5254 randomized participants, 3460 and 1737 were randomly assigned to receive AZD7442 or placebo, respectively. One participant was randomly assigned to placebo but incorrectly received AZD7442, and was therefore analyzed in the AZD7442 group for safety. In total, 3669 (69.8%) participants completed the study, 1082 (20.6%) discontinued, and 503 (9.6%) left the main study to be enrolled in a separate phase 3, open-label substudy evaluating repeat doses of AZD7442 (Supplementary Fig. S1a). Median (range) follow-up was 456 (1–605) days in the AZD7442 group and 455 (3–587) days in the placebo group (follow-up was greater than the 457 days of the study in some participants because of delayed final visits). By the end of the study, 1697 (49.3%) participants in the AZD7442 group and 880 (50.8%) in the placebo group had elected to be unblinded, and 1851 (53.8%) in the AZD7442 group and 1058 (61.1%) in the placebo group received a COVID-19 vaccine.

Baseline characteristics, which were previously reported, were generally similar between the groups [3]. Briefly, mean age was 53.5 (standard deviation 15.0) years, 43.4% of participants were aged ≥ 60 years, 53.9% were male, 73.0% reported their race as White, 79.7% reported their ethnicity as not Hispanic or Latino, and 77.7% had one or more of the following comorbidities considered risk factors for progression to severe COVID-19: history of obesity (42.4%), obesity at enrollment (41.7%), hypertension (36.4%), current smoker (21.0%), or diabetes (14.3%); in addition, 3.1% were receiving immunosuppressive treatment and 0.5% had immunosuppressive disease.

In the primary analysis of PROVENT, pre-exposure prophylaxis with AZD7442 reduced the risk of developing symptomatic COVID-19 versus placebo, with a relative risk reduction (RRR) of 76.7% [95% confidence interval (CI) 46.1, 90.0; p < 0.001); after 6 months of follow-up, the RRR was 82.8% [95% CI 65.8, 91.4) [3]. The result of the primary analysis was confirmed at the final analysis (follow-up to day 183), with an RRR of 83.0% (95% CI 67.3, 91.2; nominal p < 0.001). By day 366, the RRR was 46.3% (95% CI 23.1, 62.4; nominal p < 0.001). Kaplan–Meier and Cox proportional hazards analysis of the time to first incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness through day 366 support the primary endpoint analyses (Fig. 1a). Severe or critical symptomatic COVID-19 occurred in 0 of 3441 (0%) AZD7442 participants and 6 of 1731 (0.3%) participants in the placebo group by day 183. Severe or critical symptomatic COVID-19 through day 366 occurred in two of 3441 (0.1%) participants in the AZD7442 group versus 11 of 1731 (0.6%) in the placebo group, corresponding to an RRR of 91.4% (95% CI 61.3, 98.1; nominal p < 0.0001) (Fig. 1b).

a Time to first SARS-CoV-2 RT-PCR-positive symptomatic illness and b severe or critical COVID-19 in PROVENT over 366 days. CI confidence interval, HR hazard ratio, RT-PCR reverse transcription-polymerase chain reaction, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2. aIndicates the percentage of events within each group (AZD7442 and placebo) using the group N values as denominators, rather than the total population N for the cumulative incidence shown on the Y-axis

After a median 6 months of follow-up, the efficacy of AZD7442 was found to be consistent regardless of age (RRR of 87.8% in participants aged ≥ 60 years) or comorbidities, including obesity, hypertension, diabetes, smoking, or receipt of immunosuppressive treatment (RRR of 71.7–82.9%) [3]. Although the medical histories of some participants had been updated by the time of the final analysis, the efficacy of AZD7442 remained largely unchanged in participants aged ≥ 60 years (RRR of 88.0%) or with comorbidities, including obesity, hypertension, diabetes, smoking, or receipt of immunosuppressive treatment (RRR of 70.2–83.8%).

At day 366, sequencing data were available for 26 participants in the AZD7442 and 16 in the placebo group with symptomatic COVID-19. The most common variants detected were Delta (15 events), Omicron (14 events), and Alpha (five events). Within this small sample of participants with breakthrough infections there was no evidence of resistance to AZD7442, and substitutions in the AZD7442 binding site were balanced between the AZD7442 and placebo groups.

AEs occurred in 2016 (58.2%) participants in the AZD7442 group and 1007 (58.0%) in the placebo group. In both groups, the most common AEs (Medical Dictionary for Regulatory Activities Preferred Terms) were COVID-19, headache, cough, and fatigue (Table 1). Lower respiratory tract infection occurred in 28 (0.8%) participants in the AZD7442 group and 20 (1.2%) in the placebo group, and COVID-19 pneumonia occurred in four (0.1%) participants in the AZD7442 group and 21 (1.2%) in the placebo group (Supplementary Table S2). Most AEs were mild to moderate in severity. Grade 3–4 AEs occurred in 256 (7.4%) participants in the AZD7442 group and 125 (7.2%) in the placebo group. SAEs occurred in 215 (6.2%) participants in the AZD7442 group and 97 (5.6%) in the placebo group (Table 1).

No discernable pattern in SAEs was reported (Supplementary Table S3). Two participants in the AZD7442 group had SAEs considered possibly related to study drug by the investigator: one participant had chronic myeloid leukemia and one participant, with a history of diverticulitis and previous partial colectomy, had mesenteric artery thrombosis. There were no notable differences or trends between the AZD7442 and placebo groups in the maximum severity of the SAEs reported. AESIs occurred in 103 (3.0%) participants in the AZD7442 group and 43 (2.5%) in the placebo group (Table 1). There was no discernable pattern in AESIs reported (Supplementary Table S4). Cardiovascular AESIs occurred in 19 (0.5%) participants in the AZD7442 group and seven (0.4%) in the placebo group. Of the 88 (2.5%) and 39 (2.2%) participants in the AZD7442 and placebo groups, respectively, who had cardiovascular events evaluated by the cardiovascular event adjudication committee, 40 (1.2%) and 12 (0.7%) participants were adjudicated as having had true cardiovascular events. All participants with cardiac disorder SAEs during the study had cardiac risk factors and/or a history of cardiovascular disease at baseline, and there was no clear temporal or clinical pattern.

Twenty-two (0.6%) participants died in the AZD7442 group between study days 6 and 503, and 10 (0.6%) participants died in the placebo group between study days 13 and 313 (Table 1). The most common fatal AEs in each group were cardiac disorders (Supplementary Table S5).

Of 1131 randomized participants, 749 and 372 received AZD7442 or placebo, respectively. In total, 928 (82.1%) participants completed the study and 203 (17.9%) discontinued (Supplementary Fig.S1b). Median (range) follow-up was 455 (5–573) days in the AZD7442 group and 455 (11–527) days in the placebo groups. By the end of the study, 140 (18.5%) participants in the AZD7442 group and 98 (26.1%) in the placebo group had elected to be unblinded, and 347 (45.9%) in the AZD7442 group and 181 (48.3%) in the placebo group received a COVID-19 vaccine.

Baseline characteristics were generally similar between the groups [4]. Briefly, mean age was 46.4 (standard deviation 15.9) years, 20.0% of participants were aged ≥ 60 years, 50.3% were male, 84.1% reported their race as White, 57.5% reported their ethnicity as Hispanic or Latino, and 65.0% had one or more of the following comorbidities considered risk factors for progression to severe COVID-19: history of obesity (40.1%), obesity at enrollment (39.7%), hypertension (24.1%), current smoker (19.2%), or diabetes (11.6%); in addition, 0.7% were receiving immunosuppressive treatment. Most participants were SARS-CoV-2 RT-PCR negative (87.2%) or their SARS-CoV-2 RT-PCR status was missing (8.5%), and 4.3% were SARS-CoV-2 RT-PCR positive.

At the primary analysis of STORM CHASER, the RRR in symptomatic COVID-19 prior to day 183 was 33.3% (95% CI − 25.9, 64.7) for AZD7442 compared with placebo, which was not statistically significant (p = 0.212) [4]. However, a marginally significant RRR of 73.2% (95% CI 27.1, 90.1) was observed in an ad hoc analysis of the subgroup of participants with a negative or missing SARS-CoV-2 RT-PCR status at baseline. In the final analysis of the primary efficacy endpoint, the RRR in symptomatic COVID-19 was 43.3% at day 183 (95% CI 1.4, 67.4; nominal p = 0.044), while in the ad hoc analysis among participants with a negative or missing SARS-CoV-2 RT-PCR status at baseline, the RRR was 70.2% (95% CI 36.6, 86.0). The RRR in symptomatic COVID-19 in the primary analysis at day 366 was 3.4% (95% CI − 35.6, 31.2; nominal p = 0.842). Kaplan–Meier and Cox proportional hazards analysis of the time to first incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness through day 366 are presented in Fig. 2. Severe or critical symptomatic COVID-19 did not occur in participants in the AZD7442 group and occurred in two (0.5%) participants in the placebo group through day 366.

Time to first symptomatic COVID-19 event in STORM CHASER over 366 days. HR are from a proportional hazards model with Efron method, with p values from log-rank tests. The + symbols indicate a censored observation. CI confidence interval, HR hazard ratio. aIndicates the percentage of events within each group (AZD7442 and placebo) using the group N values as denominators, rather than the total population N for the cumulative incidence shown on the Y-axis

At day 366, sequencing data were available for isolates from 31 participants in the AZD7442 group and 22 in the placebo group with symptomatic COVID-19. The most common variants detected were Omicron (18 events), Alpha (13 events), and Delta (10 events). There was no evidence of resistance to AZD7442 within these isolates from participants with breakthrough infections and substitutions in the AZD7442 binding site were balanced between the AZD7442 and placebo groups. When the 2:1 randomization sequence was considered, the proportion of participants experiencing breakthrough infections was similar between the AZD7442 and placebo groups.

AEs occurred in 348 (46.5%) participants in the AZD7442 group and 193 (51.9%) in the placebo group (Table 1). The most common AEs in both groups were COVID-19, headache, cough, and fatigue (Supplementary Table S6). Most AEs were mild to moderate in severity. Grade 3–4 AEs occurred in 30 (4.0%) participants in the AZD7442 group and 26 (7.0%) in the placebo group. SAEs occurred in 20 (2.7%) participants in the AZD7442 group and 16 (4.3%) in the placebo group (Table 1). There was no discernable pattern in SAEs reported (Supplementary Table S7), no notable differences or trends between the AZD7442 and placebo groups in the maximum severity of SAEs reported, and no SAEs were considered possibly related to study drug by the investigator. AESIs occurred in four (0.5%) participants in the AZD7442 group and four (1.1%) in the placebo group (Table 1). There was no discernable pattern in AESIs reported (Supplementary Table S8). Cardiovascular events were not categorized as AESIs in STORM CHASER, but cardiac disorder SAEs were balanced across treatment groups [two (0.3%) and two (0.5%) participants in the AZD7442 and placebo groups, respectively] (Supplementary Table S8). Three (0.4%) participants died in the AZD7442 group between study days 131 and 335, and two (0.5%) participants died in the placebo group between study days 187 and 364 (Table 1; Supplementary Table S9).

In both PROVENT and STORM CHASER, serum concentration–time profiles for tixagevimab and cilgavimab were similar and consistent with these antibodies having an extended duration of protection (Fig. 3). Incidence and serum titers of TE-ADAs in participants receiving AZD7442 are summarized in Supplementary Table S10. Geometric mean serum concentrations of AZD7442 were similar among participants with TE-ADAs versus those without TE-ADAs, indicating that ADAs had no apparent effect on the pharmacokinetics of AZD7442 (Fig. 3).

AZD7442 serum concentrations by participant ADA status in a PROVENT and b STORM CHASER. ADA antidrug antibody, %CV percent geometric coefficient of variation, TE-ADA treatment-emergent ADA