Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia
Summary Background A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial. Methods
We did a randomised, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396).
Findings Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6–95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine.
Interpretation This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort.
Funding Moscow City Health Department, Russian Direct Investment Fund, Sberbank, and RUSAL.
Introduction The COVID-19 pandemic has led to more than 98 million confirmed cases and more than 2 million deaths (at the time of publication). There are a few provisionally licensed vaccines against COVID-19, and global efforts are focusing on developing safe and efficacious vaccines for COVID-19 prevention. According to the WHO draft landscape of COVID-19 candidate vaccines,1 64 candidates are in clinical assessment (including 13 at phase 3) and 173 are in preclinical analyses. The phase 3 vaccine candidates include a variety of vaccine platforms: vector vaccines (Gamaleya National Research Centre for Epidemiology and Microbiology [NRCEM; this study], University of Oxford/AstraZeneca,2 CanSino Biological Inc/Beijing Institute of Biotechnology, and Janssen Pharmaceutical Companies), mRNA-based vaccines (Moderna/National Institute of Allergy and Infectious Diseases3 and BioNTech/Fosun Pharma/Pfizer4), inactivated vaccines (SinoVac, Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm, and Bharat Biotech), and adjuvanted recombinant protein nanoparticles (Novavax).
The safety of adenoviral vector vaccines has been extensively studied, and adenoviral vector-based therapeutic drugs are used in clinical practice.5, 6, 7 Adenoviral vector-delivered antigens are known to induce both cellular and humoral immunity after a single immunisation, allowing their use as an emergency prophylaxis tool in a pandemic. Furthermore, the use of two immunisations gives a durable and long-lasting immune response.8, 9 These characteristics make recombinant replication-deficient adenovirus (rAd)-based vaccines suitable candidates for the WHO target product profiles for long-term protection of people at high risk of COVID-19 in outbreak settings because they stimulate rapid onset of protective immunity. Although adenoviral vectors might induce immune responses against vector components and attenuate antigen-induced responses, prime-boost heterologous vaccination with two different vectors allows minimisation of this effect.9, 10, 11 Thus, the most effective approach for generating a powerful and long-lasting immune response that does not depend on the presence of a pre-existing immune response to the vector is the heterologous prime-boost vaccination approach. We used this approach when developing a vaccine for the prevention of COVID-19.
Gam-COVID-Vac is a combined vector vaccine, based on rAd type 26 (rAd26) and rAd type 5 (rAd5)—both of which carry the gene for SARS-CoV-2 full-length glycoprotein S (rAd26-S and rAd5-S). rAd26-S and rAd5-S are administered intramuscularly separately with a 21-day interval. The phase 1/2 clinical trials of the vaccine were completed in August, 2020.12 The results showed that the vaccine was well tolerated and highly immunogenic in healthy participants. As a result, the vaccine candidate was provisionally approved in Russia according to national legislation. Such registration allows the vaccine to be used in high-risk groups, with enhanced pharmacovigilance, while a post-marketing efficacy study is conducted. Here, we present preliminary efficacy and safety results of a phase 3 multicentre study using Gam-COVID-Vac in adults, with subanalysis of adults older than 60 years.
Methods Study design and participants This is a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial to assess efficacy, immunogenicity, and safety of the Gam-COVID-Vac combined vector vaccine against SARS-CoV-2-induced COVID-19 in adults, done at 25 hospitals and polyclinics in Moscow, Russia (appendix pp 14–15). Only sites accredited by the Ministry of Health of the Russian Federation for the conduct of clinical research were approved for participation. The trial protocol was reviewed and approved by appropriate competent authorities, including the Department of State Regulation for Circulation of Medicines of the Ministry of Health of the Russian Federation (approval number 450 from Aug 25, 2020), Moscow City Independent Ethics Committee, and independent local ethics committees of clinical sites.
The study used recruitment strategies that included use of the online platform of the Moscow Government and its call centres, community outreach, and recruitment efforts by approved clinical sites to achieve a high level of participation in the study. The study involved everyone who signed informed consent and passed screening.
Eligibility criteria were age 18 years or older; negative HIV, hepatitis B and C, and syphilis test results; negative anti-SARS-CoV-2 IgM and IgG antibody and SARS-CoV-2 PCR tests; no history of COVID-19; no contact with anyone with COVID-19 in the preceding 14 days; consent to use effective contraceptive methods; negative urine pregnancy test (for women of child-bearing potential); negative drug and alcohol tests at screening visit; no history of vaccine-induced reactions; and no acute infectious or respiratory disease in the 14 days before enrolment.
Exclusion criteria were any vaccination in the 30 days before enrolment; steroids or immunoglobulins in the 30 days before enrolment; immunosuppression in the 3 months before enrolment; pregnancy or breastfeeding; acute coronary syndrome or stroke in the year before enrolment; tuberculosis or chronic systemic infections; allergy or hypersensitivity to the drug or components; neoplasms; blood donation in the 2 months before enrolment; splenectomy; neutropenia, agranulocytosis, significant blood loss, severe anaemia, or immunodeficiency in the 6 months before enrolment; active form of a disease caused by HIV, syphilis, or hepatitis B or C; anorexia or protein deficiency; large tattoos at the injection site; history of alcohol or drug addiction; participation in any other clinical trial; study centre staff or other employees directly involved in the trial or their families; or any other condition deemed a problem by the study physician. All participants provided signed informed consent to be included in the database for study participation.
Randomisation and masking Enrolled participants were divided into five age strata (18–30 years, 31–40 years, 41–50 years, 51–60 years, and >60 years) and were assigned to two study groups using stratified (block size 4) interactive web response system (IWRS) randomisation in a ratio of 3:1 to the vaccine group or the placebo group. Study participants were assigned unique randomisation numbers that remained unchanged throughout the study. The statistician generated a sequence, according to which the drug was labelled. The drug and placebo were outwardly indistinguishable (packaging, label, and content). Investigators, participants, and all study staff were masked to group assignment.
Procedures All participants who consented to participate attended a screening visit for physical examination, checks of vital signs (eg, blood pressure, heart rate, and temperature), and blood tests for infections (HIV, hepatitis B and C, and syphilis) and collection of baseline immunogenicity characteristics. Urine tests for drugs and alcohol were done in all volunteers and pregnancy tests were done in women. PCR SARS-CoV-2 swab tests were also done at screening by the central laboratory in Moscow to exclude participants with COVID-19. At screening, information on the presence of concomitant diseases and SARS-CoV-2 infection risk group was entered into the case report forms of the participants. High risk denotes those whose work involves interaction with patients with a confirmed diagnosis of COVID-19; medium risk is those who have professional contact with a large number of people, such as general practitioners, social workers, and shop assistants; and general risk denotes those with no additional risks associated with their professional activities. Intended duration of participation of individuals in the trial was 180 days after the first dose of the vaccine or placebo. One screening visit and five on-site visits to a clinical site over the course of the trial were planned.
The vaccine comprises two vector components, rAd26-S and rAd5-S. A full dose of the vaccine was 1011 viral particles per dose for each recombinant adenovirus; 0·5 mL/dose for intramuscular injection. The placebo consists of the vaccine buffer composition, but without the recombinant adenoviruses, made up to equal the vaccine volume. Vaccine and placebo were developed, manufactured, and stored by Gamaleya NRCEM (Moscow, Russia) according to Good Manufacturing Practices. The vaccine and placebo were used in liquid form (frozen). The compositions of the vaccine and placebo are described in the appendix (p 1). The vaccine (first dose rAd26, second dose rAd5) or placebo were administered intramuscularly into the deltoid muscle with a 21-day interval between doses.
Subsequent observation visits were planned for day 28 (±2 days), day 42 (±2 days), and day 180 (±14 days). During the observation visits, vital signs were assessed in all trial participants and changes in the participants’ condition and wellbeing compared with the previous visit were recorded. A PCR test was done in combination with the clinical examination on the day of the second dose (day 21) for the diagnosis of symptomatic and asymptomatic COVID-19 cases. In the presence of clinical signs of respiratory infection and a positive PCR test, the participant would not be vaccinated with the second dose and was referred to medical staff for treatment of COVID-19. Participants without signs of respiratory infection were vaccinated before PCR results were received. In the case of a positive PCR test result, participants were classified as asymptomatic and were not counted as COVID-19 cases in the efficacy analysis, according to protocol. During the trial, apart from the screening visit and day of the second dose, no additional PCR tests were done, except when COVID-19 symptoms were reported by participants.
The sponsor arranged some additional observation visits remotely as telemedicine consultations. Unscheduled telemedicine consultations were encouraged for complaints or questions from participants about study procedures. All participants were given study team contacts at signing of informed consent and were instructed to contact the team on an as-needed basis, but primarily to report any signs or symptoms that could be indicative of an adverse event. All participants were also offered electronic diaries to be installed on their smartphone devices to monitor their health status. Information from those participants who chose not to use e-diaries was collected by site staff via teleconsultation technology. Data collected from these telemedicine consultations were entered by the site investigators directly into the participant's medical record.
A city-wide electronic health record (EHR) platform—the Unified Medical Information and Analytical System (UMIAS) is in place in Moscow. The UMIAS EHR is a controlled electronic medical record used by all Moscow health-care institutions for care provision to Moscow residents. EHRs of the trial participants were updated to indicate their participation in the trial and were used as a source for electronic data capture and source data verification by contract research organisation monitors. In addition to protocol-defined visits and teleconsultations, principal investigators and study teams were able to track patient status through this city-wide EHR platform, including possible hospital admission and use of ambulatory services. Electronic diaries from participants who agreed to use e-diaries were also integrated within the UMIAS EHR. For those participants who chose not to use e-diaries, data on participant status were collected by site staff via teleconsultations and entered into the EHR by site investigators. All adverse events were followed up by a clinical investigator until resolution and were reviewed by the data safety and monitoring board and verified by the trial monitor. When COVID-19 was suspected, participants were assessed according to COVID-19 diagnostic protocols, including PCR testing at a central laboratory in Moscow. Severity of disease was established upon confirmation of the COVID-19 diagnosis by site investigators. A description of the assessment criteria for severity of COVID-19 is in the appendix (p 2).
The study was organised and monitored by the Moscow branch of the Dutch contract research organisation Crocus Medical. Data management is done through the DM 365 MainEDC system (developed by Data Management 365), a powerful cloud-based platform integrated to comprise the functions of data collection, advanced randomisation techniques, full control over drug supply and dispensing, and patient e-diaries (electronic data capture, IWRS, drug supply, and electronic patient-reported outcomes). The system complies with all applicable international regulations, including Code of Federal Regulations Title 21 Part 11, Good Clinical Practice, Good Automated Manufacturing Practice 5, Health Insurance Portability and Accountability, and General Data Protection Regulation. The system allows collection and validation of clinical data in high-load clinical trials and supports central monitoring and risk-based monitoring processes, automated coding with the Medical Dictionary for Regulatory Activities (MedDRA), WHODrug, and Logical Observation Identifiers Names and Codes, and instant mapping of the exported data to the standard Clinical Data Interchange Standards Consortium Study Data Tabulation Model.
Blood sampling was done on the day of vaccination immediately before study drug administration. Blood sampling for assessment of immunogenicity parameters was only done in some study centres, selected on the basis of the logistics chain for the delivery of biomaterial to the central laboratory where primary blood processing was done (sera collection, aliquoting, and freezing). Blood samples for antigen-specific IgG analysis are planned to be taken from up to 9520 trial participants before completion of the trial.
Immunogenicity was analysed as described previously.12 In brief, antigen-specific humoral immune response was analysed on the day of first vaccination and day 42. The titre of glycoprotein-specific antibodies in serum was ascertained by ELISA. To test anti-SARS-CoV-2 IgG, we used an ELISA that was developed at Gamaleya NRCEM and registered for clinical use in Russia (P3H 2020/10393 2020-05-18). The ELISA measures IgGs specific to the receptor-binding domain (RBD) of SARS-CoV-2 glycoprotein S. The titre of neutralising antibodies was measured on the day of first vaccination and day 42 by microneutralisation assay using SARS-CoV-2 (hCoV-19/Russia/Moscow_PMVL-1/2020) in a 96-well plate and a 50% tissue culture infective dose (TCID50) of 100. The seroconversion rate was calculated as a four-fold increase in titre at 42 days compared with the day before first vaccination. Cell-mediated immune response was measured on the day of first vaccination and day 28 by quantification of IFN-γ secretion upon antigen restimulation in peripheral blood mononuclear cell culture.
Outcomes The primary outcome was the proportion of participants with COVID-19 confirmed by PCR from day 21 after receiving the first dose. The secondary outcomes were severity of COVID-19; changes in antibody levels against SARS-CoV-2 glycoprotein S; proportion of participants with antibodies against SARS-CoV-2 N-protein; changes in SARS-CoV-2 neutralising antibody titres (increase of titres); changes in antigen-specific cellular immunity level (increase of cell-mediated immune response to antigen); and incidence and severity of adverse events. Serious adverse events were diagnosed on the basis of the event requiring hospital admission. Here, we report preliminary results on the primary outcome measure, incidence and severity of adverse events, immunogenicity, and safety.
Statistical analysis In this interim analysis, we present efficacy data at the point of confirmation of 78 COVID-19 cases in participants after receiving the second dose, as stipulated by the protocol.
In this study, the primary endpoint is the proportion of participants without COVID-19 confirmed by laboratory tests during the study. The frequency of COVID-19 in the general population, and thus the expected frequency in our placebo group, is 20 people per 1000 or 2·0%. The study aims to show that the proportion of participants with COVID-19 will be at least a third lower in the intervention group than the control group (odds ratio [OR] for the null hypothesis of 0·67)—ie, the upper limit of the 95% CI for the OR should not exceed 0·67. The expected value of the effect is about 0·500 (OR for the alternative hypothesis of 0·500). With a planned study population of 40 000 participants and randomisation 3:1 vaccine to placebo, the study power will be 85%, with a unilateral statistical significance level of 0·025.
The study protocol did not originally prespecify a target number of events in this trial. However, because of the increase in the incidence of COVID-19 in Russia, changes were made to the clinical trial protocol on Nov 5, 2020, including an interim analysis to preliminarily calculate the vaccine efficacy and to establish ethical appropriateness of further inclusion of the placebo group in the trial in the context of a growing pandemic if the vaccine is effective.
Three interim analyses were completed when 20, 39, and 78 documented cases of COVID-19 had occurred across both groups combined. Our original conservative estimate of efficacy was 50%. If the efficacy was at least 70%, then a statistically significant difference between the groups would be detected when at least 20 events were reached across the two groups. If efficacy was 65%, then the number of cases required would be 39. 60% efficacy would be statistically significant when 78 cases had been reported.
The OR and 95% CI were calculated according to previously described methods.13 The primary endpoint was calculated using the following formula: vaccine efficacy (%)=(1 – OR) × 100, where the OR is as follows:
where a is the number of vaccinated participants with COVID-19, b is the number of vaccinated participants without COVID-19, c is the number of unvaccinated participants with COVID-19, and d is the number of unvaccinated participants without COVID-19.
ORs and 95% CIs were obtained by the Baptista-Pike method, p values were obtained by χ2 test or Fisher's exact test (if the expected frequency in any cell is <5). Cumulative incidence is presented using the Kaplan-Meier method.
In the safety analysis, adverse events were coded using MedDRA, version 23.0. Adverse events were presented by group, system organ and class, and preferred term. Normality of the data distribution was assessed with the d’Agostino-Pearson test in the analysis of quantitative data (immunogenicity analyses). In the analysis of immunogenicity (analysis of parametric data) in the case when two groups of data were compared, the Mann-Whitney U test was used (eg, the vaccine group vs placebo group or men vs women) for unpaired samples and the Wilcoxon signed rank test for paired samples (eg, cellular response data on days before and after vaccination). When comparing several groups of data (eg, age strata), the Kruskal-Wallis test was used. To compare the frequency indicators between groups, the χ2 test and, if necessary, Fisher's exact test were used (if the expected frequency in any of the cells was <5).
The primary outcome analysis included all participants who had received at least two doses at the time of database lock and followed protocol without violations. The analysis of serious adverse events included all participants who had received at least one dose at the time of database lock and followed protocol without violations. The safety analysis (including rare adverse events) included all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The statistical analysis was done using Stata, version 14, and GraphPad Prism, version 9.0. This trial is registered with ClinicalTrials.gov (NCT04530396).
Role of the funding source The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results Between Sept 7 and Nov 24, 2020, 21 977 adults were eligible and randomly assigned to receive placebo (n=5476) or vaccine (n=16 501; figure 1).
The first database lock was on Nov 18, 2020, when 20 cases of COVID-19 had been reported. The interim safety analysis (analysis of rare adverse events) was done with data up to the first database lock. Since there was an increase in COVID-19 incidence in Moscow during November, the second database lock was done on Nov 24, 2020, when 78 COVID-19 cases had been reported. Data for the interim efficacy analysis and serious adverse events analysis are presented up to the second database lock. 74 participants from the vaccine group and 41 from the placebo group were excluded from analyses (figure 1). This preliminary analysis included 16 427 participants in the vaccine group and 5435 in the placebo group, who received at least one dose and continued participation in the trial. 14 964 in the vaccine group and 4902 in the placebo group had received two doses at the time of database lock (Nov 24, 2020) and were included in the primary outcome analysis (table 1). Median time from participants receiving the first dose to the date of database lock was 48 days (IQR 39–58). Among the participants who received two doses, the mean age was 45·3 years (SD 12·0) in the vaccine group and 45·3 years (SD 11·9) in the placebo group; the distribution by sex (p=0·619), incidence of concomitant diseases (p=0·420), and infection risk (p=0·851) were similar between the two groups (table 1).
Table 1 Baseline characteristics of participants who received two doses of assigned treatment and were included in primary outcome analysis Vaccine (n=14 964) Placebo (n=4902) Sex Female 5821 (38·9%) 1887 (38·5%) Male 9143 (61·1%) 3015 (61·5%) Race White 14 741 (98·5%) 4830 (98·5%) Asian 217 (1·5%) 69 (1·4%) Other* 6 (<0·1%) 3 (<0·1%) Age group, years 18–30 1596 (10·7%) 521 (10·6%) 31–40 3848 (25·7%) 1259 (25·7%) 41–50 4399 (29·4%) 1443 (29·4%) 51–60 3510 (23·5%) 1146 (23·4%) >60 1611 (10·8%) 533 (10·9%) Age, years 45·3 (12·0) 45·3 (11·9) Bodyweight, kg 81·3 (17·5) 81·6 (17·7) Height, cm 173·1 (9·1) 173·3 (9·0) Body-mass index, kg/m2 26·75 (4·56) 26·75 (4·55) Concomitant diseases (diabetes, hypertension, ischaemic heart disease, obesity)† 3687/14 944 (24·7%) 1235/4892 (25·2%) Risk of infection in volunteers† ‡ High 65/14 567 (0·4%) 23/4778 (0·5%) Medium 3853/14 567 (26·5%) 1280/4778 (26·8%) General 10649/14 567 (73·1%) 3475/4778 (72·7%) Data are n (%) and mean (SD). * Includes Black or African American, Native Hawaiian or other Pacific Islander, or undefined. † Denominator shows number of participants for whom these data were available.
‡ High risk denotes those whose work involves interaction with patients with a confirmed diagnosis of COVID-19; medium risk is those who have professional contact with a large number of people, such as general practitioners, social workers, and shop assistants; and general risk denotes those with no additional risks associated with their professional activities.
From 21 days after the first dose of vaccine (the day of dose 2), 16 COVID-19 cases were confirmed in the vaccine group (of 14 964 participants; 0·1%) and 62 cases were confirmed in the placebo group (of 4902 participants; 1·3%); vaccine efficacy was 91·6% (95% CI 85·6–95·2; table 2). The observed vaccine efficacy was greater than 87% in all age and sex subgroups. Notably, vaccine efficacy was 91·8% (67·1–98·3) in participants older than 60 years. There were no cases (vaccine group) and 20 cases (placebo group) of moderate or severe COVID-19 confirmed at least 21 days after dose 1; thus, vaccine efficacy against moderate or severe COVID-19 was 100% (94·4–100·0). From 15 to 21 days after the first dose, efficacy was 73·6% (p=0·048), then from day 21, efficacy was 100% (p<0·0001; appendix p 11).
Table 2 Interim results on vaccine efficacy Total cases Vaccine group Placebo group Vaccine efficacy (95% CI) p value First COVID-19 occurrence from 21 days after dose 1 (day of dose 2)* Overall 78 16/14 964 (0·1%) 62/4902 (1·3%) 91·6% (85·6–95·2) <0·0001 Age group (years) 18–30 5 1/1596 (0·1%) 4/521 (0·8%) 91·9% (51·2–99·3) 0·0146 31–40 17 4/3848 (0·1%) 13/1259 (1·0%) 90·0% (71·1–96·5) <0·0001 41–50 19 4/4399 (0·1%) 15/1443 (1·0%) 91·3% (73·7–96·9) <0·0001 51–60 27 5/3510 (0·1%) 22/1146 (1·9%) 92·7% (81·1–97·0) <0·0001 >60 10 2/1611 (0·1%) 8/533 (1·5%) 91·8% (67·1–98·3) 0·0004 Sex Female 32 9/5821 (0·2%) 23/1887 (1·2%) 87·5% (73·4–94·2) <0·0001 Male 46 7/9143 (0·1%) 39/3015 (1·3%) 94·2% (87·2–97·4) <0·0001 Moderate or severe cases 20 0/14 964 20/4902 (0·4%) 100% (94·4–100·0) <0·0001 First COVID-19 occurrence after dose 1† Any time after dose 1 175 79/16 427 (0·5%) 96/5435 (1·8%) 73·1% (63·7–80·1) <0·0001 From 14 days after dose 1 109 30/14 999 (0·2%) 79/4950 (1·6%) 87·6% (81·1–91·8) <0·0001 First COVID-19 occurrence after dose 2 (28 days after dose 1)* All 60 13/14 094 (0·1%) 47/4601 (1·0%) 91·1% (83·8–95·1) <0·0001 Data are n/N (%), unless otherwise stated. * Includes those who received both doses. † Includes participants who received at least one dose.