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17 septiembre, 2022

Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19

ACKGROUND

The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation.

METHODS

In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe–critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed.

RESULTS

The per-protocol population included 19,630 SARS-CoV-2–negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe–critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe–critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe–critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe–critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19–related), and 16 in the placebo group (5 were Covid-19–related).

CONCLUSIONS

A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe–critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722. opens in new tab.)

Digital Object ThumbnailQUICK TAKESingle-Dose Ad26.COV2.S Vaccine against Covid-19 02:17

Since emerging in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused high morbidity and mortality, with new variants rapidly spreading.1-4 Vaccines to prevent coronavirus disease 2019 (Covid-19) have been developed with unprecedented speed.5,6

The Ad26.COV2.S vaccine comprises a recombinant, replication-incompetent human adenovirus type 26 (Ad26) vector7 encoding a full-length, membrane-bound SARS-CoV-2 spike protein in a prefusion-stabilized conformation.8,9 Other Ad26-based vaccines, including an approved Ebola vaccine, are safe and have induced durable immune responses.8,10-13 Ad26.COV2.S induced durable protection at low doses in preclinical SARS-CoV-2 challenge studies,8,14 and initial clinical data showed that a single dose at 5×1010 viral particles was safe and induced excellent humoral and cellular immune responses.9 Ad26.COV2.S can be stored for up to 2 years in a standard freezer and up to 3 months at refrigerator temperatures, which simplifies transport, storage, and use in a pandemic.

We are conducting an ongoing phase 3 trial (ENSEMBLE) to evaluate the safety and efficacy of a single dose of Ad26.COV2.S at 5×1010 viral particles for the prevention of Covid-19 and SARS-CoV-2 infection in adults. Here, we report the results of the primary analyses.

Methods

TRIAL DESIGN AND OVERSIGHT

We are conducting this ongoing, 2-year, multicenter, randomized, double-blind, placebo-controlled, phase 3, pivotal trial in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States. All the participants provided written informed consent. The trial adheres to the principles of the Declaration of Helsinki and to the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol (available with the full text of this article at NEJM.org) and amendments were approved by institutional review boards according to local regulations. An unblinded independent data and safety monitoring board continuously monitors safety, including monitoring for vaccine-associated enhanced respiratory disease.

The trial is a collaboration between the sponsor, Janssen Research and Development, which is an affiliate of Janssen Vaccines and Prevention and part of the Janssen pharmaceutical companies of Johnson & Johnson, and the Operation Warp Speed Covid-19 Rapid Response Team (which includes the Biomedical Advanced Research and Development Authority, the National Institutes of Health, the Covid-19 Prevention Trials Network, and the Department of Defense). The trial was designed and conducted, and the data analysis and data interpretation were performed, by the sponsor and collaborators. Trial-site investigators collected and contributed to the interpretation of the data. All the data were available to the authors, who vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. Medical writers who were funded by the sponsor assisted in drafting the manuscript.

TRIAL PARTICIPANTS

Stages 1a and 2a of the trial were conducted in parallel and included 2000 adults 18 to 59 years of age and 60 years of age or older, respectively, who were in good or stable health and did not have coexisting conditions that have been associated with an increased risk of severe Covid-19. After a 3-day safety review by the data and safety monitoring board, stages 1b and 2b were initiated. Those stages additionally included adults of the same respective age ranges who had stable and well-controlled coexisting conditions. The eligibility criteria are provided in the Supplementary Methods section in the Supplementary Appendix, available at NEJM.org. Participants were not excluded on the basis of SARS-CoV-2 infection or serostatus.

PROCEDURES

Details of the trial procedures are provided in the Supplementary Methods section. Participants were randomly assigned in a 1:1 ratio, with the use of randomly permuted blocks, to receive either Ad26.COV2.S or saline placebo. Randomization was conducted with an interactive Web-response system and stratified according to trial site, age group, and the presence or absence of coexisting conditions that have been associated with an increased risk of severe Covid-19.

Vaccine or placebo was administered on day 1. Ad26.COV2.S was supplied in single-use vials at a concentration of 1×1011 viral particles per milliliter and was administered at a dose of 5×1010 viral particles as a single intramuscular injection (0.5 ml) by a health care worker who was unaware of the group assignment.

Participants reported Covid-19 symptoms electronically using the Symptoms of Infection with Coronavirus-19 questionnaire (methods described in Fig. S1 in the Supplementary Appendix). Participants and trial staff obtained nasal swabs, which were tested with the use of a Food and Drug Administration (FDA) Emergency Use Authorization reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay for SARS-CoV-2 at a local laboratory and subsequently confirmed centrally (m-2000 SARS-CoV-2 real-time RT-PCR, Abbott). Seropositivity for SARS-CoV-2 was evaluated by means of a SARS-CoV-2 nucleocapsid (N) immunoassay (Elecsys, Roche) at trial entry and on days 29 and 71. Assays were performed according to the manufacturers’ protocols.

Primary and key secondary efficacy evaluations were based on centrally confirmed cases of Covid-19. Owing to the high incidence of Covid-19 and the time taken for central confirmation, not all cases had been centrally confirmed at the time of the primary analysis. A supplementary analysis of RT-PCR–positive cases from all sources, whether centrally confirmed or not, was therefore performed for subgroups, hospitalizations, and deaths.

SAFETY ASSESSMENTS

Serious adverse events and adverse events leading to withdrawal from the trial are being recorded throughout the trial. In a safety subpopulation comprising approximately 6000 participants (see below), data on solicited local and systemic adverse events were recorded in an electronic diary for 7 days after administration and unsolicited adverse events for 28 days after administration.

EFFICACY ASSESSMENTS

The two primary end points were the efficacy of the Ad26.COV2.S vaccine against the first occurrence of centrally confirmed moderate to severe–critical Covid-19 with an onset at least 14 days after administration and at least 28 days after administration in the per-protocol population (see below). All the potential cases of severe–critical Covid-19 and cases of moderate Covid-19 with at least three signs or symptoms were classified as being severe–critical by an independent Clinical Severity Adjudication Committee whose members were unaware of the group assignments. This committee adjudicated cases on the basis of clinical judgment (e.g., a single low oxygen-saturation measurement was not classified as indicating severe Covid-19 unless other clinical findings were consistent with a severe classification). The case definitions for Covid-19 and the protocol-defined secondary and exploratory end points are described in the Supplementary Appendix.

STATISTICAL ANALYSIS

The full analysis set included all the participants who underwent randomization and received a dose of trial vaccine or placebo. The per-protocol population comprised participants who received a dose of trial vaccine or placebo, were seronegative or had an unknown serostatus at the time that the vaccine or placebo was administered, and had no protocol deviations that were likely to affect vaccine efficacy. Participants who were RT-PCR–positive between days 1 and 14 or between days 1 and 28 were excluded from the analysis of cases with an onset at least 14 days after administration and at least 28 days after administration, respectively. The per-protocol population was the main population for the efficacy analyses. Safety analyses were conducted in the full analysis set, including the safety subpopulation.

The null hypothesis was that the efficacy of Ad26.COV2.S would be no higher than 30% for each primary end point, as evaluated with a truncated sequential probability ratio test15,16 at a one-sided significance level of 0.025. The sample size was reduced from 60,000 to approximately 40,000 on the basis of the high incidence of Covid-19 during the trial. The primary analysis was triggered on a positive recommendation from the data and safety monitoring board, after the FDA-specified median 8-week follow-up was reached and prespecified data requirements were met.

If the null hypothesis was rejected for both primary end points, secondary objectives were evaluated against a null hypothesis that used a lower limit of vaccine efficacy of more than 0% with prespecified multiplicity adjustments for familywise type I error control (Fig. S2). Exact Poisson regression17 was used for the analysis of vaccine efficacy and the associated confidence interval calculations, with accounting for follow-up time. The cumulative incidence over time was estimated with the use of Kaplan–Meier methods to evaluate the onset of vaccine efficacy and vaccine efficacy over time. Participants had their data censored at the end of their follow-up.

The frequency of serious adverse events was tabulated in the full analysis set. The frequency and severity of solicited and unsolicited adverse events were tabulated in the safety subpopulation.

Results

PARTICIPANTS

 Analysis Set).

The trial began enrollment on September 21, 2020, and the data-cutoff date for the present analysis was January 22, 2021. A total of 44,325 participants underwent randomization, of whom 43,783 received vaccine or placebo; the per-protocol population included 39,321 SARS-CoV-2–negative participants, of whom 19,630 received Ad26.COV2.S and 19,691 received placebo (Fig. S3). The demographic characteristics and coexisting conditions of the participants at baseline were balanced across the two groups (Table 1 and S4). A total of 9.6% of the participants were SARS-CoV-2–seropositive at baseline. The median follow-up was 58 days (range, 1 to 124), and 55% of participants had at least 8 weeks of follow-up; later and slower recruitment of participants 60 years of age or older with coexisting conditions resulted in a shorter duration of follow-up in this subgroup (Table S5).

SAFETY

The safety subpopulation included 3356 participants in the vaccine group and 3380 in the placebo group. During the 7-day period after the administration of vaccine or placebo, more solicited adverse events were reported by Ad26.COV2.S recipients than by placebo recipients and by participants 18 to 59 years of age than by those 60 years of age or older (Figure 1). In the vaccine group, injection-site pain was the most common local reaction (in 48.6% of the participants); the most common systemic reactions were headache (in 38.9%), fatigue (in 38.2%), myalgia (in 33.2%), and nausea (in 14.2%).

The adverse events of at least grade 3 that were considered by the investigators to be possibly related to Ad26.COV2.S or placebo are listed in Table S6. Serious adverse events, excluding those related to Covid-19, were reported by 83 of 21,895 vaccine recipients (0.4%) and by 96 of 21,888 placebo recipients (0.4%). Seven serious adverse events were considered by the investigators to be related to vaccination in the Ad26.COV2.S group (Table S7).

A numeric imbalance was observed for venous thromboembolic events (11 in the vaccine group vs. 3 in the placebo group). Most of these participants had underlying medical conditions and predisposing factors that might have contributed to these events (Table S8). Imbalances were also observed with regard to seizure (which occurred in 4 participants in the vaccine group vs. 1 in the placebo group) and tinnitus (in 6 vs. 0). A causal relationship between these events and Ad26.COV2.S cannot be determined. These events will be monitored in the post-marketing setting.

Three deaths were reported in the vaccine group and 16 in the placebo group, all of which were considered by the investigators to be unrelated to the trial intervention (Table S7). No deaths related to Covid-19 were reported in the vaccine group, whereas 5 deaths related to Covid-19 were reported in the placebo group. Transverse sinus thrombosis with cerebral hemorrhage and a case of the Guillain–Barré syndrome were each seen in 1 vaccine recipient.

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Créditos: Comité científico Covid

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