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29 marzo, 2022

Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine

BACKGROUND

Active immunization with the BNT162b2 vaccine (Pfizer–BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older.

METHODS

In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-μg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose.

RESULTS

A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3).

CONCLUSIONS

A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626. opens in new tab.)

The coronavirus disease 2019 (Covid-19) pandemic remains a global public health emergency, and vaccination is a critical mitigation tool.1 The BNT162b2 vaccine (Pfizer–BioNTech) contains a nucleoside-modified messenger RNA encoding the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2 The BNT162b2 vaccine has been licensed for immunization of persons 16 years of age or older in the United States and has been issued emergency use authorization (EUA) by the Food and Drug Administration (FDA) for immunization of children between the ages of 5 and 15 years.3,4 Globally, the BNT162b2 vaccine has been authorized in 117 countries across North and South America, the United Kingdom, Europe, Africa, Asia, and Oceania.5

In an ongoing pivotal clinical trial (C4591001) involving healthy children and adults who were 12 years of age or older, two doses of the BNT162b2 vaccine (30 μg) were safe, immunogenic, and at least 95% efficacious in preventing Covid-19 from 7 days until approximately 2 months after the second injection.6-8 After the second dose, vaccine efficacy against Covid-19 had waned to 90% within 2 to 4 months and to 84% within 4 to 6 months.9 Similar estimates have been reported from real-world effectiveness and surveillance studies.10-12

The emergence of the B.1.617.2 (delta) variant of SARS-CoV-2, which coincided with breakthrough cases among vaccinated persons,13,14 raised the question as to whether the reduced effectiveness of the initial vaccine regimen was due to the emergence of the delta variant or simply to declining efficacy over time. Although protection against infection and mild disease appeared to wane in the months after vaccination, the effectiveness against severe disease and hospital admission remained high.10,11,15 Waning immunity and the potential for continued circulation of additional SARS-CoV-2 variants suggested the need for a third (booster) dose of the BNT162b2 vaccine. A third BNT162b2 dose that was administered 7 to 9 months after the primary two-dose series was shown to increase the magnitude and breadth of the immune response in a small group of participants from the pivotal trial.16

On the basis of immunogenicity data from the primary series and from the booster dose, on December 9, 2021, the FDA authorized a third BNT162b2 dose in persons 16 years of age or older who had received the primary BNT162b2 series at least 6 months earlier.17 Here, we report safety and efficacy results from an ongoing, placebo-controlled, randomized, phase 3 clinical trial (C4591031) that assessed the administration of a third BNT162b2 dose in more than 10,000 healthy participants who had received the primary two-dose series in the pivotal trial.

Methods

TRIAL OBJECTIVES, PARTICIPANTS, AND OVERSIGHT

All the trial participants were a least 16 years of age and had previously received two doses of the BNT162b2 vaccine administered 19 to 42 days apart in the ongoing pivotal trial. Participants had received the second vaccine dose at least 175 days (approximately 6 months) earlier and had received no previous clinical or microbiologic diagnosis of Covid-19. Additional inclusion and exclusion criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org, along with the protocol. All the participants provided written informed consent; in adolescents younger than 18 years of age, written informed consent was provided by a parent or guardian.

Pfizer was responsible for the design and conduct of the trial; for the collection, analysis, and interpretation of the data; and for the writing of the manuscript. Both Pfizer and BioNTech manufactured the vaccine and placebo that were used in the trial. BioNTech was the regulatory sponsor and contributed to interpretation of the data and the writing of the manuscript. All aggregated analyses of the data were available to all the authors, who vouch for the accuracy and completeness of the data and for the adherence of the trial to the protocol.

PROCEDURES

Using an interactive Web-based response system, we randomly assigned the participants in a 1:1 ratio to receive an intramuscular injection of a third dose of the BNT162b2 vaccine or saline placebo. All the participants and site personnel were unaware of the trial-group assignments, except for staff members who prepared, dispensed, or administered the injections. The trial design originally called for all the participants to remain unaware of their assigned group until after a prespecified interim analysis. This planned analysis was to occur 2 months after the third dose, with subsequent review by the data and safety monitoring committee. In anticipation of recommendations by regulatory authorities that booster doses be made available, we revised the protocol to allow for the unblinding of the trial-group assignments before the 2-month cutoff. During the interim analysis, the data monitoring committee also recommended that participants be made aware of their trial-group assignments to allow those in the placebo group to receive a third vaccine dose. This recommendation was made in consideration of the observation of waning effectiveness after two doses, the observed benefit of the third dose, and the recommendation for boosters in some countries. On September 24, 2021, on the basis of FDA issuance of the EUA for a BNT162b2 booster and at the discretion of the sponsor, participants in the placebo group were offered the opportunity to receive the BNT162b2 vaccine.

SAFETY

The incidence of adverse events and serious adverse events was the primary safety end point. Data regarding unsolicited adverse events, including reactogenicity, were collected from the time that informed consent was provided through 1 month after the administration of dose 3. We collected assessments of reactogenicity and other adverse events by telephone follow-up. The collection of reports of serious adverse events was ongoing from the time that informed consent was provided through 6 months after dose 3.

EFFICACY

The primary efficacy end point was the effectiveness of the BNT162b2 vaccine against laboratory-confirmed Covid-19 beginning at least 7 days after the administration of dose 3. This end point was analyzed both in participants who had no evidence of previous SARS-CoV-2 infection and in all participants. The efficacy of the BNT162b2 vaccine against severe Covid-19 was determined according to the definitions used by the FDA and the Centers for Disease Control and Prevention (CDC).18,19 The methods that were used for identifying SARS-CoV-2 infection and Covid-19 are summarized in the Supplementary Appendix.

STATISTICAL ANALYSIS

The sample size was chosen to provide a relatively large database to assess safety, with the intent of accruing sufficient Covid-19 cases to assess vaccine efficacy. The number of participants was not based on a projected between-group difference. We determined that the enrollment of 10,000 participants would provide 4250 participants with data that could be evaluated in each group, assuming a loss of follow-up of 15%. Included in the primary analyses were all the participants who had undergone randomization and received either a third dose of the BNT162b2 vaccine or placebo with no important deviations from the protocol.

We calculated safety end points as counts, percentages, and associated Clopper–Pearson two-sided 95% confidence intervals in the safety population (Table S1 in the Supplementary Appendix). Adverse events and serious adverse events are presented according to the terms used in the Medical Dictionary for Regulatory Activities, version 24.0. Between-group differences in percentages of participants who reported having adverse events are presented with associated two-sided Miettinen–Nurminen 95% confidence intervals for adverse events with an incidence of at least 1% in either group.

Interim efficacy analyses were performed after all the participants had reached 2 months of blinded follow-up and through the data-cutoff date; these data were reviewed by the data monitoring committee. Data from participants who were made aware of trial-group assignments before the first interim analysis because of the regulatory decision were censored at the time of the unblinding of the trial group. Details regarding the procedures that were used to determine the relative efficacy of the third dose of vaccine as compared with placebo are provided in the Supplementary Appendix.

We calculated two-sided Clopper–Pearson 95% confidence intervals for relative vaccine efficacy after adjustment for surveillance time. Confidence intervals were not adjusted for multiplicity and thus cannot be used to infer effects. Instead, the trial was designed to provide information to assist policymakers in deciding whether to recommend a third dose of vaccine, as well as the timing of this dose if recommended. Missing efficacy data (e.g., the report of a symptom without laboratory testing data) were not imputed.

PARTICIPANTS

From July 1 to August 10, 2021, a total of 10,136 participants who had received two doses of the BNT162b2 vaccine in the pivotal trial underwent randomization at 123 sites in the United States, South Africa, and Brazil. Overall, 5081 participants received a third BNT162b2 dose and 5044 received placebo (Figure 1). A larger number of participants in the placebo group than in the vaccine group withdrew from the trial in order to receive a third dose of vaccine owing to pending changes in national recommendations.

The demographic characteristics of the participants were well balanced in the two groups (Table 1) and were generally representative of the expected participant population (Table S2). The median age was 53.0 years, 23.3% of participants were 65 years of age or older, and 1% were 16 or 17 years of age; 49.1% were male; and 79.0% were White, 9.2% were Black, 5.5% were Asian, and 14.9% were Hispanic or Latinx. Almost half the participants (48.7%) had coexisting conditions, including obesity (in 35.9%), chronic pulmonary disease (in 9.2%), and diabetes without chronic complications (in 8.3%); 5.4% had evidence of current or previous SARS-CoV-2 infection at baseline. The median interval between dose 2 and dose 3 was 10.8 months (range, 5.0 to 12.6) in the vaccine group and 10.7 months (range, 5.0 to 12.8) in the placebo group. The median follow-up from dose 3 to the data-cutoff date (October 5, 2021) was 2.5 months (range, 0.3 to 3.5).

Within 1 month after the administration of dose 3, adverse events were more frequent in the vaccine group than in the placebo group (Figure 2A and Table 2). Injection-site pain was the most frequently reported adverse event in the two groups and was reportedly more often in the vaccine group (risk difference, 11.3 percentage points) (Figure 2B). From dose 3 through the data-cutoff date, serious adverse events were reported by slightly more participants in the placebo group than in the vaccine group (0.5% vs. 0.3%) (Table S3). In a blinded investigation, serious adverse events were considered by the investigator to be related to either the vaccine or placebo in 3 participants who had received the BNT162b2 vaccine and in 2 participants who had received placebo. In the vaccine group, these serious adverse events were tachycardia in 1 participant (7 days after dose 3) and increased hepatic enzyme levels in 2 participants (4 and 48 days after dose 3). Among the participants with increased hepatic enzyme levels, 1 had a medical history of Gilbert’s syndrome and both reported the use of concomitant medications (paracetamol, atorvastatin calcium, and butalbital). In the placebo group, serious adverse events that were considered to be related to placebo were myocardial infarction (8 days after the injection) and chest pain (5 days after the injection). One adverse event leading to withdrawal in a participant who had received placebo (metastatic cancer) was not considered by the investigator to be related to placebo. One death from pulmonary embolism 51 days after the injection of placebo was deemed to be unrelated to placebo. No cases of myocarditis or pericarditis were reported.

EFFICACY

Interim analyses were conducted at 2 months and on the data-cutoff date. Among the participants without evidence of previous SARS-CoV-2 infection who had an onset of Covid-19 within 7 days to 2 months after the receipt of the third dose, 5 cases were observed in the vaccine group and 109 in the placebo group, which corresponded to a relative vaccine efficacy of 95.6% (95% confidence interval [CI], 89.3 to 98.6). In the corresponding analysis conducted at the data-cutoff date, Covid-19 was identified in 6 participants in the vaccine group and in 123 in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% CI, 89.5 to 98.3) (Figure 3 and Table 3).

Among all the participants regardless of previous infection within 7 days to 2 months after receipt of the third dose, 6 cases were observed in the vaccine group and 110 cases in the placebo group, for a relative vaccine efficacy of 94.7% (95% CI, 88.2 to 98.1). In the analyses performed through the data-cutoff date, Covid-19 was identified in 7 participants in the vaccine group and in 124 in the placebo group, for a relative vaccine efficacy of 94.6% (95% CI, 88.5 to 97.9). Increased protection started within 7 days after the third dose of the BNT162b2 vaccine but was maximal after 7 days. Severe Covid-19 as defined according to the FDA criteria18 (but not the CDC criteria) was reported in no participants in the vaccine group and in 2 participants in the placebo group. The FDA definition was based solely on the peripheral-blood oxygen saturation level, and the 2 participants with lower levels were not hospitalized. Although the trial was not designed to assess efficacy according to subgroup, the relative vaccine efficacy among subgroups as defined by age, sex, race, ethnicity, geographic location, and the presence or absence of obesity or other coexisting illness was generally consistent with that observed in the overall population (Tables S4 and S5)…

https://www.nejm.org/doi/full/10.1056/NEJMoa2200674

Créditos: Comité científico Covid

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