BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve around the world, generating new variants that are of concern on the basis of their potential for altered transmissibility, pathogenicity, and coverage by vaccines and therapeutic agents1-5. Here we show that serum samples taken from twenty human volunteers, two or four weeks after their second dose of the BNT162b2 vaccine, neutralize engineered SARS-CoV-2 with a USA-WA1/2020 genetic background (a virus strain isolated in January 2020) and spike glycoproteins from the recently identified B.1.617.1, B.1.617.2, B.1.618 (all of which were first identified in India) or B.1.525 (first identified in Nigeria) lineages. Geometric mean plaque reduction neutralization titres against the variant viruses-particularly the B.1.617.1 variant-seemed to be lower than the titre against the USA-WA1/2020 virus, but all sera tested neutralized the variant viruses at titres of at least 1:40. The susceptibility of the variant strains to neutralization elicited by the BNT162b2 vaccine supports mass immunization as a central strategy to end the coronavirus disease 2019 (COVID-19) pandemic globally.

BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans.

BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in preventing COVID-191. Here we extend a previous phase-I/II trial report2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNγ+ or IL-2+ CD8+ and CD4+ T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8+ T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

BACKGROUND: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS: In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS: Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 µg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 µg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS: GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Bivalent Omicron BA.1-Adapted BNT162b2 Booster in Adults Older than 55 Years.

BACKGROUND: The emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019. METHODS: In an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-µg doses of the BNT162b2 vaccine were randomly assigned to receive 30 µg or 60 µg of BNT162b2, 30 µg or 60 µg of monovalent B.1.1.529 (omicron) BA.1-adapted BNT162b2 (monovalent BA.1), or 30 µg (15 µg of BNT162b2 + 15 µg of monovalent BA.1) or 60 µg (30 µg of BNT162b2 + 30 µg of monovalent BA.1) of BA.1-adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT50] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 µg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants. RESULTS: A total of 1846 participants underwent randomization. At 1 month after vaccination, bivalent BA.1 (30 µg and 60 µg) and monovalent BA.1 (60 µg) showed neutralizing activity against BA.1 superior to that of BNT162b2 (30 µg), with NT50 geometric mean ratios (GMRs) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3.15 (95% CI, 2.38 to 4.16), respectively. Bivalent BA.1 (both doses) and monovalent BA.1 (60 µg) were also noninferior to BNT162b2 (30 µg) with respect to seroresponse against BA.1; between-group differences ranged from 10.9 to 29.1 percentage points. Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain, with NT50 GMRs of 0.99 (95% CI, 0.82 to 1.20) and 1.30 (95% CI, 1.07 to 1.58), respectively. BA.4-BA.5 and BA.2.75 neutralizing titers were numerically higher with 30-µg bivalent BA.1 than with 30-µg BNT162b2. The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 µg). Adverse events were more common in the 30-µg monovalent-BA.1 (8.5%) and 60-µg bivalent-BA.1 (10.4%) groups than in the other groups (3.6 to 6.6%). CONCLUSIONS: The candidate monovalent or bivalent omicron BA.1-adapted vaccines had a safety profile similar to that of BNT162b2 (30 µg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626.).

Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes considerable illness in older adults. The efficacy and safety of an investigational bivalent RSV prefusion F protein-based (RSVpreF) vaccine in this population are unknown. METHODS: In this ongoing, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults (≥60 years of age) to receive a single intramuscular injection of RSVpreF vaccine at a dose of 120 µg (RSV subgroups A and B, 60 µg each) or placebo. The two primary end points were vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms. The secondary end point was vaccine efficacy against RSV-associated acute respiratory illness. RESULTS: At the interim analysis (data-cutoff date, July 14, 2022), 34,284 participants had received RSVpreF vaccine (17,215 participants) or placebo (17,069 participants). RSV-associated lower respiratory tract illness with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1000 person-years of observation) and 33 participants in the placebo group (3.58 cases per 1000 person-years of observation) (vaccine efficacy, 66.7%; 96.66% confidence interval [CI], 28.8 to 85.8); 2 cases (0.22 cases per 1000 person-years of observation) and 14 cases (1.52 cases per 1000 person-years of observation), respectively, occurred with at least three signs or symptoms (vaccine efficacy, 85.7%; 96.66% CI, 32.0 to 98.7). RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1000 person-years of observation) (vaccine efficacy, 62.1%; 95% CI, 37.1 to 77.9). The incidence of local reactions was higher with vaccine (12%) than with placebo (7%); the incidences of systemic events were similar (27% and 26%, respectively). Similar rates of adverse events through 1 month after injection were reported (vaccine, 9.0%; placebo, 8.5%), with 1.4% and 1.0%, respectively, considered by the investigators to be injection-related. Severe or life-threatening adverse events were reported in 0.5% of vaccine recipients and 0.4% of placebo recipients. Serious adverse events were reported in 2.3% of participants in each group through the data-cutoff date. CONCLUSIONS: RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns. (Funded by Pfizer; RENOIR ClinicalTrials.gov number, NCT05035212; EudraCT number, 2021-003693-31.).

Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age.

BACKGROUND: Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. METHODS: We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2-3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2-3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-µg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-µg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 µg of BNT162b2 in the pivotal trial. RESULTS: During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-µg dose) and 48 children 2 to 4 years of age (3-µg or 10-µg dose). The 3-µg dose level was selected for the phase 2-3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). CONCLUSIONS: A three-dose primary series of 3-µg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults.

In March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1, a pandemic. With rapidly accumulating numbers of cases and deaths reported globally2, a vaccine is urgently needed. Here we report the available safety, tolerability and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose-escalation study (ClinicalTrials.gov identifier NCT04368728) among 45 healthy adults (18-55 years of age), who were randomized to receive 2 doses-separated by 21 days-of 10 µg, 30 µg or 100 µg of BNT162b1. BNT162b1 is a lipid-nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes the trimerized receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 µg was not administered because of the increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared with the 30-µg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second dose. Geometric mean neutralizing titres reached 1.9-4.6-fold that of a panel of COVID-19 convalescent human sera, which were obtained at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate.

COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses.

An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18-55 years of age. Two doses of 1-50 µg of BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-µg dose) to 3.5-fold (50-µg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8+ and CD4+ T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.

Vaccine Efficacy in Adults in a Respiratory Syncytial Virus Challenge Study.

BACKGROUND: Although human respiratory syncytial virus (RSV) is an important cause of illness and death in older adults, no RSV vaccine has been licensed. METHODS: In a phase 2a study, we randomly assigned healthy adults (18 to 50 years of age), in a 1:1 ratio, to receive a single intramuscular injection of either bivalent prefusion F (RSVpreF) vaccine or placebo. Approximately 28 days after injection, participants were inoculated intranasally with the RSV A Memphis 37b challenge virus and observed for 12 days. The per-protocol prespecified primary end points were the following: reverse-transcriptase-quantitative polymerase-chain-reaction (RT-qPCR)-confirmed detectable RSV infection on at least 2 consecutive days with at least one clinical symptom of any grade from two categories or at least one grade 2 symptom from any category, the total symptom score from day 1 to discharge, and the area under the curve (AUC) for the RSV viral load in nasal-wash samples measured by means of RT-qPCR from day 2 after challenge to discharge. In addition, we assessed immunogenicity and safety. RESULTS: After participants were inoculated with the challenge virus, vaccine efficacy of 86.7% (95% CI, 53.8 to 96.5) was observed for symptomatic RSV infection confirmed by any detectable viral RNA on at least 2 consecutive days. The median AUC for the RSV viral load (hours × log10 copies per milliliter) as measured by RT-qPCR assay was 0.0 (interquartile range, 0.0 to 19.0) in the vaccine group and 96.7 (interquartile range, 0.0 to 675.3) in the placebo group. The geometric mean factor increase from baseline in RSV A-neutralizing titers 28 days after injection was 20.5 (95% CI, 16.6 to 25.3) in the vaccine group and 1.1 (95% CI, 0.9 to 1.3) in the placebo group. More local injection-site pain was noted in the vaccine group than in the placebo group. No serious adverse events were observed in either group. CONCLUSIONS: RSVpreF vaccine was effective against symptomatic RSV infection and viral shedding. No evident safety concerns were identified. These findings provide support for further evaluation of RSVpreF vaccine in a phase 3 efficacy study. (Funded by Pfizer; EudraCT number, 2020-003887-21; ClinicalTrials.gov number, NCT04785612.).

Prefusion F Protein-Based Respiratory Syncytial Virus Immunization in Pregnancy.

BACKGROUND: Respiratory syncytial virus (RSV), a major cause of illness and death in infants worldwide, could be prevented by vaccination during pregnancy. The efficacy, immunogenicity, and safety of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine in pregnant women and their infants are uncertain. METHODS: In a phase 2b trial, we randomly assigned pregnant women, at 24 through 36 weeks' gestation, to receive either 120 or 240 µg of RSVpreF vaccine (with or without aluminum hydroxide) or placebo. The trial included safety end points and immunogenicity end points that, in this interim analysis, included 50% titers of RSV A, B, and combined A/B neutralizing antibodies in maternal serum at delivery and in umbilical-cord blood, as well as maternal-to-infant transplacental transfer ratios. RESULTS: This planned interim analysis included 406 women and 403 infants; 327 women (80.5%) received RSVpreF vaccine. Most postvaccination reactions were mild to moderate; the incidence of local reactions was higher among women who received RSVpreF vaccine containing aluminum hydroxide than among those who received RSVpreF vaccine without aluminum hydroxide. The incidences of adverse events in the women and infants were similar in the vaccine and placebo groups; the type and frequency of these events were consistent with the background incidences among pregnant women and infants. The geometric mean ratios of 50% neutralizing titers between the infants of vaccine recipients and those of placebo recipients ranged from 9.7 to 11.7 among those with RSV A neutralizing antibodies and from 13.6 to 16.8 among those with RSV B neutralizing antibodies. Transplacental neutralizing antibody transfer ratios ranged from 1.41 to 2.10 and were higher with nonaluminum formulations than with aluminum formulations. Across the range of assessed gestational ages, infants of women who were immunized had similar titers in umbilical-cord blood and similar transplacental transfer ratios. CONCLUSIONS: RSVpreF vaccine elicited neutralizing antibody responses with efficient transplacental transfer and without evident safety concerns. (Funded by Pfizer; ClinicalTrials.gov number, NCT04032093.).

Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.

BACKGROUND: Safe, effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in children younger than 12 years of age. METHODS: A phase 1, dose-finding study and an ongoing phase 2-3 randomized trial are being conducted to investigate the safety, immunogenicity, and efficacy of two doses of the BNT162b2 vaccine administered 21 days apart in children 6 months to 11 years of age. We present results for 5-to-11-year-old children. In the phase 2-3 trial, participants were randomly assigned in a 2:1 ratio to receive two doses of either the BNT162b2 vaccine at the dose level identified during the open-label phase 1 study or placebo. Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-µg doses of BNT162b2. Vaccine efficacy against Covid-19 at 7 days or more after the second dose was assessed. RESULTS: During the phase 1 study, a total of 48 children 5 to 11 years of age received 10 µg, 20 µg, or 30 µg of the BNT162b2 vaccine (16 children at each dose level). On the basis of reactogenicity and immunogenicity, a dose level of 10 µg was selected for further study. In the phase 2-3 trial, a total of 2268 children were randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). At data cutoff, the median follow-up was 2.3 months. In the 5-to-11-year-olds, as in other age groups, the BNT162b2 vaccine had a favorable safety profile. No vaccine-related serious adverse events were noted. One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). Covid-19 with onset 7 days or more after the second dose was reported in three recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3). CONCLUSIONS: A Covid-19 vaccination regimen consisting of two 10-µg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

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.).

A Phase 2 Extension Study Evaluating the Immunogenicity, Safety, and Tolerability of 3 or 4 Doses of a Clostridioides difficile Vaccine in Healthy US Adults Aged 65 to 85 Years.

BACKGROUND: This phase 2 extension explored the long-term antibody persistence of an investigational Clostridioides difficile vaccine and the safety, tolerability, and immunogenicity of dose 4 approximately 12 months post-dose 3. METHODS: One year post-dose 3, healthy US 65- to 85-year-olds (N = 300) were randomized to dose 4 of vaccine at previously received antigen levels (100 or 200 µg) or placebo. Assessments included safety and percentages of participants achieving neutralizing antibody titers above prespecified thresholds (≥219 and ≥2586 neutralization units/mL for toxins A and B, respectively). RESULTS: In participants previously given three 200-µg doses and placebo in the extension, toxin A and B neutralizing antibodies were above prevaccination levels 48 months post-dose 3 (36 months after placebo); 24.0% and 26.0% had toxin A and B antibodies at or above prespecified thresholds, respectively. Neutralizing antibodies increased post-dose 4 (12 months post-dose 3) and persisted to 36 months post-dose 4. Thirty days post-dose 4, all participants had toxin A and 86.5% to 100% had toxin B titers at or above prespecified thresholds. Local reactions were more frequent in vaccine recipients. Systemic and adverse event frequencies were similar across groups. CONCLUSIONS: C difficile vaccine immune responses persisted 48 months post-dose 3. Dose 4 was immunogenic and well tolerated, supporting continued development. Clinical Trials Registration. ClinicalTrials.gov NCT02561195.

Respiratory Syncytial Virus Prefusion F Vaccination: Antibody Persistence and Revaccination.

BACKGROUND: Respiratory syncytial virus (RSV) causes substantial respiratory disease. Bivalent RSV prefusion F (RSVpreF) vaccine is licensed in ≥60-year-olds. RSVpreF was well tolerated and immunogenic in a phase 1/2 study. We evaluated antibody persistence after initial vaccination and safety and immunogenicity after revaccination from this study. METHODS: Healthy adults were randomized to receive initial vaccination and revaccination 12 months later with either placebo or RSVpreF (240 µg with or without aluminum hydroxide). RSV-A and RSV-B geometric mean neutralizing titers (GMTs) were measured through 12 months after both vaccinations. Tolerability and safety were assessed. RESULTS: There were 263 participants revaccinated (18-49 years old, n = 134; 65-85 years old, n = 129). Among 18- to 49-year-olds and 65- to 85-year-olds, geometric mean fold rises (GMFRs) for both RSV subgroups (RSV-A, RSV-B) 1 month after initial RSVpreF vaccination were 13.3 to 20.4 and 8.9 to 15.5, respectively, as compared with levels before initial vaccination; corresponding GMFRs 12 months after initial vaccination were 4.1 to 5.0 and 2.6 to 4.1. GMFRs 1 month after revaccination vs levels before revaccination were 1.4 to 2.3 and 1.4 to 2.2 for 18- to 49-year-olds and 65- to 85-year-olds. Peak GMTs after revaccination were lower than those after initial vaccination. GMTs 12 months after initial vaccination and revaccination were similar, with GMFRs ranging from 0.7 to 1.6. No safety signals occurred. CONCLUSIONS: RSVpreF revaccination was immunogenic and well tolerated among adults. Clinical Trials Registration. NCT03529773 (ClinicalTrials.gov).

CLOVER: A Phase 3 Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection.

BACKGROUND: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention. METHODS: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N=17,535) to receive 3 PF-06425090 or placebo doses (0,1,6-months). Primary endpoints were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary endpoints), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability/safety was assessed. RESULTS: The primary endpoint was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE)=31.0% (96.4%CI: -38.7%-66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE=28.6% (-28.4%-61.0%)]). Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P=0.02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE=100% [95%CI: 59.6%-100.0%]) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE=100% [54.8%-100.0%]). Local reactions were more frequent in PF-06425090 recipients and systemic events were generally similar between groups; most were mild-to-moderate. AE rates were similar between groups. CONCLUSIONS: Three PF-06425090 doses were safe and well-tolerated. Although the primary endpoint was not met, PF-06425090 reduced symptom duration, CDI requiring medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. NCT03090191.

Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents.

BACKGROUND: Until very recently, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had not been authorized for emergency use in persons younger than 16 years of age. Safe, effective vaccines are needed to protect this population, facilitate in-person learning and socialization, and contribute to herd immunity. METHODS: In this ongoing multinational, placebo-controlled, observer-blinded trial, we randomly assigned participants in a 1:1 ratio to receive two injections, 21 days apart, of 30 µg of BNT162b2 or placebo. Noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants was an immunogenicity objective. Safety (reactogenicity and adverse events) and efficacy against confirmed coronavirus disease 2019 (Covid-19; onset, ≥7 days after dose 2) in the 12-to-15-year-old cohort were assessed. RESULTS: Overall, 2260 adolescents 12 to 15 years of age received injections; 1131 received BNT162b2, and 1129 received placebo. As has been found in other age groups, BNT162b2 had a favorable safety and side-effect profile, with mainly transient mild-to-moderate reactogenicity (predominantly injection-site pain [in 79 to 86% of participants], fatigue [in 60 to 66%], and headache [in 55 to 65%]); there were no vaccine-related serious adverse events and few overall severe adverse events. The geometric mean ratio of SARS-CoV-2 50% neutralizing titers after dose 2 in 12-to-15-year-old participants relative to 16-to-25-year-old participants was 1.76 (95% confidence interval [CI], 1.47 to 2.10), which met the noninferiority criterion of a lower boundary of the two-sided 95% confidence interval greater than 0.67 and indicated a greater response in the 12-to-15-year-old cohort. Among participants without evidence of previous SARS-CoV-2 infection, no Covid-19 cases with an onset of 7 or more days after dose 2 were noted among BNT162b2 recipients, and 16 cases occurred among placebo recipients. The observed vaccine efficacy was 100% (95% CI, 75.3 to 100). CONCLUSIONS: The BNT162b2 vaccine in 12-to-15-year-old recipients had a favorable safety profile, produced a greater immune response than in young adults, and was highly effective against Covid-19. (Funded by BioNTech and Pfizer; C4591001 ClinicalTrials.gov number, NCT04368728.).

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months.

BACKGROUND: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. METHODS: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-µg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. RESULTS: BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. CONCLUSIONS: Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).

Efficacy of a 4-Antigen Staphylococcus aureus Vaccine in Spinal Surgery: The STaphylococcus aureus suRgical Inpatient Vaccine Efficacy (STRIVE) Randomized Clinical Trial.

BACKGROUND: Staphylococcus aureus is a global pathogen that is frequently responsible for healthcare-associated infections, including surgical site infections (SSIs). Current infection prevention and control approaches may be limited, with S. aureus antibiotic resistance remaining problematic. Thus, a vaccine to prevent or reduce S. aureus infection is critically needed. We evaluated the efficacy and safety of an investigational 4-antigen S. aureus vaccine (SA4Ag) in adults undergoing elective open posterior spinal fusion procedures with multilevel instrumentation. METHODS: In this multicenter, site-level, randomized, double-blind trial, patients aged 18-85 years received a single dose of SA4Ag or placebo 10-60 days before surgery. SA4Ag efficacy in preventing postoperative S. aureus bloodstream infection and/or deep incisional or organ/space SSIs was the primary end point. Safety evaluations included local reactions, systemic events, and adverse events (AEs). Immunogenicity and colonization were assessed. RESULTS: Study enrollment was halted when a prespecified interim efficacy analysis met predefined futility criteria. SA4Ag showed no efficacy (0.0%) in preventing postoperative S. aureus infection (14 cases in each group through postoperative day 90), despite inducing robust functional immune responses to each antigen compared with placebo. Colonization rates across groups were similar through postoperative day 180. Local reactions and systemic events were mostly mild or moderate in severity, with AEs reported at similar frequencies across groups. CONCLUSIONS: In patients undergoing elective spinal fusion surgical procedures, SA4Ag was safe and well tolerated but, despite eliciting substantial antibody responses that blocked key S. aureus virulence mechanisms, was not efficacious in preventing S. aureus infection. Clinical Trials Registration. NCT02388165.

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. METHODS: In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 µg per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. RESULTS: A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).