BACKGROUND:Neisseria meningitidis serogroups A, B, C, W, and Y (MenA, Men B, MenC, MenW, and MenY) cause nearly all invasive meningococcal disease globally, and clinical outcomes are often severe. We aimed to evaluate the safety and immunological non-inferiority of a MenABCWY vaccine, comprising MenB-fHbp and MenACWY-TT, compared with US-licensed vaccines MenB-fHbp and MenACWY-CRM, in healthy adolescents and young adults. METHODS:In this phase 3, observer-blinded, active-controlled trial at 75 sites in the USA, the Czech Republic, Denmark, Hungary, and Poland, healthy individuals aged 10-25 years were randomly allocated (2:1), stratified by previous MenACWY vaccination status, to receive two doses of MenABCWY vaccine (at months 0 and 6) or two doses of MenB-fHbp vaccine (months 0 and 6) plus one dose of MenACWY-CRM vaccine (month 0). This study had two primary immunogenicity objectives: evaluating MenA, MenC, MenW, and MenY immune responses following two doses of MenABCWY versus one dose of MenACWY-CRM in ACWY-naive and ACWY-primed participants, and evaluating MenB immune responses following two doses of MenABCWY versus two doses of MenB-fHbp. Immune responses were evaluated by human serum bactericidal assay using human complement against MenA, MenC, MenW, and MenY strains and four diverse, vaccine-heterologous MenB strains. Non-inferiority was shown if the lower bounds of the 95% CIs for the differences in rates of seroresponse or composite response (all MenB strains combined) exceeded -10%. Safety objectives comprised evaluating frequencies of solicited local reactions and systemic events reported within 7 days after each vaccination and adverse events up to 1 month after the second vaccination. This study is registered with ClinicalTrials.gov, NCT04440163, and with EudraCT, 2019-004313-13, and is completed. FINDINGS:Between June 17, 2020, and Aug 3, 2021, 2431 participants were recruited and randomly allocated. At baseline, the safety population (n=2412) had a median age of 16·0 years (IQR not calculated) and a mean age of 16·1 years (SD 4·55), with 1176 (49%) male and 1236 (51%) female participants. 1881 (78%) participants were White, and 621 (26%) were Hispanic or Latino in ethnicity. Among ACWY-naive participants, differences in MenA, MenC, MenW, and MenY seroresponse rates between vaccination groups receiving two MenABCWY doses versus one MenACWY-CRM dose ranged from 2·5% (95% CI -0·2 to 6·0) for MenA to 41·0% (95% CI 34·4 to 47·5) for MenC. Among ACWY-primed participants, differences in MenA, MenC, MenW, and MenY seroresponse rates between vaccination groups ranged from -3·2% (95% CI -6·5 to 0·5) for MenA to 0·7% (95% CI -2·2 to 4·3) for MenW. The differences in MenB seroresponse rates across test strains between vaccination groups receiving two MenABCWY doses versus two MenB-fHbp doses ranged from 1·4% (95% CI -1·0 to 4·3) for MenB test strains expressing fHbp variant A56 to 10·9% (95% CI 5·2 to 16·6) for MenB test strains expressing fHbp variant B24; the difference in composite response for all MenB test strains was 9·6% (95% CI 4·2 to 15·2). Reactogenicity events, mostly mild to moderate in severity, were reported at similar frequencies across groups; none led to study withdrawal. Similar proportions of each group reported one or more adverse events (368 [21%] of 1763 participants in the MenABCWY group vs 132 [20%] of 649 participants in the MenB-fHbp plus MenACWY-CRM group). INTERPRETATION:The immunological non-inferiority and safety profile of a two-dose MenABCWY series (months 0 and 6) compared with three separate injections of MenB-fHbp (months 0 and 6) and MenACWY-CRM (month 0) for protection against MenA, MenB, MenC, MenW, and MenY indicate that MenABCWY could simplify the vaccination strategy against invasive meningococcal disease through fewer injections, potentially increasing vaccination rates among adolescents and young adults. FUNDING:Pfizer.

Abstract Background This report summarizes the final results from a randomized, placebo-controlled, phase 2b trial evaluating the safety, antibody persistence, and potential efficacy of a bivalent respiratory syncytial virus prefusion F (RSVpreF) vaccine in pregnant individuals and their infants. Methods Maternal participants were randomized from 24 to 36 weeks’ gestation to receive RSVpreF (120 or 240 µg ± aluminum hydroxide) or placebo. Results This analysis included 579 pregnant individuals and their 572 infants from 4 countries (Argentina, Chile, South Africa, United States); 462 maternal participants received RSVpreF vaccine. Adverse events in the month following receipt of either RSVpreF vaccination or placebo (maternal) or birth (infant) were mostly anticipated events in pregnancy and the neonatal period. For all RSVpreF groups, combined RSV-A/B 50% neutralizing titers peaked 2 weeks after vaccination. At delivery, geometric mean titer ratios between RSVpreF and placebo recipients' infants were 10.9 to 13.6. Transplacental transfer ratios (all groups) were 1.39 to 1.83. Neutralizing geometric mean titers remained higher in infants whose mothers received RSVpreF vs placebo through their first 6 months of life, with an estimated half-life of 39 to 44 days. In an exploratory analysis, observed efficacy (95% CI) for the combined RSVpreF groups against medically attended and severe medically attended infant RSV-associated lower respiratory tract illness through the first 180 days of life was 75% (−11% to 94%) and 83% (−48% to 99%), respectively. Conclusions RSVpreF had a favorable safety profile and elicited robust neutralizing responses with efficient transplacental transfer. The potential to prevent infant RSV-associated lower respiratory tract illness was subsequently confirmed in the pivotal phase 3 efficacy trial. Clinical Trials Registration ClinicalTrials.gov (NCT04032093).

Background:Vaccination during pregnancy to protect infants against respiratory syncytial virus (RSV) disease relies on transplacental transfer of RSV neutralizing antibodies. Observational natural history studies on correlations between RSV-specific antibody levels and infant protection have, however, had variable results. Methods:This observational natural history study characterized RSV-specific neutralizing antibody levels and described infant RSV disease dynamics in South African and United States (US) maternal-infant pairs. Naturally acquired RSV serum neutralizing titers were determined from 726 pregnant individuals and their infants at birth and assessed in relationship to serum neutralizing titers conferred by serum palivizumab protective levels. Results:In the absence of vaccination, we found no correlation between RSV neutralizing titers and infant protection against RSV-associated lower respiratory tract illness. South Africa versus US comparison revealed similar, broad distributions of maternal serum RSV neutralizing titers but lower transplacental transfer rates in South Africa (0.6 [95% confidence interval {CI}, .6-.7]) than the US (1.3 [95% CI, 1.1-1.4]) and high rates of community spread of infant asymptomatic RSV infection in South Africa versus the US. Conclusions:These findings suggest that the effectiveness of maternal immunization against infant RSV relies on immunization shifting natural distribution of maternal RSV neutralizing titers into the protective range for infants, which is supported by efficacy demonstrated with RSV maternal immunization.

BACKGROUND:A hexavalent group B streptococcus (GBS) polysaccharide conjugate vaccine (GBS6) is being developed to prevent invasive group B streptococcal disease in infants through active maternal immunisation. We previously reported results for GBS6 administered to non-pregnant adults (NCT03170609). Here, we aim to extend these results to determine safety and immunogenicity of a second dose of GBS6 in non-pregnant adults who received a primary dose of GBS6. METHODS:This phase 2, open-label extension of a phase 1/2 randomised controlled trial was done at four sites in the USA to assess the safety, tolerability, and immunogenicity of a booster dose (20 μg capsular polysaccharide per serotype per dose) of GBS6 formulated with and without aluminium phosphate (AlPO4). Healthy adults who were aged 18-49 years during participation in the phase 1/2 study approximately 2 years before and received one of the six GBS6 formulations were enrolled. Participants received a single dose of GBS6 20 μg capsular polysaccharide (CPS) per serotype on study day 1, with or without AlPO4 based on the formulation received in the phase 1/2 study. Primary endpoints evaluated GBS6 safety (in participants receiving one or more doses) based on solicited local reactions and systemic events within 14 days, adverse events within 1 month, and unsolicited serious adverse events and medically attended adverse events up to 6 months after vaccination. Secondary immunogenicity endpoints (in the evaluable population of participants in compliance with key protocol criteria) included assessments of GBS serotype-specific IgG geometric mean concentrations (GMCs) and geometric mean fold-rises (GMFRs) in serum samples collected at 1 month after versus before booster vaccination. This study is registered with ClinicalTrials.gov (NCT04258995). FINDINGS:Of 297 participants who completed the base study, 151 received the GBS6 booster dose (76 participants with and 75 without AlPO4) and were included in the safety analysis. The median time to booster from primary vaccination was 2·4 years (IQR 2·3-2·5). Most participants were women (114 [75%] of 151) and White (125 [83%] of 151). The mean age was 36·7 years (SD 8·67). Pain at the injection site was the most frequently reported solicited local reaction (52 [68%] of 76 participants who received GBS6 with AlPO4 and 32 [43%] of 75 without AlPO4) and was severe in two (3%) of 76 participants who received GBS6 with AlPO4 and no participant who received the vaccine without adjuvant. Systemic events occurred at similar frequencies in both groups (45 [59%] of 76 with AlPO4 and 46 [61%] of 75 without AlPO4), and were mostly mild or moderate in severity. The number of participants reporting any type of unsolicited adverse event was low and similar for GBS6 with AlPO4 versus GBS6 without AlPO4 (11 [14%] of 76 vs 12 [16%] of 75). No adverse event was deemed to be related to GBS6. One serious adverse event, assessed as not related to the product being investigated, of thermal burn was reported in a participant who received GBS6 with AlPO4. Low rates of medically attended adverse events were reported in both groups of participants receiving a booster dose of GBS6 (nine [12%] of 76 with AlPO4 and seven [9%] of 75 without AlPO4). For all serotypes, serotype-specific anti-CPS IgG GMCs mostly waned over the 2-year period after the primary vaccination but remained elevated before the booster dose compared with before the primary dose of GBS6. A booster dose of GBS6 elicited robust GBS serotype-specific anti-CPS IgG responses that were two-fold to 18-fold higher 1 month after the booster dose (GMC range 6·025-60·304 μg/mL) than 1 month after the primary dose (0·365-35·173 μg/mL). Anti-CPS IgG GMFRs ranged from approximately ten-fold to 59-fold across the serotypes and formulations from before the booster dose (GMC range 0·130-5·274 μg/mL) to 1 month after the booster dose. INTERPRETATION:The results of this study showed that a single 20 μg booster dose of GBS6 given approximately 2 years after a primary dose to healthy, non-pregnant adults was safe and elicited robust immune responses that were consistently higher than those after the primary dose. As there is precedent for repeat doses of vaccines to augment or sustain circulating antibodies available for placental transfer with each pregnancy, results from this study might inform decisions around future dosing strategies for GBS6 for maternal immunisation with subsequent pregnancies should GBS6 be approved for use in pregnancy. FUNDING:Pfizer.

BACKGROUND AND OBJECTIVES:The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to expand protection for pneumococcal disease. It contains all 13-valent pneumococcal conjugate vaccine (PCV13) components plus conjugates for 7 additional serotypes. Our primary objective with this study was to evaluate PCV20 tolerability and safety. METHODS:In this phase 3, multi-country, double-blind study, healthy infants born at ≥34 weeks' gestation were randomly assigned 2:1 to receive PCV20 or PCV13 at 2, 4, 6, and 12 to 15 months of age. Safety assessments included local reactions and systemic events within 7 days after each vaccination, adverse events (AEs) from dose 1 to 1 month after dose 3 and from dose 4 to 1 month after dose 4, and serious AEs and newly diagnosed chronic medical conditions from dose 1 through 6 months after the last dose. RESULTS:Participants received PCV20 (N = 1000) or PCV13 (N = 504); 91.7% received all 4 doses. The frequencies of local reactions and systemic events were generally similar in PCV20 and PCV13 groups, with most reported as mild or moderate. The most common local reaction was injection site pain (PCV20, 24.7% to 40.5%; PCV13, 26.8% to 42.0%); irritability was the most common systemic event (PCV20, 54.8% to 68.2%; PCV13, 54.7% to 68.5%). AE frequencies were similar in both groups. No serious AEs were related to study vaccines. Few newly diagnosed chronic medical conditions were reported (2.8% in both groups). PCV20 was safe across multiple countries, in late preterm infants, and when administered with other vaccines. CONCLUSIONS:A 4-dose series of PCV20 had a tolerability and safety profile similar to that of PCV13.

Background: Pneumococcal infections are associated with high disease burden in older individuals in Japan, South Korea, and Taiwan. The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend protection beyond earlier pneumococcal vaccines. Methods: This phase 3 randomized, double-blind study investigated the safety and immunogenicity of PCV20 in participants >= 60 years of age from Japan, South Korea, and Taiwan. Participants were randomized to receive PCV20 or 13-valent pneumococcal conjugate vaccine (PCV13). One month after vaccination, PCV20 recipients received a saline injection and PCV13 recipients received 23-valent polysaccharide vaccine (PPSV23). Primary immunogenicity objectives were to demonstrate noninferiority of PCV20 to PCV13 (13 matched serotypes) or PPSV23 (7 additional serotypes) for serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after vaccination with PCV20, PCV13, or PPSV23. Noninferiority for each serotype was declared if the lower bound of the 2-sided 95% CI for OPA geometric mean ratio (GMR) was > 0.5. Safety endpoints included local reactions, systemic events, adverse events (AEs), and serious AEs. Results: Overall, 1421 participants were vaccinated (median age [range]: 65 [60-85] years). PCV20 was noninferior to PCV13 for all 13 matched serotypes and to PPSV23 for 6 of 7 additional serotypes. Although statistical noninferiority was missed for serotype 8 (lower bound of the 2-sided 95% CI for OPA GMR = 0.5, thus not meeting the statistical noninferiority criterion of > 0.5), secondary immunogenicity endpoints for serotype 8 were supportive of a robust immune response. The incidence of AEs and the frequency and severity of local reactions and systemic events were generally similar after PCV20 and PCV13. No safety concerns were identified. Conclusion: PCV20 generated robust immune responses to all vaccine serotypes in older adults in Japan, South Korea, and Taiwan. The safety and tolerability profile was similar to PCV13. PCV20 is expected to help protect against all 20 vaccine serotypes. NCT04875533.

BACKGROUND:A 20-valent pneumococcal conjugate vaccine (PCV20), containing 13-valent PCV (PCV13) components and 7 additional polysaccharide conjugates, was developed to extend protection for pneumococcal disease. This phase 3 study assessed the safety and immunogenicity of PCV20 in children. METHODS:In this single-arm study, children (≥15 months-<18 years of age) received 1 dose of PCV20. Children <5 years of age had ≥3 prior doses of PCV13; children ≥5 years were recruited regardless of previous PCV receipt. Serotype-specific IgG concentrations and opsonophagocytic activity (OPA) titers were measured before and 1 month after PCV20. Local reactions and systemic events, adverse events (AEs), serious AEs, and newly diagnosed chronic medical conditions were collected. RESULTS:Of 839 enrolled participants, 831 (>99%) were vaccinated, and 819 (>97%) completed all study visits. Local reactions and systemic events were mostly mild to moderate in severity. No serious AEs were considered PCV20-related. IgG geometric mean fold rises (GMFRs) from before to 1 month after PCV20 ranged from 27.9-1847.7 (7 additional serotypes) and 2.9-44.9 (PCV13 serotypes) in children <5 years of age, and 10.5-187.7 (7 additional serotypes) and 4.3-127.9 (PCV13 serotypes) in children ≥5 years old. OPA GMFRs from before to 1 month after PCV20 ranged from 12.4-983.6 to 2.8-52.9 in children <5 years of age and from 11.5-499.0 to 5.3-147.9 in children ≥5 years of age. CONCLUSIONS:Among children ≥15 months through <18 years of age, PCV20 was well tolerated and induced robust responses to all 20 serotypes, supporting the use of PCV20 in children.

BACKGROUND:The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend pneumococcal disease protection beyond 13-valent PCV (PCV13). METHODS:This phase 3, double-blind study conducted in the United States/Puerto Rico evaluated PCV20 safety and immunogenicity. Healthy infants were randomized to receive a 4-dose series of PCV20 or PCV13 at 2, 4, 6 and 12-15 months old. Objectives included demonstrating noninferiority (NI) of PCV20 to PCV13 immunoglobulin G (IgG) geometric mean concentrations after doses 3 and 4 and percentages of participants with predefined IgG concentrations after dose 3, with 7 additional PCV20 serotypes compared with the lowest result among vaccine serotypes in the PCV13 group. Safety assessments included local reactions, systemic events, adverse events, serious adverse events and newly diagnosed chronic medical conditions. RESULTS:Overall, 1991 participants were vaccinated (PCV20, n = 1001; PCV13, n = 990). For IgG geometric mean concentrations 1 month after both doses 3 and 4, all 20 serotypes met NI criteria (geometric mean ratio lower 2-sided 95% confidence interval > 0.5). For percentages of participants with predefined IgG concentrations after dose 3, NI (percentage differences lower 2-sided 95% confidence interval > -10%) was met for 8/13 matched serotypes and 6/7 additional serotypes; 4 serotypes missed the statistical NI criterion by small margins. PCV20 also elicited functional and boosting responses to all 20 serotypes. The safety profile of PCV20 was similar to PCV13. CONCLUSION:A 4-dose series of PVC20 was well tolerated and elicited robust serotype-specific immune responses expected to help protect infants and young children against pneumococcal disease due to the 20 vaccine serotypes. Clinical trial registration: NCT04382326.

Streptococcus pneumoniae causes a considerable disease burden among children in China. Many isolates exhibit antimicrobial resistance but are often serotypes covered by the 13-valent pneumococcal conjugate vaccine (PCV13). Because the approved infant immunization schedule in China allows PCV13 vaccination only for those 6 weeks to 15 months of age, this phase 3 study was conducted to evaluate PCV13 immunogenicity and safety in unvaccinated older infants and children. Eligible participants were stratified by age into four cohorts: Cohort 1 (n = 125), 6 weeks-2 months; Cohort 2 (n = 354), 7-<12 months; Cohort 3 (n = 250), 1 -<2 years; Cohort 4 (n = 207), 2-<6 years. Cohort 1 received PCV13 at ages 2, 4, and 6 months; older cohorts were randomized 2:1 to PCV13 or Haemophilus influenzae type b (Hib) vaccine using age-appropriate schedules. Within-group immune responses were assessed by immunoglobulin G (IgG) concentrations and opsonophagocytic activity (OPA) titers. Safety evaluations included solicited reactogenicity events and adverse events (AEs). IgG geometric mean concentrations and OPA geometric mean titers for all 13 PCV13 serotypes increased for all participants vaccinated with PCV13, but not those vaccinated with Hib. Immune responses in Cohorts 2-4 were generally comparable with those in Cohort 1 (the infant series) for most serotypes. PCV13 was well tolerated across cohorts, with reported AEs consistent with expectations in these age groups; no new safety signals were identified. These results suggest that PCV13 administered as a catch-up regimen to infants and children 7 months-<6 years of age in China will effectively reduce vaccine-type pneumococcal disease in this population. NCT03574389.

Background: Older adults are at increased risk of adverse outcomes from pneumococcal disease and COVID-19. Vaccination is an established strategy for preventing both illnesses. This study evaluated the safety and immunogenicity of coadministration of the 20-valent pneumococcal conjugate vaccine (PCV20) and a booster (third dose) of BNT162b2 COVID-19 vaccine.Methods: This phase 3, randomized, double-blind, multicentre study included 570 participants aged & GE;65 years randomized 1:1:1 to PCV20 and BNT162b2 coadministered, or PCV20 or BNT162b2 only (administered with saline for blinding). Primary safety endpoints included local reactions, systemic events, adverse events (AEs) and serious AEs (SAEs). Secondary objectives were immunogenicity of PCV20 and BNT162b2 when administered together or separately. Results: Coadministration of PCV20 and BNT162b2 was well tolerated. Local reactions and systemic events were generally mild-moderate; injection-site pain and fatigue were the most frequent local and systemic events, respectively. AE and SAE rates were low and similar across groups. No AEs led to discon-tinuation; no SAEs were considered vaccination-related. Robust immune responses were observed, with opsonophagocytic activity geometric mean fold rises (GMFRs; from baseline to 1 month) of 2.5-24.5 and 2.3-30.6 across PCV20 serotypes in Coadministration and PCV20-only groups, respectively. GMFRs for full-length S-binding IgG of 35.5 and 39.0, and for neutralizing titres against SARS-CoV-2-wild type virus of 58.8 and 65.4, were observed in the Coadministration and BNT162b2-only groups, respectively.Conclusions: Safety and immunogenicity of coadministered PCV20 and BNT162b2 were similar to those of PCV20 or BNT162b2 administered alone, suggesting that the 2 vaccines may be coadministered. Trial Registration: ClinicalTrials.gov, NCT04887948. & COPY; 2023 Elsevier Ltd. All rights reserved.

Use of pneumococcal conjugate vaccines (PCVs) has led to substantial reductions in the global burden of pediatric pneumococcal disease. Expansion of serotype coverage has been achieved by increasing PCV valency, but this may carry the potential risk of antibody interference. A complementary 7-valent PCV (cPCV7) including polysaccharide conjugates from 7 non-13-valent (PCV13) serotypes was developed to potentially complement PCV13-mediated protection and expand serotype coverage. This study evaluated cPCV7 and PCV13 coadministered in separate limbs or separated in time in infants. This phase 2, multicenter, open-label study included 512 infants randomized 1:1:1 to receive cPCV7 coadministered with PCV13 at ages 2, 4, 6, and 12 months (cPCV7 Coadministered); cPCV7 given at ages 3, 5, 7, and 13 months, 3-5 weeks after PCV13 (cPCV7 Separated); or PCV13 at ages 2, 4, 6, and 12 months followed by a single supplemental dose of cPCV7 at 13 months (PCV13 Control). Safety evaluations included local reactions, systemic events, and adverse events. Serotype-specific immunoglobulin G concentrations and opsonophagocytic activity titers were assessed. The safety profile of cPCV7 was similar to that of PCV13. cPCV7 was well-tolerated in infants when coadministered with or given separately from PCV13. Robust and functional immune responses for all cPCV7 serotypes were observed in both cPCV7 groups. No immunologic interference was observed for either the cPCV7 or PCV13 serotypes with coadministration. A single cPCV7 dose induced immune responses in toddlers. These findings support potential coadministration of a complementary PCV to supplement protection provided by existing PCVs.Trial registration: ClinicalTrials.gov, NCT03550313.

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.).

Introduction: Older adults are at increased risk of adverse outcomes from pneumococcal disease and influenza infections. Vaccination is an established strategy for preventing both illnesses. This study eval-uated coadministration of 20-valent pneumococcal conjugate vaccine (PCV20) and an adjuvanted quadri-valent inactivated influenza vaccine (QIV).Methods: This phase 3, randomized, double-blind, multicenter study included 1796 US adults >= 65 years of age randomized 1:1 to receive either PCV20 and QIV followed 1 month later by saline (Coadministration group) or QIV and saline followed 1 month later by PCV20 (Separate Administration group). Primary immunogenicity objectives were to show noninferiority of PCV20 and QIV coadministra-tion compared with separate administration of either vaccine based on serotype-specific opsonophago-cytic activity (OPA) titers for PCV20 and strain-specific hemagglutination inhibition assay (HAI) titers for QIV. Safety endpoints included local reactions, systemic events, and adverse events (AEs).Results: Noninferiority for pneumococcal and influenza antibody responses (lower bound 95 % CI of the OPA and HAI geometric mean ratios of > 0.5 and > 0.67, respectively) was shown for the Coadministration group compared with the Separate Administration group for all 20 pneumococcal ser-otypes and all 4 influenza vaccine strains. Local reactions and systemic events were mostly mild or mod-erate in severity across groups; injection site pain was the most frequent local reaction, and fatigue was the most frequent systemic event. Mild and moderate fatigue were reported more frequently after PCV20 and QIV coadministration compared with separate administration (mild, 20.0 % vs 10.8 %-12.6 %; moder-ate, 12.3 % vs 8.4 %-9.6 %); this was not considered clinically significant. AE reporting rates were similar across groups, and no serious AEs were considered vaccination-related.Conclusions: Immune responses after coadministration of PCV20 and QIV were noninferior to separate administration of either vaccine. The PCV20 safety profile was similar when given together with or after QIV. These findings support PCV20 and QIV coadministration.Trial Registration: ClinicalTrials.gov, NCT04526574.(c) 2022 Published by Elsevier Ltd.

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.).

Abstract Background Prevention of respiratory syncytial virus (RSV) disease in infants is an unmet vaccine need, and maternal immunization is a potential strategy to address this need. This study evaluated concomitant administration of RSV stabilized prefusion F subunit vaccine (RSVpreF) and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed (Tdap) in healthy, nonpregnant women 18‒49 years of age. Methods In this phase 2b, multicenter, placebo-controlled, observer-blind, noninferiority study, participants were randomized to receive RSVpreF in a range of doses and formulations with Tdap or alone, or Tdap alone. Safety and immunogenicity were assessed. Results Local reactions and systemic events were generally similar across vaccine groups. Noninferiority of anti-RSV-A and anti-RSV-B immune responses induced by RSVpreF with Tdap was demonstrated compared to RSVpreF alone. Noninferiority of anti-diphtheria toxoid and anti-tetanus toxoid immune responses after administration of RSVpreF with Tdap was demonstrated compared to Tdap alone; noninferiority was not met for anti-pertussis component responses. Conclusions RSVpreF was safe and well tolerated when administered with Tdap or alone in nonpregnant women 18‒49 years of age. Immune responses induced by Tdap administered with RSVpreF were noninferior for the tetanus and diphtheria components of Tdap, but not for pertussis. Clinical Trials Registration NCT04071158.

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.).

Abstract Background Group B streptococcus (GBS) is a leading cause of invasive bacterial infections in young infants and pregnant women. Pfizer is developing a hexavalent GBS vaccine (GBS6) as a maternal vaccine to prevent invasive GBS disease due to the 6 most prevalent serotypes in young infants. We previously reported Phase 1 safety and immunogenicity data for GBS6. There is precedent for repeat doses of vaccines to augment or sustain circulating antibodies available for placental transfer with each pregnancy; thus, data to inform GBS6 booster strategies were required. Methods This was a Phase 2 open-label extension study to evaluate the safety and immunogenicity of a booster dose of GBS6 (20 μg capsular polysaccharide (CPS)/serotype/dose) with or without AlPO4, given ∼2 years after primary vaccination in 151 healthy nonpregnant adults. Sera taken before and 1-month postbooster were assessed for anti-CPS IgG using a direct Luminex immunoassay. Participants recorded solicited local and systemic events for 14 days after vaccination and unsolicited safety events through 6 months after vaccination. Immunogenicity time points from the Phase 1 study are referred to as primary dose. Results Immunogenicity results For all serotypes, serotype-specific IgG geometric mean concentrations (GMCs) remained elevated compared to baseline at the prebooster time point and were higher 1-month postbooster than 1 month post primary. The 1-month postbooster IgG GMCs were 10- to 59-fold higher than at the prebooster time point. There were similar responses between the 2 formulations. Safety and tolerability results The most frequently reported local reaction was mild to moderate pain at the injection site. Greater pain was associated with AlPO4 formulation. The most frequently reported systemic events were mild to moderate headache and fatigue. The frequency of adverse events was low. Figure 1Antibody Response Line Plot of IgG GMCs by Vaccine Group - All SerotypesFigure 2.Reverse Cumulative Distribution Curves (RCDCs) for IgG 1 Month After Primary and Booster Vaccination, by Vaccine Group – All SerotypesFigure 3.IgG Geometric Mean Fold Rises (GMFRs) at 1 Month Postbooster Vaccination Conclusion A booster dose of GBS6 given ∼2 years after a primary dose to healthy nonpregnant adults was safe and elicited robust immune responses that were also consistently higher than after primary dose. This study suggests that repeat vaccination with GBS6 may confer additional benefit in pregnant women in subsequent pregnancies. Disclosures Babalwa Jongihlati, MD, MBA, Pfizer: Stocks/Bonds Judith Absalon, MD, MPH, Pfizer: Stocks/Bonds Samantha Munson, MPH, MBA, Pfizer: Stocks/Bonds Yasmin Sanchez-Pearson, PhD, Pfizer: Stocks/Bonds Raphael Simon, PhD, Pfizer: Stocks/Bonds Natalie Silmon de Monerri, PhD, Pfizer: Stocks/Bonds David Radley, MS, Pfizer: Employee|Pfizer: Stocks/Bonds Emily A. Gomme, Ph.D., Pfizer: Stocks/Bonds Michelle Gaylord, PhD, Pfizer: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Salary|Pfizer, Inc.: Stocks/Bonds Kathrin U. Jansen, PhD, Pfizer: Stocks/Bonds Daniel A. Scott, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Annaliesa S. Anderson, PhD, Pfizer: Stocks/Bonds.

The aim of this post hoc analysis was to describe the immunogenicity of the 20-valent pneumococcal conjugate vaccine (PCV20) in adults with chronic medical conditions or smoking that place them at increased risk of developing pneumococcal disease. Data from 2 phase 3, randomized, active-controlled, double-blind studies in pneumococcal vaccine-naive adults were analyzed. Study 1: adults >= 18 years were enrolled in 1 of 3 age-based cohorts (18-49, 50-59, and >= 60 years) and randomized (1:1, adults >= 60 years; 3:1, younger cohorts) to receive 1 dose of PCV20 or 13-valent PCV (PCV13). Participants >= 60 years who received PCV13 were administered 23-valent polysaccharide vaccine 1 month later. Study 2: adults 18-49 years were randomized (2:2:2:1) to receive 1 dose of PCV20 from 1 of 3 lots or PCV13. Opsonophagocytic activity (OPA) titers were measured in sera collected before and 1 month after vaccination. We investigated immune responses of PCV20 among participants 18-64 and 18-49 years of age with >= 1 medical condition or other factor (smoking) that increases the risk of serious pneumococcal disease. Of 4369 participants overall (PCV20, n = 2975; PCV13, n = 1394), 1329 participants (30%) had >= 1 risk factor; most commonly smoking, diabetes, and chronic pulmonary disease. Among participants with risk factors, substantial increases in OPA geometric mean titers were observed across the 20 vaccine serotypes from before vaccination to 1 month after PCV20. Robust immune responses to all 20 vaccine serotypes 1 month after PCV20 were observed in adults with increased risk of serious pneumococcal disease.Clinical trial registrationNCT03760146, NCT03828617.

INTRODUCTION:A 20-valent pneumococcal conjugate vaccine, PCV20, was developed to expand protection against vaccine-preventable pneumococcal disease. PCV20 contains the components of the 13-valent pneumococcal conjugate vaccine, PCV13, and includes capsular polysaccharide conjugates for 7 additional serotypes. Thus, PCV20 may cover those additional serotypes in individuals previously vaccinated with PCV13 or provide benefits of immunization with a conjugate vaccine to individuals previously immunized with a pneumococcal polysaccharide vaccine. This study described the safety and immunogenicity of PCV20 in adults ≥65 years of age with prior pneumococcal vaccination. METHODS:This phase 3, multicenter, randomized, open-label study was conducted in the United States and Sweden. Adults ≥65 years of age were enrolled into 1 of 3 cohorts based on their prior pneumococcal vaccination history (23-valent pneumococcal polysaccharide vaccine [PPSV23], PCV13, or both PCV13 and PPSV23). Participants were randomized 2:1 within their cohort to receive a single dose of PCV20 or PCV13 in those with prior PPSV23 only, and PCV20 or PPSV23 in those with prior PCV13 only; all participants with prior PCV13 and PPSV23 received PCV20. Safety was assessed by prompted local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 1 month, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination. Immune responses 1 month after PCV20 were assessed. RESULTS:The percentages of participants reporting local reactions, systemic events, and AEs after PCV20 administration were similar across cohorts and comparable with the PCV13 and PPSV23 control groups. SAE and NDCMC rates were low in all groups. Robust immune responses, including opsonophagocytic antibody responses, to the 20 vaccine serotypes were observed 1 month after PCV20 regardless of prior pneumococcal vaccination. CONCLUSIONS:PCV20 was well tolerated and immunogenic in adults ≥65 years of age previously vaccinated with different pneumococcal vaccine regimens. Clinicaltrials.gov NCT03835975.

Expanding serotype coverage of pneumococcal conjugate vaccines (PCVs) to target prevailing disease-causing serotypes could further reduce disease burden. To address this need, 2 different PCVs have been investigated: a 20-valent PCV (PCV20; includes the 13 serotypes in the 13-valent PCV [PCV13] plus 7 additional serotypes [8, 10A, 11A, 12F, 15B, 22F, 33F]) and a complementary 7-valent PCV (cPCV7; contains only the 7 additional serotypes). This phase 1b, randomized, controlled, double-blind study evaluated PCV20 and cPCV7 safety and immunogenicity in healthy Japanese adults 18–49 years of age residing in the United States for ≤5 years. Participants (n = 104) were randomized equally to receive a single dose of PCV20, cPCV7, or PCV13. Immunogenicity was assessed at baseline and 1 month after vaccination using serotype-specific opsonophagocytic activity (OPA) titers and serotype-specific immunoglobulin G (IgG) concentrations. Prompted local reactions and systemic events; adverse events (AEs); and serious AEs and newly diagnosed chronic disease were assessed 14 days, through 1 month, and upto 6 months following vaccination, respectively. OPA immune responses were robust for all 20 serotypes in the PCV20 group and for the 7 serotypes in the cPCV7 group 1 month after vaccination. IgG immune response showed similar trends. Injection site pain and muscle pain were the most common local reaction and systemic event; the majority were mild or moderate in severity. Few AEs and no severe AEs, serious AEs, or safety-related withdrawals were reported. Taken together, administration of PCV20 or cPCV7 in Japanese adults was well tolerated and induced robust serotype-specific functional immune responses. NCT03642847.