Search

The meningococcal serogroup B-factor H binding protein vaccine (MenB-FHbp) is licensed for use in children aged 10 years or older for protection against invasive serogroup B meningococcal disease. Because young children are at increased risk of invasive meningococcal disease, MenB-FHbp clinical data in this population are needed.We conducted two phase 2 randomised, controlled, observer-blinded studies including healthy toddlers (age 12-23 months) across 26 Australian, Czech, Finnish, and Polish centres, and older children (age 2-9 years) across 14 Finnish and Polish centres. Exclusion criteria included previous vaccinations against serogroup B meningococcus or hepatitis A virus (HAV), and chronic antibiotic use. Toddlers were randomly allocated (2:1) via an interactive response technology system to receive either 60 μg or 120 μg MenB-FHbp or HAV vaccine and saline (control). Older children were randomly allocated (3:1) to receive 120 μg MenB-FHbp or control, with stratification by age group (2-3 years and 4-9 years). All vaccinations were administered as three doses (0, 2, and 6 months, with only saline given at 2 months in the control group). Toddlers who received 120 μg MenB-FHbp could receive a 120 μg booster dose 24 months after the end of the primary series. The percentages of participants with serum bactericidal activity using human complement (hSBA) titres at or above the lower limit of quantification (LLOQ; all greater than the 1:4 correlate of protection) against four test strains of serogroup B meningococcus 1 month after the third dose (primary immunogenicity endpoint) were measured in the evaluable immunogenicity populations (participants who received the vaccine as randomised, had available and determinate hSBA results, and had no major protocol violations). Not all participants were tested against all strains because of serum sample volume constraints. The frequencies of reactogenicity and adverse events after each dose were recorded in the safety population (all participants who received at least one dose and had safety data available). These studies are registered with ClinicalTrials.gov (NCT02534935 and NCT02531698) and are completed.Between Aug 31, 2015, and Aug 22, 2016, for the toddler study and between Aug 27, 2015, and March 7, 2016, for the older children study, we enrolled and randomly allocated 396 toddlers (60 μg MenB-FHbp group n=44; 120 μg MenB-FHbp group n=220; control group n=132) and 400 older children (120 μg MenB-FHbp group n=294; control group n=106). 1 month after the third dose, the proportions of participants with hSBA titres at or above the LLOQ ranged across test strains from 85·0% (95% CI 62·1-96·8; 17 of 20 participants) to 100·0% (82·4-100·0; 19 of 19) in toddlers receiving 60 μg MenB-FHbp, and from 71·6% (61·4-80·4; 68 of 95) to 100·0% (96·2-100·0; 95 of 95) in toddlers receiving 120 μg MenB-FHbp, and from 79·1% (71·2-85·6; 106 of 134) to 100·0% (97·4-100·0; 139 of 139) in children aged 2-9 years receiving 120 μg MenB-FHbp. hSBA titres peaked at 1 month after the third primary dose of MenB-FHbp and then declined over time. 24 months after the third dose in the toddler study, the proportions with hSBA titres at or above the LLOQ ranged from 0·0% (0·0-17·6; 0 of 19 participants) to 41·2% (18·4-67·1; seven of 17) in those who received 60 μg MenB-FHbp and from 3·7% (0·8-10·4; three of 81) to 22·8% (14·1-33·6; 18 of 79) in those who received 120 μg MenB-FHbp. 1 month after the booster dose in toddlers, the proportions with hSBA titres at or above the LLOQ were higher than at 1 month after the primary series. MenB-FHbp reactogenicity was mostly transient and of mild to moderate severity. Adverse event frequency was similar between the MenB-FHbp and control groups and less frequent following MenB-FHbp booster than following primary doses. Two participants from the toddler study (both from the 120 μg MenB-FHbp group) and four from the older children study (three from the 120 μg MenB-FHbp group and one from the control group) were withdrawn from the study because of adverse events.MenB-FHbp was well tolerated and induced protective immune responses in a high proportion of participants. These findings support a favourable MenB-FHbp immunogenicity and reactogenicity profile in young children, a population at increased risk of adverse invasive meningococcal disease outcomes.Pfizer.

What is this summary about? This is a summary of an article about part of a clinical study for the BNT162b2 COVID-19 vaccine, also called the Pfizer-BioNTech vaccine. The article was published in the New England Journal of Medicine in May 2021. This summary describes how the vaccine worked in participants 12- to 15-years old. The part of the study described in the article is ongoing and expected to finish March 2023. This means that the final results may be different from the results included in this summary. What happened in this study? The part of the study described in this summary included participants 12- to 15-years old who had no serious health issues. The BNT162b2 vaccine had already been studied in participants 16 years of age or older. In this part of the study, the researchers wanted to find out: How effective and safe the vaccine was in participants 12- to 15-years old. What the immune response to the vaccine and the vaccine safety were like in 12- to 15-year-olds compared with 16- to 25-year-olds. How well the vaccine prevented SARS-CoV-2 infections in participants who received the vaccine compared to those who did not. This is also called efficacy of the BNT162b2 vaccine Half of the participants in this study received 2 injections of the BNT162b2 vaccine and half received 2 injections of a placebo in a muscle of the upper arm. The placebo looked like the BNT162b2 vaccine but did not have any active vaccine in it. What were the results? BNT162b2 had a favorable safety profile. The most common reactions were pain at the injection site, fatigue, and headache. None of the participants had serious reactions to the vaccine. The 12- to 15-year-old participants' immune system responses to the BNT162b2 vaccine were as good as or stronger than the 16- to 25-year-old participants' immune responses. The participants who received the BNT162b2 vaccine were less likely to get COVID-19 compared with the participants who got the placebo. Clinical Trial Registration: NCT04368728 ( ClinicalTrials.gov )

What is this summary about? This is a summary of an article about part of a clinical study for the BNT162b2 COVID-19 vaccine, also called the Pfizer-BioNTech vaccine. The article was published in the New England Journal of Medicine in September 2021. The part of the study described in the article began in July 2020 and is ongoing. This means that the final results may be different from the results included in this summary. What happened in this study? The participants in this study received 2 injections of either the BNT162b2 vaccine or a placebo, 21 days apart. The placebo looked like the BNT162b2 vaccine but had no active vaccine in it. None of the trial participants or study teams knew who received vaccine or placebo. What were the results? Most of the reactions to the injections were mild or moderate and lasted for a short period of time. The most common reactions were pain at the injection site, extreme tiredness (fatigue), and headache. These reactions usually happened in the first 7 days after receiving a vaccine dose. A small number of participants had severe reactions to the vaccine. Compared to participants who received the placebo, participants who received the BNT162b2 vaccine were much less likely to become ill if they were infected with the virus that causes COVID-19. The vaccine also had very good efficacy at preventing severe COVID-19. Participants in South Africa who received the BNT162b2 vaccine were less likely to become ill after infection with the beta variant of the virus compared to participants who received the placebo. The beta variant was very common in South Africa when the study was taking place. Clinical Trial Registration: NCT04368728 ( ClinicalTrials.gov )

Introduction Individuals with an underlying malignancy have high risk of poor COVID-19 outcomes. In clinical trials, COVID-19 vaccines were safe and efficacious against infection, hospitalization, and death, but most trials excluded participants with cancer. We report results from participants with a history of past or active neoplasm (malignant or benign/unknown) and up to 6 months’ follow-up post-dose 2 from the placebo-controlled, observer-blinded trial of the 2-dose BNT162b2 mRNA COVID-19 vaccine. Patients and methods Between July 2020–January 2021, 46,429 participants aged ≥12 years were randomized at 152 sites in 6 countries. Healthy participants with pre-existing stable neoplasm could participate; those receiving immunosuppressive therapy were excluded. Data are reported for participants, aged ≥16 years for safety and ≥12 years for efficacy, who had any history of neoplasm at baseline (data cut-off: March 13, 2021). Adverse-event (AE) data are controlled for follow-up time before unblinding and reported as incidence rates (IRs) per 100 person-years follow-up. Results At baseline, 3813 participants had a history of neoplasm; most common malignancies were breast (n = 460), prostate (n = 362), and melanoma (n = 223). Four BNT162b2 and 71 placebo recipients developed COVID-19 from 7 days post-dose 2; vaccine efficacy was 94.4% (95% CI: 85.2, 98.5) after up to 6 months’ follow-up post-dose 2. This compares favorably with vaccine efficacy of 91.1% in the overall trial population after the same follow-up. AEs were reported at IRs of 95.4 (BNT162b2) and 48.3 (placebo) per 100 person-years. Most common AEs were reactogenicity events (injection-site pain, fatigue, pyrexia). Three BNT162b2 and 1 placebo recipients withdrew because of vaccine-related AEs. No vaccine-related deaths were reported. Conclusion In participants with past or active neoplasms, BNT162b2 vaccine has a similar efficacy and safety profile as in the overall trial population. These results can inform BNT162b2 use during the COVID-19 pandemic and future trials in participants with cancer. Clinical trial number: NCT04368728

The MenB-FHbp vaccine (Trumenba®) is licensed in various countries for the prevention of meningococcal serogroup B disease in individuals ≥ 10 years of age. The clinical development program included 11 completed trials where, in each trial, MenB-FHbp had an acceptable safety profile after a primary vaccination series was administered to individuals 10-65 years of age. However, the detection of potential rare events was limited because of individual clinical trial size. The current safety analysis evaluates pooled reactogenicity and other adverse events (AEs) reported in these trials to identify new safety signals not detectable in individual trials.Eleven trials contributed safety data, of which 10 recorded local and systemic reactogenicity events; 8 of the trials were controlled, and reactogenicity data were pooled for 7 of these 8 trials. Additional AE evaluations included immediate AEs (IAEs), medically attended AEs (MAEs), serious AEs (SAEs), newly diagnosed chronic medical conditions (NDCMCs), and autoimmune or neuroinflammatory conditions.Local and systemic reactions were more frequent in the MenB-FHbp group (n = 15,294) compared with controls (n = 5509), although most reactions were transient and mild to moderate in severity. Frequencies of IAEs, SAEs, MAEs, NDCMCs, and autoimmune or neuroinflammatory conditions were similar between the MenB-FHbp and control groups.MenB-FHbp demonstrated a favorable safety and tolerability profile in the clinical development program of 15,000 vaccine recipients ≥ 10 years of age. No new safety signals were identified in the pooled analysis compared with data from the individual trials. Continued postmarketing safety surveillance is important for the identification of rare events. Clinicaltrials.gov: NCT01299480; NCT000808028; NCT00879814; NCT00780806; NCT01352845; NCT01352793; NCT01461993; NCT01323270; NCT01830855; NCT01461980; NCT01768117.

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.)

BNT162b2, a lipid nanoparticle (LNP) formulated nucleoside-modified messenger RNA (mRNA) that encodes the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) stabilized in the prefusion conformation, has demonstrated 95% efficacy in preventing coronavirus disease-19 (COVID-19)1. Here we extend our previous phase 1/2 trial report2 and present BNT162b2 prime/boost induced immune response data from a second phase 1/2 trial in healthy adults (18-55 years of age). BNT162b2 elicited strong antibody responses, with SARS-CoV-2 serum 50% neutralizing geometric mean titers up to 3.3-fold above those observed in COVID-19 human convalescent samples (HCS) one week post-boost. BNT162b2-elicited sera neutralized 22 pseudoviruses bearing SARS-CoV-2 S variants. Most participants had a strong IFNγ- or IL-2-positive CD8+ and CD4+ T helper type 1 (TH1) T cell response, detectable throughout the full observation period of nine weeks following the boost. pMHC multimer technology identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week post-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 conserved in a broad range of variants at well tolerated doses.

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.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.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).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.).

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. In a phase I/II dose-escalation clinical trial, the mRNA COVID-19 vaccine BNT162b1 elicits specific T cell and antibody responses that suggest it has protective potential.

Introduction Two phase 3 studies in adolescents and young adults demonstrated that MenB-FHbp, a meningococcal serogroup B (MenB) vaccine, elicits protective immune responses after 2 or 3 doses based on serum bactericidal antibody assays using human complement (hSBA) against 4 primary and 10 additional diverse, vaccine-heterologous MenB test strains. Lower limits of quantitation (LLOQs; titers 1:8 or 1:16; titers ≥ 1:4 correlate with protection) were used to evaluate responses to individual strains and all 4 primary strains combined (composite response). A post hoc analysis evaluated percentages of subjects with protective responses to as many as 8 strains combined (4 primary plus additional strains). Methods Immune responses were measured using hSBAs against 4 primary strains in adolescents (n = 1509, MenB-FHbp; n = 898, hepatitis A virus vaccine/saline) and young adults (n = 2480, MenB-FHbp; n = 824, saline) receiving MenB-FHbp or control at 0, 2, and 6 months. Ten additional strains were evaluated in subsets of subjects from approximately 1800 MenB-FHbp recipients across both studies. Percentages of subjects with hSBA titers ≥ LLOQ for different numbers of primary strains or primary plus additional strains combined (7 or 8 strains total per subset) were determined before vaccination, 1 month post-dose 2, and 1 month post-dose 3. Results Across the panel of primary plus additional strains, at 1 month post-dose 3, titers ≥ LLOQ were elicited in 93.7–95.7% of adolescents and 91.7–95.0% of young adults for ≥ 5 test strains combined and in 70.5–85.8% of adolescents and 67.5–81.4% of young adults for ≥ 7 strains combined. Among adolescents, 99.8%, 99.0%, 92.8%, and 82.7% had titers ≥ LLOQ against at least 1, 2, 3, and all 4 primary strains, respectively; corresponding percentages for young adults were 99.7%, 97.7%, 94.0%, and 84.5%. Conclusions Results support the ability of MenB-FHbp to provide broad coverage against MenB strains expressing diverse FHbp variants. Trial Registration ClinicalTrials.gov identifiers NCT01830855, NCT01352845. Electronic supplementary material The online version of this article (10.1007/s40121-020-00319-0) contains supplementary material, which is available to authorized users.

Background To provide continuing protection, available meningococcal vaccines must provide long-term persistence of circulating functional antibodies against prevalent serogroups causing invasive meningococcal disease (IMD). This study assessed antibody persistence and safety of the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) and the meningococcal serogroup C vaccine conjugated to Corynebacterium diphtheriae CRM197 protein (MenC-CRM) for up to 6 years after booster dosing in children. Methods In the primary vaccination study, children were vaccinated at age 12 to 23 months. In the first extension study, children who completed the primary study received a booster dose 4 years later with the same primary vaccine. The current study assessed antibody persistence at 2 to 6 years postbooster against each of the 4 meningococcal serogroups using serum bactericidal assays using rabbit (rSBA) or human (hSBA) complement with antibody titer thresholds of ≥1:8 or ≥1:4, respectively, and geometric mean titers (GMTs). Safety evaluations during this period included serious adverse events (SAEs) related to vaccination and any event related to lack of vaccine efficacy. Results A total of 184 subjects were enrolled (MenACWY-TT = 159; MenC-CRM = 25). For MenACWY-TT, the percentages of subjects with rSBA titers ≥1:8 ranged from 96.7% to 100% across serogroups at 2 years postbooster and 71.6% to 94.0% at 6 years postbooster; rSBA GMTs decreased from Year 2 to 4 and generally remained stable thereafter. The percentages of subjects in the MenACWY-TT group with hSBA titers ≥1:4 were 70.0% to 100% across serogroups at 2 years postbooster and 58.5% to 98.5% at 6 years postbooster. No lack of efficacy, SAEs, or vaccine-related adverse events were reported. Conclusions The persistence of rSBA and hSBA antibodies was shown up to 6 years postbooster (10 years postprimary vaccination) with either MenACWY-TT or MenC-CRM, suggesting that this schedule may provide long-term protection against IMD. Clinicaltrials.gov: NCT01900899.

Immunogenicity and safety up to 5 years after administration of 1 or 2 doses of quadrivalent meningococcal serogroup A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) given alone or with 13-valent pneumococcal conjugate vaccine (PCV13) in children was investigated.This phase 3 study randomized healthy 12-24-month-olds to MenACWY-TT at Month 0 (ACWY1d), MenACWY-TT at Months 0 and 2 (ACWY2d), MenACWY-TT and PCV13 at Month 0 (Co-Ad), or PCV13 at Month 0 and MenACWY-TT at Month 2 (PCV13/ACWY). Immune responses 1, 3, and 5 years after primary vaccination were evaluated with serum bactericidal activity using rabbit complement (rSBA) titers ≥ 1:8 and geometric mean titers (GMTs). Evaluation of serious adverse events up to 5 years after primary vaccination are reported.Of the 802 children randomized in the study, 619 completed the study through Year 5. Immune responses after vaccination declined over time but were higher 5 years after vaccination compared with levels before vaccination. At Year 5, the percentages of children with rSBA titers ≥ 1:8 across all serogroups were 20.5 %-58.6 %, 28.4 %-65.8 %, 23.9 %-52.8 %, and 19.4 %-55.8 % in the ACWY1d, ACWY2d, Co-Ad, and PCV13/ACWY groups, respectively. Comparable antibody persistence at Year 5 was observed for participants receiving 1 or 2 doses of MenACWY-TT, although GMTs were elevated in those who received 2 versus 1 dose. The percentage of children with protective antibody titers at Year 5 was similar in participants who received PCV13 and MenACWY-TT compared with that observed for participants who only received 1 or 2 MenACWY-TT doses. No new safety concerns were identified during the study period.Antibody responses persisted in the majority of children up to 5 years after primary vaccination with MenACWY-TT administered in a 1- or 2-dose regimen with or without PCV13, with no new safety concerns identified.gov Identifier NCT01939158; EudraCT number 2013-001083-28.

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.).

BackgroundBNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. BNT162b2 is highly efficacious against COVID-19 and is currently authorized for emergency use or conditional approval worldwide. At the time of authorization, data beyond 2 months post-vaccination were unavailable.MethodsIn an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy study, 44,165 ≥16-year-old participants and 2,264 12-15-year-old participants were randomized to receive 2 doses, 21 days apart, of 30 µg BNT162b2 or placebo. Study endpoints reported here are vaccine efficacy (VE) against laboratory-confirmed COVID-19 and safety data, both up to 6 months post-vaccination.ResultsBNT162b2 continued to be safe and well tolerated. Few participants had adverse events leading to study withdrawal. VE against COVID-19 was 91% (95% CI 89.0-93.2) through up to 6 months of follow-up, among evaluable participants and irrespective of previous SARS-CoV-2 infection. VE of 86%-100% was seen across countries and in populations with diverse characteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. VE against severe disease was 97% (95% CI 80.3−99.9). In South Africa, where the SARS-CoV-2 variant of concern, B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) VE was observed.ConclusionWith up to 6 months of follow-up and despite a gradually declining trend in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing COVID-19. (ClinicalTrials.govnumber,NCT04368728)

The MenB-FHbp vaccine is licensed to prevent meningococcal serogroup B disease on either a 2-dose (0, 6 months) or 3-dose (0, 1-2, 6 months) series. This phase 3 study further assessed the immunogenicity and safety of the 2-dose MenB-FHbp schedule.Subjects 10-25 years of age received MenB-FHbp (months 0, 6) and the quadrivalent meningococcal conjugate vaccine MenACWY-CRM (month 0). Primary immunogenicity endpoints included percentages of subjects achieving ≥ 4-fold increases from baseline in serum bactericidal antibody using human complement (hSBA) titers for 4 diverse, vaccine-heterologous primary serogroup B test strains and titers ≥ lower limit of quantitation (LLOQ; 1:8 or 1:16) for all 4 primary strains combined (composite response) after dose 2; a titer ≥ 1:4 is the accepted correlate of protection. Percentages of participants with hSBA titers ≥ LLOQ for 10 additional vaccine-heterologous strains were also assessed; positive predictive values of primary strain responses for secondary strain responses were determined. Safety was assessed.Overall, 1057 subjects received dose 1 and 946 received dose 2 of MenB-FHbp. Percentages of participants achieving ≥ 4-fold increases in hSBA titers against each primary strain after dose 2 ranged from 67.4% to 95.0% and the composite response was 74.3%. Primary strain responses were highly predictive of secondary strain responses. Most reactogenicity events were mild-to-moderate in severity and did not lead to withdrawal from the study. Adverse events (AEs) considered by the investigator to be related to vaccination occurred in 4.2% (44/1057) of subjects, and there were no serious AEs or newly diagnosed chronic medical conditions considered related to vaccination.MenB-FHbp administered at 0, 6 months was well tolerated and induced protective bactericidal antibody responses against diverse serogroup B strains. Findings provide further support for the continued use of MenB-FHbp on a 2-dose schedule in this population.

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.)

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.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.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.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.).

An effective vaccine is needed to halt the spread of the SARS-CoV-2 pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase 1/2 COVID-19 vaccine trial with BNT162b1, a lipid nanoparticle (LNP) formulated nucleoside-modified messenger RNA encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Here we present antibody and T cell responses after BNT162b1 vaccination from a second, non-randomized open-label phase 1/2 trial in healthy adults, 18-55 years of age. Two doses of 1 to 50 µg of BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those in a COVID-19 convalescent human serum panel (HCS). Day 43 SARS-CoV-2 serum neutralising geometric mean titers were 0.7-fold (1 µg) to 3.5-fold (50 µg) those of HCS. Immune sera broadly neutralised pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had TH1 skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. Interferon (IFN)γ was produced by a high 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 multiple beneficial mechanisms with potential to protect against COVID-19.

Background A previous phase 2 study demonstrated the immunogenicity of a single dose of meningococcal A, C, W, Y-tetanus toxoid conjugate (MenACWY-TT) or polysaccharide (MenACWY-PS) vaccine for up to 5 years in individuals aged 11–55 years. This follow-up study evaluated long-term antibody persistence up to 10 years and the immunogenicity and safety of a single MenACWY-TT booster dose given 10 years after primary vaccination. Methods Blood draws were conducted annually in Years 7–10. At Year 10, all subjects received a MenACWY-TT booster dose. Blood was drawn at 1 month and safety data were collected ≤6 months postbooster. Study endpoints included immunogenicity during the persistence phase (primary), and immunogenicity and safety during the booster phase (secondary). Statistical analyses were descriptive. Results A total of 311 subjects were enrolled in the persistence phase (MenACWY-TT, 235; MenACWY-PS, 76); 220 were enrolled in the booster phase (MenACWY-TT, 164; MenACWY-PS, 56). Descriptive analyses indicated that at Years 7–10, the percentages of subjects achieving serum bactericidal antibody assay using baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128 were higher for serogroups A, W, and Y in the MenACWY-TT versus MenACWY-PS group; percentages were similar across groups for serogroup C. rSBA geometric mean titers (GMTs) for serogroups A, W, and Y were higher in the MenACWY-TT group and slightly higher in the MenACWY-PS group for serogroup C. One month postbooster, all primary MenACWY-TT and ≥98.1% of primary MenACWY-PS recipients had rSBA titers ≥1:8. For all serogroups, rSBA GMTs postbooster were higher in the MenACWY-TT versus MenACWY-PS group. Most local and general reactogenicity events were similar between groups and mild to moderate in severity. Adverse events at 1 month postbooster were 9.1% for the MenACWY-TT and 3.6% for the MenACWY-PS groups; all were nonserious. Conclusions Immune responses to a single MenACWY-TT primary dose administered at age 11–55 years persisted in >70% of individuals evaluated at Years 7–10. A MenACWY-TT booster dose administered at Year 10 was safe and immunogenic with no new safety signals observed. These results provide important insights regarding long-term protection from primary vaccination and the benefits of booster dosing. Trial registration Clinicaltrials.gov, NCT01934140. Registered September 2013.

A previous phase 3, randomized, multicenter study showed the immunogenicity of a primary vaccination of subjects aged 11 to 17 years with the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) or the quadrivalent meningococcal polysaccharide vaccine (MenACWY-PS). This extension study evaluated the safety and immunogenicity of a MenACWY-TT booster 10 years after receiving a primary dose of either MenACWY-TT or MenACWY-PS. The primary immunogenicity endpoint was booster response, evaluated using serum bactericidal antibody assays with rabbit complement (rSBA), 1 month postbooster. Safety endpoints included the percentage of subjects experiencing local and general adverse events (AEs) ≤4 days after MenACWY-TT booster. Of 229 subjects enrolled, 169 and 58 in the MenACWY-TT and MenACWY-PS groups, respectively, completed the booster phase. The 1 month postbooster response for each serogroup ranged from 81.5% to 95.7% for MenACWY-TT and 66.7% to 94.1% for MenACWY-PS. Similar percentages of MenACWY-TT and MenACWY-PS recipients had a booster response to serogroups A, W, and Y, whereas more MenACWY-TT recipients than MenACWY-PS recipients had a booster response to serogroup C. For the MenACWY-TT and MenACWY-PS groups, respectively, the MenACWY-TT booster elicited rSBA titers ≥1:8 in 100% and ≥98.0% of subjects across all serogroups; 100% and ≥96.1% of all subjects had titers ≥1:128. No new safety signals were observed during the booster phase. In conclusion, a MenACWY-TT booster dose after receiving either a primary dose of MenACWY-TT or MenACWY-PS elicited robust immune responses and was well tolerated. Functional antibody responses last up to 10 years after primary MenACWY-TT vaccination.

MenB-FHbp is a recombinant meningococcal serogroup B (MenB) vaccine composed of 2 factor H binding proteins (FHbps). Meningococcal vaccines targeting polysaccharide serogroup A, C, Y, and W capsules were licensed upon confirmation of bactericidal antibody induction after initial efficacy studies with serogroup A and C vaccines. Unlike meningococcal polysaccharide vaccines, wherein single strains demonstrated bactericidal antibodies per serogroup for each vaccine, MenB-FHbp required a more robust approach to demonstrate that bactericidal antibody induction could kill strains with diverse FHbp sequences. Serum bactericidal assays using human complement were developed for 14 MenB strains, representing breadth of meningococcal FHbp diversity of ~80% of circulating MenB strains. This work represents an innovative approach to license a non-toxin protein vaccine with 2 antigens representing a single virulence factor by an immune correlate, and uniquely demonstrates that such a vaccine provides coverage across bacterial strains by inducing broadly protective antibodies., Meningococcal B vaccine: measuring efficacy Neisseria meningitidis is an important cause of invasive meningococcal disease, effective vaccines exist for some serogroups but immunogenicity to the MenB group is poor. Thomas R. Jones and colleagues examine serum bactericidal responses from volunteers challenged with MenB-FHbp – a recombinant MenB vaccine containing two Factor H (FH)-binding proteins. Serum bactericidal responses are tested against 14 MenB clinical isolates selected in an unbiased manner to cover the vast breadth of FHbp antigen and epidemiological diversity. This work demonstrates the broad efficacy of the MenB-FHbp vaccine using a serum bactericidal activity as a surrogate of protection.

Background To demonstrate extended protection against meningococcal serogroup B (MenB) disease after MenB-FHbp (bivalent rLP2086) vaccination, this study evaluated immunopersistence through 26 months following MenB-FHbp boosting after 2 or 3 primary doses in adolescents. Study design This phase 3, open-label study was an extension of 3 phase 2 studies with participants aged 11–18 years randomized to receive primary MenB-FHbp vaccination following 1 of 5 dosing schedules or control. A booster dose was administered 48 months after the primary series. Immunopersistence through 48 months after the last primary dose (persistence stage) and 26 months postbooster (booster stage) was determined by serum bactericidal assays using human complement (hSBAs) against 4 vaccine-heterologous test strains. Safety evaluations included adverse events (AEs) and local and systemic reactions. Results Overall, 698 and 304 subjects enrolled in the persistence and booster stages, respectively. hSBA titers declined in all groups during 12 months postprimary vaccination, then remained stable through 48 months. One month postbooster, 93.4–100.0% of subjects achieved hSBA titers ≥ lower limit of quantitation against each test strain; percentages at 12 and 26 months postbooster were higher than at similar time points following primary vaccination. Primary and booster MenB-FHbp vaccinations were well tolerated, with ≤ 12.5% of subjects reporting AEs during each stage. The most common local (reported by 84.4–93.8% of subjects) and systemic (68.8–76.6%) reactions to the booster were injection site pain and fatigue and headache, respectively; ≤ 3.7% of subjects reported severe systemic events. Conclusion Protective hSBA titers initially declined but were retained by many subjects for 4 years irrespective of primary MenB-FHbp vaccination schedule. Boosting at 48 months after primary vaccination was safe, well tolerated, and induced immune responses indicative of immunological memory that persisted through 26 months. Booster vaccination during late adolescence may prolong protection against MenB disease.

Routine prophylactic vaccination and mass vaccination strategies have been used to control both endemic and epidemic disease caused by Neisseria meningitidis globally. This review discusses real-world examples of these vaccination strategies, their implementation, and outcomes of these efforts, with the overall goal of providing insights on how to achieve optimal control of meningococcal disease through vaccination in varied settings. Tailoring immunization programs to fit the needs of the target population has the potential to optimally reduce disease incidence.

Background: Patients with cancer are at higher risk of developing COVID-19 disease, adverse outcomes, and increased mortality. Phase III COVID-19 vaccine trials have demonstrated safety/efficacy against COVID-19 and prevented hospitalizations and deaths;however, most excluded ptcpts with cancer. We present phase 3 tozinameran mRNA COVID-19 vaccine trial results from ptcpts with a cancer history at baseline, either ongoing or not, per the Charlson Comorbidity Index and up to 6 months of follow-up. Methods: Between Jul 2020-Jan 2021, 46429 ptcpts ≥12 y at 152 sites in 6 countries were randomized in a placebo-controlled, observer-blinded trial of 2-dose tozinameran, showing 95% protection against COVID-19 and favorable safety (Polack et al NEJM, Dec 2020). After emergency use authorization, ptcpts were allowed to unblind and placebo recipients received vaccine. Data prior to unblinding for crossover up to 13 Mar 2021 are presented for ptcpts ≥16 y for safety and ≥12 y for efficacy. Adverse event (AE) data are controlled for follow-up time before unblinding and reported as incidence rate (IR) per 100-person-y of follow-up. Results: Of ptcpts ≥16 y, 1647 had a prior diagnosis of cancer and were not on active immunosuppressive treatment (755 M;892 F;median age 66 y [range 22-91]). Most common solid cancers included breast (n=458), prostate (n=360), and melanoma (n=210). AEs were reported at IRs of 94.0 (vaccine) and 49.3 (placebo) per 100-person-y;most common AEs were reactogenicity events (injection-site pain [IR: 40.2 vaccine;4.2 placebo];fatigue [IR: 21.4 vaccine;7.6 placebo];pyrexia [IR: 19.8 vaccine;0.7 placebo]). 1 vaccine ptcpt withdrew due to a vaccine-related AE. No vaccine-related deaths were reported. Among ptcpts ≥12 y with cancer, 3 vaccine and 27 placebo recipients developed COVID-19 from 7 days post-Dose 2;vaccine efficacy (VE) was 89.7% (95% CI 66.5-98.0%). This compares favorably with overall VE of 91.1%. Updated results will be presented. Conclusions: Tozinameran has similar efficacy/safety in ptcpts with cancer as in the overall population. These results inform tozinameran use in COVID-19 and in future trials in patients with cancer. Clinical trial identification: NCT04368728. Editorial acknowledgement: Editorial assistance was provided by Erin Bekes, PhD, of CMC AFFINITY, McCann Health Medical Communications, and was funded by Pfizer. Legal entity responsible for the study: Study sponsored by BioNTech, managed by Pfizer. Funding: Pfizer and BioNTech. Disclosure: S.J. Thomas: Financial Interests, Personal and Institutional, Research Grant, Advisory role: Pfizer. J.L. Perez: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. S.P. Lockhart: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. S. Hariharan: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. N. Kitchin: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. R. Bailey: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. K. Liau: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. E. Lagkadinou: Financial Interests, Personal, Full or part-time Employment: BioNTech. O. Tureci: Financial Interests, Personal, Research Grant: BioNTech. U. Sahin: Financial Interests, Personal, Research Grant: BioNTech. X. Xu: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. S.S. Dychter: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. C. Lu: Financial Interests, Personal, Full or part-time Employment: Pfizer. W. Gruber: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. All other authors have declared no conflicts of interest.

Summary Background Bivalent rLP2086 is a recombinant factor H binding protein-based vaccine approved in the USA for prevention of meningococcal serogroup B disease in 10–25-year-olds. We aimed to assess the persistence of bactericidal antibodies up to 4 years after a three-dose schedule of bivalent rLP2086. Methods We did this randomised, single-blind, placebo-controlled, phase 2 trial at 25 sites in Australia, Poland, and Spain. In stage 1 of the study (February, 2009–May, 2010), healthy adolescents (aged 11–18 years) were randomly assigned, via an interactive voice and web-response system with computer-generated sequential random numbers, to receive either ascending doses of vaccine (60 μg, 120 μg, and 200 μg) or placebo at months 0, 2, and 6. Dispensing staff were not masked to group allocation, but allocation was concealed from principal investigators, participants and their guardians, and laboratory personnel. In stage 2 of the study (reported here), we enrolled healthy adolescents who had received three doses of 120 μg bivalent rLP2086 (the optimum dose level identified in stage 1) or saline. Immunogenicity was determined in serum bactericidal antibody assay using human complement (hSBA) by use of four meningococcal serogroup B test strains expressing vaccine-heterologous factor H binding protein variants: PMB80 (A22), PMB2001 (A56), PMB2948 (B24), and PMB2707 (B44). Immunogenicity in stage 2 was assessed at months 6, 12, 24, and 48 post-vaccination. We did analysis by intention to treat. This trial is registered as ClinicalTrials.gov number NCT00808028. Findings Between March 17, 2010, and Feb 8, 2011, 170 participants who received 120 μg of bivalent rLP2086 and 80 participants who received placebo in stage 1 of the study were entered into stage 2; 210 participants completed stage 2 up to 48 months. 1 month after the third vaccination, 93% (n=139/149) to 100% (n=48/48) of vaccine recipients achieved protective hSBA titres equal to or greater than the lower limit of quantification to each test strain, compared with 0% (n=0/25) to 35% (n=8/23) of control recipients. Despite initial declines in seroprotective hSBA titres for all four test strains, for three test strains (A22, A56, and B24), more than 50% of bivalent rLP2086 recipients continued to achieve titres equal to or greater than the lower limit of quantification at months 6 (57% [n=93/163] to 89% [n=42/47]), 12 (54% [n=84/155] to 69% [n=33/48]), 24 (53% [n=26/49] to 54% [n=82/152]), and 48 (51% [n=24/47] to 59% [n=79/134]); corresponding values in the control group were 14% (n=11/80) to 22% (n=5/23) at month 6, 13% (n=10/78) to 29% (n=22/76) at month 12, 16% (n=12/74) to 36% (n=8/22) at month 24, and 24% (n=16/68) to 35% (n=8/23) at month 48. For test strain B44, hSBA titres equal to or greater than the lower limit of quantification were shown in 37% (n=18/49) of vaccine recipients at 6 months, in 29% (n=14/48) at 12 months, in 22% (n=11/49) at 24 months, and in 20% (n=10/49) at 48 months, compared with 0% (n=0/25) of control recipients at month 6, 4% (n=1/25) at months 12 and 24, and 12% (n=3/25) at month 48. Adverse events were reported in seven (4%) of 170 participants in the bivalent rLP2086 group and two (3%) of 80 participants in the control group; no event was deemed related to vaccine. Interpretation After three doses of bivalent rLP2086, protective hSBA titres above the correlate of protection (≥1/4) were elicited up to 4 years in more than 50% of participants for three of four meningococcal serogroup B test strains representative of disease-causing meningococci expressing vaccine-heterologous antigens. Further studies will be needed to assess possible herd immunity effects with meningococcal serogroup B vaccines and the need for a booster dose to sustain individual protection against invasive meningococcal disease. Funding Pfizer.

Background As a peak in meningococcal disease often occurs during adolescence, meningococcal vaccination programs are available for this age group in various regions across the globe. Quadrivalent meningococcal (MenACWY) conjugate vaccines are being incorporated in an increasing number of programs in response to changing meningococcal serogroup epidemiology. MenACWY-TT (Nimenrix®) is a MenACWY conjugate vaccine available in the European Union and 50 other countries for preventive vaccination of serogroup A, C, W, and Y disease (Figure 1). MenACWY-TT is licensed in some countries as a 2-dose primary series in individuals as young as 6 weeks of age, while a single dose may be given to previously unvaccinated individuals ≥ 6 months of age, adolescents, and adults. Here, we provide an overview of the 3 primary and 5 extension studies evaluating the clinical development of MenACWY-TT in adolescents (Table 1). Figure 1. Global Registration Status of MenACWY-TT (Nimenrix®) in Adolescents Table 1. Pivotal Clinical Studies of MenACWY-TT (Nimenrix®) Supporting Licensure in Adolescents Methods Immunogenicity and safety data from these 8 clinical studies are summarized. Results Across studies, MenACWY-TT antibody responses against all vaccine serogroups were comparable to those of other MenACWY vaccines 1 month post vaccination (Table 1). Antibody responses to MenACWY-TT persisted for up to 10 years in those vaccinated during adolescence. A MenACWY-TT booster given 10 years after primary meningococcal vaccination in early childhood or adolescence elicited robust antibody responses. MenACWY-TT had an acceptable safety profile, with reactogenicity events most commonly reported. Reactogenicity profiles with MenACWY-TT booster were similar to those seen after primary MenACWY-TT. Conclusion The MenACWY-TT clinical study program demonstrated the immunogenicity and safety of primary and booster dosing in adolescents. Immune responses persisted through 10 years after primary vaccination. Funding Pfizer. Disclosures Paula Peyrani, MD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)

Background Meningococcal serogroups A, B, C, W and Y cause nearly all meningococcal disease globally. Vaccination is complicated by different dosing recommendations for serogroup B (MenB) and quadrivalent (MenACWY) vaccines, which could be solved with a single pentavalent vaccine. This study in adolescents and young adults evaluated a new pentavalent MenABCWY vaccine that combines 2 licensed vaccines, MenB-FHbp (Trumenba®; bivalent rLP2086) and MenACWY-TT (Nimenrix®), into a single vaccine. Methods In this ongoing, randomized, controlled, observer-blinded, multicenter study (NCT03135834), MenB vaccine-naive and MenACWY-naive or -experienced healthy 10–25-year-olds were randomized 1:2 to MenABCWY (Month 0,6) or MenB-FHbp (Month 0,6) and MenACWY-CRM (Month 0). Immune responses were measured by serum bactericidal activity assays with human complement (hSBA) against serogroup A, C, W and Y strains and 4 diverse, vaccine-heterologous MenB strains. Endpoints included percentages of subjects achieving ≥ 4-fold rises in titers from baseline. Noninferiority of immune responses was assessed at the 10% margin (95% CI lower limit > −10%). Safety was assessed. Results Following dose 2, high percentages of MenABCWY (n=543) and MenB-FHbp (n=1057) recipients achieved ≥ 4-fold rises against each of the 4 MenB strains (75.8−94.7% vs 67.4−95.0%) and titers reaching at least the lower limit of quantification against all 4 strains combined (79.9% vs 74.3%; Figure 1A). MenABCWY was noninferior to MenB-FHbp for all 5 endpoints. MenABCWY was also noninferior to a single MenACWY-CRM dose with 75.5−96.9% and 93.0−97.4% of MenABCWY recipients after dose 1 or 2, respectively, achieving ≥ 4-fold rises against serogroup A, C, W and Y depending on prior MenACWY experience (Figure 1B). Local reactions and systemic events after MenABCWY or MenB-FHbp were similarly frequent, mostly mild/moderate in severity (Figure 2), and unaffected by MenACWY experience. Figure 1. Immune Responses as Measured in hSBA to (A) MenB Test Strains at 1 Month After Dose 2 and (B) MenA, MenC, MenW, and MenY Test Strains at 1 Month After Doses 1 and 2 Figure 2. (A) Local Reactions and (B) Systemic Events Reported Within 7 Days After Any Dose Conclusion MenABCWY 4-fold immune responses from baseline were robust and noninferior to MenB-FHbp and MenACWY-CRM administered separately. Vaccination was safe and well tolerated. The favorable benefit-risk profile supports further MenABCWY development as a simplified alternative to current meningococcal vaccination practices. Funded by Pfizer. Disclosures James Peterson, MD, Pfizer (Scientific Research Study Investigator) Daniel Drazan, MD, Pfizer (Scientific Research Study Investigator) Hanna Czajka, MD, PhD, Pfizer (Scientific Research Study Investigator) Jason Maguire, MD, Pfizer (Employee, Shareholder) Jean-Louis Pregaldien, MS, Pfizer (Employee, Shareholder) Ilkka Seppa, MD, Pfizer (Scientific Research Study Investigator) Roger Maansson, MS, Pfizer (Employee, Shareholder) Robert O’Neill, PhD, Pfizer (Employee, Shareholder) Annaliesa S. Anderson, PhD, Pfizer (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) Johannes Beeslaar, MD, Pfizer (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)

Neisseria meningitidis serogroup B (MenB) is an important cause of invasive meningococcal disease. The development of safe and effective vaccines with activity across the diversity of MenB strains has been challenging. While capsular polysaccharide conjugate vaccines have been highly successful in the prevention of disease due to meningococcal serogroups A, C, W, and Y, this approach has not been possible for MenB owing to the poor immunogenicity of the MenB capsular polysaccharide. Vaccines based on outer membrane vesicles have been successful in the prevention of invasive MenB disease caused by the single epidemic strain from which they were derived, but they do not confer broad protection against diverse MenB strains. Thus, alternative approaches to vaccine development have been pursued to identify vaccine antigens that can provide broad protection against the epidemiologic and antigenic diversity of invasive MenB strains. Human factor H binding protein (fHBP) was found to be such an antigen, as it is expressed on nearly all invasive disease strains of MenB and can induce bactericidal responses against diverse MenB strains. A bivalent vaccine (Trumenba®, MenB-FHbp, bivalent rLP2086) composed of equal amounts of 2 fHBP variants from each of the 2 immunologically diverse subfamilies of fHBP (subfamilies A and B) was the first MenB vaccine licensed in the United States under an accelerated approval pathway for prevention of invasive MenB disease. Due to the relatively low incidence of meningococcal disease, demonstration of vaccine efficacy for the purposes of licensure of bivalent rLP2086 was based on vaccine-elicited bactericidal activity as a surrogate marker of efficacy, as measured in vitro by the serum bactericidal assay using human complement. Because bacterial surface proteins such as fHBP are antigenically variable, an important component for evaluation and licensure of bivalent rLP2086 included stringent criteria for assessment of breadth of coverage across antigenically diverse and epidemiologically important MenB strains. This review describes the rigorous approach used to assess broad coverage of bivalent rLP2086. Alternative nonfunctional assays proposed for assessing vaccine coverage are also discussed.

Invasive meningococcal disease (IMD), a rapidly progressing and potentially fatal illness, disproportionately affects adolescents and young adults. While IMD is best prevented by vaccination, vaccine uptake in these groups is low. An evidence-based understanding of the safety and effectiveness of concomitant vaccination of meningococcal vaccines, including the newer MenB protein vaccines and the more established MenACWY conjugate vaccines, with other vaccines recommended for adolescents and young adults may help maximize vaccination opportunities. We identified 21 studies assessing concomitant administration of meningococcal vaccines with other vaccines in adolescents and adults. Although studies varied in methodology, concomitant administration generally did not affect immunogenicity of the meningococcal or coadministered vaccines. In some cases, reactogenicity increased following concomitant administration, but no definitive safety concerns were raised. In general, data suggest that meningococcal vaccines can be safely and effectively coadministered with other vaccines.

Background A peak in meningococcal carriage and invasive meningococcal disease (IMD) occurs during adolescence and young adulthood. In the United States, preventive vaccination with a quadrivalent meningococcal (MenACWY) conjugate vaccine is recommended at age 11–12 years, with a booster dose given at age 16 years. MenACWY-TT (Nimenrix®), a MenACWY tetanus toxoid conjugate vaccine, was first licensed in 2012 and is available in the European Union and 50 other countries. Immune responses to other MenACWY conjugate vaccines decline over several years following vaccination. Here, we review 2 recent studies evaluating the long-term persistence of MenACWY-TT immune responses in adolescents as well as safety and immunogenicity of a booster dose given 10 years after primary vaccination. Methods Both studies (ClinicalTrials.gov NCT01934140, NCT03189745) were extensions of phase 2 or 3 studies of subjects 11–17 years of age given a single dose of MenACWY-TT or MenACWY polysaccharide vaccine (MenACWY-PS). Immune responses through 10 years after primary vaccination and after a Year 10 MenACWY-TT booster dose were measured by serum bactericidal antibody assays using baby rabbit complement (rSBA). Specific endpoints included percentages of subjects with rSBA titers ≥1:8 and ≥1:128 and geometric mean titers (GMTs). Booster dose safety and tolerability were also evaluated. Results In both studies, the percentages of subjects with rSBA titers ≥1:8 through 10 years postvaccination were generally higher or similar among MenACWY-TT (69.3%–91.2% at Year 10; n=137–163) compared with MenACWY-PS (24.4%–88.9%; n=45–53) recipients for all 4 serogroups (Figure); similar results were observed for GMTs (146.0–446.9 vs 12.9–191.0 at Year 10). One month after a MenACWY-TT booster dose, 97.7%–100% of subjects across groups had titers ≥1:8 (Figure), and GMTs were markedly higher than prebooster values. No new safety signals were identified following the booster dose. Figure 1. Subjects in each of the 2 studies with rSBA titers ≥1:8 before and at 1 month, 5 years, and 10 years after primary vaccination with MenACWY-TT or MenACWY-PS at 11–17 years of age and 1 month after booster vaccination with MenACWY-TT at 10 years following primary vaccination. Conclusion Functional antibodies for all 4 serogroups persisted through 10 years after MenACWY-TT adolescent vaccination, suggesting that this vaccine may help prevent IMD throughout the lengthy risk period in this group. A MenACWY-TT booster dose may further extend protection regardless of the primary vaccine received. Funded by Pfizer. Disclosures Paula Peyrani, MD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)

Bivalent rLP2086, targeting meningococcal serogroup B, will extend prevention of meningococcal disease beyond that provided by quadrivalent serogroup ACWY vaccines; coadministration with recommended vaccines may improve adherence to vaccine schedules. This phase 2, randomized, active-controlled, observer-blinded study assessed whether immune responses induced by coadministration of Menactra (meningococcal A, C, Y and W-135 polysaccharide conjugate vaccine [MCV4]) and Adacel (tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine [Tdap]) with bivalent rLP2086 (Trumenba [meningococcal serogroup B vaccine], approved in the United States) were noninferior to MCV4 + Tdap or bivalent rLP2086 alone.Healthy adolescents aged 10 to13 years received MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap or bivalent rLP2086. Bivalent rLP2086 response was assessed with serum bactericidal assays using human complement with 2 meningococcal serogroup B test strains expressing vaccine-heterologous factor H-binding protein variants; MCV4 with SBAs using rabbit complement; and Tdap with multiplexed Luminex assays. Safety was evaluated.Two thousand six hundred forty-eight subjects were randomized. Immune responses to MCV4 + Tdap + bivalent rLP2086 were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. Seroprotective serum bactericidal assays using human complement titers were documented for 62.3%-68.0% and 87.5%-90% of MCV4 + Tdap + bivalent rLP2086 recipients after doses 2 and 3, respectively. A ≥4-fold rise in serum bactericidal assays using human complement titers from baseline was achieved by 56.3%-64.3% and 84.0%-85.7% of subjects after doses 2 and 3, respectively. Bivalent rLP2086 alone induced similar responses. Concomitant administration did not substantially increase reactogenicity compared with bivalent rLP2086 alone.Bivalent rLP2086 given concomitantly with MCV4 + Tdap met all noninferiority immunogenicity criteria without a clinically meaningful increase in reactogenicity. MCV4 and bivalent rLP2086 coadministration would provide coverage against the 5 major disease-causing serogroups.

Background: Neisseria meningitidis serogroup B (MnB) is an important cause of invasive meningococcal disease (IMD). A MnB vaccine (bivalent rLP2086, Trumenba®) consisting of 2 factor H binding protein variants received accelerated approval in the United States for the prevention of IMD caused by MnB in individuals 10-25 years of age. This randomized, active-controlled, observer-blind study further assessed the safety and tolerability of bivalent rLP2086. Methods: Eligible subjects ≥10 to ®) at months 0 and 6, and saline at month 2. The primary endpoints were serious adverse events (SAEs) throughout the study and medically-attended adverse events (MAEs) within 30 days after vaccination. Additional safety assessments included SAEs at other study intervals and adverse events (AEs) during the vaccination phase. Results: Of 5712 subjects randomized, 84.6% (n = 3219) of bivalent rLP2086 recipients and 87.2% (n = 1663) of HAV/saline recipients completed the study. Throughout the study, SAEs were reported for 1.6% and 2.5% of bivalent rLP2086 and HAV/saline recipients, respectively. SAEs related to either vaccine were rare. MAEs occurred in 7.0% and 6.1% of subjects after vaccination 1; 5.5% and 6.1% after vaccination 2; and 5.3% and 5.5% after vaccination 3 in the bivalent rLP2086 and HAV/saline groups, respectively. A greater proportion of subjects reported AEs during the vaccination phase after bivalent rLP2086 compared with HAV/saline recipients; however, when reactogenicity events were excluded, the proportion between groups was similar. Conclusion: This safety study, the largest randomized, active-controlled trial evaluating a recombinant MnB vaccine, demonstrated that bivalent rLP2086 is safe and tolerable in healthy individuals ≥10 to

Background The bivalent rLP2086 vaccine is approved in the United States to prevent meningococcal disease caused by Neisseria meningitidis serogroup B (MnB) in individuals aged 10–25 years. The immunogenicity and safety of bivalent rLP2086 were evaluated in microbiologists 24–62 years old who handle MnB. Methods Seven subjects vaccinated at 0, 2, and 6 months had functional antibodies measured before vaccination and 1 month after each dose by serum bactericidal assays using human complement (hSBAs) and 4 vaccine-heterologous MnB test strains. Results Six subjects qualified for analysis. All demonstrated hSBA titers ≥the lower limit of quantitation (LLOQ) against 3 of 4 strains; 3 subjects achieved titers ≥LLOQ for the fourth. Safety-related events following vaccination were generally mild to moderate in severity. Conclusions Three doses of bivalent rLP2086 were generally well tolerated in laboratory personnel and elicited protective functional immune responses reflective of broad coverage against MnB disease.

Background: The period of heightened risk of invasive meningococcal disease in adolescence extends for >10 years. This study aimed to evaluate persistence of the immune response to the serogroup B meningococcal (MenB) vaccine MenB-FHbp (Trumenba ® , Bivalent rLP2086) under two- and three-dose primary vaccination schedules, both of which are approved in the United States and the European Union, and to assess safety and immunogenicity of a booster dose. Methods: This was an open-label extension study of a phase 2 randomized MenB-FHbp study (primary study). This interim analysis includes data through 1 month after booster vaccination. In the primary study, adolescents 11–18 years of age were randomized using an interactive voice or web-based response system to receive 120 μg MenB-FHbp under 0-, 1-, 6-month; 0-, 2-, 6-month; 0-, 6-month; 0-, 2-month; or 0-, 4-month schedules (termed study groups for the current analysis). For the primary study, participants were blinded to their vaccine study group allocation, but investigators and the study sponsor were unblinded. Immune responses in subjects from the primary study were evaluated through 48 months after primary vaccination (persistence stage; 17 sites in Czech Republic, Denmark, Germany, and Sweden). Safety and immunogenicity of a booster dose given at 48 months after primary vaccination (booster stage; 14 sites in Czech Republic, Denmark, and Sweden) were also assessed. Immune responses were evaluated in serum bactericidal assays with human complement (hSBAs) using four MenB test strains representative of disease-causing MenB strains in the United States and Europe and expressing factor H binding proteins (FHbps) heterologous to the vaccine antigens. The primary immunogenicity endpoints were the proportions of subjects with hSBA titers greater than or equal to the assays’ lower limit of quantitation (LLOQ; 1:8 or 1:16 depending on strain) at 12, 18, 24, 36, and 48 months after primary vaccination (persistence stage) and 1 and 48 months after the primary vaccination series and 1 month after receipt of the booster dose (booster stage). Safety evaluations during the booster stage included local reactions and systemic events by severity, antipyretic use, adverse events (AEs), immediate AEs, serious AEs (SAEs), medically attended AEs (MAEs), newly diagnosed chronic medical conditions (NDCMCs), and missed days of school and work because of AEs. The modified intent-to-treat (mITT) population was used for immunogenicity evaluations in the persistence stage. The booster stage immunogenicity evaluations used the evaluable immunogenicity population; analyses were also performed in the mITT population. For the persistence stage, safety evaluations included subjects with at least one blood draw, whereas for the booster stage, they included subjects who received the booster dose and had available safety data. This trial is registered at ClinicalTrials.gov number NCT01543087. Findings: A total of 465 subjects were enrolled in the persistence stage, and 271 subjects were enrolled in the booster stage. Sera for the extension phase of this interim analysis were collected from September 7, 2012 to December 7, 2015. One month after primary vaccination, 73.8–100.0% of subjects depending on study group responded with hSBA titers ≥LLOQ. Response rates declined during the 12 months after last primary vaccination and then remained stable through 48 months, with 18.0–61.3% of subjects depending on study group having hSBA titers ≥LLOQ at this time point. One month after receipt of the booster dose, 91.9–100.0% of subjects depending on study group had hSBA titers ≥LLOQ against the four primary strains individually and 91.8–98.2% had hSBA titers ≥LLOQ against all four strains combined (composite response). Geometric mean titers were higher after booster vaccination than at 1 month after primary vaccination. Immune responses were generally similar across study groups, regardless of whether a two- or three-dose primary series was received. None of the AEs (2.2–6.9% of subjects depending on study group) or NDCMCs (1.8–5.0%) that were reported during the persistence stage were considered related to the investigational product. Local reactions and systemic events were reported by 84.4–93.8% and 68.8–76.6% of subjects depending on study group, respectively, in the booster stage; these were generally similar across study groups, transient, and less frequent than after any primary vaccination. Additionally, there was no general progressive worsening in severity of reactogenicity events (ie, potentiation; ≤3 subjects per group), and reactogenicity events did not lead to any study withdrawals. No NDCMCs or immediate AEs were reported during the booster stage. AEs were reported by 3.7–12.5% of subjects depending on study group during the booster stage. The two possibly related AEs included a mild worsening of psoriasis and a severe influenza-like illness that resolved in 10 days. Interpretation: Immune responses declined after the primary vaccination series; however, a substantially greater number of subjects retained protective responses at 48 months after primary vaccination compared with subjects having protective responses before vaccination. Persistence trends were similar across all 5 study groups regardless of whether a two- or three-dose primary schedule was received. Furthermore, a booster dose given 48 months after primary vaccination was safe, well-tolerated, and elicited robust immune responses indicative of immunologic memory; these responses were similar between two- and three-dose primary schedule study groups. Use of a booster dose may help further extend protection against MenB disease in adolescents. Funding: Pfizer Inc.

In prophylactic vaccine studies in healthy populations, many subjects do not experience a single adverse event (AE). Thus, the number of AEs observed in such clinical trials may be difficult to model because of an excess of zeroes relative to the parametric distributions assumed. To determine which type of modeling provides a better fit for observed AE data, a variety of models were applied to data from an integrated safety database from clinical trials of the meningococcal vaccine MenB-FHbp (Trumenba®, bivalent rLP2086; Pfizer Inc, Philadelphia, PA). MenB-FHbp was the first vaccine approved in the United States to prevent meningococcal serogroup B disease in individuals aged 10 to 25 years. Specifically, this report presents an integrated analysis of AEs from 8 randomized controlled trials that compared MenB-FHbp to placebo or active controls. The number of AEs occurring from dose one to 30 days after the last dose was analyzed. Six models were compared: standard Poisson and negative binomial models and their corresponding zero-inflation and hurdle models. Models were evaluated for their ability to predict the number of AEs and by goodness-of-fit statistics. Models based on the Poisson distribution were a poor fit. The zero-inflated negative binomial model and negative binomial hurdle model provided the closest fit. These results suggest that zero-inflated or hurdle models may provide a better fit to AE data from healthy populations compared with conventional parametric models.

Introduction: Given the characteristics of meningococcal carriage and transmission and the sudden, often severe onset and long-term consequences of disease, vaccination can most effectively provide large-scale control of invasive disease. Six serogroups (A, B, C, W, X, and Y) cause nearly all meningococcal disease globally. Capsular polysaccharide conjugate vaccines can prevent serogroups A, C, W, and Y disease. More recently, recombinant protein vaccines for preventing serogroup B meningococcal (MenB) disease have become available, with a major target of vaccine-induced immune response for both vaccines being bacterial factor H binding protein (FHbp). Importantly, FHbp segregates into only two distinct subfamilies (A [also classified as variants 2 and 3] and B [variant 1]). This review summarizes the complete clinical development program supporting licensure of MenB-FHbp (Trumenba®, Bivalent rLP2086), the only MenB vaccine containing antigens from both FHbp subfamilies. Areas covered: Eleven published clinical studies assessing MenB-FHbp efficacy and safety among 20,803 adolescents and adults are examined. Particular focus is on the methodology of immunogenicity assessments used as a surrogate for clinical efficacy. Expert commentary: Clinical studies in adolescents and adults consistently demonstrated MenB-FHbp safety and induction of immunologic responses against antigenically and epidemiologically diverse MenB isolates, supporting licensure and immunization recommendations.

Background: MenB-FHbp (bivalent rLP2086) is licenced at a 120- µg dose given on a two- or three-dose schedule to prevent meningococcal serogroup B (MenB) disease in adolescents and adults. This phase 2, observer-blinded, active-controlled, dose-escalation, sentinel-design study evaluated MenB-FHbp safety and immunogenicity in toddlers 12 to

Background The quadrivalent meningococcal ACWY polysaccharide tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix) is licensed in various countries to prevent disease caused by meningococcal serogroups A, C, W, and Y. In a previous study (NCT00464815), subjects aged 11‒17 years received a primary dose of MenACWY-TT or a quadrivalent polysaccharide vaccine (MenACWY-PS). Here, we report the long-term antibody persistence of the primary dose and the immunogenicity and safety of a booster dose given 10 years after primary vaccination of subjects. Methods Participants were enrolled from the Philippines and received a booster dose of MenACWY-TT at 10 years postvaccination. Antibody persistence 10 years postprimary vaccination and immunogenicity 1 month after the booster dose were evaluated by serum bactericidal activity assays using rabbit complement (rSBA) to assess the percentages of subjects with titers ≥ 1:8 and ≥ 1:128 and geometric mean titers (GMTs) for each serogroup. Safety was assessed for the booster dose. Results Of 229 subjects enrolled in this extension study, 169 and 58 subjects in the MenACWY-TT and MenACWY-PS groups, respectively, completed the booster phase. The percentages of primary MenACWY-TT recipients with prebooster rSBA titers ≥ 1:8 and ≥ 1:128 at year 10 ranged from 71.6%‒90.7% and 64.8%‒85.2% for all serogroups, respectively, compared with 43.1%‒82.4% and 25.5%‒76.5% of primary MenACWY-PS recipients; rSBA GMTs for all serogroups were higher in the MenACWY-TT group than in the MenACWY-PS group at year 10. For the MenACWY-TT and MenACWY-PS groups, respectively, the MenACWY-TT booster dose elicited rSBA titers ≥ 1:8 in 100% and ≥ 98.0% of subjects (figure); 100% and ≥ 96.1% of all subjects had titers ≥ 1:128. For all serogroups, rSBA GMTs at 1 month after the booster dose were higher than before the booster dose. No new safety signals were observed during the booster phase. Conclusion Functional antibody responses elicited by MenACWY-TT persisted 10 years after primary vaccination; the booster dose was well tolerated and elicited robust immune responses. ClinicalTrials.gov NCT03189745, EudraCT # 2013-001512-29. Funded by Pfizer. Disclosures All authors: No reported disclosures.

Vaccines have had a major impact on the reduction of many diseases globally. Vaccines targeted against invasive meningococcal disease (IMD) due to serogroups A, C, W, and Y are used to prevent these diseases. Until recently no vaccine had been identified that could confer broad protection against Neisseria meningitidis serogroup B (MnB). MnB causes IMD in the very young, adolescents and young adults and thus represents a significant unmet medical need. In this brief review, we describe the discovery and development of a vaccine that has the potential for broad protection against this devastating disease.

Background The quadrivalent meningococcal ACWY polysaccharide tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix) is licensed in various countries to prevent disease caused by meningococcal serogroups A, C, W, and Y. In a previous study (NCT00464815), subjects aged 11‒17 years received a primary dose of MenACWY-TT or a quadrivalent polysaccharide vaccine (MenACWY-PS). Here, we report the long-term antibody persistence of the primary dose and the immunogenicity and safety of a booster dose given 10 years after primary vaccination of subjects. Methods Participants were enrolled from the Philippines and received a booster dose of MenACWY-TT at 10 years postvaccination. Antibody persistence 10 years postprimary vaccination and immunogenicity 1 month after the booster dose were evaluated by serum bactericidal activity assays using rabbit complement (rSBA) to assess the percentages of subjects with titers ≥1:8 and ≥1:128 and geometric mean titers (GMTs) for each serogroup. Safety was assessed for the booster dose. Results Of 229 subjects enrolled in this extension study, 169 and 58 subjects in the MenACWY-TT and MenACWY-PS groups, respectively, completed the booster phase. The percentages of primary MenACWY-TT recipients with prebooster rSBA titers ≥ 1:8 and ≥ 1:128 at year 10 ranged from 71.6%‒90.7% and 64.8%‒85.2% for all serogroups, respectively, compared with 43.1%‒82.4% and 25.5%‒76.5% of primary MenACWY-PS recipients; rSBA GMTs for all serogroups were higher in the MenACWY-TT group than in the MenACWY-PS group at year 10. For the MenACWY-TT and MenACWY-PS groups, respectively, the MenACWY-TT booster dose elicited rSBA titers ≥1:8 in 100% and ≥98.0% of subjects (figure); 100% and ≥96.1% of all subjects had titers ≥1:128. For all serogroups, rSBA GMTs at 1 month after the booster dose were higher than before the booster dose. No new safety signals were observed during the booster phase. Conclusion Functional antibody responses elicited by MenACWY-TT persisted 10 years after primary vaccination; the booster dose was well tolerated and elicited robust immune responses. ClinicalTrials.gov: NCT03189745, EudraCT # 2013-001512-29. Funded by Pfizer. Disclosures All authors: No reported disclosures.

Background MenB-FHbp (bivalent rLP2086), a meningococcal serogroup B vaccine, is approved in several countries for adolescents and young adults. MenB-FHbp elicited robust immune responses and had an acceptable safety profile during an extensive clinical development program. Because immune responses to vaccines can vary by subject demographics, this subgroup analysis pooled data across 7 randomized MenB-FHbp clinical studies to evaluate potential differences in immunogenicity by sex, age, or race/ethnicity in a larger dataset relative to individual studies. Methods Data from subjects who received 120 µg MenB-FHbp at 0, 2, and 6 months and had valid immunogenicity results for 4 vaccine-heterologous test strains were included. Immune responses were evaluated by serum bactericidal assays using human complement (hSBA). Immunogenicity endpoints (assessed 1 month after dose 3) were percentages of subjects achieving ≥ 4-fold rise in hSBA titer against each strain, percentages achieving hSBA titers ≥ the lower limit of quantification (LLOQ) against each strain and against all 4 strains combined (composite response), geometric mean hSBA titers against each strain, and percentages achieving hSBA titers ≥ 1:4 (correlate of protection) against each strain. Results This analysis included 8026 subjects aged 10‒25 years (51.7% males, 80.7% adolescents aged 10‒18 years, 87.0% white, 9.3% black, 0.8% Asian, 3.0% other race). One month after dose 3, percentages of subjects achieving a ≥ 4-fold rise from baseline titer against each strain and achieving a composite response were similar across age and race (table). A marginally greater percentage of males vs. females achieved ≥ 4-fold rise in titer against each strain, but these differences were not considered clinically meaningful because of the high percentages of responders in both groups. Conclusion MenB-FHbp immunogenicity was similar across sex, age, and race in this pooled analysis, with high percentages of responders in all evaluated subgroups. The marginally lower response rates among females compared with males were not considered clinically meaningful. These findings support currently recommended MenB-FHbp vaccination practices without modification by sex, age, or race. Funding: Pfizer Disclosures All authors: No reported disclosures.