Immunogenicity and safety of a pentavalent meningococcal ABCWY vaccine in adolescents and young adults: an observer-blind, active-controlled, randomised trial.

BACKGROUND: Meningococcal serogroups A, B, C, W, and Y cause nearly all meningococcal disease, and comprehensive protection requires vaccination against all five serogroups. We aimed to assess the immunogenicity and safety of a pentavalent MenABCWY vaccine comprising two licensed vaccines-meningococcal serogroup B-factor H binding protein vaccine (MenB-FHbp) and a quadrivalent meningococcal serogroup ACWY tetanus toxoid conjugate vaccine (MenACWY-TT)-compared with two doses of MenB-FHbp and a single dose of quadrivalent meningococcal serogroup ACWY CRM197-conjugate vaccine (MenACWY-CRM) as the active control. We previously reported the primary safety and immunogenicity data relating to the two-dose MenB-FHbp schedule. Here we report secondary outcomes and ad-hoc analyses relating to MenABCWY immunogenicity and safety. METHODS: We did an observer-blind, active-controlled trial at 68 sites in the USA, Czech Republic, Finland, and Poland. Healthy individuals (aged 10-25 years) who had or had not previously received a MenACWY vaccine were randomly assigned (1:2) using an interactive voice or web-based response system, stratified by previous receipt of a MenACWY vaccine, to receive 0·5 mL of MenABCWY (months 0 and 6) and placebo (month 0) or MenB-FHbp (months 0 and 6) and MenACWY-CRM (month 0) via intramuscular injection into the upper deltoid. All individuals were masked to group allocation, except staff involved in vaccine dispensation, preparation, and administration; and protocol adherence. Endpoints for serogroups A, C, W, and Y included the proportion of participants who achieved at least a four-fold increase in serum bactericidal antibody using human complement (hSBA) titres between baseline and 1 month after each vaccination. For serogroup B, secondary endpoints included the proportion of participants who achieved at least a four-fold increase in hSBA titres from baseline for each of four primary test strains and the proportion of participants who achieved titres of at least the lower limit of quantitation against all four test strains combined at 1 month after the second dose. Endpoints for serogroups A, C, W, and Y were assessed in the modified intent-to-treat (mITT) population, which included all randomly assigned participants who received at least one vaccine dose and had at least one valid and determinate MenB or serogroup A, C, W, or Y assay result before vaccination up to 1 month after the second dose, assessed in ACWY-experienced and ACWY-naive participants separately. Secondary endpoints for serogroup B were analysed in the evaluable immunogenicity population, which included all participants in the mITT population who were randomly assigned to the group of interest, received all investigational products as randomly assigned, had blood drawn for assay testing within the required time frames, had at least one valid and determinate MenB assay result after the second vaccination, and had no important protocol deviations; outcomes were assessed in both ACWY-experienced and ACWY-naive populations combined. Non-inferiority of MenABCWY to MenACWY-CRM and MenB-FHbp was determined using a -10% non-inferiority margin for these endpoints. Reactogenicity and adverse events were assessed among all participants who received at least one vaccine dose and who had available safety data. This trial is registered with Clinicaltrials.gov, NCT03135834, and is complete. FINDINGS: Between April 24 and November 10, 2017, 1610 participants (809 MenACWY-naive; 801 MenACWY-experienced) were randomly assigned: 544 to receive MenABCWY and placebo (n=272 MenACWY-naive; n=272 MenACWY-experienced) and 1066 to receive MenB-FHbp and MenACWY-CRM (n=537 MenACWY-naive; n=529 MenACWY-experienced). Among MenACWY-naive or MenACWY-experienced MenABCWY recipients, 75·5% (95% CI 69·8-80·6; 194 of 257; serogroup C) to 96·9% (94·1-98·7; 254 of 262; serogroup A) and 93·0% (88·4-96·2; 174 of 187; serogroup Y) to 97·4% (94·4-99·0; 224 of 230; serogroup W) achieved at least four-fold increases in hSBA titres against serogroups ACWY after dose 1 or 2, respectively, in ad-hoc analyses. Additionally, 75·8% (71·5-79·8; 320 of 422) to 94·7% (92·1-96·7; 396 of 418) of MenABCWY and 67·4% (64·1-70·6; 563 of 835) to 95·0% (93·3-96·4; 782 of 823) of MenB-FHbp recipients achieved at least four-fold increases in hSBA titres against MenB strains after dose 2 in secondary analyses; 79·9% (334 of 418; 75·7-83·6) and 74·3% (71·2-77·3; 605 of 814), respectively, achieved composite responses. MenABCWY was non-inferior to MenACWY-CRM (single dose) and to MenB-FHbp in ad-hoc analyses based on the proportion of participants with at least a four-fold increase in hSBA titres from baseline and (for MenB-FHbp only) composite responses. Reactogenicity events after vaccination were similarly frequent across groups, were mostly mild or moderate, and were unaffected by MenACWY experience. No adverse events causing withdrawals were related to the investigational product. Serious adverse events were reported in four (1·5%; 0·4-3·7) MenACWY-naive individuals in the MenABCWY group versus six (2·2%; 0·8-4·8) among MenACWY-experienced individuals in the MenABCWY group and 14 (1·3%; 0·7-2·2) in the active control group (MenACWY-experienced and MenACWY-naive individuals combined); none of these were considered related to the investigational product. INTERPRETATION: MenABCWY immune responses were robust and non-inferior to MenACWY-CRM and MenB-FHbp administered separately, and MenABCWY was well tolerated. The favourable benefit-risk profile supports further MenABCWY evaluation as a simplified schedule compared with current adolescent meningococcal vaccination programmes. FUNDING: Pfizer.

Modeling persistence of hSBA titers over time following a primary series and a booster dose of MenB-FHbp.

MenB-FHbp is a meningococcal serogroup B vaccine. Persistence of hSBA titers against 4 diverse test strains ≤ 4 years after a 2-dose MenB-FHbp primary series and ≤ 26 months after a booster dose administered 4 years post-primary has been demonstrated. Here, we developed a power law model (PLM) to estimate the persistence of hSBA titers up to 5 years after a MenB-FHbp primary series and a booster dose using hSBA data from previous MenB-FHbp clinical trials in healthy adolescents. The PLM-predicted hSBA titers closely followed observed values after a 0, 6 month MenB-FHbp primary series and a booster dose 4 years later. At 5 years post-primary and 5 years post-booster, the PLM predicted that 15.2 %-50.0 % and 51.2 %-70.9 % of individuals, respectively, would have hSBA titers ≥ 1:8 or 1:16. The PLM supports that the persistence of hSBA titers is maintained for at least 5 years post-primary MenB-FHbp vaccination and post-booster.

Safety and immunogenicity of a primary series and booster dose of the meningococcal serogroup B-factor H binding protein vaccine (MenB-FHbp) in healthy children aged 1-9 years: two phase 2 randomised, controlled, observer-blinded studies.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Pfizer.

Safety data from the MenB-FHbp clinical development program in healthy individuals aged 10 years and older.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A phase 3 study to assess the immunogenicity, safety, and tolerability of MenB-FHbp administered as a 2-dose schedule in adolescents and young adults.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Persistence of hSBA titers elicited by the meningococcal serogroup B vaccine menB-FHbp for up to 4 years after a 2- or 3-dose primary series and immunogenicity, safety, and tolerability of a booster dose through 26 months.

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.

MenB-FHbp Vaccine Protects Against Diverse Meningococcal Strains in Adolescents and Young Adults: Post Hoc Analysis of Two Phase 3 Studies.

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.

Sex, Age, and Race Effects on Immunogenicity of MenB-FHbp, A Bivalent Meningococcal B Vaccine: Pooled Evaluation of Clinical Trial Data.

INTRODUCTION: An extensive clinical development program showed that the meningococcal serogroup B-factor H binding protein (MenB-FHbp) vaccine affords protection against MenB disease for adolescents and adults. Data were pooled from multiple studies within the program to examine whether MenB-FHbp immunogenicity was influenced by sex, age, or race. METHODS: Immunogenicity was assessed in subjects from seven studies who received 120 µg MenB-FHbp (at 0, 2, 6 months) and had evaluated immune responses against four representative test strains via serum bactericidal assays using human complement (hSBAs). Immune responses were presented by sex (male, female), age group (10-14, 15-18, 19-25, 10-25 years), and race (white, black, Asian, other). RESULTS: Among 8026 subjects aged 10-25 years included in this analysis, MenB-FHbp elicited robust immune responses in a high percentage of subjects regardless of demographic characteristics. Across all test strains and demographic subsets, a ≥ 4-fold rise in titer from baseline was achieved in 76.7-95.0% of subjects, with no major differences by sex, age groups assessed, or races evaluated. Corresponding percentages achieving titers ≥ the lower limit of quantification (LLOQ) against all four strains combined were 79.7-87.3% (sex), 81.6-85.5% (age), and 80.0-88.1% (race). Minor differences were observed for geometric mean titers and percentages of subjects achieving titers ≥ LLOQ against each strain based on demographics. CONCLUSION: These data suggested no clinically meaningful differences in MenB-FHbp immunogenicity when administered as a three-dose schedule based on sex, ages assessed, or races evaluated. This analysis supports the continued recommended use of MenB-FHbp to prevent MenB disease in adolescents and young adults. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT00808028, NCT01830855, NCT01323270, NCT01461993, NCT01461980, NCT01352845, and NCT01299480.

Understanding immunogenicity assessments for meningococcal serogroup B vaccines.

Invasive meningococcal disease (IMD) is a potentially devastating infection associated with high mortality and long-term sequelae; however, vaccines are available to protect against the five common disease-causing serogroups (A, B, C, W, and Y). Because traditional field efficacy clinical trials were not feasible due to low IMD incidence that necessitates a very large number of participants, serum bactericidal antibody (SBA) assays using rabbit (rSBA) or human (hSBA) complement were established as in vitro surrogates of meningococcal vaccine efficacy and are now routinely used to support vaccine licensure. Specifically, rSBA assays have been used to evaluate responses to meningococcal capsular polysaccharide-protein conjugate vaccines against serogroups A, C, W, and Y; the accepted correlate of protection for rSBA assays is a titer ≥1:8. Importantly, because the bacterial capsular polysaccharide antigen is conserved across strains, only one test strain that expresses an invariant polysaccharide capsule for each serogroup is required to assess coverage. rSBA assays are unsuitable for subcapsular protein-based serogroup B (MenB) vaccines, and therefore, hSBA assays have been used for licensure; titers ≥1:4 are considered the correlate of protection against IMD for hSBA. In contrast to MenACWY vaccines, because bacterial surface proteins are antigenically variable, MenB vaccines must be tested with hSBA assays using multiple test strains that represent the antigenic diversity of disease-causing isolates. As this complexity regarding SBA assessment methods can make data interpretation difficult, herein we describe the use of hSBA assays to evaluate MenB vaccine efficacy and to support licensure. In addition, we highlight how the two recently approved MenB vaccines differ in their use of hSBA assays in clinical studies to demonstrate broad protection against MenB IMD.

Persistence and 4-year boosting of the bactericidal response elicited by two- and three-dose schedules of MenB-FHbp: A phase 3 extension study in adolescents.

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.

Concomitant administration of meningococcal vaccines with other vaccines in adolescents and adults: a review of available evidence.

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.

From research to licensure and beyond: clinical development of MenB-FHbp, a broadly protective meningococcal B vaccine.

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.

Clinical data supporting a 2-dose schedule of MenB-FHbp, a bivalent meningococcal serogroup B vaccine, in adolescents and young adults.

Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is a potentially devastating condition that can result in death and is associated with serious long-term sequelae in survivors. Vaccination is the preferred preventative strategy. Quadrivalent polysaccharide-based vaccines that protect against infection caused by meningococcal serogroups A, C, W, and Y are not effective against meningococcal serogroup B (MenB), which was responsible for approximately 60% and 35% of confirmed IMD cases in the European Union and the United States in 2016, respectively. A recombinant protein MenB vaccine (MenB-FHbp [bivalent rLP2086; Trumenba®]) has been approved for protection against MenB infection in persons 10-25 years of age in the United States and Canada and for individuals ≥10 years of age in the European Union and Australia. In these regions, MenB-FHbp is approved as a 2- or 3-dose primary vaccination schedule. This report will review the current evidence supporting administration of MenB-FHbp as a 2-dose primary vaccination schedule. Different contexts in which a 2- or 3-dose primary vaccination schedule might be preferred (eg, routine prospective vaccination vs outbreak control) are reviewed.

Modeling excess zeroes in an integrated analysis of vaccine safety.

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.

A Bivalent Meningococcal B Vaccine in Adolescents and Young Adults.

BACKGROUND: MenB-FHbp is a licensed meningococcal B vaccine targeting factor H-binding protein. Two phase 3 studies assessed the safety of the vaccine and its immunogenicity against diverse strains of group B meningococcus. METHODS: We randomly assigned 3596 adolescents (10 to 18 years of age) to receive MenB-FHbp or hepatitis A virus vaccine and saline and assigned 3304 young adults (18 to 25 years of age) to receive MenB-FHbp or saline at baseline, 2 months, and 6 months. Immunogenicity was assessed in serum bactericidal assays that included human complement (hSBAs). We used 14 meningococcal B test strains that expressed vaccine-heterologous factor H-binding proteins representative of meningococcal B epidemiologic diversity; an hSBA titer of at least 1:4 is the accepted correlate of protection. The five primary end points were the proportion of participants who had an increase in their hSBA titer for each of 4 primary strains by a factor of 4 or more and the proportion of those who had an hSBA titer at least as high as the lower limit of quantitation (1:8 or 1:16) for all 4 strains combined after dose 3. We also assessed the hSBA responses to the primary strains after dose 2; hSBA responses to the 10 additional strains after doses 2 and 3 were assessed in a subgroup of participants only. Safety was assessed in participants who received at least one dose. RESULTS: In the modified intention-to-treat population, the percentage of adolescents who had an increase in the hSBA titer by a factor of 4 or more against each primary strain ranged from 56.0 to 85.3% after dose 2 and from 78.8 to 90.2% after dose 3; the percentages of young adults ranged from 54.6 to 85.6% and 78.9 to 89.7%, after doses 2 and 3, respectively. Composite responses after doses 2 and 3 in adolescents were 53.7% and 82.7%, respectively, and those in young adults were 63.3% and 84.5%, respectively. Responses to the 4 primary strains were predictive of responses to the 10 additional strains. Most of those who received MenB-FHbp reported mild or moderate pain at the vaccination site. CONCLUSIONS: MenB-FHbp elicited bactericidal responses against diverse meningococcal B strains after doses 2 and 3 and was associated with more reactions at the injection site than the hepatitis A virus vaccine and saline. (Funded by Pfizer; ClinicalTrials.gov numbers, NCT01830855 and NCT01352845 ).

Meningococcal serogroup B-specific responses after vaccination with bivalent rLP2086: 4 year follow-up of a randomised, single-blind, placebo-controlled, phase 2 trial.

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.

A phase 3, randomized, active-controlled study to assess the safety and tolerability of meningococcal serogroup B vaccine bivalent rLP2086 in healthy adolescents and young adults.

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 < 26 years were randomized (2:1) to receive bivalent rLP2086 at months 0, 2, and 6, or hepatitis A virus vaccine (HAV, Havrix(®)) 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 < 26 years of age.

Immunogenicity, Safety, and Tolerability of Bivalent rLP2086 Meningococcal Group B Vaccine Administered Concomitantly With Diphtheria, Tetanus, and Acellular Pertussis and Inactivated Poliomyelitis Vaccines to Healthy Adolescents.

KEY POINTS: Concomitant administration of bivalent rLP2086 (Trumenba [Pfizer, Inc] and diphtheria, tetanus, and acellular pertussis and inactivated poliovirus vaccine (DTaP/IPV) was immunologically noninferior to DTaP/IPV and saline and was safe and well tolerated. Bivalent rLP2086 elicited robust and broad bactericidal antibody responses to diverse Neisseria meningitidis serogroup B strains expressing antigens heterologous to vaccine antigens after 2 and 3 vaccinations. BACKGROUND: Bivalent rLP2086, a Neisseria meningitidis serogroup B (MnB) vaccine (Trumenba [Pfizer, Inc]) recently approved in the United States to prevent invasive MnB disease in individuals aged 10-25 years, contains recombinant subfamily A and B factor H binding proteins (fHBPs). This study evaluated the coadministration of Repevax (diphtheria, tetanus, and acellular pertussis and inactivated poliovirus vaccine [DTaP/IPV]) (Sanofi Pasteur MSD, Ltd) and bivalent rLP2086. METHODS: Healthy adolescents aged ≥11 to <19 years received bivalent rLP2086 + DTaP/IPV or saline + DTaP/IPV at month 0 and bivalent rLP2086 or saline at months 2 and 6. The primary end point was the proportion of participants in whom prespecified levels of antibodies to DTaP/IPV were achieved 1 month after DTaP/IPV administration. Immune responses to bivalent rLP2086 were measured with serum bactericidal assays using human complement (hSBAs) against 4 MnB test strains expressing fHBP subfamily A or B proteins different from the vaccine antigens. RESULTS: Participants were randomly assigned to receive bivalent rLP2086 + DTaP/IPV (n = 373) or saline + DTaP/IPV (n = 376). Immune responses to DTaP/IPV in participants who received bivalent rLP2086 + DTaP/IPV were noninferior to those in participants who received saline + DTaP/IPV.The proportions of bivalent rLP2086 + DTaP/IPV recipients with prespecified seroprotective hSBA titers to the 4 MnB test strains were 55.5%-97.3% after vaccination 2 and 81.5%-100% after vaccination 3. The administration of bivalent rLP2086 was well tolerated and resulted in few serious adverse events. CONCLUSIONS: Immune responses to DTaP/IPV administered with bivalent rLP2086 to adolescents were noninferior to DTaP/IPV administered alone. Bivalent rLP2086 was well tolerated and elicited substantial and broad bactericidal responses to diverse MnB strains in a high proportion of recipients after 2 vaccinations, and these responses were further enhanced after 3 vaccinations.ClinicalTrials.gov identifier NCT01323270.

Meningococcal Serogroup B Bivalent rLP2086 Vaccine Elicits Broad and Robust Serum Bactericidal Responses in Healthy Adolescents.

BACKGROUND: Neisseria meningitidis serogroup B (MnB) is a leading cause of invasive meningococcal disease in adolescents and young adults. A recombinant factor H binding protein (fHBP) vaccine (Trumenba(®); bivalent rLP2086) was recently approved in the United States in individuals aged 10-25 years. Immunogenicity and safety of 2- or 3-dose schedules of bivalent rLP2086 were assessed in adolescents. METHODS: Healthy adolescents (11 to <19 years) were randomized to 1 of 5 bivalent rLP2086 dosing regimens (0,1,6-month; 0,2,6-month; 0,2-month; 0,4-month; 0,6-month). Immunogenicity was assessed by serum bactericidal antibody assay using human complement (hSBA). Safety assessments included local and systemic reactions and adverse events. RESULTS: Bivalent rLP2086 was immunogenic when administered as 2 or 3 doses; the most robust hSBA responses occurred with 3 doses. The proportion of subjects with hSBA titers ≥1:8 after 3 doses ranged from 91.7% to 95.0%, 98.9% to 99.4%, 88.4% to 89.0%, and 86.1% to 88.5% for MnB test strains expressing vaccine--heterologous fHBP variants A22, A56, B24, and B44, respectively. After 2 doses, responses ranged from 90.8% to 93.5%, 98.4% to 100%, 69.1% to 81.1%, and 70.1% to 77.5%. Geometric mean titers (GMTs) were highest among subjects receiving 3 doses and similar between the 2- and 3-dose regimens. After 2 doses, GMTs trended numerically higher among subjects with longer intervals between the first and second dose (6 months vs 2 and 4 months). Bivalent rLP2086 was well tolerated. CONCLUSIONS: Bivalent rLP2086 was immunogenic and well tolerated when administered in 2 or 3 doses. Three doses yielded the most robust hSBA response rates against MnB strains expressing vaccine-heterologous subfamily B fHBPs.

Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine. METHODS: This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 µg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028. FINDINGS: 539 participants were enrolled and 511 received all three study vaccinations--116 in the placebo group, 21 in the 60 µg group, 191 in the 120 µg group, and 183 in the 200 µg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 µg dose and 67·9 to 99·0% for the 200 µg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 µg dose, 103 of 111 (92·8%) participants for the 120 µg dose, 94 of 100 (94·0%) participants for the 200 µg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 µg dose, 97 of 112 (86·6%) participants for the 120 µg dose, 89 of 105 (84·8%) participants for the 200 µg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 µg dose, 437 with the 120 µg dose, 464 with the 200 µg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 µg group, 77 (38·9%) in the 120 µg group, 92 (47·2%) in the 200 µg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 µg group, 24 in the 120 µg group, 35 in the 200 µg group, and five in the placebo group; range, 0-6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 µg). INTERPRETATION: The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease. FUNDING: Wyeth, Pfizer.