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.

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.

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.

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.

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.

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 ).

Impact of baseline covariates on the immunogenicity of the 9-valent HPV vaccine - A combined analysis of five phase III clinical trials.

BACKGROUND: The immunogenicity profile of the 9-valent HPV (9vHPV) vaccine was evaluated across five phase III clinical studies conducted in girls and boys 9-15 years of age and young women 16-26 years of age. The effect of baseline characteristics of subjects on vaccine-induced HPV antibody responses was assessed. METHODS: Immunogenicity data from 11,304 subjects who received ≥1 dose of 9vHPV vaccine in five Phase III studies were analyzed. Vaccine was administered as a 3-dose regimen. HPV antibody titers were assessed 1 month after dose 3 using a competitive Luminex immunoassay and summarized as geometric mean titers (GMTs). Covariates examined were age, gender, race, region of residence, and HPV serostatus and PCR status at day 1. RESULTS: GMTs to all 9 vaccine HPV types decreased with age at vaccination initiation, and were otherwise generally similar among the demographic subgroups defined by gender, race and region of residence. For all subgroups defined by race or region of residence, GMTs were higher in girls and boys than in young women. Vaccination of subjects who were seropositive at day 1 to a vaccine HPV type resulted in higher GMTs to that type, compared with those in subjects who were seronegative for that type at day 1. CONCLUSIONS: 9vHPV vaccine immunogenicity was robust among subjects with differing baseline characteristics. It was generally comparable across subjects of different races and from different regions. Greater immunogenicity in girls and boys versus young women (the population used to establish 9vHPV vaccine efficacy in clinical studies) indicates that the anti-HPV responses generated by the vaccine in adolescents from all races or regions were sufficient to induce high-level protective efficacy. This immunogenicity profile supports a widespread 9vHPV vaccination program and early vaccination.

Coadministration of a 9-Valent Human Papillomavirus Vaccine With Meningococcal and Tdap Vaccines.

BACKGROUND: This study in 11- to 15-year-old boys and girls compared the immunogenicity and safety of GARDASIL 9 (9-valent human papillomavirus [9vHPV] vaccine) administered either concomitantly or nonconcomitantly with 2 vaccines routinely administered in this age group (Menactra [MCV4; Neisseria meningitidis serotypes A/C/Y/W-135] or Adacel [Tdap; diphtheria/tetanus/acellular pertussis]). METHODS: Participants received 9vHPV vaccine at day 1 and months 2 and 6; the concomitant group (n = 621) received MCV4/Tdap concomitantly with 9vHPV vaccine at day 1; the nonconcomitant group (n = 620) received MCV4/Tdap at month 1. Antibodies to HPV-, MCV4-, and Tdap-relevant antigens were determined. Injection-site and systemic adverse events (AEs) were monitored for 15 days after any vaccination; serious AEs were monitored throughout the study. RESULTS: The geometric mean titers for all HPV types in 9vHPV vaccine 4 weeks after dose 3, proportion of subjects with a fourfold rise or greater in titers for 4 N meningitidis serotypes 4 weeks after injection with MCV4, proportion of subjects with antibody titers to diphtheria and tetanus ≥0.1 IU/mL, and geometric mean titers for pertussis antigens 4 weeks after injection with Tdap were all noninferior in the concomitant group compared with the nonconcomitant group. Injection-site swelling occurred more frequently in the concomitant group. There were no vaccine-related serious AEs. CONCLUSIONS: Concomitant administration of 9vHPV vaccine with MCV4/Tdap was generally well tolerated and did not interfere with the antibody response to any of these vaccines. This strategy would minimize the number of visits required to deliver each vaccine individually.

Immunogenicity and Safety of a 9-Valent HPV Vaccine.

OBJECTIVES: Prophylactic vaccination of youngwomen aged 16 to 26 years with the 9-valent (6/11/16/18/31/33/45/52/58) human papillomavirus (HPV) virus-like particle (9vHPV) vaccine prevents infection and disease. We conducted a noninferiority immunogenicity study to bridge the findings in young women to girls and boys aged 9 to 15 years. METHODS: Subjects (N = 3066) received a 3-dose regimen of 9vHPV vaccine administered at day 1, month 2, and month 6. Anti-HPV serologic assays were performed at day 1 and month 7. Noninferiority required that the lower bound of 2-sided 95% confidence intervals of geometric mean titer ratios (boys:young women or girls:young women) be >0.67 for each HPV type. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored. RESULTS: At 4 weeks after dose 3, >99% of girls, boys, and young women seroconverted for each vaccine HPV type. Increases in geometric mean titers to HPV types 6/11/16/18/31/33/45/52/58 were elicited in all vaccine groups. Responses in girls and boys were noninferior to those of young women. Persistence of anti-HPV responses was demonstrated through 2.5 years after dose 3. Administration of the 9vHPV vaccine was generally well tolerated. A lower proportion of girls (81.9%) and boys (72.8%) than young women (85.4%) reported injection-site AEs, most of which were mild to moderate in intensity. CONCLUSIONS: These data support bridging the efficacy findings with 9vHPV vaccine in young women 16 to 26 years of age to girls and boys 9 to 15 years of age and implementing gender-neutral HPV vaccination programs in preadolescents and adolescents.

Phase III, randomized controlled trial in girls 9-15 years old to evaluate lot consistency of a novel nine-valent human papillomavirus L1 virus-like particle vaccine.

A 9-valent human papillomavirus (6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine has recently been proven highly efficacious in preventing disease associated with vaccine HPV types in a pivotal Phase III study. The demonstration of lot-to-lot consistency to confirm the reliability of the manufacturing process is a regulatory requirement for vaccine licensure in the United States. A randomized trial was conducted to demonstrate that three lots of 9vHPV vaccine elicit equivalent antibody response for all 9 vaccine types. The study required thorough planning because it required success on 27 separate statistical comparisons. An innovative statistical approach was used taking into account between-lot variance for more conservative power calculations. The study demonstrated equivalence of three lots of 9vHPV vaccine for all 9 vaccine types.

Phase II studies to select the formulation of a multivalent HPV L1 virus-like particle (VLP) vaccine.

Our objective was to develop a multivalent prophylactic HPV vaccine that protects against infection and disease caused by HPV16/18 (oncogenic types in existing prophylactic vaccines) plus additional oncogenic types by conducting 3 Phase II studies comparing the immunogenicity (i.e., anti-HPV6/11/16/18 geometric mean titers [GMT]) and safety of 7 vaccine candidates with the licensed quadrivalent HPV6/11/16/18 vaccine (qHPV vaccine) in young women ages 16-26. In the first study (Study 1), subjects received one of 3 dose formulations of an 8-valent HPV6/11/16/18/31/45/52/58 vaccine or qHPV vaccine (control). In Study 2, subjects received one of 3 dose formulations (termed low-, mid-, and high-dose formulations, respectively) of a 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine (9vHPV vaccine) or qHPV vaccine (control). In Study 3, subjects concomitantly received qHPV vaccine plus 5-valent HPV31/33/45/52/58 or qHPV vaccine plus placebo (control). All vaccines were administered at day 1/month 2/month 6. In studies 1 and 3, anti-HPV6/11/16/18 GMTs at month 7 were non-inferior in the experimental arms compared with the control arm; however, there was a trend for lower antibody responses for all 4 HPV types. In Study 2, this immune interference was overcome with the mid- and high-dose formulations of the 9vHPV vaccine by increasing antigen and adjuvant doses. In all 3 studies, all vaccine candidates were strongly immunogenic with respect to HPV31/33/45/52/58 and were well tolerated. Based on the totality of the results, the middle dose formulation of the 9vHPV vaccine was selected for Phase III evaluation. Each 0.5mL dose contains 30µg/40µg/60µg/40µg/20µg/20µg/20µg/20µg/20µg of HPV6/11/16/18/31/33/45/52/58 virus-like particles, and 500µg of amorphous aluminum hydroxyphosphate sulfate adjuvant.ClinicalTrials.gov numbers NCT00260039, NCT00543543, and NCT00551187.

An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age.

BACKGROUND: A 9-valent human papillomavirus (9vHPV) vaccine has recently been reported to be safe and highly efficacious against infection and disease related to HPV6/11/16/18/31/33/45/52/58. We evaluated the immunogenicity and safety of the 9vHPV vaccine administered concomitantly with REPEVAX (diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine). METHODS: This open-label, randomized, multicenter study enrolled 1054 males and females ages 11-15 years. Subjects were randomly assigned to each group in a 1:1 ratio. Subjects received a 0.5 mL dose of 9vHPV vaccine intramuscularly at day 1, months 2 and 6 and a 0.5 mL dose of REPEVAX either on day 1 (concomitant vaccination group; n = 526) or at month 1 (nonconcomitant vaccination group, n = 528). Serologic responses for each vaccine component were tested by 1-sided tests of noninferiority between groups. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored. RESULTS: Noninferiority of anti-HPV geometric mean titers and seroconversion rates for all 9vHPV antigens were demonstrated for the concomitant group compared with the nonconcomitant group. Seroconversion rates for the 9vHPV vaccine types were ≥99.8% in both groups at month 7. For REPEVAX, noninferiority of immune response was established for diphtheria, tetanus, all polio and pertussis antigens for both groups. There were no vaccine-related serious AEs. CONCLUSION: Overall, concomitant administration of 9vHPV vaccine and REPEVAX was generally well tolerated and did not interfere with the immune response to either vaccine. This strategy would minimize the number of visits required to deliver each vaccine individually.

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.

OBJECTIVES: To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). DESIGN: Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months' follow-up. SETTING: Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. PARTICIPANTS: 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. INTERVENTION: Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. MAIN OUTCOME MEASURES: Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. RESULTS: In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. CONCLUSIONS: Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. TRIAL REGISTRATIONS: NCT00092521 and NCT00092534.

Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection.

OBJECTIVE: In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL/SILGARD) clinical program, 73% of women aged 16-26 were naïve to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. METHODS: 18,174 women were enrolled into 3 clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for >or=1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing, and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. RESULTS: Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment. CONCLUSIONS: These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.

A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions.

Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18-related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18-related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18-related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.