Preventing invasive meningococcal disease in early infancy.

This review considers the pathogenesis, diagnosis, and epidemiology of invasive meningococcal disease in infants, to examine and critique meningococcal disease prevention in this population through vaccination. High rates of meningococcal disease and poor outcomes, particularly for very young infants, highlight the importance of meningococcal vaccination in early infancy. Although effective and safe meningococcal vaccines are available for use from 6 weeks of age, they are not recommended globally. Emerging real-world data from the increased incorporation of these vaccines within immunization programs inform recommendations regarding effectiveness, appropriate vaccination schedule, possible long-term safety effects, and persistence of antibody responses. Importantly, to protect infants from IMD, national vaccination recommendations should be consistent with available data regarding vaccine safety, effectiveness, and disease risk.

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.

Economic evaluation of meningococcal vaccines: considerations for the future.

In 2018, a panel of health economics and meningococcal disease experts convened to review methodologies, frameworks, and decision-making processes for economic evaluations of vaccines, with a focus on evaluation of vaccines targeting invasive meningococcal disease (IMD). The panel discussed vaccine evaluation methods across countries; IMD prevention benefits that are well quantified using current methods, not well quantified, or missing in current cost-effectiveness methodologies; and development of recommendations for future evaluation methods. Consensus was reached on a number of points and further consideration was deemed necessary for some topics. Experts agreed that the unpredictability of IMD complicates an accurate evaluation of meningococcal vaccine benefits and that vaccine cost-effectiveness evaluations should encompass indirect benefits, both for meningococcal vaccines and vaccines in general. In addition, the panel agreed that transparency in the vaccine decision-making process is beneficial and should be implemented when possible. Further discussion is required to ascertain: how enhancing consistency of frameworks for evaluating outcomes of vaccine introduction can be improved; reviews of existing tools used to capture quality of life; how indirect costs are considered within models; and whether and how the weighting of quality-adjusted life-years (QALY), application of QALY adjustment factors, or use of altered cost-effectiveness thresholds should be used in the economic evaluation of vaccines.

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.

Meningococcal disease in adolescents and young adults: a review of the rationale for prevention through vaccination.

Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is characterized by high mortality and morbidity. While IMD incidence peaks in both infants and adolescents/young adults, carriage rates are often highest in the latter age groups, increasing IMD risk and the likelihood of transmission. Effective vaccines are available for 5 of 6 disease-causing serogroups. Because adolescents/young adults represent a significant proportion of cases, often have the highest carriage rate, and have characteristically low vaccination adherence, efforts should be focused on educating this population regarding long-term consequences of infection and the importance of meningococcal vaccination in prevention. This review describes the role of adolescents/young adults in meningococcal transmission and the clinical consequences and characteristics of IMD in this population. With a focus on countries with advanced economies that have specific meningococcal vaccination recommendations, the epidemiology of meningococcal disease and vaccination recommendations in adolescents/young adults will also be discussed.

Meningococcal Group A, C, W, and Y Tetanus Toxoid Conjugate Vaccine: A Review of Clinical Data in Adolescents.

MenACWY-TT (Nimenrix) is a quadrivalent meningococcal vaccine containing polysaccharides from serogroups A, C, W, and Y conjugated to a tetanus toxoid carrier protein. MenACWY-TT is licensed in some countries as a three-dose primary series in individuals as young as 6 weeks of age and as a single dose in individuals ≥12 months of age. MenACWY-TT use is supported by long-term immunogenicity and safety across age groups, including data from several phase 2, 3, and 4 clinical studies in adolescents and young adults. Adolescents are an important population in the epidemiology, transmission, and prevention of invasive meningococcal disease, with this age-based population having the highest risk for carriage and transmission as well as one of the highest risks of disease. This age group is emerging as a target population in meningococcal vaccination programs globally, as vaccinating adolescents and young adults could potentially not only decrease disease rates directly for those vaccinated but also indirectly for unvaccinated individuals by decreasing carriage and eliciting herd protection. This review will consider available data for MenACWY-TT in adolescents, including safety and immunogenicity, booster and memory responses, persistence, and coadministration with other vaccines, with an emphasis on the rationale for use of MenACWY-TT and other quadrivalent meningococcal vaccines in adolescents to address the changing epidemiology of meningococcal disease.

Optimal use of meningococcal serogroup B vaccines: moving beyond outbreak control.

Neisseria meningitidis is a major cause of meningitis and septicemia globally. Vaccines directed against N. meningitidis serogroup B (MenB) have been used to control sporadic and sustained disease in industrialized and non-industrialized countries. Early outer membrane vesicle (OMV) vaccines effectively reduced MenB disease in countries such as Norway, New Zealand, and France; however, these vaccines were highly specific for their targeted outbreak strain, did not elicit a durable immune response, and were ineffective for widespread use due to the diversity of MenB-disease-causing isolates. Recently developed recombinant protein-based MenB vaccines that target conserved surface proteins have the potential to induce a broader immune response against the diversity of disease-causing strains. Given the deleterious consequences and sporadic nature of MenB disease, the use of optimal vaccination strategies is crucial for prevention. Reactive vaccination strategies used in the past have significant limitations, including delayed implementation, substantial use of resources, and time constraints. The broad coverage potential of recombinant protein-based MenB vaccines suggests that routine use could result in a reduced burden of disease. Despite this, routine use of MenB vaccines is currently limited in practice.

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.

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.

A Review of Meningococcal Disease and Vaccination Recommendations for Travelers.

International travel has been steadily increasing since the middle of the twentieth century, including travel to regions with high levels of endemic meningococcal disease and areas with sporadic or sustained meningococcal outbreaks. Although invasive meningococcal disease (IMD) is relatively rare in travelers since the advent of quadrivalent meningococcal vaccines, it remains a serious concern because of its rapid progression, poor prognosis and outcomes, associated treatment delays, and the potential to precipitate outbreaks. Moreover, fatality occurs in up to 22% of those infected. This review will focus on IMD in travelers, with an emphasis on IMD epidemiology and the geographic regions of potential concern for international travelers. As vaccination is the best approach for preventing IMD among travelers, currently available meningococcal vaccines and corresponding country-specific national meningococcal vaccination recommendations, where available, will be summarized by age and type of vaccine recommended. The use of the quadrivalent meningococcal vaccines, specifically the tetanus toxoid conjugate vaccine (including MenACWY-TT; Nimenrix®), as a protective measure against IMD in travelers will be emphasized. FUNDING: Pfizer Inc.

Vaccination strategies for the prevention of meningococcal disease.

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

Impact of meningococcal vaccination on carriage and disease transmission: A review of the literature.

Colonization of the human nasopharyngeal tract by the bacterium Neisseria meningitidis is usually asymptomatic, but life-threatening meningococcal disease with a clinical presentation of meningitis, septicemia, or more rarely, gastrointestinal symptoms, can develop. Invasive meningococcal disease (IMD) can be fatal within 24 hours, but IMD is vaccine-preventable. Vaccines used to protect against IMD caused by 5 of the 6 most common serogroups (A, B, C, W, and Y) may also influence carriage prevalence in vaccinated individuals. Lower carriage among vaccinated people may reduce transmission to nonvaccinated individuals to provide herd protection against IMD. This article reviews observational and clinical studies examining effects of vaccination on N. meningitidis carriage prevalence in the context of mass vaccination campaigns and routine immunization programs. Challenges associated with carriage studies are presented alongside considerations for design of future studies to assess the impact of vaccination on carriage.

Telephone care co-ordination for tobacco cessation: randomised trials testing proactive versus reactive models.

OBJECTIVES: We conducted two parallel studies evaluating the effectiveness of proactive and reactive engagement approaches to telephone treatment for smoking cessation. METHODS: Patients who smoked and were interested in quitting were referred to this study and were eligible if they were current smokers and had an address and a telephone number. The data were collected at 35 Department of Veterans Affairs (VA) sites, part of four VA medical centres in both California and Nevada. In study 1, participants received multisession counselling from the California Smokers' Helpline (quitline). In study 2, they received self-help materials only. Patients were randomly assigned by week to either proactive or reactive engagement, and primary care staff were blind to this assignment. Providers gave brief advice and referred them via the electronic health record to a tobacco co-ordinator. All patients were offered cessation medications. OUTCOME: Using complete case analysis, in study 1 (quitline), patients in the proactive condition were more likely than those in the reactive condition to report abstinence at 6 months (21.0% vs 16.4%, p=0.03). No difference was found between conditions in study 2 (self-help) (16.9% vs 16.5%, p=0.88). Proactive outreach resulted in increased use of cessation medications in both the quitline (70.1% vs 57.6%, p<0.0001) and the self-help studies (74.5% vs 48.2%, p<0.0001). CONCLUSION: Proactive outreach with quitline intervention was associated with greater long-term abstinence. Both studies resulted in high rates of medication use. Sites should use a proactive outreach approach and provide counselling whenever possible. TRIAL REGISTRATION NUMBER: NCT00123682.

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 ).

Characteristics of a new meningococcal serogroup B vaccine, bivalent rLP2086 (MenB-FHbp; Trumenba®).

Neisseria meningitidis is a common cause of bacterial meningitis, often leading to permanent sequelae or death. N. meningitidis is classified into serogroups based on the composition of the bacterial capsular polysaccharide; the 6 major disease-causing serogroups are designated A, B, C, W, X, and Y. Four of the 6 disease-causing serogroups (A, C, Y, and W) can be effectively prevented with available quadrivalent capsular polysaccharide protein conjugate vaccines; however, capsular polysaccharide conjugate vaccines are not effective against meningococcal serogroup B (MnB). There is no vaccine available for serogroup X. The public health need for an effective serogroup B vaccine is evident, as MnB is the most common cause of meningococcal disease in the United States and is responsible for almost half of all cases in persons aged 17 to 22 years. In fact, serogroup B meningococci were responsible for the recent meningococcal disease outbreaks on college campuses. However, development of a suitable serogroup B vaccine has been challenging, as serogroup B polysaccharide-based vaccines were found to be poorly immunogenic. Vaccine development for MnB focused on identifying potential outer membrane protein targets that elicit broadly protective immune responses across strains from the vast number of proteins that exist on the bacterial surface. Human factor H binding protein (fHBP; also known as LP2086), a conserved surface-exposed bacterial lipoprotein, was identified as a promising vaccine candidate. Two recombinant protein-based serogroup B vaccines that contain fHBP have been successfully developed and licensed in the United States under an accelerated approval process: bivalent rLP2086 (MenB-FHbp; Trumenba®) and 4CMenB (MenB-4 C; Bexsero®). This review will focus on bivalent rLP2086 only, including vaccine components, mechanism of action, and potential coverage across serogroup B strains in the United States.

A Phase 2, Randomized, Active-controlled, Observer-blinded Study to Assess the Immunogenicity, Tolerability and Safety of Bivalent rLP2086, a Meningococcal Serogroup B Vaccine, Coadministered With Tetanus, Diphtheria and Acellular Pertussis Vaccine and Serogroup A, C, Y and W-135 Meningococcal Conjugate Vaccine in Healthy US Adolescents.

BACKGROUND: Bivalent rLP2086, targeting meningococcal serogroup B, will extend prevention of meningococcal disease beyond that provided by quadrivalent serogroup ACWY vaccines; coadministration with recommended vaccines may improve adherence to vaccine schedules. This phase 2, randomized, active-controlled, observer-blinded study assessed whether immune responses induced by coadministration of Menactra (meningococcal A, C, Y and W-135 polysaccharide conjugate vaccine [MCV4]) and Adacel (tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine [Tdap]) with bivalent rLP2086 (Trumenba [meningococcal serogroup B vaccine], approved in the United States) were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. METHODS: Healthy adolescents aged 10 to <13 years received MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap or bivalent rLP2086. Bivalent rLP2086 response was assessed with serum bactericidal assays using human complement with 2 meningococcal serogroup B test strains expressing vaccine-heterologous factor H-binding protein variants; MCV4 with SBAs using rabbit complement; and Tdap with multiplexed Luminex assays. Safety was evaluated. RESULTS: Two thousand six hundred forty-eight subjects were randomized. Immune responses to MCV4 + Tdap + bivalent rLP2086 were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. Seroprotective serum bactericidal assays using human complement titers were documented for 62.3%-68.0% and 87.5%-90% of MCV4 + Tdap + bivalent rLP2086 recipients after doses 2 and 3, respectively. A ≥4-fold rise in serum bactericidal assays using human complement titers from baseline was achieved by 56.3%-64.3% and 84.0%-85.7% of subjects after doses 2 and 3, respectively. Bivalent rLP2086 alone induced similar responses. Concomitant administration did not substantially increase reactogenicity compared with bivalent rLP2086 alone. CONCLUSIONS: Bivalent rLP2086 given concomitantly with MCV4 + Tdap met all noninferiority immunogenicity criteria without a clinically meaningful increase in reactogenicity. MCV4 and bivalent rLP2086 coadministration would provide coverage against the 5 major disease-causing serogroups.

Immunogenicity, Tolerability and Safety in Adolescents of Bivalent rLP2086, a Meningococcal Serogroup B Vaccine, Coadministered with Quadrivalent Human Papilloma Virus Vaccine.

BACKGROUND: This study in healthy adolescents (11 to <18 years) evaluated coadministration of quadrivalent human papillomavirus vaccine (HPV-4), with bivalent rLP2086, a meningococcal serogroup B (MnB) vaccine. METHODS: Subjects received bivalent rLP2086 + HPV-4, bivalent rLP2086 + saline or saline + HPV-4 at 0, 2 and 6 months. Immune responses to HPV-4 antigens were assessed 1 month after doses 2 and 3. Serum bactericidal assays using human complement (hSBAs) with 4 MnB test strains expressing vaccine-heterologous human complement factor H binding protein (fHBP) variants determined immune responses to bivalent rLP2086. Coprimary objectives were to demonstrate noninferior immune responses with concomitant administration compared with either vaccine alone. Additional endpoints included the proportions of subjects achieving prespecified protective hSBA titers to all 4 MnB test strains (composite response) and ≥4-fold increases in hSBA titer from baseline for each test strain after dose 3; these endpoints served as the basis of licensure of bivalent rLP2086 in the US. RESULTS: The noninferiority criteria were met for all MnB test strains and HPV antigens except HPV-18; ≥99% of subjects seroconverted for all 4 HPV antigens. Bivalent rLP2086 elicited a composite response in >80% of subjects and increased hSBA titers ≥4-fold in ≥77% of subjects for each test strain after dose 3. A substantial bactericidal response was also observed in a large proportion of subjects after dose 2. Local reactions and systemic events did not increase with concomitant administration. CONCLUSIONS: Concomitant administration of bivalent rLP2086 and HPV-4 elicits robust immune responses to both vaccines without increasing reactogenicity compared with bivalent rLP2086 alone. Concurrent administration may increase compliance with both vaccine schedules.

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.