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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.

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

The prevention of paediatric bacterial meningitis and septicaemia has recently entered a new era with the availability of two vaccines against capsular group B meningococcus (MenB). Both of these vaccines are based on sub-capsular proteins of the meningococcus, an approach that overcomes the challenges set by the poorly immunogenic MenB polysaccharide capsule but adds complexity to predicting and measuring the impact of their use. This review describes the development and use of MenB vaccines to date, from the use of outer membrane vesicle (OMV) vaccines in MenB outbreaks around the world, to emerging evidence on the effectiveness of the newly available vaccines. While recent data from the United Kingdom supports the potential for protein-based vaccines to provide direct protection against MenB disease in immunised children, further research is required to understand the breadth and duration of this protection. A more detailed understanding of the impact of immunisation with these vaccines on nasopharyngeal carriage of the meningococcus is also required, to inform both their potential to induce herd immunity and to preferentially select for carriage of strains not susceptible to vaccine-induced antibodies. Although a full understanding of the potential impact of these vaccines will only be possible with this additional information, the availability of new tools to prevent the devastating effect of invasive MenB disease is a significant breakthrough in the fight against childhood sepsis and meningitis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives Bivalent rLP2086 (Trumenba®; MenB-FHbp), composed of two factor H binding proteins (FHbps), is a vaccine approved in the United States for prevention of Neisseria meningitidis serogroup B (MnB) invasive meningococcal disease (IMD). Bactericidal activity of sera from subjects vaccinated with bivalent rLP2086 was assessed against MnB isolates from recent disease outbreaks in France. Methods MnB isolates from IMD cases were characterized by whole genome sequencing and FHbp expression was assessed using a flow cytometry-based assay. Sera from subjects (11–<19 years old) vaccinated with bivalent rLP2086 at 0, 2, and 6 months were evaluated. Bactericidal activity was measured in serum bactericidal assays using human complement (hSBAs). The response rate (RR) represents the percentage of subjects with an hSBA titer ⩾1:4. Results The six MnB outbreak isolates expressed diverse FHbp variants: A22, B03, B24 (two isolates), B44, and B228. FHbp expression levels ranged from 1309 to 8305 (mean fluorescence intensity units). The RR of preimmune sera from subjects was 7% to 27%. RRs increased for all isolates after each vaccine dose. After two doses, RRs ranged from 40% to 93%. After dose 3, RRs were ⩾73% for all isolates (range, 73%–100%). Conclusions Each of the representative French outbreak isolates was killed by sera from subjects vaccinated with bivalent rLP2086. Vaccination elicited an immune response with bactericidal activity against these diverse isolates in a large proportion of subjects at risk. These results provide additional support for the licensure strategy of testing MnB strains expressing vaccine-heterologous FHbp variants in hSBAs and further illustrate the breadth of efficacy of this protein-based MnB vaccine. [ABSTRACT FROM AUTHOR]

Trumenba (bivalent rLP2086) is a vaccine licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B (NmB) in individuals 10-25 years of age in the USA. The vaccine is composed of two factor H binding protein (fHbp) variants that were recombinantly expressed in Escherichia coli as native lipoproteins: rLP2086-A05 and rLP2086-B01. The vaccine was shown to induce potent bactericidal antibodies against a broad range of NmB isolates expressing fHbp that were different in sequence from the fHbp vaccine antigens. Here, we describe the characterization of the vaccine antigens including the elucidation of their structure which is characterized by two distinct motifs, the polypeptide domain and the N-terminal lipid moiety. In the vaccine formulation, the lipoproteins self-associate to form micelles driven by the hydrophobicity of the lipids and limited by the size of the folded polypeptides. The micelles help to increase the structural stability of the lipoproteins in the absence of bacterial cell walls. Analysis of the lipoproteins in Toll-like receptor (TLR) activation assays revealed their TLR2 agonist activity. This activity was lost with removal of the O-linked fatty acids, similar to removal of all lipids, demonstrating that this moiety plays an adjuvant role in immune activation. The thorough understanding of the structure and function of each moiety of the lipoproteins, as well as their relationship, lays the foundation for identifying critical parameters to guide vaccine development and manufacture. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

Objective: To outline the reasoning behind use of bivalent rLP2086 in a Rhode Island college meningococcal B disease outbreak, highlighting the timeline from outbreak declaration to vaccination clinic, emphasizing that these two time points are <3 days apart. Participants: Staff, faculty, and students at College X eligible for vaccination. Methods: An outbreak response was initiated, advantages/disadvantages of available MenB vaccines were discussed, and a vaccination clinic was coordinated. Results: Bivalent rLP2086 was chosen as the vaccination intervention. We achieved a 94% coverage rate for the first dose. To date, this intervention has prevented further cases of Neisseria meningitidis serogroup B disease at College X. Conclusions: The close, efficient collaboration of public health stakeholders and College X led 94% of the eligible population to be safely vaccinated with at least one dose of bivalent rLP2086. This outbreak marked the first time bivalent rLP2086 was effectively used as an intervention response. [ABSTRACT FROM AUTHOR]

The phrase "Process is the Product" is often applied to biologics, including multicomponent vaccines composed of complex components that evade complete characterization. Vaccine production processes must be defined and locked early in the development cycle to ensure consistent quality of the vaccine throughout scale-up, clinical studies, and commercialization. This approach of front-loading the development work helped facilitate the accelerated approval of the Biologic License Application for the well-characterized vaccine bivalent rLP2086 (Trumenba®, Pfizer Inc) in 2014 under Breakthrough Therapy Designation. Bivalent rLP2086 contains two rLP2086 antigens and is licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B in individuals 10-25years of age in the United States. This paper discusses the development of the manufacturing process of the two antigens for the purpose of making it amenable to any manufacturing facility. For the journey to commercialization, the operating model used to manage this highly accelerated program led to a framework that ensured "right the first time" execution, robust process characterization, and proactive process monitoring. This framework enabled quick problem identification and proactive resolutions, resulting in a robust control strategy for the commercial process., (Copyright © 2017 Elsevier Ltd. All rights reserved.)