Laura J. York

A multi-country evaluation of Neisseria meningitidis serogroup B factor H-binding proteins and implications for vaccine coverage in different age groups.

Background: Recombinant vaccines containing factor H–binding protein (fHBP) have been developed for the purpose of protection from invasive meningococcal serogroup B disease. Neisseria meningitidis fHBP sequences can be divided into 2 genetically and immunologically distinct subfamilies (A and B); thus, cross protection is conferred within but not between subfamilies. A comprehensive understanding of fHBP epidemiology is required to accurately assess the potential vaccine impact when considering different vaccination implementation strategies. Methods: Systematically collected invasive meningococcal serogroup B isolates from England, Wales, Northern Ireland, the United States, Norway, France and the Czech Republic were previously characterized for fHBP sequence. This study expanded the evaluation with additional meningococcal serogroup B disease isolates from Spain (n = 346) and Germany (n = 205). This expanded set (n = 1841), collected over a 6-year period (2001 to 2006), was evaluated for fHBP sequence and fHBP subfamily relative to patient age. Results: All 1841 isolates contained fhbp. fHBP sequences from Spain and Germany fell within the previously described subfamilies, with 69% of isolates belonging to subfamily B and 31% to subfamily A; prevalent sequence variants were also similar. Stratification of data by age indicated that disease in infants <1 year of age was caused by a significantly higher proportion of isolates with fHBP subfamily A variants than that seen in adolescents and young adults 11–25 years (47.7% versus 19.5%, P < 0.0001, respectively). Conclusions: These observations highlight a difference in epidemiology of fHBP subfamilies in different age groups, with fHBP subfamily A strains causing more disease in vulnerable populations, such as infants, than in adolescents.

Potential impact of the bivalent rLP2806 vaccine on Neisseria meningitidis carriage and invasive serogroup B disease.

Asymptomatic throat carriage of Neisseria meningitidis is common in healthy individuals. In unusual cases, the bacteria become invasive, resulting in life-threatening disease. Effective meningococcal serogroup B (MnB) vaccines should provide broad protection against disease-causing strains and may confer indirect protection by impacting carriage and subsequent transmission. Factor H binding proteins (fHBPs), components of MnB vaccines in development, are classified into two immunologically distinct subfamilies (A and B). fHBP variants of MnB strains carried by adolescents are similar to those detected in infants with MnB disease. A vaccine containing subfamily A and B fHBP variants elicited bactericidal antibody responses (titers ≥ 1:4) against MnB strains expressing fHBP variants common to carriage strains and strains that cause disease in adolescents and infants in 75–100% of adolescent study subjects. This suggests that the bivalent fHBP vaccine has the potential to provide protection against invasive MnB strains and interrupt meningococcal carriage, which may also reduce infant MnB disease.

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.

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

ABSTRACT 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.

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

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.

Immunogenicity, safety, and tolerability of the meningococcal serogroup B bivalent rLP2086 vaccine in adult laboratory workers.

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.

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.

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

ABSTRACT 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.