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

Timo Vesikari, Lars Østergaard, Javier Diez-Domingo, Jacek Wysocki, Carl-Erik Flodmark, Johannes Beeslaar, Joseph Eiden, Qin Jiang, Kathrin U Jansen, Thomas R Jones, Shannon L Harris, Robert E O'Neill, Laura J York, Graham Crowther, John L Perez, Timo Vesikari, Lars Østergaard, Javier Diez-Domingo, Jacek Wysocki, Carl-Erik Flodmark, Johannes Beeslaar, Joseph Eiden, Qin Jiang, Kathrin U Jansen, Thomas R Jones, Shannon L Harris, Robert E O'Neill, Laura J York, Graham Crowther, John L Perez

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01299480.

Keywords: Neisseria meningitidis serogroup B; bivalent rLP2086; clinical trial; functional immunogenicity; safety.

© The Author 2015. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society.

Figures

Figure 1.
Figure 1.
Subject disposition. *Values in this row used as denominators for percentages.
Figure 2.
Figure 2.
Percentage of subjects with hSBA titers ≥1:8 against N meningitidis serogroup B test strains A22, A56, B24, and B44 at baseline and 1 month after injection with bivalent rLP2086 or saline. Errors shown are 95% confidence intervals. hSBA, human serum bactericidal antibody assay using human complement.
Figure 3.
Figure 3.
Geometric mean titers (GMTs) against N meningitidis serogroup B test strains A22, A56, B24, and B44 at baseline and 1 month after injection with bivalent rLP2086 or saline.
Figure 4.
Figure 4.
Local injection-site reactogenicity (recorded by electronic diary [e-diary]). Data have been aggregated across groups to show reactogenicity after each dose.
Figure 5.
Figure 5.
Systemic reactogenicity (recorded by electronic diary [e-diary]). Data have been aggregated across groups to show reactogenicity after each dose. *Fever: 38.0–38.4°C = mild; 38.5–38.9°C = moderate; and ≥39°C = severe.

References

    1. EU-IBIS Network. Invasive Neisseria meningitidis in Europe 2006. Available at: Accessed 27 March 2015.
    1. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (Abcs) Report, Emerging Infections Program Network, Neisseria meningitidis, 2011. Available at: Accessed 19 August 2014.
    1. Finne J, Leinonen M, Makela PH. Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet 1983; 2:355–7.
    1. Tappero JW, Lagos R, Ballesteros AM et al. . Immunogenicity of 2 serogroup B outer-membrane protein meningococcal vaccines: a randomized controlled trial in Chile. JAMA 1999; 281:1520–7.
    1. Holst J, Feiring B, Naess LM et al. . The concept of “tailor-made”, protein-based, outer membrane vesicle vaccines against meningococcal disease. Vaccine 2005; 23:2202–5.
    1. Martin DR, Ruijne N, McCallum L et al. . The VR2 epitope on the PorA P1.7-2,4 protein is the major target for the immune response elicited by the strain-specific group B meningococcal vaccine MeNZB. Clin Vaccine Immunol 2006; 13:486–91.
    1. Bexsero. Health Canada. Available at: Accessed 19 August 2014.
    1. European Medicines Agency. Bexsero. Available at: Accessed 5 November 2014.
    1. Australian Government Department of Health. Australian Public Assessment Report for Multi-Component Meningococcal B vaccine. Available at: Accessed 19 August 2014.
    1. Bexsero Full Prescribing Information. Cambridge, MA: Novartis Vaccines and Diagnostics, Inc; 2015.
    1. US Food and Drug Administration. First vaccine approved by FDA to prevent serogroup B meningococcal disease. Available at: Accessed 29 October 2014.
    1. Fletcher LD, Bernfield L, Barniak V et al. . Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect Immun 2004; 72:2088–100.
    1. Madico G, Welsch JA, Lewis LA et al. . The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J Immunol 2006; 177:501–10.
    1. Murphy E, Andrew L, Lee KL et al. . Sequence diversity of the factor H binding protein vaccine candidate in epidemiologically relevant strains of serogroup B Neisseria meningitidis. J Infect Dis 2009; 200:379–89.
    1. Lucidarme J, Tan L, Exley RM et al. . Characterization of Neisseria meningitidis isolates that do not express the virulence factor and vaccine antigen factor H binding protein. Clin Vaccine Immunol 2011; 18:1002–14.
    1. Jiang HQ, Hoiseth SK, Harris SL et al. . Broad vaccine coverage predicted for a bivalent recombinant factor H binding protein based vaccine to prevent serogroup B meningococcal disease. Vaccine 2010; 28:6086–93.
    1. Nissen MD, Marshall HS, Richmond PC et al. . A randomized, controlled, phase 1/2 trial of a Neisseria meningitidis serogroup B bivalent rLP2086 vaccine in healthy children and adolescents. Pediatr Infect Dis J 2012; 32:364–71.
    1. Richmond PC, Marshall HS, Nissen MD et al. . Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 2012; 12:597–607.
    1. Richmond PC, Nissen MD, Marshall HS et al. . A bivalent Neisseria meningitidis recombinant lipidated factor H binding protein vaccine in young adults: results of a randomised, controlled, dose-escalation phase 1 trial. Vaccine 2012; 30:6163–74.
    1. Zlotnick GW, Jones TR, Liberator P et al. . The discovery and development of a novel vaccine to protect against Neisseria meningitidis serogroup B disease. Hum Vaccin Immunother 2015; 11:5–13.
    1. Borrow R, Balmer P, Miller E. Meningococcal surrogates of protection–serum bactericidal antibody activity. Vaccine 2005; 23:2222–7.
    1. Frasch CE, Borrow R, Donnelly J. Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease. Vaccine 2009; 27(Suppl 2):B112–6.
    1. World Medical Association General Assembly. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Available at: Accessed 13 August 2014.
    1. International Conference on Harmonisation. ICH topic E6 guideline for good clinical practice. In: Step 5, consolidated guideline. Available at: Accessed 13 August 2014.
    1. McNeil LK, Murphy E, Zhao XJ et al. . Detection of LP2086 on the cell surface of Neisseria meningitidis and its accessibility in the presence of serogroup B capsular polysaccharide. Vaccine 2009; 27:3417–21.
    1. Cohn AC, MacNeil JR, Clark TA et al. . Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013; 62:1–28.
    1. Jafri RZ, Ali A, Messonnier NE et al. . Global epidemiology of invasive meningococcal disease. Popul Health Metr 2013; 11:17.
    1. Princeton University. Emergency Guidelines for Campus Community: Meningitis Information. Princeton, NJ, 2013.
    1. Santa Barbara County Public Health Department. 4th Confirmed Case of Meningococcal Disease in Santa Barbara County. Available at: Accessed 22 January 2014.
    1. Zimmerman RK, Nowalk MP, Lin CJ et al. . Randomized trial of an alternate human papillomavirus vaccine administration schedule in college-aged women. J Womens Health (Larchmt) 2010; 19:1441–7.
    1. Lin CJ, Zimmerman RK, Nowalk MP et al. . Randomized controlled trial of two dosing schedules for human papillomavirus vaccination among college age males. Vaccine 2014; 32:693–9.
    1. Marshall HS, Richmond PC, Nissen MD et al. . A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults. Vaccine 2013; 31:1569–75.
    1. Sheldon E, Schwartz H, Jiang Q et al. . A phase 1, randomized, open-label, active-controlled trial to assess the safety of a meningococcal serogroup B bivalent rLP2086 vaccine in healthy adults. Hum Vaccin Immunother 2012; 8:888–95.

Source: PubMed

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