ArticlesImmunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study
Introduction
Epidemic and sporadic Neisseria meningitidis disease caused by six major serogroups, A, B, C, W-135, Y, and the recently emerging X, causes substantial morbidity and mortality in otherwise healthy people, with large variations in global epidemiology.1 Initially, vaccines against serogroups A, C, W135, and Y were developed on the basis of serogroup-specific capsular polysaccharides; vaccines were subsequently improved with the development of polysaccharide-protein conjugates.2, 3 Quadrivalent (A,C,W-135,Y) meningococcal glycoconjugate vaccines for all age groups are now licensed or in late-stage development.4, 5 Following successful implementation of routine childhood vaccination with serogroup C meningococcal conjugate vaccines, serogroup B is now the most serious cause of meningococcal disease in Europe and elsewhere, with a substantial medical burden.6 In the UK, for example, up to 19% of laboratory-confirmed cases of invasive serogroup B disease between 1999 and 2006 were fatal.7 In North America, prevalence of serogroups B, C, and Y is almost equal,1 and serogroup B is the most prevalent in the southern cone of Latin America; over 60% of meningococcal-disease cases in Chile are caused by serogroup B.8
The capsular-polysaccharide strategy cannot be applied to the development of a serogroup B vaccine, because serogroup B polysaccharide immunologically resembles the surface of neural-cell adhesion molecules, resulting in poor immunogenicity and the potential for induction of autoimmune antibodies.9, 10, 11 Vaccines successfully developed to combat epidemic outbreaks of serogroup B meningococcal disease used outer membrane vesicles from the local outbreak strains to induce immune responses.1, 12 Since effectiveness was limited to the clonal outbreak strains, these vaccines do not provide a solution to endemic meningococcal B disease caused by heterologous meningococcal strains worldwide.12, 13
To develop broadly protective vaccines against serogroup B, whole genome sequencing was used to identify proteins on the surface of many meningococcal strains.14 In-vitro and in-vivo assessment of targets for bactericidal activity and large-scale production identified three protein components for vaccine development: factor H binding protein, neisserial adhesin A, and neisseria heparin binding antigen.15, 16 Neisseria heparin binding antigen and factor H binding protein components were each presented as fusion proteins with other proteins identified from genome mining.17 A formulation of these components in an investigational serogroup B meningococcal vaccine with outer membrane vesicles from the New Zealand outbreak strain 98/254 (4CMenB) yielded promising results in feasibility studies in infants and adults.17, 18, 19 We report the results of the first large-scale trial of 4CMenB, in adolescents, the aim of which was to assess the immunogenicity and tolerability of 4CMenB in different schedules.
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Study design and participants
We did a phase 2b/3 randomised, observer-blind, placebo-controlled study at 12 sites in Santiago and Valparaíso, Chile, following good clinical practice and the principles outlined in the Declaration of Helsinki. Ethical committee approval was obtained from Comité de Ética en Investigación en Seres Humanos (Facultad de Medicina, Universidad de Chile, Chile), Comité de Ética de la Investigación del Servicio de Salud (Metropolitano Norte, Santiago, Chile), Comité de Ética Científico Pediátrico,
Results
Between June, 2008, and December, 2010, 1631 adolescents were enrolled, of which 1378 (84%) completed assessments after the primary doses (table 1, figure 1). At 6 months 1431 (88%) adolescents continued their participation, of whom 456 received a dose of 4CMenB and 975 received a placebo injection. 367 (80%) of those who received a dose of 4CMenB and 794 (81%) of those who received a placebo injection had sera analysed at 7 months. Drop-outs occurred at similar rates in all groups throughout
Discussion
In adolescents given 4CMenB vaccine, protective hSBA titres against three meningococcal serogroup B strains developed in over 90% of participants after one dose, increasing to 99–100% when two doses were administered at 1 month, 2 month, or 6 month intervals (panel). A third dose of 4CMenB provided no additional immunological benefit. Reactogenicity did not increase with subsequent doses of 4CMenB, rather it declined slightly, which together with the low drop-out rates show overall good
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Collaborators listed at end of paper