Broad vaccine protection against Neisseria meningitidis using factor H binding protein

Abstract

Neisseria meningitidis, the causative agent of invasive meningococcal disease (IMD), is classified into different serogroups defined by their polysaccharide capsules. Meningococcal serogroups A, B, C, W, and Y are responsible for most IMD cases, with serogroup B (MenB) causing a substantial percentage of IMD cases in many regions. Vaccines using capsular polysaccharides conjugated to carrier proteins have been successfully developed for serogroups A, C, W, and Y. However, because the MenB capsular polysaccharide is poorly immunogenic, MenB vaccine development has focused on alternative antigens. The 2 currently available MenB vaccines (MenB-4C and MenB-FHbp) both include factor H binding protein (FHbp), a surface-exposed protein harboured by nearly all meningococcal isolates that is important for survival of the bacteria in human blood. MenB-4C contains a nonlipidated FHbp from subfamily B in addition to other antigens, including Neisserial Heparin Binding Antigen, Neisserial adhesin A, and outer membrane vesicles, whereas MenB-FHbp contains a lipidated FHbp from each subfamily (A and B). FHbp is highly immunogenic and a main target of bactericidal activity of antibodies elicited by both licensed MenB vaccines. FHbp is also an important vaccine component, in contrast to some other meningococcal antigens that may have limited cross-protection across strains, as FHbp-specific antibodies can provide broad cross-protection within each subfamily. Limited cross-protection between subfamilies necessitates the inclusion of FHbp variants from both subfamilies to achieve broad FHbp-based vaccine coverage. Additionally, immune responses to the lipidated form of FHbp have a superior cross-reactive profile to those elicited by the nonlipidated form. Taken together, the inclusion of lipidated FHbp variants from both FHbp subfamilies is expected to provide broad protection against the diverse disease-causing meningococcal strains expressing a wide range of FHbp sequence variants. This review describes the development of vaccines for MenB disease prevention, with a focus on the FHbp antigen.

Keywords: Factor H binding protein; Immune selection; Meningococcal serogroup B vaccine; Neisseria meningitidis.

Figure 1.

Phylogenetic tree for FHbp, adapted with permission from Ostergaard et al. N Engl J Med. 2017;377:2349–2362 [76]. The grouping of variants into subfamilies A and B [22] is indicated; an alternative classification scheme involving 3 variant groups [37] is also depicted. Coloured circles indicate FHbp antigens included in MenB-4C [11] and MenB-FHbp [12] as well as strains used to evaluate immune responses to both vaccines in clinical studies [58,75]. For MenB-4C, the indicator strain used to evaluate FHbp-mediated bactericidal immune responses expresses FHbp variant B24 and is thus homologous to the vaccine antigen for FHbp [58]. The 4 primary and 10 additional strains used to measure the immune response to MenB-FHbp express sequence-diverse FHbp variants that are different from the vaccine antigens [9,74]. The scale bar indicates phylogenetic distance using protein sequence. FHbp=factor H binding proteins; hSBA=serum bactericidal antibody assay using human complement; MenB-4C=Bexsero^®, 4CMenB; MenB-FHbp=Trumenba^®, bivalent rLP2086.

Figure 2.

Percentages of subjects with hSBA titres ≥1:4 before and after MenB-4C vaccination in infants and toddlers [52] (A) and adults (B) [54] across MenB indicator and diverse strains. In the infant/toddler study presented in panel A, infants received MenB-4C at 2, 4, 6, and 12 months of age; serum samples were taken at 2, 5, 7, 12, and 13 months of age. In the adult study presented in panel B, participants received 3 doses of MenB-4C, each spaced 1 month apart. Indicator strains 44/76-SL, NZ98/254, and 5/99 are intended to highlight responses against FHbp, PorA, and NadA, respectively [58]. Classification of the strains for each study in terms of the MenB-4C antigens is provided below the x-axis of each graph using data from the original studies, with – indicating low expression, +/− indicating medium expression, and +,++, and +++ indicating increasingly high expression. FHbp variants are indicated using the subfamily A/B classification scheme [22] as well as an alternative classification scheme involving 3 variant groups [37]. FHbp=factor H binding protein; hSBA=serum bactericidal antibody assay using human complement; MenB-4C= Bexsero^®, 4CMenB; NadA=Neisserial adhesin A; ND=not determined; NHBA=Neisserial Heparin Binding Antigen; PorA=porin A.

Figure 3.

Percentages of adolescents (A) and young adults (B) with hSBA titres ≥LLOQ against the 4 primary and 10 additional MenB test strains following vaccination with MenB-FHbp, adapted with permission from Ostergaard et al. N Engl J Med. 2017;377:2349–2362 [76]. Strains are indicated by their corresponding FHbp sequence variants using Pfizer nomenclature (http://pubmlst.org/neisseria/fHbp). The LLOQ was 1:8 or 1:16 depending on test strain. FHbp=factor H binding protein; hSBA=serum bactericidal antibody assay using human complement; LLOQ=lower limit of quantitation; MenB=meningococcal serogroup B; MenB-FHbp= Trumenba^®, bivalent rLP2086.