The new multicomponent vaccine against meningococcal serogroup B, 4CMenB: immunological, functional and structural characterization of the antigens

Abstract

Neisseria meningitidis is a major cause of endemic cases and epidemics of meningitis and devastating septicemia. Although effective vaccines exist for several serogroups of pathogenic N. meningitidis, conventional vaccinology approaches have failed to provide a universal solution for serogroup B (MenB) which consequently remains an important burden of disease worldwide. The advent of whole-genome sequencing changed the approach to vaccine development, enabling the identification of potential vaccine candidates starting directly with the genomic information, with a process named reverse vaccinology. The application of reverse vaccinology to MenB allowed the identification of new protein antigens able to induce bactericidal antibodies. Three highly immunogenic antigens (fHbp, NadA and NHBA) were combined with outer membrane vesicles and formulated for human use in a multicomponent vaccine, named 4CMenB. This is the first MenB vaccine based on recombinant proteins able to elicit a robust bactericidal immune response in adults, adolescents and infants against a broad range of serogroup B isolates. This review describes the successful story of the development of the 4CMenB vaccine, with particular emphasis on the functional, immunological and structural characterization of the protein antigens included in the vaccine.

Figure 1. Schematic representation of the 4CMenB vaccine antigens on the surface of N. meningitidis

The different bacterial compartments (outer membrane, periplasmic space, cytoplasmic membrane) and the main antigens identified through reverse vaccinology approach (NHBA, fHbp and NadA) are depicted. The representation of NHBA and fHbp in the picture is derived from the NMR structural data available and reported as cartoon. NadA is a model based on the structural homology with other members of the Oca family. Other components of the meningococcal membranes are also shown (pilus, polysaccharide capsule, lipooligosaccharide and integral inner and outer membrane proteins).

Figure 2. Structures of fHbp

The currently known structures of the factor H binding protein (fHbp) from N. meningitidis serogroup B all share the same overall fold: two beta-barrel domains (one domain N-terminal and the other C-terminal, as indicated) connected by a short linker (arrowed), evident in panels A-C.(A) The NMR solution structure of a variant 1 fHbp from strain MC58 (PDB entry 2KC0) and (B) the crystal structure of an engineered form of fHbp variant 1 (strain MC58) containing 22 point mutations (PDB entry 2Y7S); the crystal structure of fHbp variant 1 has also been determined in complex with domains 6 and 7 of human Factor H (PDB entry 2W80): panel (C) shows the fHbp alone, panel (D) shows the same orientation of fHbp as a surface representation (dark green) with bound Factor H domains 6 (orange) and 7(yellow) shown as ribbons.

Figure 3. NHBA and structurally similar proteins

(A) The structure of the conserved C-terminal region of NHBA (GNA2132) (PDB code 2LFU) from N. meningitidis serogroup B strain 2996, determined by NMR spectroscopy. The NHBA C-terminal domain structure (A) is architecturally related to the beta-barrel domains (shown as coloured regions) in the transferrin-binding protein B (TbpB) from Actinobacillus pleuropneumoniae (B)(PDB code 3PQS) and in fHbp (blue) C).