Table 1.

Relevant publications concerning the 4CMenB vaccine antigens

Antigen	Content - main message	Reference
fHbp
Function
	Discovery of GNA1870. Identification of the three genetic and immunogenic variants of GNA1870.	[44]
	GNA1870 is the fH binding protein of N. meningitidis	[50]
	Characterization of fHbp deletion mutants: they were sensitive to killing in ex vivo human whole blood and serum models of meningococcal bacteremia with respect to the isogenic wild-type strains.	[51]
	fHbp binds only human fH suggesting that N. meningitidis evolved to survive and grow only in human blood and explaining why this pathogen is strictly human specific.	[57]
	fHbp is regulated by oxygen limitation in a FNR-dependent manner.	[60]
Immunogenicity
	Characterization of 12 fHbp subvariants for their level of surface exposure and ability to bind fH, to mediate serum resistance, and to induce bactericidal antibodies.	[69]
	Evaluation of the contribution of amino acid sequence variability of fHbp to the strain coverage of sub-variants 1.	[59]
	Identification of the fHbp protein region containing bactericidal epitopes.	[64]
	The ability of fHbp vaccines to elicit protective antibodies, can be enhanced if the antibody repertoire is of high avidity and includes fH-blocking activity.	[67]
	N. meningitidis strains can cause invasive disease even if they do not express fHbp.	[62]
Structure
	Structure determination by NMR spectroscopy and functional epitope mapping of the full-length fHbp.	[53, 112]
	Crystal structure of mature fHbp determined at 2 Å resolution.	[54]
	The crystal structure of the complex between human fH and fHbp of N. meningitidis. fHbp mimics host cell carbohydrates in binding fH.	[55]
	Rational designed of a chimeric fHbp able to induce cross-protective bactericidal antibodies against the three variants.	[56]
NHBA
Function
	The application of the reverse vaccinology approach identify the GNA2132 as a surface- exposed lipoprotein able to induce bactericidal antibodies in mice.	[42]
	NHBA antigen induces protective immunity in humans and it is recognized by sera of patients after meningococcal disease. The protein binds heparin in vitro through an Arg-rich region and this property correlates with increased survival of the unencapsulated bacterium in human serum.	[74]
Immunogenicity
	NHBA antiserum passively protected infant rats against meningococcal bacteremia after challenge with different meningococcus strains.	[65]
	Cooperative serum bactericidal activity exists between human Ab against antigens fHbp and NHBA.	[70]
Structure
	Structure of NHBA C-terminal domain solved by NMR spectroscopy; it consists of an eight strands β-barrel that closely resembles to the C-terminal domains of other surface-exposed lipoproteins (e.g. fHbp and TbpB).	[81]
NadA
Function
	Characterization of NadA as antigen able to induce bactericidal antibodies and protective immunity in the infant rat model.	[90]
	NadA is an adhesin and invasin of N. meningitidis.	[94]
	NadA expressed in a noninvasive Yersinia enterocolitica mutant strain binds β-1 integrin	[95]
	NadA expression is regulated by the NadR repressor, and may be induced during colonization of the oropharynx by the 4-hydroxyphenylacetic acid, a metabolite of aromatic amino acid catabolism that is secreted in saliva..	[102]
	NadA interacts with human Heat Shock Protein 90 (Hsp90) interfering with the adhesion and invasion process mediated by NadA.	[96]
Immunogenicity
	Presence and conservation of NadA in carrier isolates of MenB.	[99]
	NadA is recognized by serum antibodies of young children convalescing after meningococcal disease.	[100]