Abstract
Factor H-binding protein (fHbp) is an important meningococcal vaccine antigen. Native outer membrane vesicles with over-expressed fHbp (NOMV OE fHbp) have been shown to induce antibodies with broader functional activity than recombinant fHbp (rfHbp). Improved understanding of this broad coverage would facilitate rational vaccine design. We performed a pair-wise analysis of 48 surface-exposed amino acids involved in interacting with factor H, among 383 fHbp variant group 1 sequences. We generated isogenic NOMV-producing meningococcal strains from an African serogroup W isolate, each over-expressing one of four fHbp variant group 1 sequences (ID 1, 5, 9, or 74), including those most common among invasive African meningococcal isolates. Mice were immunised with each NOMV, and sera tested for IgG levels against each of the rfHbp ID and for ability to kill a panel of heterologous meningococcal isolates. At the fH-binding site, ID pairs differed by a maximum of 13 (27%) amino acids. ID 9 shared an amino acid sequence common to 83 ID types. The selected ID types differed by up to 6 amino acids, in the fH-binding site. All NOMV and rfHbp induced high IgG levels against each rfHbp. Serum killing from mice immunised with rfHbp was generally less efficient and more restricted compared to NOMV, which induced antibodies that killed most meningococci tested, with decreased stringency for ID type differences. Breadth of killing was mostly due to anti-fHbp antibodies, with some restriction according to ID type sequence differences. Nevertheless, under our experimental conditions, no relationship between antibody cross-reactivity and variation fH-binding site sequence was identified. NOMV over-expressing different fHbp IDs belonging to variant group 1 induce antibodies with fine specificities against fHbp, and ability to kill broadly meningococci expressing heterologous fHbp IDs. The work reinforces that meningococcal NOMV with OE fHbp is a promising vaccine strategy, and provides a basis for rational selection of antigen sequence types for over-expression on NOMV.
Highlights
Neisseria meningitidis is a leading cause of bacterial meningitis worldwide, and recurrent epidemics in Sub-Saharan Africa [1, 2]
On the basis of amino acid sequence, factor H-binding protein (fHbp) is classified into two sub-families (A and B) [10], or three variant groups (v.1, v.2, v.3) [5]. fHbp can be further divided into more than 1,000 subvariants, with each individual amino acid sequence distinguished by an identification number (ID); the majority of these sub-variants are included in variant group 1, which currently contains 580 IDs, while variant groups 2 and 3 have 215 IDs each
The biggest difference compared to the consensus sequence was identified among 5 fHbp IDs: ID 217 and ID 359 both had 10 amino acid differences compared to the consensus sequence; ID 120 and ID 215 had 8 aa differences compared to the consensus sequence; ID 55 had 8 aa differences, compared to the consensus sequence, with its factor H (fH)-binding sequence being one of the 41 unique IDs
Summary
Neisseria meningitidis is a leading cause of bacterial meningitis worldwide, and recurrent epidemics in Sub-Saharan Africa [1, 2]. FHbp is an outer-membrane surface-exposed lipoprotein, expressed by almost all meningococcal strains, albeit at varying levels [3,4,5,6,7]. It binds human factor H (fH), a negative regulator of the alternative pathway of the complement cascade, allowing meningococci to escape innate immunity [8, 9]. On the basis of amino acid sequence, fHbp is classified into two sub-families (A and B) [10], or three variant groups (v.1, v.2, v.3) [5]. FHbp sequence diversity within each variant group limits breadth of bactericidal activity [3, 5, 6, 10, 16, 17]
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