Recombinant Neisseria meningitidis Transferrin Binding Protein A Protects against Experimental Meningococcal Infection

Abstract

To better characterize the vaccine potential of Neisseria meningitidis transferrin binding proteins (Tbps), we have overexpressed TbpA and TbpB from Neisseria meningitidis isolate K454 in Escherichia coli. The ability to bind human transferrin was retained by both recombinant proteins, enabling purification by affinity chromotography. The recombinant Tbps were evaluated individually and in combination in a mouse intraperitoneal-infection model to determine their ability to protect against meningococcal infection and to induce cross-reactive and bactericidal antibodies. For the first time, TbpA was found to afford protection against meningococcal challenge when administered as the sole immunogen. In contrast to the protection conferred by TbpB, this protection extended to a serogroup C isolate and strain B16B6, a serogroup B isolate with a lowermolecular-weight TbpB than that from strain K454. However, serum from a TbpB-immunized rabbit was found to be significantly more bactericidal than that from a TbpA-immunized animal. Our evidence demonstrates that TbpA used as a vaccine antigen may provide protection against a wider range of meningococcal strains than does TbpB alone. This protection appears not to be due to complement-mediated lysis and indicates that serum bactericidal activity may not always be the most appropriate predictor of efficacy for protein-based meningococcal vaccines.

A Universal Vaccine for Serogroup B Meningococcus

“…The presence of BCA was tested in sera obtained by immunizing mice with each of the antigens formulated with aluminum hydroxide or FCA (Table 1). With the exception of GNA2091, which, although unable to induce BCA, had been selected for its ability to induce protection in the mouse protection assay (19,20) (data not shown), each of the other individual antigens induced BCA against one or more of the three strains. The proteins GNA2132, GNA1030, and GNA1870 induced better titers when formulated with FCA than when formulated with aluminum.…”

“…The antigens selected by reverse vaccinology were prioritized based on their ability to induce broad protection as inferred by BCA or observed in passive protection in the infant rat or mouse protection assays (19,20). The three top antigens that met the prioritization criteria were GNA2132 (21), GNA1870 (16,22,23), and NadA (17,24).…”

Gonococcal transferrin binding protein chimeras induce bactericidal and growth inhibitory antibodies in mice

“…Vaccine studies using meningococcal Tbps have demonstrated elicitation of antibodies that are cross-reactive against heterologous strains, are bactericidal, and can block transferrin utilization [14][15][16][17]. Furthermore, in a meningococcal mouse model, mice immunized with TbpA or TbpA and TbpB were completely protected from lethal challenge [16]. These studies suggest that the neisserial transferrin binding proteins could serve as protective antigens to prevent neisserial diseases.…”

“…The transferrin binding proteins fit these criteria [12,13]. Vaccine studies using meningococcal Tbps have demonstrated elicitation of antibodies that are cross-reactive against heterologous strains, are bactericidal, and can block transferrin utilization [14][15][16][17]. Furthermore, in a meningococcal mouse model, mice immunized with TbpA or TbpA and TbpB were completely protected from lethal challenge [16].…”

Oral administration of recombinantNeisseria meningitidisPorA genetically fused toH. pyloriHpaA antigen increases antibody levels in mouse serum, suggesting that PorA behaves as a putative adjuvant

“…12,50 Until now, several proteins from the outer membrane of meningococcal B have been tested using different vaccine strategies. Among these proteins, PorA, 28,34,39,[50][51][52] NspA, 53 Transferrin-binding proteins, 54,55 LP 2086, 56 GNA 1870, 15 GNA 2132 57 and NadA 58 are the most studied.…”