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Intranasal Administration of Recombinant Neisseria gonorrhoeae Transferrin Binding Proteins A and B Conjugated to the Cholera Toxin B Subunit Induces Systemic and Vaginal Antibodies in Mice

Department of Microbiology and Immunology, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia 23298-0678, USA.
Infection and Immunity (Impact Factor: 4.16). 08/2005; 73(7):3945-53. DOI: 10.1128/IAI.73.7.3945-3953.2005
Source: PubMed

ABSTRACT The transferrin binding proteins (TbpA and TbpB) comprise the gonococcal transferrin receptor and are considered potential antigens for inclusion in a vaccine against Neisseria gonorrhoeae. Intranasal (IN) immunization has shown promise in development of immunity against sexually transmitted disease pathogens, in part due to the induction of antigen-specific genital tract immunoglobulin A (IgA) and IgG. Conjugation of antigens to the highly immunogenic cholera toxin B subunit (Ctb) enhances antibody responses in the serum and mucosal secretions following IN vaccination. In the current study, we characterized the anti-Tbp immune responses following immunization of mice IN with recombinant transferrin binding proteins (rTbpA and rTbpB) conjugated to rCtb. We found that both rTbpA-Ctb and rTbpB-Ctb conjugates administered IN induced antibody responses in the serum and genital tract. IN immunization resulted in both IgA and IgG in the genital tract; however, subcutaneous immunization mainly generated IgG. Surprisingly, rTbpA alone was immunogenic and induced serum and mucosal antibody responses similar to those elicited against the rTbpA-Ctb conjugate. Overall, rTbpB was much more immunogenic than rTbpA, generating serum IgG levels that were greater than those elicited against rTbpA. Bactericidal assays conducted with sera collected from mice immunized IN with TbpA and/or TbpB indicated that both antigens generated antibodies with bactericidal activity. Anti-TbpA antibodies were cross-bactericidal against heterologous gonococcal strains, whereas TbpB-specific antibodies were less cross-reactive. By contrast, antibodies elicited via subcutaneous immunization were not cross-bactericidal against heterologous strains, indicating that IN vaccination could be the preferred route for elicitation of biologically functional antibodies.

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    • "Antigenic and sequence variability of TbpB proteins is more extensive (Cornelissen et al., 1997a), but neither protein is subject to high-frequency phase or antigenic variation, as is the case with many other neisserial surface antigens . Both transferrin binding proteins are antigenic when animals are immunized with the purified proteins (Price et al., 2005; 2007); however, natural gonococcal infections , which do not elicit protective immunity, also do not generate high titre anti-Tbp antibodies (Price et al., 2004). Meningococcal transferrin binding proteins are immunogenic in both animals (Rokbi et al., 1997) and humans (Gorringe et al., 1995), which is consistent with the hypothesis that gonococci are capable of immune suppression during infection (Liu et al., 2011). "
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    ABSTRACT: Two pathogenic species within the genus Neisseria cause the diseases gonorrhoea and meningitis. While vaccines are available to protect against four N. meningitidis serogroups, there is currently no commercial vaccine to protect against serogroup B or against N. gonorrhoeae. Moreover, the available vaccines have significant limitations and with antibiotic resistance becoming an alarming issue, the search for effective vaccine targets to elicit long-lasting protection against Neisseria species is becoming more urgent. One strategy for vaccine development has targeted the neisserial iron import systems. Without iron, the Neisseriae cannot survive and, therefore, these iron import systems tend to be relatively well conserved and are promising vaccine targets, having the potential to offer broad protection against both gonococcal and meningococcal infections. These efforts have been boosted by recent reports of the crystal structures of the neisserial receptor proteins TbpA and TbpB, each solved in complex with human transferrin, an iron binding protein normally responsible for delivering iron to human cells. Here, we review the recent structural reports and put them into perspective with available functional studies in order to derive the mechanism(s) for how the pathogenic Neisseriae are able to hijack human iron transport systems for their own survival and pathogenesis.
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    • "Identification of membrane associated candidate drug targets The surface localized Phospholipase-A (PldA) (Bos et al., 2005) and Transferrin-binding proteins (TbpA and TbpB) (Thomas et al., 2006; Price et al., 2005) are identified as candidate drug targets against N. gonorrhoeae. However, till date no effective drug is available. "
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    • "Purified chimeras were bound to G M1 ganglioside in an ELISA format and complexes with binding competent Ctb pentamers were confirmed to contain NB and L2 with specific antibodies [19] "
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    ABSTRACT: We have previously demonstrated the full-length gonococcal transferrin binding proteins (TbpA and TbpB) to be promising antigens in the development of a protective vaccine against Neisseria gonorrhoeae. In the current study we employed a genetic chimera approach fusing domains from TbpA and TbpB to the A2 domain of cholera toxin, which naturally binds in a non-covalent fashion to the B subunit of cholera toxin during assembly. For one construct, the N-terminal half of TbpB (NB) was fused to the A2 subunit of cholera toxin. In a second construct, the loop 2 region (L2) of TbpA was genetically fused between the NB domain and the A2 domain, generating a double chimera. Both chimeras were immunogenic and induced serum bactericidal and vaginal growth-inhibiting antibodies. This study highlights the potential of using protective epitopes instead of full-length proteins in the development of an efficacious gonococcal vaccine.
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