9q07 | pdb_00009q07
Structure-based design of a nutrient acquisition protein enhances neutralizing antibodies and protection for the development of a gonococcal vaccine
Structural highlights
Publication Abstract from PubMedGonorrhea is increasingly resistant to treatment and has been labelled an urgent threat due to the diminishing effectiveness of existing therapeutics. To address this challenge, we targeted the Neisseria gonorrhoeae transferrin binding protein B (TbpB), which is critical for iron acquisition and neisserial growth, as a vaccine target. Building on previous studies investigating the application of TbpB as an immunogen against various bacterial pathogens, we aimed to optimize this antigen for a broad protective effect. We compared the efficacy of wild type TbpB immunogens with engineered TbpB mutants that do not bind human transferrin (hTf) using infection studies in transgenic mice expressing hTf, which were required because the strict specificity of neisserial TbpB precludes its complexing with non-human transferrin. Comprehensive biophysical analyses confirmed that the introduced single residue mutations abolished hTf binding without compromising antigen structure. Immunization with the mutant antigens conferred increased resistance to infection by N. gonorrhoeae relative to that provided by the wild-type antigen in the humanized mice. When considering effector functions of the humoral response, we observed that the mutated antigen elicited more effective bactericidal and function-neutralizing activity. Through strategic mutations, we therefore enhanced vaccine effectiveness in a physiologically relevant model without significantly affecting the structure or immunogenicity of the antigen. This study highlights the use of rational structure-guided antigen design to drive effective immune responses and the potential interference of immunogen binding to host factors, and reinforces the utility of targeting TbpB in a gonococcal vaccine. Structure-based engineering of a nutrient acquisition protein enhances neutralizing antibodies and protection for the development of a gonococcal vaccine.,Au NYT, Zhong EZL, Fegan JE, Islam EA, Xu SX, Ng D, Shah M, Caruso LL, Lai CCL, Schryvers AB, Gray-Owen SD, Moraes TF bioRxiv [Preprint]. 2025 Nov 8:2025.11.06.685839. doi: 10.1101/2025.11.06.685839. PMID:41279537[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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