Background The bacterial transferrin receptor has long been considered an outstanding vaccine target against pathogenic Neisseria species as it is surface-exposed and essential for bacterial survival and virulence in vivo. Required for iron uptake from the human protein transferrin (hTf), this receptor is composed of two proteins, an integral membrane channel (transferrin binding protein A; TbpA), and a surface anchored lipoprotein (TbpB). Vaccine development has predominantly focused on TbpB as it is a soluble, stable antigen that is highly immunogenic and easy to produce in large quantities. However, TbpB is also highly variable and so achieving broad cross-protection in a vaccine has been considered challenging. In comparison, TbpA is highly conserved but the production of this integral membrane protein is technically challenging and not considered practicable for large-scale development.
Methods We performed protein structure-based engineering to remove variable unstructured surface loops on TbpB to provide a soluble, stable and immunologically cross-protective scaffold upon which surface-exposed loops of TbpA have been displayed. These chimeric immunogens have been used to immunize rabbits and mice, including ‘humanized’ transgenic mice that express human hTf. Immunological cross-reactivity against a broad panel of N. gonorrhoeae isolates and the presence of functional antibodies targeting the gonococcal transferrin receptor were monitored by ELISA, hTf-binding and growth-based analyses, and immunized mice were challenged with genital N. gonorrhoeae infection.
Results The chimeric immunogens elicit antibodies against both TbpA and TbpB. The antisera is broadly cross-reactive against the gonococcal strain panel, is bactericidal, blocks transferrin-based iron acquisition and growth, and protects mice against gonococcal infection. While wild type TbpB-based immunogens have reduced functional antibody in hTf-expressing mice, the binding-defective Tbp-based immunogens are equally efficacious in both wild type and hTf-transgenic animals.
Conclusion Our rationally-designed hybrid immunogens simultaneously target two components of an essential iron acquisition pathway, eliciting broad cross-protection against gonococcal colonization and disease.
Disclosure No significant relationships.
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