Hybrid antigens expressing surface loops of BauA from Acinetobacter baumannii are capable of inducing protection against infection

Abstract

Acinetobacter baumannii is a human bacterial pathogen of increasing concern in clinical settings due to the emergence of antibiotic resistant strains and the lack of effective therapeutics. Researchers have been exploring new treatment options such as novel drug candidates and vaccines to prevent severe infections and mortality. Bacterial surface antigens that are essential to A. baumannii for acquiring micronutrients (e.g. iron, zinc) from nutrient restricted environments are being considered as targets for vaccines or immunotherapy due to their crucial role for growth and pathogenesis in the human host. BauA, the outer membrane receptor for the siderophore acinetobactin was targeted for vaccine development in this study. Due to challenges in the commercial production of membrane proteins for vaccines, a novel hybrid antigen method developed by our group was used. Exposed loops of BauA were selected and displayed on a foreign scaffold to generate novel hybrid antigens designed to elicit an immune response against the native BauA protein. The potential epitopes were incorporated into a scaffold derived from the C-lobe of Neisseria meningitidis transferrin binding protein B (TbpB), named the loopless C-lobe (LCL). Hybrid proteins displaying three selected loops (5, 7 and 8) individually or in combination were designed and produced and evaluated in an A. baumannii murine sepsis model as vaccine antigens. Immunization with the recombinant BauA protein protected 100% of the mice while immunization with hybrid antigens displaying individual loops achieved between 50 and 100% protection. The LCL scaffold did not induce a protective immune response, enabling us to attribute the observed protection elicited by the hybrid antigens to the displayed loops. Notably, the mice immunized with the hybrid antigen displaying loop 7 were completely protected from infection. Taken together, these results suggest that our hybrid antigen approach is a viable method for generating novel vaccine antigens that target membrane surface proteins necessary for bacterial growth and pathogenesis and the loop 7 hybrid antigen can be a foundation for approaches to combat A. baumannii infections.

A subtractive proteomics approach for the identification of immunodominant Acinetobacter baumannii vaccine candidate proteins

“…The rest of the unconsidered proteins may still be revisited for their potential to be a vaccine candidate. In a recent study, A. baumannii BauA protein was fused to C-lobe of Neisseria meningitidis transferrin binding protein B (TbpB) and elicited between 50% and 100% protection in mice ( 18 ). Novel hybrid and chimeric antigen technologies could be applicable for those disregarded proteins due to their low solubility.…”

“…A. baumannii ATCC ® BAA-1710™ is resistant to cefazolin, cefepime, cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, levofloxacin, piperacillin, piperacillin-tazobactam, ticarcillin, tetracycline, and trimethoprim-sulfamethoxazole, and this strain is susceptible to ampicillin-sulbactam, doripenem, imipenem, meropenem, and tigecycline ( ). A. baumannii ATCC ® 17978™ is susceptible strain that is preferred as reference strain in similar studies ( ) ( 17 , 18 ).…”

Subunit vaccines for Acinetobacter baumannii

“…Immunizing mice with hybrid antigens resulted in rather high antigen titers. BauA can provide complete protection against A. baumannii and is a promising candidate subunit vaccine ( 39 ).…”

Non-antibiotic prevention and treatment against Acinetobacter baumannii infection: Are vaccines and adjuvants effective strategies?

“…Similarly, exposed loops (Mirzaei et al, 2020 ; Vrancianu et al, 2020 ; Alamneh et al, 2022 ) of the outer membrane receptor BauA displayed on LCL, among them, loop 7 hybrid antigen and recombinant BauA completely protected mice from infection, and the virtual absence of colonies in lungs, spleen, and liver. BauA loop 7 was as effective as immunization with recombinant BauA (Chaudhuri et al, 2022 ). This analogous operation is also applied to Omp34 in the latest study, the superior protection of Omp34 loop 3 also proves the hybrid antigen strategy is a viable method (Golestani et al, 2022 ).…”