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bioRxiv · 10.1101/2023.05.31.543151

Progress toward the development of an effective vaccine for Extraintestinal pathogenic E. coli (ExPEC): The application of the multiple-protein subunits vaccine in different murine models

Xing, Y.·Clark, J. R.·Chang, J. D.·Zulk, J. J.·Chirman, D. M.·Piedra, F.-A.·Patras, K. A.·Maresso, A. W.
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Abstract

Extraintestinal pathogenic E. coli (ExPEC) is the primary Gram-negative bacterial pathogen, and the leading cause of life-threatening sepsis and urinary tract infections (UTI) in adults. The emergence and increasing prevalence of multidrug-resistance (MDR) ExPEC strains have led to considerable treatment failures, increased hospitalization rates, morbidity, and mortality. A prophylactic vaccine against ExPEC has the potential to reduce severe infection-related morbidity and mortality, helping to address the escalating antimicrobial resistance (AMR) crisis worldwide. The -hemolysin (HlyA) is a critical, frequently detected secreted cytotoxic virulence factor in ExPEC, with HlyA-expressing ExPEC strains correlating with increased severity and infection dissemination in clinical levels. In this study, we assessed the protective efficacy of pro-HlyA (the inactive and immature precursor of HlyA) and Dual-Hit (a combination of pro-HlyA and SinH-3, the previously reported immunoglobulin-like domain-3 of the invasin-like autotransporter protein SinH), as ExPEC vaccine candidates. We demonstrated that immunizing mice with pro-HlyA or Dual-Hit significantly reduced bacterial burden and increased survival rates against pandemic ExPEC sequence type strains, ST73 (CFT073) and ST95 (UTI89), in the model of bacteremia and mortality. Both pro-HlyA or Dual-Hit immunizations also provided significant protection against UTI89 colonization in the bladder in the murine UTI model. Furthermore, vaccination with Dual-Hit provided enduring and robust protection against a mixture of ten typical high-virulent sequence types of ExPEC strains, resulting in a promising broad-spectrum vaccine candidate. These findings suggest that pro-HlyA and Dual-Hit might serve as highly effective vaccine targets and highlight the potential of these vaccine candidates for further development and evaluation.

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Xing, Y., Clark, J. R., Chang, J. D., Zulk, J. J., Chirman, D. M., Piedra, F.-A., Patras, K. A., Maresso, A. W.. 2023-06-01. Progress toward the development of an effective vaccine for Extraintestinal pathogenic E. coli (ExPEC): The application of the multiple-protein subunits vaccine in different murine models. https://doi.org/10.1101/2023.05.31.543151

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