Progress toward a vaccine for extraintestinal pathogenic E. coli (ExPEC) II: efficacy of a toxin-autotransporter dual antigen approach

• Published in: Infection and immunity Vol. 92; no. 5; p. e0044023
• Main Authors: Xing, Yikun, Clark, Justin R, Chang, James D, Zulk, Jacob J, Chirman, Dylan M, Piedra, Felipe-Andres, Vaughan, Ellen E, Hernandez Santos, Haroldo J, Patras, Kathryn A, Maresso, Anthony W
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 07-05-2024
• Subjects: Animals; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Bacteriology; Disease Models, Animal; Escherichia coli Infections - immunology; Escherichia coli Infections - microbiology; Escherichia coli Infections - prevention & control; Escherichia coli Proteins - genetics; Escherichia coli Proteins - immunology; Escherichia coli Vaccines - immunology; Extraintestinal Pathogenic Escherichia coli - genetics; Extraintestinal Pathogenic Escherichia coli - immunology; Female; Hemolysin Proteins - genetics; Hemolysin Proteins - immunology; Humans; Mice; Microbial Immunity and Vaccines; Type V Secretion Systems - genetics; Type V Secretion Systems - immunology; Virulence Factors - genetics; Virulence Factors - immunology; vaccines; sepsis; ExPEC
• ISSN: 0019-9567; 1098-5522; 1098-5522
• DOI: 10.1128/iai.00440-23

Extraintestinal pathogenic
(ExPEC) is a leading cause of worldwide morbidity and mortality, the top cause of antimicrobial-resistant (AMR) infections, and the most frequent cause of life-threatening sepsis and urinary tract infections (UTI) in adults. The development of an effective and universal vaccine is complicated by this pathogen's pan-genome, its ability to mix and match virulence factors and AMR genes via horizontal gene transfer, an inability to decipher commensal from pathogens, and its intimate association and co-evolution with mammals. Using a pan virulome analysis of >20,000 sequenced
strains, we identified the secreted cytolysin α-hemolysin (HlyA) as a high priority target for vaccine exploration studies. We demonstrate that a catalytically inactive pure form of HlyA, expressed in an autologous host using its own secretion system, is highly immunogenic in a murine host, protects against several forms of ExPEC infection (including lethal bacteremia), and significantly lowers bacterial burdens in multiple organ systems. Interestingly, the combination of a previously reported autotransporter (SinH) with HlyA was notably effective, inducing near complete protection against lethal challenge, including commonly used infection strains ST73 (CFT073) and ST95 (UTI89), as well as a mixture of 10 of the most highly virulent sequence types and strains from our clinical collection. Both HlyA and HlyA-SinH combinations also afforded some protection against UTI89 colonization in a murine UTI model. These findings suggest recombinant, inactive hemolysin and/or its combination with SinH warrant investigation in the development of an
vaccine against invasive disease.