Progress Toward a Vaccine for Extraintestinal Pathogenic . Coli (ExPEC) II: Efficacy of a Toxin-Autotransporter Dual Antigen Approach

Authors

Yikun Xing
Justin R Clark
James D Chang
Jacob J Zulk
Dylan M Chirman
Felipe-Andres Piedra
Ellen E Vaughan
Haroldo J Hernandez Santos
Kathryn A Patras
Anthony W Maresso

Publication Date

5-7-2024

Journal

Infection and Immunity

DOI

10.1128/iai.00440-23

PMID

38591882

PMCID

PMC11075464

PubMedCentral® Posted Date

4-9-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Extraintestinal Pathogenic Escherichia coli, Escherichia coli Infections, Mice, Hemolysin Proteins, Escherichia coli Proteins, Escherichia coli Vaccines, Antigens, Bacterial, Female, Virulence Factors, Type V Secretion Systems, Disease Models, Animal, Humans, ExPEC, sepsis, vaccines

Abstract

Extraintestinal pathogenic Escherichia coli (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 E. coli 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 E. coli vaccine against invasive disease.

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