Preclinical Immunogenicity and Efficacy of Optimized O25b O-Antigen Glycoconjugates To Prevent MDR ST131 E. coli Infections

• Published in: Infection and immunity Vol. 90; no. 4; p. e0002222
• Main Authors: Chorro, Laurent, Li, Zhenghui, Chu, Ling, Singh, Suddham, Gu, Jianxin, Kim, Jin-Hwan, Dutta, Kaushik, Pan, Rosalind, Kodali, Srinivas, Ndreu, Duston, Patel, Axay, Hawkins, Julio C, Ponce, Chris, Silmon de Monerri, Natalie, Keeney, David, Illenberger, Arthur, Jones, C Hal, Andrew, Lubomira, Lotvin, Jason, Prasad, A Krishna, Kanevsky, Isis, Jansen, Kathrin U, Anderson, Annaliesa S, Donald, Robert G K
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 21.04.2022
• Subjects: Animals; Bacterial Infections; Bacteriology; Carrier Proteins; Escherichia coli; Escherichia coli Infections - prevention & control; Glycoconjugates; Mice; O Antigens; Spotlight Selection; glycoconjugate vaccine; MDR; O antigen; O25b; Escherichia coli; ST131
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/iai.00022-22

Multivalent O-antigen polysaccharide glycoconjugate vaccines are under development to prevent invasive infections caused by pathogenic . Sequence type 131 (ST131) Escherichia coli of serotype O25b has emerged as the predominant lineage causing invasive multidrug-resistant extraintestinal pathogenic E. coli (ExPEC) infections. We observed the prevalence of E. coli O25b ST131 among a contemporary collection of isolates from U.S. bloodstream infections from 2013 to 2016 (  = 444) and global urinary tract infections from 2014 to 2017 (  = 102) to be 25% and 24%, respectively. To maximize immunogenicity of the serotype O25b O antigen, we investigated glycoconjugate properties, including CRM carrier protein cross-linking (single-end versus cross-linked "lattice") and conjugation chemistry (reductive amination chemistry in dimethyl sulfoxide [RAC/DMSO] versus ((2-((2-oxoethyl)thio)ethyl)carbamate [eTEC] linker). Using opsonophagocytic assays (OPAs) to measure serum functional antibody responses to vaccination, we observed that higher-molecular-mass O25b long-chain lattice conjugates showed improved immunogenicity in mice compared with long- or short-chain O antigens conjugated via single-end attachment. The lattice conjugates protected mice from lethal challenge with acapsular O25b ST131 strains as well as against hypervirulent O25b isolates expressing K5 or K100 capsular polysaccharides. A single 1-μg dose of long-chain O25b lattice conjugate constructed with both chemistries also elicited robust serum IgG and OPA responses in cynomolgus macaques. Our findings show that key properties of the O-antigen carrier protein conjugate such as saccharide epitope density and degree of intermolecular cross-linking can significantly enhance functional immunogenicity.