Improved Tolerability of a Salmonella enterica Serovar Typhimurium Live-Attenuated Vaccine Strain Achieved by Balancing Inflammatory Potential with Immunogenicity.

Autor: Higginson EE; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA., Ramachandran G; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA., Panda A; Program of Comparative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA., Shipley ST; Program of Comparative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Kriel EH; Program of Comparative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA., DeTolla LJ; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Program of Comparative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA., Lipsky M; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Perkins DJ; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Salerno-Goncalves R; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA., Sztein MB; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA., Pasetti MF; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA., Levine MM; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA., Tennant SM; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA stennant@som.umaryland.edu.; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Jazyk: angličtina
Zdroj: Infection and immunity [Infect Immun] 2018 Nov 20; Vol. 86 (12). Date of Electronic Publication: 2018 Nov 20 (Print Publication: 2018).
DOI: 10.1128/IAI.00440-18
Abstrakt: A notable proportion of Salmonella -associated gastroenteritis in the United States is attributed to Salmonella enterica serovar Typhimurium. We have previously shown that live-attenuated S Typhimurium vaccine candidate CVD 1921 (I77 Δ guaBA Δ clpP ) was safe and immunogenic in rhesus macaques but was shed for an undesirably long time postimmunization. In mice, occasional mortality postvaccination was also noted (approximately 1 in every 15 mice). Here we describe a further attenuated vaccine candidate strain harboring deletions in two additional genes, htrA and pipA We determined that S Typhimurium requires pipA to elicit fluid accumulation in a rabbit ileal loop model of gastroenteritis, as an S Typhimurium Δ pipA mutant induced significantly less fluid accumulation in rabbit loops than the wild-type strain. New vaccine strain CVD 1926 (I77 Δ guaBA Δ clpP Δ pipA Δ htrA ) was assessed for inflammatory potential in an organoid model of human intestinal mucosa, where it induced less inflammatory cytokine production than organoids exposed to the precursor vaccine, CVD 1921. To assess vaccine safety and efficacy, mice were given three doses of CVD 1926 (10 9 CFU/dose) by oral gavage, and at 1 or 3 months postimmunization, mice were challenged with 700 or 100 LD 50 (50% lethal doses), respectively, of wild-type strain I77. CVD 1926 was well tolerated and exhibited 47% vaccine efficacy following challenge with a high inoculum and 60% efficacy after challenge with a low inoculum of virulent S Typhimurium. CVD 1926 is less reactogenic yet equally as immunogenic and protective as previous iterations in a mouse model.
(Copyright © 2018 American Society for Microbiology.)
Databáze: MEDLINE
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