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

Abstract

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 ΔguaBA ΔclpP) 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 ΔpipA mutant induced significantly less fluid accumulation in rabbit loops than the wild-type strain. New vaccine strain CVD 1926 (I77 ΔguaBA ΔclpP ΔpipA ΔhtrA) 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 (109 CFU/dose) by oral gavage, and at 1 or 3 months postimmunization, mice were challenged with 700 or 100 LD50 (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.

• Authors: Ellen E Higginson, Girish Ramachandran, Aruna Panda, Steven T Shipley, Edwin H Kriel, Louis J DeTolla, Michael Lipsky, Darren J Perkins, Rosangela Salerno-Goncalves, Marcelo B Sztein, Marcela F Pasetti, Myron M Levine, Sharon M Tennant
• Journal: Infection and immunity (Infect Immun) Vol. 86 Issue 12 (12 2018) ISSN: 1098-5522 [Electronic] United States
• PMID: 30249748 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 American Society for Microbiology.

Chemical References

• Antibodies, Bacterial
• Bacterial Proteins
• Cytokines
• Salmonella Vaccines
• Vaccines, Attenuated

Topics

• Animals
• Antibodies, Bacterial (blood)
• Bacterial Proteins (genetics, immunology)
• Cytokines (immunology)
• Disease Models, Animal
• Female
• Gene Deletion
• Humans
• Immunogenicity, Vaccine
• Inflammation (immunology)
• Intestinal Mucosa (immunology, microbiology)
• Mice
• Mice, Inbred BALB C
• Mutation
• Organoids (immunology, microbiology)
• Rabbits
• Salmonella Infections (immunology, prevention & control)
• Salmonella Vaccines (adverse effects, immunology)
• Salmonella typhimurium (immunology)
• Vaccines, Attenuated (immunology)