title: Toll-Like Receptor Activation by Generalized Modules for Membrane Antigens from Lipid A Mutants of Salmonella enterica Serovars Typhimurium and Enteritidis.
abstract: Invasive nontyphoidal Salmonella (iNTS) disease is a neglected disease with high mortality in children and HIV-positive individuals in sub-Saharan Africa, caused primarily by Africa-specific strains of Salmonella enterica serovars Typhimurium and Enteritidis. A vaccine using GMMA (generalized modules for membrane antigens) fromS.Typhimurium andS.Enteritidis containing lipid A modifications to reduce potential in vivo reactogenicity is under development. GMMA with penta-acylated lipid A showed the greatest reduction in the level of cytokine release from human peripheral blood monocytes from that for GMMA with wild-type lipid A. Deletion of the lipid A modification genes msbB and pagP was required to achieve pure penta-acylation. Interestingly, ΔmsbBΔ pagP GMMA from S. Enteritidis had a slightly higher stimulatory potential than those from S. Typhimurium, a finding consistent with the higher lipopolysaccharide (LPS) content and Toll-like receptor 2 (TLR2) stimulatory potential of the former. Also, TLR5 ligand flagellin was found in Salmonella GMMA. No relevant contribution to the stimulatory potential of GMMA was detected even when the flagellin protein FliC from S. Typhimurium was added at a concentration as high as 10% of total protein, suggesting that flagellin impurities are not a major factor for GMMA-mediated immune stimulation. Overall, the stimulatory potential of S. Typhimurium and S. Enteritidis ΔmsbB ΔpagP GMMA was close to that of Shigella sonnei GMMA, which are currently in phase I clinical trials.
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Omar
authors: O
authors: Rossi
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Mariaelena
authors: M
authors: Caboni
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Aurel
authors: A
authors: Negrea
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Francesca
authors: F
authors: Necchi
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Renzo
authors: R
authors: Alfini
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Francesca
authors: F
authors: Micoli
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Allan
authors: A
authors: Saul
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy.
authors: Calman A
authors: CA
authors: MacLennan
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy simona.x.rondini@gsk.com gerkechris@gmail.com.
authors: Simona
authors: S
authors: Rondini
authors: Novartis Vaccines Institute for Global Health, S.r.l., Siena, Italy simona.x.rondini@gsk.com gerkechris@gmail.com.
authors: Christiane
authors: C
authors: Gerke
mesh_terms: D017954:Africa South of the Sahara; D000942:Antigens, Bacterial / Q000276:immunology*; D006801:Humans; D008050:Lipid A / Q000235:genetics*; D009154:Mutation; D022562:Salmonella Vaccines / Q000235:genetics / Q000276:immunology*; D012477:Salmonella enteritidis / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D008050:Lipid A; D022562:Salmonella Vaccines; D051193:Toll-Like Receptors; D014614:Vaccines, Synthetic