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Updated: Jun 19, 2026
High-throughput Assay to Phenotype Salmonella enterica Typhimurium Association, Invasion, and Replication in Macrophages
Published on: August 11, 2014
Development of a GMMA-based candidate vaccine against invasive nontyphoidal Salmonella disease
Francesco Citiulo1, Oliver Koeberling1,2, Omar Rossi1
1GSK Vaccines Institute for Global Health S.r.l. (GVGH), Siena, Italy.
Insights
A new bivalent vaccine candidate, iNTS-GMMA, shows promise for preventing invasive nontyphoidal Salmonella (iNTS) disease, a major cause of death in sub-Saharan Africa. Pre-clinical studies demonstrate its safety and efficacy in inducing immune responses against key Salmonella serovars.
Area of Science:
- Vaccinology
- Microbiology
- Immunology
Background:
- Invasive nontyphoidal Salmonella (iNTS) disease causes significant mortality in sub-Saharan Africa, particularly in young children.
- iNTS disease is a leading cause of bacteremia and death in the region, with a high case fatality ratio.
Purpose of the Study:
- To describe the pre-clinical development of a bivalent Generalized Modules for Membrane Antigens (GMMA)-based vaccine candidate (iNTS-GMMA) against iNTS disease.
- To evaluate the immunogenicity and safety of the iNTS-GMMA vaccine candidate.
Main Methods:
- Genetically modified Salmonella Typhimurium and Enteritidis strains to produce GMMA with reduced inflammatory properties.
- Produced and purified GMMA at scale under non-GMP and GMP conditions using a two-step filtration process.
- Formulated GMMA components individually on Alhydrogel and combined them to create the bivalent vaccine candidate.
Main Results:
- The iNTS-GMMA vaccine candidate successfully induced high levels of IgG antibodies against Salmonella Typhimurium and Enteritidis LPS O-antigens in mice and rabbits.
- Animal sera demonstrated strong in vitro bactericidal activity against relevant Salmonella strains.
- A toxicology study in rabbits indicated that the iNTS-GMMA vaccine candidate was well-tolerated at the highest anticipated human dose.
Conclusions:
- The pre-clinical data support the further clinical evaluation of the iNTS-GMMA vaccine candidate.
- This vaccine represents a potentially crucial intervention for combating iNTS disease in sub-Saharan Africa.
Introduction:
Invasive nontyphoidal Salmonella (iNTS) disease is one of the most common causes of bacteremia in sub-Saharan Africa (sSA), mostly affecting children less than 5 years of age and with an associated 14.7% case fatality ratio. This disease is responsible for 62,018 deaths worldwide annually with more than 80% of those occurring in sSA.
Methods:
This work describes the pre-clinical development of a Generalized Modules for Membrane Antigens (GMMA)-based bivalent vaccine candidate against iNTS disease, known as iNTS-GMMA. Salmonella enterica serovars Typhimurium (S. Typhimurium) and Enteritidis (S. Enteritidis) were genetically modified to induce hyperblebbing of outer membrane vesicles, referred to as GMMA, with a penta-acylated lipid A of the lipopolysaccharide (LPS), characterized by a reduced induction of proinflammatory cytokine release from monocytes compared to GMMA carrying wild-type species of lipid A. GMMA derived from the genetically modified Salmonella strains were produced at scale with high yields and purity under both non-good manufacturing practice (GMP) conditions and under GMP conditions. A simple two-step filtration process was used to purify the GMMA drug substances. Subsequently, the S. Typhimurium GMMA and S. Enteritidis GMMA were individually formulated on Alhydrogel to produce the drug products. Mixing of the two components prior to injection results in the iNTS-GMMA vaccine candidate.
Results:
The iNTS-GMMA vaccine candidate induced in mice and rabbits high levels of IgG anti-S. Typhimurium and S. Enteritidis LPS O-antigens, the target antigens of the vaccine. Moreover, animal sera elicited strong in vitro bactericidal activity against S. Typhimurium and S. Enteritidis strains. Additionally, the highest envisioned human dose of iNTS-GMMA was well tolerated in a GLP repeated-dose toxicology study in rabbits.
Conclusions:
These data supported clinical evaluation of this urgently needed vaccine against iNTS disease in sSA.
