Abstract
Salmonella Typhimurium (STm) represents the most prevalent cause of invasive non-typhoidal Salmonella (iNTS) disease, and currently no licensed vaccine is available. In this work we characterized the long-term anti-bacterial immunity elicited by a STm vaccine based on Generalized Modules of Membrane Antigens (GMMA) delivering O:4,5 antigen, using a murine model of systemic infection. Subcutaneous immunization of mice with STmGMMA/Alhydrogel elicited rapid, high, and persistent antigen-specific serum IgG and IgM responses. The serum was bactericidal in vitro. O:4,5-specific IgG were also detected in fecal samples after immunization and positively correlated with IgG observed in intestinal washes. Long-lived plasma cells and O:4,5-specific memory B cells were detected in spleen and bone marrow. After systemic STm challenge, a significant reduction of bacterial load in blood, spleen, and liver, as well as a reduction of circulating neutrophils and G-CSF glycoprotein was observed in STmGMMA/Alhydrogel immunized mice compared to untreated animals. Taken together, these data support the development of a GMMA-based vaccine for prevention of iNTS disease.
Highlights
Invasive non-typhoidal Salmonella infections are a serious health concern causing about 535,000 cases per year, of which more than 400,000 were in sub-Saharan Africa, where the highest incidence is observed (34.5 cases per 100,000 person-years) [1]. iNTS is an under recognized leading cause of bacterial bloodstream infections in febrile children and immunocompromised individuals in sub-Saharan Africa, with a high case fatality rate of around 14.5% and up to 39% of community-acquired bloodstream infections [1,2,3,4,5,6]. iNTS infections cause approximately 59,100 global deaths each year, with about 31,200 cases in children under five years [1]
For the first time, the long-term immune response to STmGMMA/Alhydrogel and its ability to reduce the bacterial load in different compartments after systemic challenge was extensively characterized
After systemic challenge with a virulent serovar Typhimurium (STm) strain, the reduction of the bacterial load in different compartments, the decrease of neutrophils in blood and the modulation of different cytokine/chemokine production were further analyzed in mice immunized with STmGMMA/Alhydrogel compared to untreated animals
Summary
Invasive non-typhoidal Salmonella (iNTS) infections are a serious health concern causing about 535,000 cases per year, of which more than 400,000 were in sub-Saharan Africa, where the highest incidence is observed (34.5 cases per 100,000 person-years) [1]. iNTS is an under recognized leading cause of bacterial bloodstream infections in febrile children and immunocompromised individuals in sub-Saharan Africa, with a high case fatality rate of around 14.5% and up to 39% of community-acquired bloodstream infections [1,2,3,4,5,6]. iNTS infections cause approximately 59,100 global deaths each year, with about 31,200 cases in children under five years [1]. The higher incidence and increased severity of iNTS disease have been observed in patients with malaria, anemia, malnutrition, HIV, sickle cell disease, and hemolysis [1,5,10,11,12,13,14]. These are critical risk factors for iNTS infection, this under recognized disease is common in low-HIV-prevalence areas [3,5,13,15]. Growing efforts are focused on identifying novel prime-boost strategies and advanced immunization technologies for iNTS vaccine development [11,17,19,21,22,23,24,25,26,27,28,29]
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