In industrialized countries, non-typhoidal Salmonella (NTS) are important causes of bacterial gastroenteritis that can manifest as invasive disease in infants. In sub-Saharan Africa, multi-drug resistant NTS are a major cause of severe invasive bacterial disease in infants, with a high case fatality rate between 10 - 24 %. Notably, ~ 75-90% of invasive NTS (iNTS) infections in sub-Saharan Africa are accounted for by S. Typhimurium and S. Enteritidis. There are no current or imminent iNTS vaccines for humans. The O polysaccharides (OPS) and flagellin proteins of NTS have been shown to be important virulence factors and protective antigens against fatal iNTS infections in animal models. Bacterial polysaccharides are generally poorly immunogenic in infants and fail to confer immunologic memory at any age. However, these limitations can be overcome by conjugation to proteins. We have developed a novel S. Enteritidis glycoconjugate vaccine using S. Enteritidis flagellin as a carrier protein for chemically linked homologous strain Core and OPS (COPS), and shown improved anti- polysaccharide immune responses and protection against invasive S. Enteritidis infection in adult mice. Infants and toddlers are high priority targets for iNTS vaccines and there is precedent for conjugate vaccines in preventing invasive bacterial infections (e.g. pneumococcal, Hib) in these critical groups. The purpose of this application is to investigate the immunogenicity and protective efficacy of COPS:FliC vaccines in a mouse model of maternal and early life immunization. Immunoprophylactic strategies to protect infants include active immunization initiated during the first 6 months of life and placental transfer of maternal antibodies. The magnitude and quality of immune responses, and the longevity of protection imparted by COPS:FliC vaccines in infants, will determine their potential use as pediatric vaccines. The possible interference of maternally transferred antibodies with COPS:FliC vaccination in infants is also an important point of consideration, as maternal antibodies are known to interfere with the take of several vaccines, including glycoconjugates. This is particularly important for highly endemic areas, where maternal antibodies to NTS antigens are expected due to natural exposure. The use of iNTS conjugate vaccines to prevent disease early in life has never been investigated.
In Aim 1, we will evaluate the immunogenicity and protective efficacy of COPS:FliC in infant mice testing a range of dosage levels, intervals for immunization and protective efficacy after single or multiple immunizations. Parallel studies in adult mice will compare vaccine performance at difference life stages.
In Aim 2, we will assess the duration of vaccine-induced immunity and anamnestic responses.
In Aim 3, we will assess the protective efficacy of COPS:FliC induced maternal antibody for infant pups, and determine whether maternal antibodies elicited through vaccination or natural infection with wild-type African iNTS strains interfere with active vaccination of the offspring. These important studies will elucidate the potential use of COPS:FliC conjugates as pediatric vaccines and will facilitate further study as public health tools to protect human infants.

Public Health Relevance

Invasive non-typhoidal Salmonella (iNTS) infections are widespread among young children in sub-Saharan Africa where they are fatal in up to 24 % of cases. We have developed a promising candidate iNTS vaccine candidate comprised of LPS derived core and O polysaccharide chemically linked to the homologous strain flagellin protein and have demonstrated that it is highly immunogenic and protective in adult mice. The preclinical studies proposed in this application are designed to address several important fundamental questions regarding the feasibility of this vaccine to prevent iNTS infections in human infants and toddlers, who represent the highest priority target population for iNTS vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases (VMD)
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Alexander, William A
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University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
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