Year: 2014
Type: article
Abstract: While non-typhoidal Salmonella (NTS) have long been known to be a cause of self-limited gastroenteritis, it is becoming increasingly recognized that multiple antibiotic-resistant strains are also emerging as important causes of invasive bacteremia and focal infections, resulting in hospitalizations and deaths. Surveys from multiple sites in sub-Saharan Africa reveal that ∼ 75-90% of NTS from cases of invasive disease are Salmonella Typhimurium (and the monophasic S. Typhimurium variant S. I 4,[5],12:i:-), serovars that fall into Salmonella group B, or Salmonella Enteritidis, a group D Salmonella serovar. An effective NTS vaccine directed against these serovars could thus provide broad protection. We have constructed attenuated S. Typhimurium and S. Enteritidis strains that can serve as live oral vaccines as well as “reagent strains” for improved production of conjugate vaccine components. Live oral vaccine strains CVD 1931 (S. Typhimurium D65 ΔguaBA ΔclpX) and CVD 1944 (S. Enteritidis R11 ΔguaBA ΔclpX) were shown to protect mice against a high challenge dose (10,000 X LD50) with invasive African clinical isolates. Cross-protection experiments revealed that these live NTS vaccines also protect mice against other invasive Group B and D serovars. In parallel, we have developed S. Enteritidis conjugate vaccines using S. Enteritidis flagellin FliC as a carrier protein, chemically linked to homologous lipopolysaccharide-derived Core and O-polysaccharide (COPS), purified from S. Enteritidis R11 ΔguaBA ΔclpPX expressing flagellin at high levels. Various candidate conjugates were constructed by linkage to solvent-exposed lysines on FliC either at random COPS hydroxyls with CDAP chemistry, or at the Core-KDO terminus with thioether chemistry. Mice immunized with COPS:FliC conjugates were significantly protected from lethal challenge with an invasive African S. Enteritidis clinical isolate, demonstrating 80-100% vaccine efficacy. Protection was further maintained in mice immunized with fractional COPS:FliC doses that did not stimulate high COPS-specific antibody levels, indicating the potency of our conjugate vaccines. Since S. Typhimurium and S. Enteritidis are the most common NTS serovars associated with invasive disease, this research can pave the way for development of highly effective, broad spectrum vaccines against NTS.
Authors: S. Tennant, R. Simon, J.Y. Wang, M. Pasetti, R. Ernst, A. Lees, J. Galen, M. Levine
Institution: University of Maryland, Baltimore
Language: English
Subfield: Food Science
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,900
OpenAlex ID: W2008933019