Enteric fever is a clinical syndrome caused by Salmonella enterica serovar Typhi and Paratyphi A or B. Recent increases in the frequency of S. Paratyphi A (SPA) in Asia and emergence of antibiotic resistance have complicated treatment and posed a risk to U.S. travelers. In contrast to S. Typhi, there is no vaccine to prevent SPA, a category B priority bioterror threat to U.S. food sources. We have engineered two SPA candidate live oral vaccine strains by deleting the guaBA chromosomal locus (which encodes two enzymes in the distal de novo purine biosynthesis pathway) and also introducing deletions in either c/pX (encoding an ATPase) or dpP (encoding a protease), to create strains CVD 1902 and CVD 1903, respectively. Deleting guaBA has been a promising strategy for attenuating pathogenic S.Typhi. Introducing a deletion in either component of the dpXP complex provides a second, independent attenuating mutation to minimize the risk of a recombination that could theoretically restore the wild type genotype and may also enhance protection by hyper-expression of flagellar protein, a protective antigen that elicits both humoral and cell-mediated immune responses. Salmonella deleted in dpP, dpX, orclpXP have decreased ability to produce systemic infection yet the resultant dpXP mutants remain capable of protecting mice against wild type challenge. We propose to conduct a Phase 1 trial to evaluate the safety, tolerability, and immunogenicity of escalating dosages (107, 108, and 109 CPU) of CVD 1902 and CVD 1903. Three consecutive cohorts (each receiving a higher dosage of vaccine) of 14 healthy subjects 18-45 years of age will be admitted to the CVD Research Isolation Ward for 20 days followed by 4 outpatient visits and a telephone contact at 6 months. Subjects in each cohort will be randomized (double-blind) to receive a single oral inoculation with either CVD 1902 (N=6) or CVD 1903 (N=6) vaccine or placebo (N=2). During their 180-day participation, subjects will be closely observed for clinical response and will donate serial samples of blood and stool to detect colonization with the vaccine strain, to ensure that the strain was eliminated by per-protocol antibiotics, and to evaluate the ability of the vaccines to stimulate relevant mucosal, humoral, and cell-mediated immune responses. The results will be analyzed with the aim of selecting a well-tolerated and immunogenic vaccine strain and dosage for further clinical development.

Public Health Relevance

The frequency of enteric fever due to S. Paratyphi A (SPA) is increasing in Asia and multi-antibiotic resistant strains have emerged, making it difficult to treat and posing a risk to U.S. travelers to these areas. SPA also is a category B bioterror threat to U.S. food sources. Besides being a first step towards a possible oral SPA vaccine, this Phase 1 trial will shed light on the suitability of the gi;aB/4,c/pXand guaBA.dpP strategies for attenuating non-typhoidal Salmonella, also emerging pathogens of interest to the MARGE consortium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057168-10
Application #
8442380
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Li, Huiguang; Hwang, Young; Perry, Kay et al. (2016) Structure and Metal Binding Properties of a Poxvirus Resolvase. J Biol Chem 291:11094-104
Ramachandran, Girish; Tennant, Sharon M; Boyd, Mary A et al. (2016) Functional Activity of Antibodies Directed towards Flagellin Proteins of Non-Typhoidal Salmonella. PLoS One 11:e0151875
Ray, Greeshma; Schmitt, Phuong Tieu; Schmitt, Anthony P (2016) C-Terminal DxD-Containing Sequences within Paramyxovirus Nucleocapsid Proteins Determine Matrix Protein Compatibility and Can Direct Foreign Proteins into Budding Particles. J Virol 90:3650-60
Chou, Yi-ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-510
Fraley, Stephanie I; Athamanolap, Pornpat; Masek, Billie J et al. (2016) Nested Machine Learning Facilitates Increased Sequence Content for Large-Scale Automated High Resolution Melt Genotyping. Sci Rep 6:19218
Levy, Revital; Rotfogel, Ziv; Hillman, Dalia et al. (2016) Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction. Proc Natl Acad Sci U S A 113:E6437-E6446
Molleston, Jerome M; Sabin, Leah R; Moy, Ryan H et al. (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658-70
Riblett, Amber M; Blomen, Vincent A; Jae, Lucas T et al. (2016) A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection. J Virol 90:1414-23
Ramachandran, Girish; Boyd, Mary Adetinuke; MacSwords, Jennifer et al. (2016) Opsonophagocytic Assay To Evaluate Immunogenicity of Nontyphoidal Salmonella Vaccines. Clin Vaccine Immunol 23:520-3
Plaut, Roger D; Stibitz, Scott (2015) Improvements to a Markerless Allelic Exchange System for Bacillus anthracis. PLoS One 10:e0142758

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