Wahid, R., Salerno-Goncalves, R., Tacket, C.O., Levine, M.M. & Sztein, M.B. Cell-mediated immune responses in humans after immunization with one or two doses of oral live attenuated typhoid vaccine CVD 909. Vaccine 25, 1416-1425

Center for Vaccine Development, Department of Pediatrics, University of Maryland, Baltimore, MD 21201, USA.
Vaccine (Impact Factor: 3.62). 03/2007; 25(8):1416-25. DOI: 10.1016/j.vaccine.2006.10.040
Source: PubMed


CVD 909 is a novel live attenuated S. Typhi oral vaccine candidate derived from strain CVD 908-htrA which constitutively expresses Vi. Herein we investigated whether the genetic manipulations involved in modifying CVD 908-htrA altered its ability to induce potent T-cell immune responses (CMI) after a single dose (five subjects) and, in a separate trial, whether a second dose (eight subjects) further enhanced its immunogenicity. In these clinical trials we observed that CVD 909 immunization elicits a wide array of CMI, including cytotoxic T cells (CTL), IFN-gamma, TNF-alpha and IL-10 (but not IL-2, IL-4 or IL-5) production, and proliferation to S. Typhi antigens. However, the administration of a second dose did not result in increases in CMI. These results suggest that the genetic manipulations to constitutively express Vi did not adversely affect the ability of CVD 909 to elicit a wide array of CMI responses. These observations add impetus for the continuing evaluation of CVD 909 as a typhoid vaccine candidate.

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Available from: Rezwanul Wahid, Jun 23, 2014
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    • "Induction of other cytokines in response to S. Typhi infection include IL-6 and IL-8 which are secreted into the serum during the acute phase of typhoid fever (Butler et al., 1993; Keuter et al., 1994; Gasem et al., 2003). PBMCs from immunized volunteers orally vaccinated with an attenuated S. Typhi vaccine secrete Th1 cytokines including IFN-γ, TNF-α, and IL-10, following sensitization with a number of S. Typhi antigens including flagella (Wahid et al., 2007). Collectively, these findings indicate that the human immune response to S. Typhi infection is predominantly Th1-associated. "
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    ABSTRACT: Human infections by the bacterial pathogen Salmonella enterica represent major disease burdens worldwide. This highly ubiquitous species consists of more than 2600 different serovars that can be divided into typhoidal and non-typhoidal Salmonella (NTS) serovars. Despite their genetic similarity, these two groups elicit very different diseases and distinct immune responses in humans. Comparative analyses of the genomes of multiple Salmonella serovars have begun to explain the basis of the variation in disease manifestations. Recent advances in modeling both enteric fever and intestinal gastroenteritis in mice will facilitate investigation into both the bacterial- and host-mediated mechanisms involved in salmonelloses. Understanding the genetic and molecular mechanisms responsible for differences in disease outcome will augment our understanding of Salmonella pathogenesis, host immunity, and the molecular basis of host specificity. This review outlines the differences in epidemiology, clinical manifestations, and the human immune response to typhoidal and NTS infections and summarizes the current thinking on why these differences might exist.
    Frontiers in Microbiology 08/2014; 5:391. DOI:10.3389/fmicb.2014.00391 · 3.99 Impact Factor
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    • "The mutant strains show either an attenuated or no effect on tight junction disassembly and paracellular permeability compared to the more aggressive phenotype detected in cells exposed to the wild-type strain. It is reasonable to hypothesize that the observed differences between attenuated and wild-type S. Typhi strains might be essential for the lack of reactogenicity and remarkable immunogenicity observed when these vaccine strains were fed to volunteers in Phase 1 and 2 clinical trials (Tacket et al., 2000b, 2004; Levine et al., 2001; Salerno-Goncalves et al., 2003, 2004; Sztein, 2007; Wahid et al., 2007, 2008, 2011, 2012; McArthur and Sztein, 2012). Another aspect of importance in intestinal mucosal defense is the capability of intestinal epithelial cells to “prime” the gut associated lymphoid tissue to possible danger caused by enteric pathogens by releasing pro-inflammatory cytokines and chemokines, including IL-8. "
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    ABSTRACT: Typhoid fever, caused by S. Typhi, is responsible for approximately 200,000 deaths per year worldwide. Little information is available regarding epithelium-bacterial interactions in S. Typhi infection. We have evaluated in vitro the effects of wild-type S. Typhi, the licensed Ty21a typhoid vaccine and the leading strains CVD 908-htrA and CVD 909 vaccine candidates on intestinal barrier function and immune response. Caco2 monolayers infected with wild-type S. Typhi exhibited alterations in the organization of tight junctions, increased paracellular permeability, and a rapid decrease in Trans-Epithelial Electrical Resistance as early as 4 h post-exposure. S. Typhi triggered the secretion of interleukin (IL)-8 and IL-6. Caco2 cells infected with the attenuated strains exhibited a milder pro-inflammatory response with minimal disruption of the barrier integrity. We conclude that wild-type S. Typhi causes marked transient alterations of the intestinal mucosa that are more pronounced than those observed with Ty21a or new generation attenuated typhoid vaccine candidates.
    Frontiers in Immunology 02/2013; 4:17. DOI:10.3389/fimmu.2013.00017
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    • "Typhoid fever is responsible for an estimated 21 million illnesses and 200,000 deaths annually and increasing antibiotic resistance among S. Typhi isolates has further exacerbated the problem [1], [2], [3], [4], [5], [6], [7], [8]. T cells, and particularly CD8+ T cells are thought to play an important role in the immune response against S. Typhi by producing interferon-γ (IFN-γ) and other T helper (Th) 1/T cytotoxic (Tc) 1 cytokines [9], [10], [11], [12], [13], [14], [15], [16], [17], as well as killing S. Typhi infected cells [10], [18]. Additionally, multifunctional CD8+ T cells have been identified in volunteers immunized with live-attenuated typhoid vaccine Ty21a [13]. "
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    ABSTRACT: Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, continues to cause significant morbidity and mortality world-wide. CD8+ T cells are an important component of the cell mediated immune (CMI) response against S. Typhi. Recently, interleukin (IL)-17A has been shown to contribute to mucosal immunity and protection against intracellular pathogens. To investigate multifunctional IL-17A responses against S. Typhi antigens in T memory subsets, we developed multiparametric flow cytometry methods to detect up to 6 cytokines/chemokines (IL-10, IL-17A, IL-2, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1β (MIP-1β)) simultaneously. Five volunteers were immunized with a 4 dose regimen of live-attenuated S. Typhi vaccine (Ty21a), peripheral blood mononuclear cells (PBMC) were isolated before and at 11 time points after immunization, and CMI responses were evaluated. Of the 5 immunized volunteers studied, 3 produced detectable CD8+ T cell responses following stimulation with S. Typhi-infected autologous B lymphoblastoid cell lines (B-LCL). Additionally, 2 volunteers had detectable levels of intracellular cytokines in response to stimulation with S. Typhi-infected HLA-E restricted cells. Although the kinetics of the responses differed among volunteers, all of the responses were bi- or tri-phasic and included multifunctional CD8+ T cells. Virtually all of the IL-17A detected was derived from multifunctional CD8+ T cells. The presence of these multifunctional IL-17A+ CD8+ T cells was confirmed using an unsupervised analysis program, flow cytometry clustering without K (FLOCK). This is the first report of IL-17A production in response to S. Typhi in humans, indicating the presence of a Tc17 response which may be important in protection. The presence of IL-17A in multifunctional cells co-producing Tc1 cytokines (IL-2, IFN-γ and TNF-α) may also indicate that the distinction between Tc17 and Tc1 responses in humans is not as clearly delineated as suggested by in vitro experiments and animal models.
    PLoS ONE 06/2012; 7(6):e38408. DOI:10.1371/journal.pone.0038408 · 3.23 Impact Factor
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