Live Oral Typhoid Vaccine Ty21a Induces Cross-Reactive Humoral Immune Responses against Salmonella enterica Serovar Paratyphi A and S. Paratyphi B in Humans

Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Clinical and vaccine Immunology: CVI (Impact Factor: 2.47). 04/2012; 19(6):825-34. DOI: 10.1128/CVI.00058-12
Source: PubMed


Enteric fever caused by Salmonella enterica serovar Paratyphi A infection has emerged as an important public health problem. Recognizing that in randomized controlled field trials oral immunization with attenuated S. enterica serovar Typhi live vaccine Ty21a conferred significant cross-protection against S. Paratyphi B but not S. Paratyphi A disease, we undertook a clinical study to ascertain whether humoral immune responses could explain the field trial results. Ty21a immunization of adult residents of Maryland elicited predominantly IgA antibody-secreting cells (ASC) that recognize S. Typhi lipopolysaccharide (LPS). Cross-reactivity to S. Paratyphi A LPS was significantly lower than that to S. Paratyphi B LPS. ASC producing IgG and IgA that bind LPS from each of these Salmonella serovars expressed CD27 and integrin α4β7 (gut homing), with a significant proportion coexpressing CD62L (secondary lymphoid tissue homing). No significant differences were observed in serum antibody against LPS of the different serovars. Levels of IgA B memory (B(M)) cells to S. Typhi LPS were significantly higher than those against S. Paratyphi A or B LPS, with no differences observed between S. Paratyphi A and B. The response of IgA B(M) to outer membrane proteins (OMP) from S. Typhi was significantly stronger than that to OMP of S. Paratyphi A but similar to that to OMP of S. Paratyphi B. The percentages of IgG or IgA B(M) responders to LPS or OMP from these Salmonella strains were similar. Whereas cross-reactive humoral immune responses to S. Paratyphi A or B antigens are demonstrable following Ty21a immunization, they cannot explain the efficacy data gleaned from controlled field trials.

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Available from: Rezwanul Wahid, Jun 23, 2014
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    • "Currently, two types of vaccines—oral live attenuated Salmonella Typhi Ty21a (Vivotif ® ) and the parenteral capsular Vi polysaccharide preparations (Typherix ® or Typhim Vi ® )—are available against typhoid fever, while none are licensed against paratyphoid or NTS serotypes. Interestingly, Ty21a and, to a lesser extent, the Vi vaccine have been shown to elicit cross-reactive immune responses against paratyphoid serotypes [3] [4] [5] [6] [7] [8] [9] and the most common NTS Salmonellae [10] [11]. The main underlying cause of cross-reactivity are the O-antigenic structures these strains share with S. Typhi: while S. Typhi expresses O-9,12, S. Paratyphi A and B carry the O-12, and many NTS Salmonellae express either O-9,12 (e.g. S. Enteritidis) or O-12 (e.g. S. Typhimurium). "
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    ABSTRACT: Background: Since protective efficacy of the current typhoid vaccines-oral whole-cell Salmonella Typhi Ty21a and parenteral Vi-capsular polysaccharide preparation-is not optimal, and no vaccines are available against paratyphoid or non-typhoidal Salmonella (NTS) serotypes, new approaches deserve to be explored. The immunological mechanisms elicited by the two typhoid vaccines are mainly targeted against different structures. We studied whether these vaccines would enhance S. Typhi-specific immune response and cross-reactivity against other Salmonellae, if administered concomitantly. Materials and methods: Volunteers were immunized simultaneously with Ty21a and Vi vaccines (Ty21a+Vi group) or with either of the two singly (Ty21a and Vi groups). All volunteers were investigated for circulating specific and cross-reactive plasmablasts, identified by ELISPOT as IgA, IgG or IgM antibody-secreting cells (ASC) reactive with S. Typhi, S. Paratyphi A/B/C, or selected NTS serotypes (S. Enteritidis, S. Typhimurium). Results: In the Ty21a+Vi group, no specific or cross-reactive plasmablasts were detected before vaccination. After vaccination, the number of S. Typhi-specific plasmablasts (878 ASC/10(6) PBMC, 95%CI 554-1201) proved higher than in the Ty21a (339 ASC/10(6) PBMC; p<0.001) and Vi (149 ASC/10(6) PBMC; p<0.001) groups. Likewise, cross-reactive responses in the Ty21a+Vi group were higher than in the Ty21a and Vi groups (Ty21a+Vi vs Ty21a: ASC against S. Paratyphi A/B, S. Enteritidis and S. Typhimurium p<0.05, against S. Paratyphi C p<0.01; Ty21a+Vi vs Vi: against S. Paratyphi C not significant, others p<0.0001). A gut-directed homing profile was seen among O antigen-specific and a systemic one among Vi antigen-specific plasmablasts. Conclusions: Concomitant administration of Ty21a and Vi vaccines is well tolerated and induces an additive immune response to the two vaccines. Thus it enhances the magnitude of both typhoid-specific plasmablast responses and those cross-reacting with paratyphoid and most important NTS serotypes. The data encourage concomitant use of Ty21 and Vi vaccines for those at risk.
    Vaccine 11/2014; 33(3). DOI:10.1016/j.vaccine.2014.11.030 · 3.62 Impact Factor
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    • "Levels of serum IgA and IgG against S. Typhi LPS were measured by ELISA using previously described methods [39]. Post-vaccination fold increases of anti-LPS antibody titers were calculated as titers post-vaccination divided by the corresponding pre-vaccination titers multiplied by 100. "
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    ABSTRACT: The resident microbial consortia of the human gastrointestinal tract play an integral role in modulating immune responses both locally and systemically. However, detailed information regarding the effector immune responses after vaccine administration in relation to the gastrointestinal microbiota is absent. In this study, the licensed oral live-attenuated typhoid vaccine Ty21a was administered in a clinical study to investigate whether oral immunization resulted in alterations of the microbiota and to identify whether a given microbiota composition, or subsets of the community, are associated with defined S. Typhi-specific immunological responses. The fecal microbiota composition and temporal dynamics were characterized using bacterial 16S rRNA pyrosequencing from individuals who were either immunized with the Ty21a typhoid vaccine (n = 13) or served as unvaccinated controls (n = 4). The analysis revealed considerable inter- and intra-individual variability, yet no discernible perturbations of the bacterial assemblage related to vaccine administration were observed. S. Typhi-specific cell mediated immune (CMI) responses were evaluated by measurement of intracellular cytokine production using multiparametric flow cytometry, and humoral responses were evaluated by measurement of serum anti-LPS IgA and IgG titers. Volunteers were categorized according to the kinetics and magnitude of their responses. While differences in microbial composition, diversity, or temporal stability were not observed among individuals able to mount a positive humoral response, individuals displaying multiphasic CMI responses harbored more diverse, complex communities. In line with this preliminary observation, over two hundred operational taxonomic units (OTUs) were found to differentiate multiphasic and late CMI responders, the vast majority of which classified within the order Clostridiales. These results provide an unprecedented view into the dramatic temporal heterogeneity of both the gut microbiota and host immune responses.
    PLoS ONE 04/2013; 8(4):e62026. DOI:10.1371/journal.pone.0062026 · 3.23 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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