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Myron M Levine - One of the best experts on this subject based on the ideXlab platform.
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cross reactive multifunctional cd4 t cell responses against salmonella enterica serovars typhi paratyphi a and paratyphi b in humans following immunization with live oral typhoid vaccine Ty21a
Clinical Immunology, 2016Co-Authors: Rezwanul Wahid, Myron M Levine, Stephanie Fresnay, Marcelo B SzteinAbstract:Abstract The live oral typhoid vaccine Ty21a elicits predominantly CD8+, as well as CD4+ T cells mediated immune responses. Clinical field studies showed that Ty21a is moderately effective against S. Typhi and S. Paratyphi B, but not S. Paratyphi A infections. In this study we describe the in depth characterization of S. Typhi, S. Paratyphi A and S. Paratyphi B cross-reactive CD4+ T cell responses elicited following immunization with Ty21a. PBMC samples were collected from 16 healthy volunteers before and 42/84 days after Ty21a immunization and stimulated ex-vivo with Salmonella-infected targets. Multiparametric flow cytometry was used to detect the vaccine elicited Salmonella-specific responses in T effector/memory (TEM) and CD45RA+ T effector/memory (TEMRA) CD4+ cell subsets, by measuring CD4+ multifunctional (MF) cells that concomitantly produced IFN-γ, TNF-α, IL-2, MIP-1β, IL-17A and/or expressed CD107a. Post-vaccination increases in S. Typhi-specific MF cells were observed in CD4+ TEM and TEMRA subsets which predominantly produced IFN-γ and/or TNF-α, while IL-2 was produced by a smaller cell subset. A small proportion of those MF cells also produced MIP-1β, IL-17A and expressed CD107a (a marker associated with cytotoxicity). Approximately one third of these specific MF cells have the potential to migrate to the gut mucosa, as evidenced by co-expression of the gut-homing molecule integrin α4β7. In contrast to our previous observations with CD8+ T cells, MF CD4+ T cell responses to the different Salmonella serovars evaluated were similar in magnitude and characteristics. We conclude that although induction of cross-reactive CD4+ MF effector T cells suggest a possible role in Salmonella-immunity, these responses are unlikely to provide an immunological basis for the observed efficacy of Ty21a against S. Typhi and S. Paratyphi B, but not to S. Paratyphi A.
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immunization with Ty21a live oral typhoid vaccine elicits crossreactive multifunctional cd8 t cell responses against salmonella enterica serovar typhi s paratyphi a and s paratyphi b in humans
Mucosal Immunology, 2015Co-Authors: Rezwanul Wahid, Myron M Levine, Stephanie Fresnay, Marcelo B SzteinAbstract:Previously we have extensively characterized Salmonella enterica serovar Typhi (S. Typhi)-specific cell-mediated immune (CMI) responses in volunteers orally immunized with the licensed Ty21a typhoid vaccine. In this study we measured Salmonella-specific multifunctional (MF) CD8+ T-cell responses to further investigate whether Ty21a elicits crossreactive CMI against S. Paratyphi A and S. Paratyphi B that also cause enteric fever. Ty21a-elicited crossreactive CMI responses against all three Salmonella serotypes were predominantly observed in CD8+ T effector/memory (TEM) and, to a lesser extent, in CD8+CD45RA+ TEM (TEMRA) subsets. These CD8+ T-cell responses were largely mediated by MF cells coproducing interferon-γ and macrophage inflammatory protein-1β and expressing CD107a with or without tumor necrosis factor-α. Significant proportions of Salmonella-specific MF cells expressed the gut-homing molecule integrin α4β7. In most subjects, similar MF responses were observed to S. Typhi and S. Paratyphi B, but not to S. Paratyphi A. These results suggest that Ty21a elicits MF CMI responses against Salmonella that could be critical in clearing the infection. Moreover, because S. Paratyphi A is a major public concern and Ty21a was shown in field studies not to afford cross-protection to S. Paratyphi A, these results will be important in developing a S. Typhi/S. Paratyphi A bivalent vaccine against enteric fevers.
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live oral salmonella enterica serovar typhi vaccines Ty21a and cvd 909 induce opsonophagocytic functional antibodies in humans that cross react with s paratyphi a and s paratyphi b
Clinical and Vaccine Immunology, 2014Co-Authors: Rezwanul Wahid, Marcela F Pasetti, Myron M Levine, Monica A Mcarthur, Shah J Zafar, Marcelo B SzteinAbstract:ABSTRACT Live oral Salmonella enterica serovar Typhi vaccine Ty21a induces specific antibodies that cross-react against Salmonella enterica serovar Paratyphi A and Salmonella enterica serovar Paratyphi B, although their functional role in clearance remains unknown. We utilized an in vitro assay with THP-1 macrophages to compare the phagocytosis and survival of Salmonella opsonized with heat-inactivated human sera obtained before and after vaccination with Ty21a or a live oral S . Typhi vaccine, CVD 909. Opsonization with postvaccination sera predominantly increased the phagocytosis of S . Typhi relative to the corresponding prevaccination sera, and increases were also observed with S . Paratyphi A and S . Paratyphi B, albeit of lower magnitudes. Relative to prevaccination sera, opsonization with the postvaccination sera reduced the survival inside macrophages of S . Typhi but not of S . Paratyphi A or S . Paratyphi B. Higher anti- S . Typhi O antigen (lipopolysaccharide [LPS]) IgG, but not IgA, antibody titers correlated significantly with postvaccination increases in opsonophagocytosis. No differences were observed between immunization with four doses of Ty21a or one dose of CVD 909. Ty21a and CVD 909 induced cross-reactive functional antibodies, predominantly against S . Typhi. IgG anti-LPS antibodies may be important in phagocytic clearance of these organisms. Therefore, measurement of functional antibodies might be important in assessing the immunogenicity of a new generation of typhoid and paratyphoid A vaccines. (The CVD 909 study has been registered at ClinicalTrials.gov under registration no. NCT00326443.)
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live oral typhoid vaccine Ty21a induces cross reactive humoral immune responses against salmonella enterica serovar paratyphi a and s paratyphi b in humans
Clinical and Vaccine Immunology, 2012Co-Authors: Rezwanul Wahid, Myron M Levine, Shah J Zafar, Raphael Simon, Marcelo B SzteinAbstract: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 (BM) 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 BM 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 BM 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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Ty21a live oral typhoid vaccine and prevention of paratyphoid fever caused by salmonella enterica serovar paratyphi b
Clinical Infectious Diseases, 2007Co-Authors: Myron M Levine, Robert E Black, Catterine Ferreccio, Oriana San Martin, Rosanna Lagos, William C BlackwelderAbstract:: In randomized, controlled field trials in Area Norte and Area Occidente of Santiago, Chile, 2 (Norte) or 3 (Occidente) doses of live oral typhoid vaccine Ty21a in enteric-coated capsules conferred protection against confirmed Salmonella enterica serovar Typhi disease (53% efficacy in Norte; 67% efficacy in Occidente) during 3 years of follow-up. There was also a trend in each trial showing protection against S. enterica serovar Paratyphi B disease (56% efficacy in Norte; 42% efficacy in Occidente). To enhance statistical power, an analysis was performed using pooled data from the 2 trials; this pooling of data was justified by the following facts: epidemiologic surveillance and microbiological methods were identical, the trials overlapped during 22 of the 36 months of follow-up in each trial, the estimates of efficacy against paratyphoid B fever in the 2 trials were roughly similar, and the ratio of follow-up of vaccine recipients to control subjects in both trials was ~1 : 1. In the pooled analysis, Ty21a conferred significant protection against paratyphoid B fever (efficacy, 49%; 95% confidence interval, 8%-73%; P=.019).
Marcelo B Sztein - One of the best experts on this subject based on the ideXlab platform.
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oral typhoid vaccine Ty21a elicits antigen specific resident memory cd4 t cells in the human terminal ileum lamina propria and epithelial compartments
Journal of Translational Medicine, 2020Co-Authors: Jayaum S Booth, Eric M Goldberg, Robin S Barnes, Bruce D Greenwald, Marcelo B SzteinAbstract:Salmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9–20.6 million infections and ~ 130,000–223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5–7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (TRM) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces TRM in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+TRM subsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments. Terminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+TRM immune responses were determined using either S. Typhi-infected or non-infected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)γ, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)α] in 36 volunteers (18 vaccinees and 18 controls volunteers). Although the frequencies of LPMC CD103+ CD4+TRM were significant decreased, both CD103+ and CD103− CD4+TRM subsets spontaneously produced significantly higher levels of cytokines (IFNγ and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases in S. Typhi-specific LPMC CD103+ CD4+TRM (IFNγ and IL-17A) and CD103− CD4+TRM (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+TRM subsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103− CD4+TRM (increase) following immunization. Finally, we observed that IEL CD103− CD4+TRM, but not CD103+ CD4+TRM, produced increased cytokines (IFNγ, TNFα and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization. Oral Ty21a-immunization elicits distinct compartment specific immune responses in CD4+TRM (CD103+ and CD103−) subsets. This study provides novel insights in the generation of local vaccine-specific responses. Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304, Registered 29 May 2019—Retrospectively registered, http://www.ClinicalTrials.gov/NCT03970304)
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characteristics of regulatory t cell populations before and after Ty21a typhoid vaccination in children and adults
Clinical Immunology, 2019Co-Authors: Robin S Barnes, Mark E Rudolph, Monica A Mcarthur, Laurence S Magder, Wilbur H Chen, Marcelo B SzteinAbstract:Abstract Typhoid fever, caused by the pathogen Salmonella enterica serovar Typhi (S. Typhi), is a serious global health concern. Challenge studies with wild type S. Typhi identified associations between gut-homing regulatory T cells (Treg) and development of typhoid disease. Whether oral live-attenuated Ty21a vaccination induces gut-homing Treg remains unclear. Here, we analyze pediatric and adult Treg pre- and post-Ty21a vaccination in an autologous S. Typhi-antigen presentation model to address this knowledge gap. We show that peripheral memory Treg populations change from childhood to adulthood, but not following Ty21a vaccination. Unsupervised dimensionality reduction with t-distributed stochastic neighbor embedding (tSNE) identifies homing, memory, and functional features which evidence age-associated maturation of multifunctional S. Typhi-responsive Treg, which were not impacted by Ty21a vaccination. These findings improve understanding of pediatric regulatory T cells, while identifying age-related differences in S. Typhi-responsive Treg, which may aid in the development of improved pediatric vaccination strategies against S. Typhi.
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diversity of salmonella typhi responsive cd4 and cd8 t cells before and after Ty21a typhoid vaccination in children and adults
International Immunology, 2019Co-Authors: Robin S Barnes, Mark E Rudolph, Monica A Mcarthur, Laurence S Magder, Wilbur H Chen, Marcelo B SzteinAbstract:: Typhoid fever is a life-threatening disease caused by the human-restricted pathogen Salmonella enterica serovar Typhi (S. Typhi). The oral live attenuated Ty21a typhoid vaccine protects against this severe disease by eliciting robust, multifunctional cell-mediated immunity (CMI), shown to be associated with protection in wild-type S. Typhi challenge studies. Ty21a induces S. Typhi-responsive CD8+ and CD4+ T cells but little is known about the response to this vaccine in children. To address this important gap in knowledge, we have used mass cytometry to analyze pediatric and adult pre- and post-Ty21a vaccination CMI in an autologous S. Typhi antigen presentation model. Here, using conventional supervised analytical tools, we show adult T cells are more multifunctional at baseline than those obtained from children. Moreover, pediatric and adult T cells respond similarly to Ty21a vaccination, but adult responders remain more multifunctional. The use of the unsupervised dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding) allowed us to confirm these findings, as well as to identify increases and decreases in well-defined specific CD4+ and CD8+ T-cell populations that were not possible to uncover using the conventional gating strategies. These findings evidenced age-associated maturation of multifunctional S. Typhi-responsive T-cell populations, including those which we have previously shown to be associated with protection from, and/or delayed onset of, typhoid disease. These findings are likely to play an important role in improving pediatric vaccination strategies against S. Typhi and other enteric pathogens.
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attenuated oral typhoid vaccine Ty21a elicits lamina propria and intra epithelial lymphocyte tissue resident effector memory cd8 t responses in the human terminal ileum
Frontiers in Immunology, 2019Co-Authors: Jayaum S Booth, Seema A Patil, Eric M Goldberg, Robin S Barnes, Bruce D Greenwald, Marcelo B SzteinAbstract:Tissue-resident memory T cells (TRM) are newly defined memory T cells (TM) distinct from circulating TM subsets which have the potential to mount rapid protective immune responses at the site of infection. However, very limited information is available regarding the role and contribution of TRM in vaccine-mediated immune responses in humans at the site of infection. Here, we studied the role and contribution of tissue resident memory T cells (TRM) located in the terminal ileum (TI) (favored site of infection for S. Typhi) following oral Ty21a immunization in humans. We examined TI-lamina propria mononuclear cells (LPMC) and intra-epithelial lymphocytes (IEL) CD8+ TRM subsets obtained from healthy volunteers undergoing medically-indicated colonoscopies that were either immunized with Ty21a or unvaccinated. No significant differences in the frequencies of LPMC CD8+ TRM and CD8+CD69+CD103- T cells subsets were observed following Ty21a-immunization. However, LPMC CD8+ TRM exhibited significantly higher levels of cytokines (IFN, IL-17A, and TNF) ex-vivo in Ty21a-vaccinated than in unvaccinated volunteers. LPMC CD8+ TRM S. Typhi-specific responses were evaluated using S. Typhi-infected targets and found to produce significantly higher levels of S. Typhi-specific IL-17A. In contrast, LPMC CD8+CD69+CD103- T cells produced significantly increased S. Typhi-specific levels of IFN, IL-2 and IL-17A. Finally, we assessed CD8+ TRM in IEL and observed that the frequency of IEL- CD8+ TRM is significantly lower following Ty21a immunization. However, ex-vivo IEL- CD8+ TRM elicited by Ty21a immunization spontaneously produced significantly higher levels of cytokines (IFN, IL-17A, IL-2 and TNF). This study provides the first demonstration of the effect of oral Ty21a vaccination on CD8+ TRM subsets (non-specific and S. Typhi-specific) responses in the LPMC and IEL compartment of the human terminal ileum mucosa, contributing novel information to our understanding of the generation of mucosal immune responses following oral Ty21a-immunization.
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age associated heterogeneity of Ty21a induced t cell responses to hla e restricted salmonella typhi antigen presentation
Frontiers in Immunology, 2019Co-Authors: Robin S Barnes, Mark E Rudolph, Monica A Mcarthur, Laurence S Magder, Wilbur H Chen, Marcelo B SzteinAbstract:: Human-restricted Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever-a life-threatening disease of great global health significance, particularly in the developing world. Ty21a is an oral live-attenuated vaccine that protects against the development of typhoid disease in part by inducing robust T cell responses, among which multifunctional CD8+ cytotoxic T lymphocytes (CTL) play an important role. Following Ty21a vaccination, a significant component of adult CTL have shown to be targeted to S. Typhi antigen presented by the conserved major histocompatibility complex (MHC) class Ib molecule, human leukocyte antigen-E (HLA-E). S. Typhi challenge studies have shown that baseline, multifunctional HLA-E responsive T cells are associated with protection from, and delayed onset of, typhoid disease. However, despite the overwhelming burden of typhoid fever in school-aged children, and due to limited availability of pediatric samples, incomplete information is available regarding these important HLA-E-restricted responses in children, even though studies have shown that younger children may be less likely to develop protective cell mediated immune (CMI) responses than adults following vaccination. To address this gap, we have studied this phenomenon in depth by using mass cytometry to analyze pediatric and adult T cell responses to HLA-E-restricted S. Typhi antigen presentation, before and after Ty21a vaccination. Herein, we show variable responses in all age strata following vaccination among T effector memory (TEM) and T effector memory CD45RA+ (TEMRA) cells based on conventional gating analysis. However, by utilizing the dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding), we are able to identify diverse, highly multifunctional gut-homing- TEM and TEMRA clusters of cells which are more abundant in adult and older pediatric participants than in younger children. These findings highlight a potential age-associated maturation of otherwise conserved HLA-E restricted T cell responses. Such insights, coupled with the marked importance of multifunctional T cell responses to combat infection, may better inform future pediatric vaccination strategies against S. Typhi and other infectious diseases.
S J Cryz - One of the best experts on this subject based on the ideXlab platform.
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local and systemic immune responses to combined vibrio cholerae cvd103 hgr and salmonella typhi Ty21a live oral vaccines after primary immunization and reimmunization
Vaccine, 2000Co-Authors: Herwig Kollaritsch, S J Cryz, C Herzog, Alois B Lang, G WiedermannAbstract:Abstract The local and systemic antibody responses elicited following concomitant primary immunization and reimmunization with the live oral attenuated Vibrio cholerae CVD103-HgR and Salmonella typhi Ty21a vaccine strains were determined in healthy adult volunteers. A more pronounced serum vibriocidal antibody response was generated after primary immunization compared to reimmunization 2.5 or 3.5 yr later. The seroconversion rate (≥4-fold rise over baseline) was 81% subsequent to primary immunization versus 57% ( p =0.018) and 65% ( p =0.639) upon reimmunization at 2.5 and 3.5 yr, respectively. A similar trend was observed for serum anti- S. typhi lipopolysaccharide (LPS) antibodies. After primary immunization, 48% of subjects manifested a significant rise in coproantibody levels to V. cholerae LPS while 60% did so for cholera toxin (CT). Upon reimmunization, the response rate for LPS ranged from 38% at 2.5 yr to 56% at 3.5 yr ( p >0.05), while that for CT varied from 31% ( p =0.007) to 50% ( p =0.541) at 2.5 and 3.5 yr, respectively. The anti- S. typhi IgA coproantibody response rate was 70% subsequent to primary immunization versus 47% at 2.5 yr ( p =0.021) and 63% at 3.5 yr ( p =0.77).
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duration of efficacy of Ty21a attenuated salmonella typhi live oral vaccine
Vaccine, 1999Co-Authors: Myron M Levine, Catterine Ferreccio, Paulina Abrego, Oriana San Martin, Edith Ortiz, S J CryzAbstract:Currently, two different formulations of Ty21a live oral typhoid vaccine are commercialized. The enteric-coated capsule formulation was licensed based on results of three years of follow-up of a randomized, placebo-controlled, double-blind field trial in Area Occidente, Santiago, Chile, which demonstrated that three doses of this formulation, given on an every other day immunization schedule, conferred the best protection among several options evaluated. Subsequently, a liquid formulation (lyophilized vaccine organisms reconstituted with buffer and water into a vaccine cocktail) was commercialized after it was shown to provide superior protection than enteric-coated capsules over three years of follow-up in a randomized, placebo-controlled field trial in Area Sur Oriente and Area Norte, Santiago. Surveillance in the Area Occidente trial was continued for four additional years (i.e., total seven years of follow-up) and in the Area Sur Oriente/Area Norte trial for two additional years (i.e., a total of five years of follow-up). These additional surveillance data, which were analyzed to ascertain the longevity of protection conferred by these formulations of Ty21a, revealed that three doses of Ty21a in enteric-coated capsules (every other day schedule) conferred 67% protection over three years and 62% protection over seven years of follow-up, whereas three doses of liquid formulation (every other day schedule) elicited 77% protection over three years and 78% over five years of follow-up. Based on its excellent clinical acceptability, ease of oral administration, proven practicality in school-based mass immunization, and long-term efficacy enduring at least seven years, it is proposed that school-based immunization with Ty21a be utilized as a control measure in areas where the incidence of typhoid fever is high and Salmonella typhi are antibiotic-resistant.
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randomized double blind placebo controlled trial to evaluate the safety and immunogenicity of combined salmonella typhi Ty21a and vibrio cholerae cvd 103 hgr live oral vaccines
Infection and Immunity, 1996Co-Authors: Herwig Kollaritsch, G Wiedermann, E Furer, C Herzog, S J CryzAbstract:Healthy adults (n=330) were randomized to receive either a bivalent vaccine composed of Vibrio cholerae CVD 103-HgR and Salmonella typhi Ty21a or a placebo. The combined vaccine was well tolerated. Approximately 80% of vaccines manifested a significant rise in anti-S. typhi immunoglobulin G or immunoglobulin A lipopolysaccharide antibody levels. Significant (fourfold or greater) rises in anti-Inaba or anti-Ogawa vibriocidal antibody titer were achieved by 94 and 80% of vaccine recipients, respectively. Elevated baseline vibriocidal antibody titers showed a modest suppressive effect on the rate of seroconversion.
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safety and immunogenicity of a live oral bivalent typhoid fever salmonella typhi Ty21a cholera vibrio cholerae cvd 103 hgr vaccine in healthy adults
Infection and Immunity, 1995Co-Authors: S J Cryz, Myron M Levine, G Wiedermann, Herwig KollaritschAbstract:: The safety and immunogenicity of the live oral attenuated vaccine strains vibrio cholerae CVD 103-HgR and Salmonella typhi Ty21a were evaluated alone or in a combined bivalent formulation in four groups composed of 185 healthy European adults. All presentations were well tolerated. The serum anti-S. typhi lipopolysaccharide immunoglobulin G and immunoglobulin A antibody responses were comparable for all groups (66 to 72% seroconversion). The serum vibriocidal antibody seroconversion rate ranged from 78 to 92.5% (P > 0.05) among the groups. However, the peak and geometric mean vibriocidal antibody titers were significantly higher (P < 0.005) in the groups which received the bivalent formulation along with two doses of Ty21a than in the group which received CVD 103-HgR followed by two doses of killed Escherichia coli K-12 placebo. The ingestion of a placebo shortly after CVD 103-HgR may have suppressed the magnitude of the immune response. These findings demonstrate the feasibility of producing multivalent live oral attenuated vaccines.
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safety and immunogenicity of salmonella typhi Ty21a vaccine in young thai children
Infection and Immunity, 1993Co-Authors: S J Cryz, Myron M Levine, Genevieve Losonsky, N Vanprapar, Usa Thisyakorn, T Olanratmanee, S ChearskulAbstract:Salmonella typhi Ty21a vaccine in a liquid formulation was evaluated in 634 Thai children 2 to 6 years of age. The seroconversion rate was 69% for those who received vaccine versus 14% for those who received placebo (P
Anu Kantele - One of the best experts on this subject based on the ideXlab platform.
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specific and cross reactive immune response to oral salmonella typhi Ty21a and parenteral vi capsular polysaccharide typhoid vaccines administered concomitantly
Vaccine, 2015Co-Authors: Sari H Pakkanen, Jussi M Kantele, Laura E Savolainen, Lars Rombo, Anu KanteleAbstract:Abstract Background Since protective efficacy of the current typhoid vaccines—oral whole-cell S almonella 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 6 PBMC; p S . Paratyphi A/B, S . Enteritidis and S . Typhimurium p S . Paratyphi C p S . Paratyphi C not significant, others p 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.
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head to head comparison of humoral immune responses to vi capsular polysaccharide and salmonella typhi Ty21a typhoid vaccines a randomized trial
PLOS ONE, 2013Co-Authors: Sari H Pakkanen, Anu Kantele, Riitta Karttunen, Jussi M KanteleAbstract:Background The two typhoid vaccines, the parenteral Vi capsular polysaccharide and the oral live whole-cell Salmonella Typhi Ty21a vaccine, provide similar levels of protection in field trials. Sharing no antigens, they are thought to confer protection by different mechanisms. This is the first head-to-head study to compare the humoral immune responses to these two vaccines. Methods 50 age- and gender-matched volunteers were immunized, 25 with the Vi and 25 with the Ty21a vaccine. Circulating plasmablasts reactive with whole-cell Salmonella Typhi or one of the typhoidal antigenic structures, Vi, O-9,12, and H-d antigens, were identified as antibody-secreting cells (ASC) with ELISPOT. Homing receptor (HR) expressions were determined. These results were compared with ASC in four patients with typhoid fever. Antibodies to S. Typhi lipopolysaccharides were assessed in cultures of ALS (antibodies in lymphocyte supernatants) and in serum with ELISA. Results In 49 out of 50 vaccinees, no typhoid-specific plasmablasts were seen before vaccination. On day 7, response to Vi antigen was mounted in 24/25 volunteers in the Vi, and none in the Ty21a group; response to S. Typhi and O-9,12 was mounted in 49/50 vaccinees; and to H-d in 3/50. The numbers of typhoid-specific plasmablasts (total of ASC to Vi, O-9,12 and H-d antigens) proved equal in the vaccination groups. The HR expressions indicated a mainly systemic homing in the Vi and intestinal in the Ty21a group, the latter resembling that in natural infection. Plasmablasts proved more sensitive than serum and ALS in assessing the immune response. Conclusions The typhoid-specific humoral responses to Vi and Ty21a vaccines are similar in magnitude, but differ in expected localization and antigen-specificity. The unforeseen O antigen-specific response in the Vi group is probably due to lipopolysaccharide contaminating the vaccine preparation. Only the response to Ty21a vaccine was found to imitate that in natural infection. Trial Registration Current Controlled Trials Ltd. c/o BioMed Central ISRCTN68125331
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live oral typhoid vaccine salmonella typhi Ty21a a surrogate vaccine against non typhoid salmonella
Vaccine, 2012Co-Authors: Anu Kantele, Sari H Pakkanen, Anja Siitonen, Riitta Karttunen, Jussi M KanteleAbstract:Abstract Background Non-typhoid Salmonella (NTS) is a leading cause of food-borne illness with more than 90 million annual cases and an emerging antimicrobial resistance among the strains worldwide. Paradoxically, no vaccines are available against these pathogens. Numerous NTS strains share surface O-antigens with Salmonella enterica serotype Typhi. As intestinal antibodies against O-antigens have proven protective against NTS in animal experiments, it appears conceivable that the oral whole-cell typhoid vaccine, Salmonella Typhi Ty21a (Vivotif ® ), which effectively elicits intestinal antibodies against O-antigens, could exhibit cross-protective efficacy against NTS. We sought immunological evidence in support of cross-protective efficacy of Ty21a against NTS. Materials and methods 35 volunteers receiving Ty21a vaccine and five patients with enteric fever were investigated with ELISPOT for circulating plasmablasts secreting antibodies reactive with Salmonella Typhi and six different NTS serotypes. These plasmablasts were also analysed for homing receptor expressions. Results In all vaccinees and patients, a strong gut-directed cross-reactive plasmablast response was found against serotypes sharing the two O-antigens with Salmonella Typhi (O-9,12) (in vaccinees, mean: 95%CI 268: 228–508 and 363: 234–493 plasmablasts/10 6 PBMC against Salmonella Typhi and Enteritidis). Responses against strains sharing one O-antigen (O-12) were weaker (222: 105–338 against Salmonella Typhimurium), while no significant reactivity was detected against strains without typhoidal O-antigens. Conclusions Intestinal antibodies against O-antigens protect against NTS in animal experiments. Ty21a was found to elicit intestinal immune responses cross-reactive with NTS strains sharing O-antigens with Ty21a. These include the most common NTS, Salmonella Enteritidis and Typhimurium. The data suggest that Ty21a may have cross-protective efficacy against numerous NTS strains.
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cross reactive gut directed immune response against salmonella enterica serovar paratyphi a and b in typhoid fever and after oral Ty21a typhoid vaccination
Vaccine, 2012Co-Authors: Sari H Pakkanen, Jussi M Kantele, Anu KanteleAbstract:Abstract Background There are no vaccines against paratyphoid fever in clinical use. The disease has become more wide-spread and there is a growing problem of antibiotic resistance among the strains. Previous reports suggest that the oral live Salmonella Typhi Ty21a-vaccine confers protection against paratyphoid B fever. Data on efficacy against paratyphoid A fever are somewhat contentious. The present study investigated the immunological basis for such efficacy reports at a single-cell level: plasmablasts (identified as antibody-secreting cells, ASC) were studied for secretion of antibodies cross-reactive with Salmonella Paratyphi in the circulation of patients with enteric fever and of volunteers vaccinated with Ty21a. Materials and methods Thirty volunteers immunized with Ty21a and five patients with enteric fever were investigated for Salmonella Typhi and Salmonella Paratyphi A/B/C-specific circulating plasmablasts. PBMC were sorted by their expression of homing receptors (HR) for the intestine (α4β7), peripheral lymph node ( l -selectin) and skin (CLA) and typhoid- and paratyphoid-specific plasmablasts were enumerated with ELISPOT. Results Before vaccination, no cross-reactive ASC were found in the volunteers. In addition to the Salmonella Typhi-specific response, a significant cross-reactive immune response was mounted against Salmonella Paratyphi A and B both in the patients and the vaccinees. The magnitude of the response increased in the order Salmonella Paratyphi A (median 30 ASC/10 6 PBMC) → Salmonella Paratyphi B (median 81) → Salmonella Typhi (median 301) in the vaccinees. Both in patients and in vaccinees, the homing receptor (HR) selection favored homing to the gut, indicating a humoral intestinal immune response. Conclusions These immunological data provide evidence consistent with previous reports describing certain levels of cross-protective efficacy of Ty21a against paratyphoid fever. Controlled studies are needed to evaluate cross-protective efficacy. In the current situation where paratyphoid fever is emerging and no vaccines are available, any level of cross-protective capacity is valuable.
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comparison of the human immune response to live oral killed oral or killed parenteral salmonella typhi Ty21a vaccines
Microbial Pathogenesis, 1991Co-Authors: Anu Kantele, Jussi M Kantele, Heikki Arvilommi, L Rintala, P H MakelaAbstract:Abstract The live oral typhoid vaccine Ty21a has proved to confer protection against the disease at least as effectively as killed parenteral vaccines, whereas killed oral vaccines have not been protective in field trials. This prompted us to compare the immune response of subjects vaccinated either with live oral, killed oral or killed parenteral Salmonella typhi Ty21a vaccine. The immune responses were studied by analysis of peripheral blood antibody-secreting cells (ASC), believed to reflect the mucosal immune response. Live and killed bacteria administered by the oral route elicited immune responses of similar specificity and Ig class profile (IgA dominating), but the response to the live vaccine was significantly stronger and lasted longer The administration route, on the other hand, influenced the antigenic specificity of the ASC response suggesting different processing of the antigen by the systemic and local immune systems. Thus, the response after oral vaccination was almost exclusively directed to the surface O-antigen, whereas after parenteral vaccination an equally strong response was seen to the O-antigen, to lipopolysaccharide core and to flagella.
Jussi M Kantele - One of the best experts on this subject based on the ideXlab platform.
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specific and cross reactive immune response to oral salmonella typhi Ty21a and parenteral vi capsular polysaccharide typhoid vaccines administered concomitantly
Vaccine, 2015Co-Authors: Sari H Pakkanen, Jussi M Kantele, Laura E Savolainen, Lars Rombo, Anu KanteleAbstract:Abstract Background Since protective efficacy of the current typhoid vaccines—oral whole-cell S almonella 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 6 PBMC; p S . Paratyphi A/B, S . Enteritidis and S . Typhimurium p S . Paratyphi C p S . Paratyphi C not significant, others p 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.
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head to head comparison of humoral immune responses to vi capsular polysaccharide and salmonella typhi Ty21a typhoid vaccines a randomized trial
PLOS ONE, 2013Co-Authors: Sari H Pakkanen, Anu Kantele, Riitta Karttunen, Jussi M KanteleAbstract:Background The two typhoid vaccines, the parenteral Vi capsular polysaccharide and the oral live whole-cell Salmonella Typhi Ty21a vaccine, provide similar levels of protection in field trials. Sharing no antigens, they are thought to confer protection by different mechanisms. This is the first head-to-head study to compare the humoral immune responses to these two vaccines. Methods 50 age- and gender-matched volunteers were immunized, 25 with the Vi and 25 with the Ty21a vaccine. Circulating plasmablasts reactive with whole-cell Salmonella Typhi or one of the typhoidal antigenic structures, Vi, O-9,12, and H-d antigens, were identified as antibody-secreting cells (ASC) with ELISPOT. Homing receptor (HR) expressions were determined. These results were compared with ASC in four patients with typhoid fever. Antibodies to S. Typhi lipopolysaccharides were assessed in cultures of ALS (antibodies in lymphocyte supernatants) and in serum with ELISA. Results In 49 out of 50 vaccinees, no typhoid-specific plasmablasts were seen before vaccination. On day 7, response to Vi antigen was mounted in 24/25 volunteers in the Vi, and none in the Ty21a group; response to S. Typhi and O-9,12 was mounted in 49/50 vaccinees; and to H-d in 3/50. The numbers of typhoid-specific plasmablasts (total of ASC to Vi, O-9,12 and H-d antigens) proved equal in the vaccination groups. The HR expressions indicated a mainly systemic homing in the Vi and intestinal in the Ty21a group, the latter resembling that in natural infection. Plasmablasts proved more sensitive than serum and ALS in assessing the immune response. Conclusions The typhoid-specific humoral responses to Vi and Ty21a vaccines are similar in magnitude, but differ in expected localization and antigen-specificity. The unforeseen O antigen-specific response in the Vi group is probably due to lipopolysaccharide contaminating the vaccine preparation. Only the response to Ty21a vaccine was found to imitate that in natural infection. Trial Registration Current Controlled Trials Ltd. c/o BioMed Central ISRCTN68125331
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live oral typhoid vaccine salmonella typhi Ty21a a surrogate vaccine against non typhoid salmonella
Vaccine, 2012Co-Authors: Anu Kantele, Sari H Pakkanen, Anja Siitonen, Riitta Karttunen, Jussi M KanteleAbstract:Abstract Background Non-typhoid Salmonella (NTS) is a leading cause of food-borne illness with more than 90 million annual cases and an emerging antimicrobial resistance among the strains worldwide. Paradoxically, no vaccines are available against these pathogens. Numerous NTS strains share surface O-antigens with Salmonella enterica serotype Typhi. As intestinal antibodies against O-antigens have proven protective against NTS in animal experiments, it appears conceivable that the oral whole-cell typhoid vaccine, Salmonella Typhi Ty21a (Vivotif ® ), which effectively elicits intestinal antibodies against O-antigens, could exhibit cross-protective efficacy against NTS. We sought immunological evidence in support of cross-protective efficacy of Ty21a against NTS. Materials and methods 35 volunteers receiving Ty21a vaccine and five patients with enteric fever were investigated with ELISPOT for circulating plasmablasts secreting antibodies reactive with Salmonella Typhi and six different NTS serotypes. These plasmablasts were also analysed for homing receptor expressions. Results In all vaccinees and patients, a strong gut-directed cross-reactive plasmablast response was found against serotypes sharing the two O-antigens with Salmonella Typhi (O-9,12) (in vaccinees, mean: 95%CI 268: 228–508 and 363: 234–493 plasmablasts/10 6 PBMC against Salmonella Typhi and Enteritidis). Responses against strains sharing one O-antigen (O-12) were weaker (222: 105–338 against Salmonella Typhimurium), while no significant reactivity was detected against strains without typhoidal O-antigens. Conclusions Intestinal antibodies against O-antigens protect against NTS in animal experiments. Ty21a was found to elicit intestinal immune responses cross-reactive with NTS strains sharing O-antigens with Ty21a. These include the most common NTS, Salmonella Enteritidis and Typhimurium. The data suggest that Ty21a may have cross-protective efficacy against numerous NTS strains.
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cross reactive gut directed immune response against salmonella enterica serovar paratyphi a and b in typhoid fever and after oral Ty21a typhoid vaccination
Vaccine, 2012Co-Authors: Sari H Pakkanen, Jussi M Kantele, Anu KanteleAbstract:Abstract Background There are no vaccines against paratyphoid fever in clinical use. The disease has become more wide-spread and there is a growing problem of antibiotic resistance among the strains. Previous reports suggest that the oral live Salmonella Typhi Ty21a-vaccine confers protection against paratyphoid B fever. Data on efficacy against paratyphoid A fever are somewhat contentious. The present study investigated the immunological basis for such efficacy reports at a single-cell level: plasmablasts (identified as antibody-secreting cells, ASC) were studied for secretion of antibodies cross-reactive with Salmonella Paratyphi in the circulation of patients with enteric fever and of volunteers vaccinated with Ty21a. Materials and methods Thirty volunteers immunized with Ty21a and five patients with enteric fever were investigated for Salmonella Typhi and Salmonella Paratyphi A/B/C-specific circulating plasmablasts. PBMC were sorted by their expression of homing receptors (HR) for the intestine (α4β7), peripheral lymph node ( l -selectin) and skin (CLA) and typhoid- and paratyphoid-specific plasmablasts were enumerated with ELISPOT. Results Before vaccination, no cross-reactive ASC were found in the volunteers. In addition to the Salmonella Typhi-specific response, a significant cross-reactive immune response was mounted against Salmonella Paratyphi A and B both in the patients and the vaccinees. The magnitude of the response increased in the order Salmonella Paratyphi A (median 30 ASC/10 6 PBMC) → Salmonella Paratyphi B (median 81) → Salmonella Typhi (median 301) in the vaccinees. Both in patients and in vaccinees, the homing receptor (HR) selection favored homing to the gut, indicating a humoral intestinal immune response. Conclusions These immunological data provide evidence consistent with previous reports describing certain levels of cross-protective efficacy of Ty21a against paratyphoid fever. Controlled studies are needed to evaluate cross-protective efficacy. In the current situation where paratyphoid fever is emerging and no vaccines are available, any level of cross-protective capacity is valuable.
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comparison of the human immune response to live oral killed oral or killed parenteral salmonella typhi Ty21a vaccines
Microbial Pathogenesis, 1991Co-Authors: Anu Kantele, Jussi M Kantele, Heikki Arvilommi, L Rintala, P H MakelaAbstract:Abstract The live oral typhoid vaccine Ty21a has proved to confer protection against the disease at least as effectively as killed parenteral vaccines, whereas killed oral vaccines have not been protective in field trials. This prompted us to compare the immune response of subjects vaccinated either with live oral, killed oral or killed parenteral Salmonella typhi Ty21a vaccine. The immune responses were studied by analysis of peripheral blood antibody-secreting cells (ASC), believed to reflect the mucosal immune response. Live and killed bacteria administered by the oral route elicited immune responses of similar specificity and Ig class profile (IgA dominating), but the response to the live vaccine was significantly stronger and lasted longer The administration route, on the other hand, influenced the antigenic specificity of the ASC response suggesting different processing of the antigen by the systemic and local immune systems. Thus, the response after oral vaccination was almost exclusively directed to the surface O-antigen, whereas after parenteral vaccination an equally strong response was seen to the O-antigen, to lipopolysaccharide core and to flagella.
