The Experts below are selected from a list of 9759 Experts worldwide ranked by ideXlab platform
Ann-mari Svennerholm - One of the best experts on this subject based on the ideXlab platform.
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induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia Coli Vaccine
Vaccine, 2016Co-Authors: Anna Lundgren, Marianne Jertborn, Ann-mari SvennerholmAbstract:Abstract We have evaluated the capacity of an oral multivalent enterotoxigenic Escherichia Coli (ETEC) Vaccine (MEV) to induce mucosal immunological memory. MEV consists of four inactivated E. Coli strains over-expressing the major colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the LTB-related toxoid LCTB A . Memory responses were analyzed by comparing the magnitudes and kinetics of intestine-derived antibody-secreting cell responses to a single dose of MEV in three groups of adult Swedish volunteers ( n = 16–19 subjects per group) in a Phase I trial: non-immunized controls (I) and subjects who in a previous Phase I trial 13–23 months earlier had received two biweekly doses of MEV (II) or MEV + double mutant LT (dmLT) adjuvant (III). Responses against CFs and LTB were analyzed in antibodies in lymphocyte secretions (ALS) of blood mononuclear cells collected before (day 0) and 4/5 and 7 days after immunization. Specific circulating memory B cells present at the time of the single dose vaccination were also studied to determine if such cells may reflect mucosal memory. Considerably higher and significantly more frequent IgA ALS responses against all CFs and LTB were induced by the single Vaccine dose in the previously immunized than in non-immunized volunteers. Furthermore, peak IgA ALS responses against all antigens were observed on days 4/5 in most of the previously immunized subjects whereas only a few previously non-vaccinated individuals responded before day 7. Priming with adjuvant did not influence memory responses. Circulating Vaccine specific IgA memory B cells were not detected, whereas anti-toxin IgG memory B cells were identified 13–23 months after priming vaccination. We conclude that MEV induces functional mucosal immunological memory which remains at least 1–2 years. Furthermore, our results support that analysis of antibody-secreting cell responses after booster vaccination may be a useful approach to evaluate longstanding mucosal immunological memory in humans. Clinical trials registration: ISRCTN27096290.
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recent progress toward an enterotoxigenic Escherichia Coli Vaccine
Expert Review of Vaccines, 2012Co-Authors: Ann-mari Svennerholm, Anna LundgrenAbstract:Enterotoxigenic Escherichia Coli(ETEC) is the most common cause of bacterial diarrhea in children in Africa, Asia and Latin America and in travelers to these regions. Despite this, no effective Vaccine for ETEC is available. ETEC causes disease by colonizing the small intestine with colonization factors, most of which are fimbriae, and production of heat-labile and/or heat-stable enterotoxins. Antibodies against heat-labile enterotoxin and the colonization factors have been shown to be protective, and local immunity in the gut seems to be of prime importance for protection. Hence, several inactivated and live candidate ETEC Vaccines consisting of toxin antigens, alone or together with colonization factors, have been evaluated in clinical trials. In this review, the authors describe ETEC Vaccine development in progress and the rationale for constructing different types of Vaccines. They also discuss possibilities of enhancing immune responses to candidate ETEC Vaccines, particularly in children.
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dose dependent circulating immunoglobulin a antibody secreting cell and serum antibody responses in swedish volunteers to an oral inactivated enterotoxigenic Escherichia Coli Vaccine
Clinical and Vaccine Immunology, 2001Co-Authors: Marianne Jertborn, Christina Ahren, Ann-mari SvennerholmAbstract:The immunogenicity of different preparations of an oral inactivated enterotoxigenic Escherichia Coli (ETEC) Vaccine was evaluated in Swedish volunteers previously unexposed to ETEC infection. The Vaccine preparations consisted of recombinant cholera toxin B subunit (CTB) and various amounts of formalin-killed whole bacteria expressing the most prevalent colonization factor antigens (CFAs). Significant immunoglobulin A (IgA) antibody-secreting cell (ASC) responses against CTB and the various CFA components were seen in a majority of volunteers after two doses of ETEC Vaccine independent of the Vaccine lot given. The IgA ASC responses against CTB were significantly higher after the second than after the first immunization, whereas the CFA-specific IgA ASC responses were almost comparable after the first and second doses of ETEC Vaccine. Two immunizations with one-third of a full dose of CFA-ETEC bacteria induced lower frequencies of IgA ASC responses against all the different CFAs than two full Vaccine doses, i.e., 63 versus 80% for CFA/I, 56 versus 70% for CS1, 31 versus 65% for CS2, and 56 versus 75% for CS4. The proportion of Vaccinees responding with rises in the titer of serum IgA antibody against the various CFA antigens was also lower after immunization with the reduced dose of CFA-ETEC bacteria. These findings suggest that measurements of circulating IgA ASCs can be used not only for qualitative but also for quantitative assessments of the immunogenicity of individual fimbrial antigens in various preparations of ETEC Vaccine.
Clayton Harro - One of the best experts on this subject based on the ideXlab platform.
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interrogation of a live attenuated enterotoxigenic Escherichia Coli Vaccine highlights features unique to wild type infection
NPJ Vaccines, 2019Co-Authors: Subhra Chakraborty, Arlo Randall, Tim J Vickers, Doug Molina, Clayton Harro, Barbara Denearing, Jessica Brubaker, David A Sack, Louis Bourgeois, Philip L FelgnerAbstract:Enterotoxigenic Escherichia Coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC Vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, Vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the Vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, Vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, Vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in Vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide Vaccine antigen selection for these pathogens of global importance.
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development of a novel multiplex electrochemiluminescent based immunoassay to aid enterotoxigenic Escherichia Coli Vaccine development and evaluations
Journal of Immunological Methods, 2019Co-Authors: Subhra Chakraborty, Clayton Harro, Jessica Brubaker, Thomas Weirzba, David A SackAbstract:Enterotoxigenic Escherichia Coli (ETEC) is a leading cause of bacterial diarrhea both among children in low and middle income countries and in travelers to these regions. Although there are several approaches to develop an effective Vaccine for ETEC, no licensed Vaccines are currently available. The most advanced ETEC Vaccine candidates include multiple colonization factors along with the heat labile toxin B subunit. In the absence of known correlates of protection, and to understand the mechanism of protection, monitoring immune responses to a majority of the Vaccine associated antigens using various types of samples is needed. Unfortunately, a traditional ELISA is time consuming, labor intensive and requires substantial amounts of antigens and sample volumes. To address these constraints, we developed and validated a novel high throughput electrochemiluminescent (ECL) - based multiplex immunoassay using Meso Scale Discovery (MSD) platform for analyzing immune responses to ETEC antigens. The ETEC multiplex ECL assay is an 8-plex assay which includes the ETEC colonization factor antigens (CFA/I, CS1, CS2, CS3, CS5 and CS6) along with the two subunits of heat labile toxin (LTA and LTB). Our data suggested that a single dilution of sample provides a quantifiable result for a wide range of sample titers. To compare ETEC multiplex ECL with ELISA, we carried out assays using the same antigens with the two immunoassay platforms using a common sample set of serum and ALS (antibodies in lymphocyte supernatant) specimens. The MSD platform achieved excellent correlations with ELISA for the antigens tested, consistently detecting comparable antibody levels in the samples. The ETEC multiplex ECL can serve as a fundamental platform in evaluating performances of candidate ETEC Vaccines in future field trials.
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characterization of mucosal immune responses to enterotoxigenic Escherichia Coli Vaccine antigens in a human challenge model response profiles after primary infection and homologous rechallenge with strain h10407
Clinical and Vaccine Immunology, 2016Co-Authors: Subhra Chakraborty, Clayton Harro, Barbara Denearing, Andrea Feller, Louis A Bourgeois, Richard I Walker, Malathi Ram, Alicia Cage, Nicole Bauers, David A SackAbstract:Enterotoxigenic Escherichia Coli (ETEC) bacteria are the most common bacterial cause of diarrhea in children in resource-poor settings as well as in travelers. Although there are several approaches to develop an effective Vaccine for ETEC, no licensed Vaccines are currently available. A significant challenge to successful Vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. In this study, ETEC-specific mucosal immune responses were characterized and compared in subjects challenged with ETEC strain H10407 and in subjects rechallenged with the homologous organism. IgA responses to lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and colonization factor antigen I (CFA/I) in antibody in lymphocyte supernatant (ALS), feces, lavage fluid, and saliva samples were evaluated. In all assay comparisons, ALS was the most sensitive indicator of a local immune response, but serum IgA was also a useful indirect marker of immune response to oral antigens. Volunteers challenged and then rechallenged with strain H10407 were protected from illness following rechallenge. Comparing mucosal antibody responses after primary and homologous rechallenge, protection against disease was reflected in reduced antibody responses to key ETEC antigens and in reduced fecal shedding of the H10407 challenge strain. Subjects challenged with strain H10407 mounted stronger antibody responses to LPS and LTB than subjects in the rechallenge group, while responses to CFA/I in the rechallenge group were higher than in the challenge group. We anticipate that this study will help provide an immunological benchmark for the evaluation of ETEC Vaccines and immunization regimens in the future.
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the oral live attenuated enterotoxigenic Escherichia Coli Vaccine ace527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease
Clinical and Vaccine Immunology, 2012Co-Authors: Michael J Darsley, Subhra Chakraborty, Barbara Denearing, David A Sack, Andrea Feller, Charlotte Buchwaldt, Louis A Bourgeois, Richard I Walker, Clayton HarroAbstract:An oral, live attenuated, three-strain recombinant bacterial Vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia Coli (ETEC) in human volunteers. The Vaccine was safe and well tolerated at doses of up to 10(11) CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of Vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the Vaccine for both travelers and infants in countries where ETEC is endemic. The Vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in Vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 Vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings.
David A Sack - One of the best experts on this subject based on the ideXlab platform.
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interrogation of a live attenuated enterotoxigenic Escherichia Coli Vaccine highlights features unique to wild type infection
NPJ Vaccines, 2019Co-Authors: Subhra Chakraborty, Arlo Randall, Tim J Vickers, Doug Molina, Clayton Harro, Barbara Denearing, Jessica Brubaker, David A Sack, Louis Bourgeois, Philip L FelgnerAbstract:Enterotoxigenic Escherichia Coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC Vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, Vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the Vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, Vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, Vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in Vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide Vaccine antigen selection for these pathogens of global importance.
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development of a novel multiplex electrochemiluminescent based immunoassay to aid enterotoxigenic Escherichia Coli Vaccine development and evaluations
Journal of Immunological Methods, 2019Co-Authors: Subhra Chakraborty, Clayton Harro, Jessica Brubaker, Thomas Weirzba, David A SackAbstract:Enterotoxigenic Escherichia Coli (ETEC) is a leading cause of bacterial diarrhea both among children in low and middle income countries and in travelers to these regions. Although there are several approaches to develop an effective Vaccine for ETEC, no licensed Vaccines are currently available. The most advanced ETEC Vaccine candidates include multiple colonization factors along with the heat labile toxin B subunit. In the absence of known correlates of protection, and to understand the mechanism of protection, monitoring immune responses to a majority of the Vaccine associated antigens using various types of samples is needed. Unfortunately, a traditional ELISA is time consuming, labor intensive and requires substantial amounts of antigens and sample volumes. To address these constraints, we developed and validated a novel high throughput electrochemiluminescent (ECL) - based multiplex immunoassay using Meso Scale Discovery (MSD) platform for analyzing immune responses to ETEC antigens. The ETEC multiplex ECL assay is an 8-plex assay which includes the ETEC colonization factor antigens (CFA/I, CS1, CS2, CS3, CS5 and CS6) along with the two subunits of heat labile toxin (LTA and LTB). Our data suggested that a single dilution of sample provides a quantifiable result for a wide range of sample titers. To compare ETEC multiplex ECL with ELISA, we carried out assays using the same antigens with the two immunoassay platforms using a common sample set of serum and ALS (antibodies in lymphocyte supernatant) specimens. The MSD platform achieved excellent correlations with ELISA for the antigens tested, consistently detecting comparable antibody levels in the samples. The ETEC multiplex ECL can serve as a fundamental platform in evaluating performances of candidate ETEC Vaccines in future field trials.
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characterization of mucosal immune responses to enterotoxigenic Escherichia Coli Vaccine antigens in a human challenge model response profiles after primary infection and homologous rechallenge with strain h10407
Clinical and Vaccine Immunology, 2016Co-Authors: Subhra Chakraborty, Clayton Harro, Barbara Denearing, Andrea Feller, Louis A Bourgeois, Richard I Walker, Malathi Ram, Alicia Cage, Nicole Bauers, David A SackAbstract:Enterotoxigenic Escherichia Coli (ETEC) bacteria are the most common bacterial cause of diarrhea in children in resource-poor settings as well as in travelers. Although there are several approaches to develop an effective Vaccine for ETEC, no licensed Vaccines are currently available. A significant challenge to successful Vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. In this study, ETEC-specific mucosal immune responses were characterized and compared in subjects challenged with ETEC strain H10407 and in subjects rechallenged with the homologous organism. IgA responses to lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and colonization factor antigen I (CFA/I) in antibody in lymphocyte supernatant (ALS), feces, lavage fluid, and saliva samples were evaluated. In all assay comparisons, ALS was the most sensitive indicator of a local immune response, but serum IgA was also a useful indirect marker of immune response to oral antigens. Volunteers challenged and then rechallenged with strain H10407 were protected from illness following rechallenge. Comparing mucosal antibody responses after primary and homologous rechallenge, protection against disease was reflected in reduced antibody responses to key ETEC antigens and in reduced fecal shedding of the H10407 challenge strain. Subjects challenged with strain H10407 mounted stronger antibody responses to LPS and LTB than subjects in the rechallenge group, while responses to CFA/I in the rechallenge group were higher than in the challenge group. We anticipate that this study will help provide an immunological benchmark for the evaluation of ETEC Vaccines and immunization regimens in the future.
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the oral live attenuated enterotoxigenic Escherichia Coli Vaccine ace527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease
Clinical and Vaccine Immunology, 2012Co-Authors: Michael J Darsley, Subhra Chakraborty, Barbara Denearing, David A Sack, Andrea Feller, Charlotte Buchwaldt, Louis A Bourgeois, Richard I Walker, Clayton HarroAbstract:An oral, live attenuated, three-strain recombinant bacterial Vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia Coli (ETEC) in human volunteers. The Vaccine was safe and well tolerated at doses of up to 10(11) CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of Vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the Vaccine for both travelers and infants in countries where ETEC is endemic. The Vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in Vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 Vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings.
Subhra Chakraborty - One of the best experts on this subject based on the ideXlab platform.
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interrogation of a live attenuated enterotoxigenic Escherichia Coli Vaccine highlights features unique to wild type infection
NPJ Vaccines, 2019Co-Authors: Subhra Chakraborty, Arlo Randall, Tim J Vickers, Doug Molina, Clayton Harro, Barbara Denearing, Jessica Brubaker, David A Sack, Louis Bourgeois, Philip L FelgnerAbstract:Enterotoxigenic Escherichia Coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC Vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, Vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the Vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, Vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, Vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in Vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide Vaccine antigen selection for these pathogens of global importance.
-
development of a novel multiplex electrochemiluminescent based immunoassay to aid enterotoxigenic Escherichia Coli Vaccine development and evaluations
Journal of Immunological Methods, 2019Co-Authors: Subhra Chakraborty, Clayton Harro, Jessica Brubaker, Thomas Weirzba, David A SackAbstract:Enterotoxigenic Escherichia Coli (ETEC) is a leading cause of bacterial diarrhea both among children in low and middle income countries and in travelers to these regions. Although there are several approaches to develop an effective Vaccine for ETEC, no licensed Vaccines are currently available. The most advanced ETEC Vaccine candidates include multiple colonization factors along with the heat labile toxin B subunit. In the absence of known correlates of protection, and to understand the mechanism of protection, monitoring immune responses to a majority of the Vaccine associated antigens using various types of samples is needed. Unfortunately, a traditional ELISA is time consuming, labor intensive and requires substantial amounts of antigens and sample volumes. To address these constraints, we developed and validated a novel high throughput electrochemiluminescent (ECL) - based multiplex immunoassay using Meso Scale Discovery (MSD) platform for analyzing immune responses to ETEC antigens. The ETEC multiplex ECL assay is an 8-plex assay which includes the ETEC colonization factor antigens (CFA/I, CS1, CS2, CS3, CS5 and CS6) along with the two subunits of heat labile toxin (LTA and LTB). Our data suggested that a single dilution of sample provides a quantifiable result for a wide range of sample titers. To compare ETEC multiplex ECL with ELISA, we carried out assays using the same antigens with the two immunoassay platforms using a common sample set of serum and ALS (antibodies in lymphocyte supernatant) specimens. The MSD platform achieved excellent correlations with ELISA for the antigens tested, consistently detecting comparable antibody levels in the samples. The ETEC multiplex ECL can serve as a fundamental platform in evaluating performances of candidate ETEC Vaccines in future field trials.
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characterization of mucosal immune responses to enterotoxigenic Escherichia Coli Vaccine antigens in a human challenge model response profiles after primary infection and homologous rechallenge with strain h10407
Clinical and Vaccine Immunology, 2016Co-Authors: Subhra Chakraborty, Clayton Harro, Barbara Denearing, Andrea Feller, Louis A Bourgeois, Richard I Walker, Malathi Ram, Alicia Cage, Nicole Bauers, David A SackAbstract:Enterotoxigenic Escherichia Coli (ETEC) bacteria are the most common bacterial cause of diarrhea in children in resource-poor settings as well as in travelers. Although there are several approaches to develop an effective Vaccine for ETEC, no licensed Vaccines are currently available. A significant challenge to successful Vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. In this study, ETEC-specific mucosal immune responses were characterized and compared in subjects challenged with ETEC strain H10407 and in subjects rechallenged with the homologous organism. IgA responses to lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and colonization factor antigen I (CFA/I) in antibody in lymphocyte supernatant (ALS), feces, lavage fluid, and saliva samples were evaluated. In all assay comparisons, ALS was the most sensitive indicator of a local immune response, but serum IgA was also a useful indirect marker of immune response to oral antigens. Volunteers challenged and then rechallenged with strain H10407 were protected from illness following rechallenge. Comparing mucosal antibody responses after primary and homologous rechallenge, protection against disease was reflected in reduced antibody responses to key ETEC antigens and in reduced fecal shedding of the H10407 challenge strain. Subjects challenged with strain H10407 mounted stronger antibody responses to LPS and LTB than subjects in the rechallenge group, while responses to CFA/I in the rechallenge group were higher than in the challenge group. We anticipate that this study will help provide an immunological benchmark for the evaluation of ETEC Vaccines and immunization regimens in the future.
-
the oral live attenuated enterotoxigenic Escherichia Coli Vaccine ace527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease
Clinical and Vaccine Immunology, 2012Co-Authors: Michael J Darsley, Subhra Chakraborty, Barbara Denearing, David A Sack, Andrea Feller, Charlotte Buchwaldt, Louis A Bourgeois, Richard I Walker, Clayton HarroAbstract:An oral, live attenuated, three-strain recombinant bacterial Vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia Coli (ETEC) in human volunteers. The Vaccine was safe and well tolerated at doses of up to 10(11) CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of Vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the Vaccine for both travelers and infants in countries where ETEC is endemic. The Vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in Vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 Vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings.
Marianne Jertborn - One of the best experts on this subject based on the ideXlab platform.
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induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia Coli Vaccine
Vaccine, 2016Co-Authors: Anna Lundgren, Marianne Jertborn, Ann-mari SvennerholmAbstract:Abstract We have evaluated the capacity of an oral multivalent enterotoxigenic Escherichia Coli (ETEC) Vaccine (MEV) to induce mucosal immunological memory. MEV consists of four inactivated E. Coli strains over-expressing the major colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the LTB-related toxoid LCTB A . Memory responses were analyzed by comparing the magnitudes and kinetics of intestine-derived antibody-secreting cell responses to a single dose of MEV in three groups of adult Swedish volunteers ( n = 16–19 subjects per group) in a Phase I trial: non-immunized controls (I) and subjects who in a previous Phase I trial 13–23 months earlier had received two biweekly doses of MEV (II) or MEV + double mutant LT (dmLT) adjuvant (III). Responses against CFs and LTB were analyzed in antibodies in lymphocyte secretions (ALS) of blood mononuclear cells collected before (day 0) and 4/5 and 7 days after immunization. Specific circulating memory B cells present at the time of the single dose vaccination were also studied to determine if such cells may reflect mucosal memory. Considerably higher and significantly more frequent IgA ALS responses against all CFs and LTB were induced by the single Vaccine dose in the previously immunized than in non-immunized volunteers. Furthermore, peak IgA ALS responses against all antigens were observed on days 4/5 in most of the previously immunized subjects whereas only a few previously non-vaccinated individuals responded before day 7. Priming with adjuvant did not influence memory responses. Circulating Vaccine specific IgA memory B cells were not detected, whereas anti-toxin IgG memory B cells were identified 13–23 months after priming vaccination. We conclude that MEV induces functional mucosal immunological memory which remains at least 1–2 years. Furthermore, our results support that analysis of antibody-secreting cell responses after booster vaccination may be a useful approach to evaluate longstanding mucosal immunological memory in humans. Clinical trials registration: ISRCTN27096290.
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dose dependent circulating immunoglobulin a antibody secreting cell and serum antibody responses in swedish volunteers to an oral inactivated enterotoxigenic Escherichia Coli Vaccine
Clinical and Vaccine Immunology, 2001Co-Authors: Marianne Jertborn, Christina Ahren, Ann-mari SvennerholmAbstract:The immunogenicity of different preparations of an oral inactivated enterotoxigenic Escherichia Coli (ETEC) Vaccine was evaluated in Swedish volunteers previously unexposed to ETEC infection. The Vaccine preparations consisted of recombinant cholera toxin B subunit (CTB) and various amounts of formalin-killed whole bacteria expressing the most prevalent colonization factor antigens (CFAs). Significant immunoglobulin A (IgA) antibody-secreting cell (ASC) responses against CTB and the various CFA components were seen in a majority of volunteers after two doses of ETEC Vaccine independent of the Vaccine lot given. The IgA ASC responses against CTB were significantly higher after the second than after the first immunization, whereas the CFA-specific IgA ASC responses were almost comparable after the first and second doses of ETEC Vaccine. Two immunizations with one-third of a full dose of CFA-ETEC bacteria induced lower frequencies of IgA ASC responses against all the different CFAs than two full Vaccine doses, i.e., 63 versus 80% for CFA/I, 56 versus 70% for CS1, 31 versus 65% for CS2, and 56 versus 75% for CS4. The proportion of Vaccinees responding with rises in the titer of serum IgA antibody against the various CFA antigens was also lower after immunization with the reduced dose of CFA-ETEC bacteria. These findings suggest that measurements of circulating IgA ASCs can be used not only for qualitative but also for quantitative assessments of the immunogenicity of individual fimbrial antigens in various preparations of ETEC Vaccine.