The Experts below are selected from a list of 1215 Experts worldwide ranked by ideXlab platform

Alan J A Mcbride - One of the best experts on this subject based on the ideXlab platform.

  • an overview of human Leptospirosis Vaccine design and future perspectives
    Expert Opinion on Drug Discovery, 2020
    Co-Authors: Carolina Rodrigues Felix, Bianca S Siedler, Liana Nunes Barbosa, Gabriana R Timm, Johnjoe Mcfadden, Alan J A Mcbride
    Abstract:

    Introduction: It's been 20 years since the first report of a recombinant Vaccine that protected against Leptospirosis. Since then, numerous recombinant Vaccines have been evaluated; however, no recombinant Vaccine candidate has advanced to clinical trials. With the ever-increasing burden of Leptospirosis, there is an urgent need for a universal Vaccine against Leptospirosis.Areas covered: This review covers the most promising Vaccine candidates that induced significant, reproducible, protection and how advances in the field of bioinformatics has led to the discovery of hundreds of novel protein targets. The authors also discuss the most recent findings regarding the innate immune response and host-pathogen interactions and their impact on the discovery of novel Vaccine candidates. In addition, the authors have identified what they believe are the most challenging problems for the discovery and development of a universal Vaccine and their potential solutions.Expert opinion: A universal Vaccine for Leptospirosis will likely only be achieved using a recombinant Vaccine as the bacterins are of limited use due to the lack of a cross-protective immune response. Although there are hundreds of novel targets, due to the lack of immune correlates and the need for more research into the basic microbiology of Leptospira spp., a universal Vaccine is 10-15 years away.

  • discovery of novel Leptospirosis Vaccine candidates using reverse and structural vaccinology
    Frontiers in Immunology, 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan J A Mcbride, Frederico Schmitt Kremer, Júlia Cougo Dos Santos, Luciano Da Silva Pinto
    Abstract:

    Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing Leptospirosis, a public health problem with global implications. Thousands of people die every year due to Leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers and the lack of an effective Vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) Vaccine, however, success has been limited. A prospective Vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied towards the discovery of novel leptospiral Vaccine candidates. The L. interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologues of the prospective Vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and eight OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g. TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each Vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis and physiology, in addition to Vaccine development.

  • high yield expression of Leptospirosis Vaccine candidates liga and lipl32 in the methylotrophic yeast pichia pastoris
    Microbial Cell Factories, 2010
    Co-Authors: Daiane D Hartwig, Alan J A Mcbride, Thais Larre Oliveira, Fabiana Kommling Seixas, Karine M Forster, Caroline Rizzi, Claudia Pinho Hartleben, Odir Antonio Dellagostin
    Abstract:

    Background Leptospirosis, a zoonosis caused by Leptospira spp., is recognized as an emergent infectious disease. Due to the lack of adequate diagnostic tools, Vaccines are an attractive intervention strategy. Recombinant proteins produced in Escherichia coli have demonstrated promising results, albeit with variable efficacy. Pichia pastoris is an alternative host with several advantages for the production of recombinant proteins.

Andre Alex Grassmann - One of the best experts on this subject based on the ideXlab platform.

  • discovery of novel Leptospirosis Vaccine candidates using reverse and structural vaccinology
    Frontiers in Immunology, 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan J A Mcbride, Frederico Schmitt Kremer, Júlia Cougo Dos Santos, Luciano Da Silva Pinto
    Abstract:

    Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing Leptospirosis, a public health problem with global implications. Thousands of people die every year due to Leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers and the lack of an effective Vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) Vaccine, however, success has been limited. A prospective Vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied towards the discovery of novel leptospiral Vaccine candidates. The L. interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologues of the prospective Vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and eight OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g. TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each Vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis and physiology, in addition to Vaccine development.

  • a universal Vaccine against Leptospirosis are we going in the right direction
    Frontiers in Immunology, 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride
    Abstract:

    Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the Leptospirosis Vaccine since the advent of bacterins over a hundred years ago. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short-term, serovar restricted and the Vaccine can cause serious side-effects. The urgent need for a new Vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant Vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the Lig proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed Vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal Vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against Leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls and possible solutions for the development of a universal Leptospirosis Vaccine.

  • A Universal Vaccine against Leptospirosis: Are We Going in the Right Direction?
    Frontiers Media S.A., 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride
    Abstract:

    Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the Leptospirosis Vaccine since the advent of bacterins over 100 years. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short term, serovar restricted, and the Vaccine can cause serious side effects. The urgent need for a new Vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant Vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the leptospiral immunoglobulin-like proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available, this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed Vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal Vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against Leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls, and possible solutions for the development of a universal Leptospirosis Vaccine

  • Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology
    Frontiers Media S.A., 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride, Frederico Schmitt Kremer, Júlia Cougo Dos Santos, Luciano Da Silva Pinto
    Abstract:

    Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing Leptospirosis, a public health problem with global implications. Thousands of people die every year due to Leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers, and the lack of an effective Vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) Vaccine; however, success has been limited. A prospective Vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied toward the discovery of novel leptospiral Vaccine candidates. The Leptospira interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologs of the prospective Vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified, and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and 8 OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g., TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery, and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each Vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis, and physiology, in addition to Vaccine development

  • Leptospirosis Vaccine search for subunit candidates
    Procedia in Vaccinology, 2009
    Co-Authors: Samuel Rodrigues Felix, Everton Fagonde Da Silva, Sandra Denize Dorneles Jouglard, D M Hartmann, Andre Alex Grassmann, Odir Antonio Dellagostin
    Abstract:

    Abstract Subunit Vaccines are a potential intervention strategy against Leptospirosis, which is a major public health problem in developing countries. Thus far, several proteins have been evaluated as potential Vaccine candidates, but all those tested in aluminum hydroxide adjuvant have failed to protect animals against lethal challenge. Seven new leptospiral lipoproteins were evaluated as Vaccine candidates. The coding sequences of these lipoproteins were amplified by PCR from Leptospira interrogans serovar Copenhageni, strain Fiocruz L1-130, cloned and expressed in Escherichia coli . The purified proteins were adsorbed in aluminum adjuvant and used in the immunization of four to six weeks old hamsters. After two doses of 60 μg of recombinant protein, hamsters were challenged with a lethal dose of L. interrogans . All seven tested proteins failed to fully protect the animals from disease or death. Further study must be undertaken toward developing an efficient subunit Vaccine against Leptospirosis for humans, livestock and pets.

Alan John Alexander Mcbride - One of the best experts on this subject based on the ideXlab platform.

  • a universal Vaccine against Leptospirosis are we going in the right direction
    Frontiers in Immunology, 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride
    Abstract:

    Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the Leptospirosis Vaccine since the advent of bacterins over a hundred years ago. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short-term, serovar restricted and the Vaccine can cause serious side-effects. The urgent need for a new Vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant Vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the Lig proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed Vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal Vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against Leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls and possible solutions for the development of a universal Leptospirosis Vaccine.

  • A Universal Vaccine against Leptospirosis: Are We Going in the Right Direction?
    Frontiers Media S.A., 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride
    Abstract:

    Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the Leptospirosis Vaccine since the advent of bacterins over 100 years. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short term, serovar restricted, and the Vaccine can cause serious side effects. The urgent need for a new Vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant Vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the leptospiral immunoglobulin-like proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available, this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed Vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal Vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against Leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls, and possible solutions for the development of a universal Leptospirosis Vaccine

  • Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology
    Frontiers Media S.A., 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride, Frederico Schmitt Kremer, Júlia Cougo Dos Santos, Luciano Da Silva Pinto
    Abstract:

    Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing Leptospirosis, a public health problem with global implications. Thousands of people die every year due to Leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers, and the lack of an effective Vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) Vaccine; however, success has been limited. A prospective Vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied toward the discovery of novel leptospiral Vaccine candidates. The Leptospira interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologs of the prospective Vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified, and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and 8 OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g., TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery, and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each Vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis, and physiology, in addition to Vaccine development

Jéssica Dias Souza - One of the best experts on this subject based on the ideXlab platform.

  • discovery of novel Leptospirosis Vaccine candidates using reverse and structural vaccinology
    Frontiers in Immunology, 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan J A Mcbride, Frederico Schmitt Kremer, Júlia Cougo Dos Santos, Luciano Da Silva Pinto
    Abstract:

    Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing Leptospirosis, a public health problem with global implications. Thousands of people die every year due to Leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers and the lack of an effective Vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) Vaccine, however, success has been limited. A prospective Vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied towards the discovery of novel leptospiral Vaccine candidates. The L. interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologues of the prospective Vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and eight OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g. TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each Vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis and physiology, in addition to Vaccine development.

  • a universal Vaccine against Leptospirosis are we going in the right direction
    Frontiers in Immunology, 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride
    Abstract:

    Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the Leptospirosis Vaccine since the advent of bacterins over a hundred years ago. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short-term, serovar restricted and the Vaccine can cause serious side-effects. The urgent need for a new Vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant Vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the Lig proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed Vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal Vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against Leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls and possible solutions for the development of a universal Leptospirosis Vaccine.

  • A Universal Vaccine against Leptospirosis: Are We Going in the Right Direction?
    Frontiers Media S.A., 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride
    Abstract:

    Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the Leptospirosis Vaccine since the advent of bacterins over 100 years. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short term, serovar restricted, and the Vaccine can cause serious side effects. The urgent need for a new Vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant Vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the leptospiral immunoglobulin-like proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available, this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed Vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal Vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against Leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls, and possible solutions for the development of a universal Leptospirosis Vaccine

  • Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology
    Frontiers Media S.A., 2017
    Co-Authors: Andre Alex Grassmann, Jéssica Dias Souza, Alan John Alexander Mcbride, Frederico Schmitt Kremer, Júlia Cougo Dos Santos, Luciano Da Silva Pinto
    Abstract:

    Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing Leptospirosis, a public health problem with global implications. Thousands of people die every year due to Leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers, and the lack of an effective Vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) Vaccine; however, success has been limited. A prospective Vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied toward the discovery of novel leptospiral Vaccine candidates. The Leptospira interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologs of the prospective Vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified, and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and 8 OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g., TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery, and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each Vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis, and physiology, in addition to Vaccine development

Bianca S Siedler - One of the best experts on this subject based on the ideXlab platform.

  • an overview of human Leptospirosis Vaccine design and future perspectives
    Expert Opinion on Drug Discovery, 2020
    Co-Authors: Carolina Rodrigues Felix, Bianca S Siedler, Liana Nunes Barbosa, Gabriana R Timm, Johnjoe Mcfadden, Alan J A Mcbride
    Abstract:

    Introduction: It's been 20 years since the first report of a recombinant Vaccine that protected against Leptospirosis. Since then, numerous recombinant Vaccines have been evaluated; however, no recombinant Vaccine candidate has advanced to clinical trials. With the ever-increasing burden of Leptospirosis, there is an urgent need for a universal Vaccine against Leptospirosis.Areas covered: This review covers the most promising Vaccine candidates that induced significant, reproducible, protection and how advances in the field of bioinformatics has led to the discovery of hundreds of novel protein targets. The authors also discuss the most recent findings regarding the innate immune response and host-pathogen interactions and their impact on the discovery of novel Vaccine candidates. In addition, the authors have identified what they believe are the most challenging problems for the discovery and development of a universal Vaccine and their potential solutions.Expert opinion: A universal Vaccine for Leptospirosis will likely only be achieved using a recombinant Vaccine as the bacterins are of limited use due to the lack of a cross-protective immune response. Although there are hundreds of novel targets, due to the lack of immune correlates and the need for more research into the basic microbiology of Leptospira spp., a universal Vaccine is 10-15 years away.