a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning o... more a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning of May it had caused over 130 human infections and 36 deaths. human-to-human transmission of avian-origin h7N9 influenza a has been limited to a few family clusters, but the high mortality rate (27%) associated with human infection has raised concern about the potential for this virus to become a significant human pathogen. european, american, and asian vaccine companies have already initiated the process of cloning h7 antigens such as hemagglutinin (ha) into standardized vaccine production vehicles. Unfortunately, previous h7 ha-containing vaccines have been poorly immunogenic. We used well-established immunoinformatics tools to analyze the h7N9 protein sequences and compare their T cell epitope content to other circulating influenza a strains as a means of estimating the immunogenic potential of the new influenza antigen. We found that the ha proteins derived from closely related human-derived h7N9 strains contain fewer T cell epitopes than other recently circulating strains of influenza, and that conservation of T cell epitopes with other strains of influenza was very limited. here, we provide a detailed accounting of the type and location of T cell epitopes contained in h7N9 and their conservation in other h7 and circulating (a/california/07/2009, a/Victoria/361/2011, and a/Texas/50/2012) influenza a strains. Based on this analysis, avian-origin h7N9 2013 appears to be a "stealth" virus, capable of evading human cellular and humoral immune response. should h7N9 develop pandemic potential, this analysis predicts that novel strategies for improving vaccine immunogenicity for this unique low-immunogenicity strain of avian-origin influenza will be urgently needed.
a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning o... more a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning of May it had caused over 130 human infections and 36 deaths. human-to-human transmission of avian-origin h7N9 influenza a has been limited to a few family clusters, but the high mortality rate (27%) associated with human infection has raised concern about the potential for this virus to become a significant human pathogen. european, american, and asian vaccine companies have already initiated the process of cloning h7 antigens such as hemagglutinin (ha) into standardized vaccine production vehicles. Unfortunately, previous h7 ha-containing vaccines have been poorly immunogenic. We used well-established immunoinformatics tools to analyze the h7N9 protein sequences and compare their T cell epitope content to other circulating influenza a strains as a means of estimating the immunogenic potential of the new influenza antigen. We found that the ha proteins derived from closely related human-derived h7N9 strains contain fewer T cell epitopes than other recently circulating strains of influenza, and that conservation of T cell epitopes with other strains of influenza was very limited. here, we provide a detailed accounting of the type and location of T cell epitopes contained in h7N9 and their conservation in other h7 and circulating (a/california/07/2009, a/Victoria/361/2011, and a/Texas/50/2012) influenza a strains. Based on this analysis, avian-origin h7N9 2013 appears to be a "stealth" virus, capable of evading human cellular and humoral immune response. should h7N9 develop pandemic potential, this analysis predicts that novel strategies for improving vaccine immunogenicity for this unique low-immunogenicity strain of avian-origin influenza will be urgently needed.
Advances in the field of T cell immunology have contributed to the understanding that cross-react... more Advances in the field of T cell immunology have contributed to the understanding that cross-reactivity is an intrinsic characteristic of the T cell receptor (TCR), and that each TCR can potentially interact with many different T cell epitopes. To better define the potential for TCR cross-reactivity between epitopes derived from the human genome, the human microbiome, and human pathogens, we developed a new immunoinformatics tool, JanusMatrix, that represents an extension of the validated T cell epitope mapping tool, EpiMatrix. Initial explorations, summarized in this synopsis, have uncovered what appear to be important differences in the TCR cross-reactivity of selected regulatory and effector T cell epitopes with other epitopes in the human genome, human microbiome, and selected human pathogens. In addition to exploring the T cell epitope relationships between human self, commensal and pathogen, JanusMatrix may also be useful to explore some aspects of heterologous immunity and to ...
Despite years of research, vaccines against HIV and HCV are not yet available, due largely to eff... more Despite years of research, vaccines against HIV and HCV are not yet available, due largely to effective viral immunoevasive mechanisms. A novel escape mechanism observed in viruses that cause chronic infection is suppression of viral-specific effector CD4 + and CD8 + T cells by stimulating regulatory T cells (Tregs) educated on host sequences during tolerance induction. Viral class II MHC epitopes that share a T cell receptor (TCR)-face with host epitopes may activate Tregs capable of suppressing protective responses. We designed an immunoinformatic algorithm, JanusMatrix, to identify such epitopes and discovered that among human-host viruses, chronic viruses appear more human-like than viruses that cause acute infection. Furthermore, an HCV epitope that activates Tregs in chronically infected patients, but not clearers, shares a TCR-face with numerous human sequences. To boost weak CD4 + T cell responses associated with persistent infection, vaccines for HIV and HCV must circumvent potential Treg activation that can handicap efficacy. Epitope-driven approaches to vaccine design that involve careful consideration of the T cell subsets primed during immunization will advance HIV and HCV vaccine development.
Immune responses to cross-conserved T cell epitopes in novel H1N1 influenza may explain reports o... more Immune responses to cross-conserved T cell epitopes in novel H1N1 influenza may explain reports of diminished influenza-like illnesses and confirmed infection among older adults, in the absence of cross-reactive humoral immunity, during the 2009 pandemic. These cross-conserved epitopes may prove useful for the development of a universal H1N1 influenza vaccine, therefore, we set out to identify and characterize cross-conserved H1N1 T cell epitopes. An immunoinformatic analysis was conducted using all available pandemic and pre-pandemic HA-H1 and NA-N1 sequences dating back to 1980. Using an approach that balances potential for immunogenicity with conservation, we derived 13 HA and four NA immunogenic consensus sequences (ICS) from a comprehensive analysis of 5,738 HA-H1 and 5,396 NA-N1 sequences. These epitopes were selected because their combined epitope content is representative of greater than 84% of pre-pandemic and pandemic H1N1 influenza strains, their predicted immunogenicity ...
One useful application of pattern matching algorithms is identification of major histocompatabili... more One useful application of pattern matching algorithms is identification of major histocompatability complex (MHC) ligands and T-cell epitopes. Peptides that bind to MHC molecules and interact with T cell receptors to stimulate the immune system are critical antigens for protection against infectious pathogens. We describe a genomes-to-vaccine approach to H. pylori vaccine design that takes advantage of immunoinformatics algorithms to rapidly identify T-cell epitope sequences from large genomic datasets. To design a globally relevant vaccine, we used computational methods to identify a core genome comprised of 676 open reading frames (ORFs) from amongst seven genetically and phenotypically diverse H. pylori strains from around the world. Of the 1,241,153 9-mer sequences encoded by these ORFs, 106,791 were identical amongst all seven genomes and 23,654 scored in the top 5% of predicted HLA ligands for at least one of eight archetypal Class II HLA alleles when evaluated by EpiMatrix. T...
H. pylori persists in the human stomach over decades and promotes several adverse clinical sequel... more H. pylori persists in the human stomach over decades and promotes several adverse clinical sequelae including gastritis, peptic ulcers and gastric cancer that are linked to the induction and subsequent evasion of chronic gastric inflammation. Emerging evidence indicates that H. pylori infection may also protect against asthma and some other immune-mediated conditions through regulatory T cell effects outside the stomach. To characterize the complexity of the CD4+ T cell response generated during H. pylori infection, computational methods were previously used to generate a panel of 90 predicted epitopes conserved among H. pylori genomes that broadly cover HLA Class II diversity for maximum population coverage. Here, these sequences were tested individually for their ability to induce in vitro responses in peripheral blood mononuclear cells by interferon-γ ELISpot assay. The average number of spot-forming cells/million PBMCs was significantly elevated in H. pylori-infected subjects ov...
Methods for identifying physiologically relevant T-cell epitopes are critically important for dev... more Methods for identifying physiologically relevant T-cell epitopes are critically important for development of vaccines and the design of therapeutic proteins. As the number of proteins that are being evaluated for putative immunogenicity expands, rapid and accurate tools are in great demand. Several methods to identify T-cell epitopes have been developed, the most recent of which is a cell free system consisting of a minimal set of proteases incubated with HLA DRB1*0101, HLA-DM and whole antigen. Isolation and sequencing of the HLA bound peptides using mass spectrometry allows for the prospective identification of immunodominant T-cell epitopes. We present here, a comparison of this cell free in vitro antigen processing system to an immunoinformatics approach using the EpiMatrix algorithm. Our comparison reveals that in addition to identifying a similar set of epitopes to the cell-free system, the immunoinformatics approach prospectively identifies more HLA-DRB1*0101 epitopes and can...
a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning o... more a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning of May it had caused over 130 human infections and 36 deaths. human-to-human transmission of avian-origin h7N9 influenza a has been limited to a few family clusters, but the high mortality rate (27%) associated with human infection has raised concern about the potential for this virus to become a significant human pathogen. european, american, and asian vaccine companies have already initiated the process of cloning h7 antigens such as hemagglutinin (ha) into standardized vaccine production vehicles. Unfortunately, previous h7 ha-containing vaccines have been poorly immunogenic. We used well-established immunoinformatics tools to analyze the h7N9 protein sequences and compare their T cell epitope content to other circulating influenza a strains as a means of estimating the immunogenic potential of the new influenza antigen. We found that the ha proteins derived from closely related human-derived h7N9 strains contain fewer T cell epitopes than other recently circulating strains of influenza, and that conservation of T cell epitopes with other strains of influenza was very limited. here, we provide a detailed accounting of the type and location of T cell epitopes contained in h7N9 and their conservation in other h7 and circulating (a/california/07/2009, a/Victoria/361/2011, and a/Texas/50/2012) influenza a strains. Based on this analysis, avian-origin h7N9 2013 appears to be a "stealth" virus, capable of evading human cellular and humoral immune response. should h7N9 develop pandemic potential, this analysis predicts that novel strategies for improving vaccine immunogenicity for this unique low-immunogenicity strain of avian-origin influenza will be urgently needed.
a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning o... more a new avian-origin influenza virus emerged near shanghai in February 2013, and by the beginning of May it had caused over 130 human infections and 36 deaths. human-to-human transmission of avian-origin h7N9 influenza a has been limited to a few family clusters, but the high mortality rate (27%) associated with human infection has raised concern about the potential for this virus to become a significant human pathogen. european, american, and asian vaccine companies have already initiated the process of cloning h7 antigens such as hemagglutinin (ha) into standardized vaccine production vehicles. Unfortunately, previous h7 ha-containing vaccines have been poorly immunogenic. We used well-established immunoinformatics tools to analyze the h7N9 protein sequences and compare their T cell epitope content to other circulating influenza a strains as a means of estimating the immunogenic potential of the new influenza antigen. We found that the ha proteins derived from closely related human-derived h7N9 strains contain fewer T cell epitopes than other recently circulating strains of influenza, and that conservation of T cell epitopes with other strains of influenza was very limited. here, we provide a detailed accounting of the type and location of T cell epitopes contained in h7N9 and their conservation in other h7 and circulating (a/california/07/2009, a/Victoria/361/2011, and a/Texas/50/2012) influenza a strains. Based on this analysis, avian-origin h7N9 2013 appears to be a "stealth" virus, capable of evading human cellular and humoral immune response. should h7N9 develop pandemic potential, this analysis predicts that novel strategies for improving vaccine immunogenicity for this unique low-immunogenicity strain of avian-origin influenza will be urgently needed.
Advances in the field of T cell immunology have contributed to the understanding that cross-react... more Advances in the field of T cell immunology have contributed to the understanding that cross-reactivity is an intrinsic characteristic of the T cell receptor (TCR), and that each TCR can potentially interact with many different T cell epitopes. To better define the potential for TCR cross-reactivity between epitopes derived from the human genome, the human microbiome, and human pathogens, we developed a new immunoinformatics tool, JanusMatrix, that represents an extension of the validated T cell epitope mapping tool, EpiMatrix. Initial explorations, summarized in this synopsis, have uncovered what appear to be important differences in the TCR cross-reactivity of selected regulatory and effector T cell epitopes with other epitopes in the human genome, human microbiome, and selected human pathogens. In addition to exploring the T cell epitope relationships between human self, commensal and pathogen, JanusMatrix may also be useful to explore some aspects of heterologous immunity and to ...
Despite years of research, vaccines against HIV and HCV are not yet available, due largely to eff... more Despite years of research, vaccines against HIV and HCV are not yet available, due largely to effective viral immunoevasive mechanisms. A novel escape mechanism observed in viruses that cause chronic infection is suppression of viral-specific effector CD4 + and CD8 + T cells by stimulating regulatory T cells (Tregs) educated on host sequences during tolerance induction. Viral class II MHC epitopes that share a T cell receptor (TCR)-face with host epitopes may activate Tregs capable of suppressing protective responses. We designed an immunoinformatic algorithm, JanusMatrix, to identify such epitopes and discovered that among human-host viruses, chronic viruses appear more human-like than viruses that cause acute infection. Furthermore, an HCV epitope that activates Tregs in chronically infected patients, but not clearers, shares a TCR-face with numerous human sequences. To boost weak CD4 + T cell responses associated with persistent infection, vaccines for HIV and HCV must circumvent potential Treg activation that can handicap efficacy. Epitope-driven approaches to vaccine design that involve careful consideration of the T cell subsets primed during immunization will advance HIV and HCV vaccine development.
Immune responses to cross-conserved T cell epitopes in novel H1N1 influenza may explain reports o... more Immune responses to cross-conserved T cell epitopes in novel H1N1 influenza may explain reports of diminished influenza-like illnesses and confirmed infection among older adults, in the absence of cross-reactive humoral immunity, during the 2009 pandemic. These cross-conserved epitopes may prove useful for the development of a universal H1N1 influenza vaccine, therefore, we set out to identify and characterize cross-conserved H1N1 T cell epitopes. An immunoinformatic analysis was conducted using all available pandemic and pre-pandemic HA-H1 and NA-N1 sequences dating back to 1980. Using an approach that balances potential for immunogenicity with conservation, we derived 13 HA and four NA immunogenic consensus sequences (ICS) from a comprehensive analysis of 5,738 HA-H1 and 5,396 NA-N1 sequences. These epitopes were selected because their combined epitope content is representative of greater than 84% of pre-pandemic and pandemic H1N1 influenza strains, their predicted immunogenicity ...
One useful application of pattern matching algorithms is identification of major histocompatabili... more One useful application of pattern matching algorithms is identification of major histocompatability complex (MHC) ligands and T-cell epitopes. Peptides that bind to MHC molecules and interact with T cell receptors to stimulate the immune system are critical antigens for protection against infectious pathogens. We describe a genomes-to-vaccine approach to H. pylori vaccine design that takes advantage of immunoinformatics algorithms to rapidly identify T-cell epitope sequences from large genomic datasets. To design a globally relevant vaccine, we used computational methods to identify a core genome comprised of 676 open reading frames (ORFs) from amongst seven genetically and phenotypically diverse H. pylori strains from around the world. Of the 1,241,153 9-mer sequences encoded by these ORFs, 106,791 were identical amongst all seven genomes and 23,654 scored in the top 5% of predicted HLA ligands for at least one of eight archetypal Class II HLA alleles when evaluated by EpiMatrix. T...
H. pylori persists in the human stomach over decades and promotes several adverse clinical sequel... more H. pylori persists in the human stomach over decades and promotes several adverse clinical sequelae including gastritis, peptic ulcers and gastric cancer that are linked to the induction and subsequent evasion of chronic gastric inflammation. Emerging evidence indicates that H. pylori infection may also protect against asthma and some other immune-mediated conditions through regulatory T cell effects outside the stomach. To characterize the complexity of the CD4+ T cell response generated during H. pylori infection, computational methods were previously used to generate a panel of 90 predicted epitopes conserved among H. pylori genomes that broadly cover HLA Class II diversity for maximum population coverage. Here, these sequences were tested individually for their ability to induce in vitro responses in peripheral blood mononuclear cells by interferon-γ ELISpot assay. The average number of spot-forming cells/million PBMCs was significantly elevated in H. pylori-infected subjects ov...
Methods for identifying physiologically relevant T-cell epitopes are critically important for dev... more Methods for identifying physiologically relevant T-cell epitopes are critically important for development of vaccines and the design of therapeutic proteins. As the number of proteins that are being evaluated for putative immunogenicity expands, rapid and accurate tools are in great demand. Several methods to identify T-cell epitopes have been developed, the most recent of which is a cell free system consisting of a minimal set of proteases incubated with HLA DRB1*0101, HLA-DM and whole antigen. Isolation and sequencing of the HLA bound peptides using mass spectrometry allows for the prospective identification of immunodominant T-cell epitopes. We present here, a comparison of this cell free in vitro antigen processing system to an immunoinformatics approach using the EpiMatrix algorithm. Our comparison reveals that in addition to identifying a similar set of epitopes to the cell-free system, the immunoinformatics approach prospectively identifies more HLA-DRB1*0101 epitopes and can...
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Papers by F. Terry