The Experts below are selected from a list of 18381 Experts worldwide ranked by ideXlab platform
Peter Palese - One of the best experts on this subject based on the ideXlab platform.
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An immuno-assay to quantify Influenza Virus Hemagglutinin with correctly folded stalk domains in vaccine preparations.
'Public Library of Science (PLoS)', 2018Co-Authors: Madhusudan Rajendran, Raffael Nachbagauer, Peter Palese, Ericka Kirkpatrick, Weina Sun, Phillip Comella, Teddy John Wohlbold, Fatima Amanat, Florian KrammerAbstract:The standard method to quantify the Hemagglutinin content of Influenza Virus vaccines is the single radial immunodiffusion assay. This assay primarily relies on polyclonal antibodies against the head domain of the Influenza Virus Hemagglutinin, which is the main target antigen of Influenza Virus vaccines. Novel Influenza Virus vaccine candidates that redirect the immune response towards the evolutionary more conserved Hemagglutinin stalk, including chimeric Hemagglutinin and headless Hemagglutinin constructs, are highly dependent on the structural integrity of the protein to present conformational epitopes for neutralizing antibodies. In this study, we describe a novel enzyme-linked immunosorbent assay that allows quantifying the amount of Hemagglutinin with correctly folded stalk domains and which could be further developed into a potency assay for stalk-based Influenza Virus vaccines
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Hemagglutinin stalk immunity reduces Influenza Virus replication and transmission in ferrets
Journal of Virology, 2016Co-Authors: Raffael Nachbagauer, Peter Palese, Florian Krammer, Rong Hai, Alex B. Ryder, Matthew S. Miller, John K. Rose, Adolfo Garciasastre, Randy A AlbrechtAbstract:We assessed whether Influenza Virus Hemagglutinin stalk-based immunity protects ferrets against aerosol-transmitted H1N1 Influenza Virus infection. Immunization of ferrets by a universal Influenza Virus vaccine strategy based on viral vectors expressing chimeric Hemagglutinin constructs induced stalk-specific antibody responses. Stalk-immunized ferrets were cohoused with H1N1-infected ferrets under conditions that permitted Virus transmission. Hemagglutinin stalk-immunized ferrets had lower viral titers and delayed or no Virus replication at all following natural exposure to Influenza Virus.
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Age Dependence and Isotype Specificity of Influenza Virus Hemagglutinin Stalk-Reactive Antibodies in Humans
American Society for Microbiology, 2016Co-Authors: Raffael Nachbagauer, Peter Palese, Angela Choi, Ruvim Izikson, Manon M. Cox, Florian KrammerAbstract:Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the Virus undergoes extensive antigenic drift. Antibodies that target the highly conserved Hemagglutinin stalk can protect against drifted Viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal Influenza Virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant Hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and Influenza B Virus Hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low Influenza Virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.
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assessment of Influenza Virus Hemagglutinin stalk based immunity in ferrets
Journal of Virology, 2014Co-Authors: Florian Krammer, Peter Palese, Rong Hai, Mark A. Yondola, Gene S. Tan, Alex B. Ryder, Matthew S. Miller, John K. Rose, Victor H Leyvagrado, Adolfo GarciasastreAbstract:Therapeutic monoclonal antibodies that target the conserved stalk domain of the Influenza Virus Hemagglutinin as well as stalk-based universal Influenza Virus vaccine strategies are being developed as promising countermeasures for Influenza Virus infections. The pan-H1 reactive monoclonal antibody 6F12 has been extensively characterized and shows broad efficacy against divergent H1N1 strains in the mouse model. Here we demonstrate its efficacy against a pandemic H1N1 challenge Virus in the ferret model of Influenza disease. Furthermore, we recently developed a universal Influenza Virus vaccine strategy based on chimeric Hemagglutinin constructs that focuses the immune response towards the conserved stalk domain of the Hemagglutinin. Here we set out to test this vaccination strategy in the ferret model. Both strategies, pre-treatment of animals with stalk-reactive monoclonal antibody as well as vaccination with chimeric Hemagglutinin based constructs were able to significantly reduce viral titers in nasal turbinates, lungs and olfactory bulbs. In addition, vaccinated animals also showed reduced nasal wash viral titers. In summary both strategies showed efficacy in reducing viral loads after Influenza Virus challenge in the ferret model.
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Influenza Virus Hemagglutinin stalk based antibodies and vaccines
Current Opinion in Virology, 2013Co-Authors: Florian Krammer, Peter PaleseAbstract:Antibodies against the conserved stalk domain of the Hemagglutinin are currently being discussed as promising therapeutic tools against Influenza Virus infections. Because of the conservation of the stalk domain these antibodies are able to broadly neutralize a wide spectrum of Influenza Virus strains and subtypes. Broadly protective vaccine candidates based on the epitopes of these antibodies, for example, chimeric and headless Hemagglutinin structures, are currently under development and show promising results in animals models. These candidates could be developed into universal Influenza Virus vaccines that protect from infection with drifted seasonal as well as novel pandemic Influenza Virus strains therefore obviating the need for annual vaccination, and enhancing our pandemic preparedness.
Florian Krammer - One of the best experts on this subject based on the ideXlab platform.
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the Influenza Virus Hemagglutinin head evolves faster than the stalk domain
Scientific Reports, 2018Co-Authors: Ericka Kirkpatrick, Xueting Qiu, Patrick C Wilson, Justin Bahl, Florian KrammerAbstract:The limited ability of current Influenza Virus vaccines to protect from antigenically drifted or shifted Viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current Influenza Virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the Hemagglutinin, the major surface glycoprotein of the Virus, the Hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between Influenza A Virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the Hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and Influenza B Viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these Virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 Hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact Virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses.
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An immuno-assay to quantify Influenza Virus Hemagglutinin with correctly folded stalk domains in vaccine preparations.
'Public Library of Science (PLoS)', 2018Co-Authors: Madhusudan Rajendran, Raffael Nachbagauer, Peter Palese, Ericka Kirkpatrick, Weina Sun, Phillip Comella, Teddy John Wohlbold, Fatima Amanat, Florian KrammerAbstract:The standard method to quantify the Hemagglutinin content of Influenza Virus vaccines is the single radial immunodiffusion assay. This assay primarily relies on polyclonal antibodies against the head domain of the Influenza Virus Hemagglutinin, which is the main target antigen of Influenza Virus vaccines. Novel Influenza Virus vaccine candidates that redirect the immune response towards the evolutionary more conserved Hemagglutinin stalk, including chimeric Hemagglutinin and headless Hemagglutinin constructs, are highly dependent on the structural integrity of the protein to present conformational epitopes for neutralizing antibodies. In this study, we describe a novel enzyme-linked immunosorbent assay that allows quantifying the amount of Hemagglutinin with correctly folded stalk domains and which could be further developed into a potency assay for stalk-based Influenza Virus vaccines
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Hemagglutinin stalk immunity reduces Influenza Virus replication and transmission in ferrets
Journal of Virology, 2016Co-Authors: Raffael Nachbagauer, Peter Palese, Florian Krammer, Rong Hai, Alex B. Ryder, Matthew S. Miller, John K. Rose, Adolfo Garciasastre, Randy A AlbrechtAbstract:We assessed whether Influenza Virus Hemagglutinin stalk-based immunity protects ferrets against aerosol-transmitted H1N1 Influenza Virus infection. Immunization of ferrets by a universal Influenza Virus vaccine strategy based on viral vectors expressing chimeric Hemagglutinin constructs induced stalk-specific antibody responses. Stalk-immunized ferrets were cohoused with H1N1-infected ferrets under conditions that permitted Virus transmission. Hemagglutinin stalk-immunized ferrets had lower viral titers and delayed or no Virus replication at all following natural exposure to Influenza Virus.
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age dependence and isotype specificity of Influenza Virus Hemagglutinin stalk reactive antibodies in humans
Mbio, 2016Co-Authors: Raffael Nachbagauer, Manon M J Cox, Angela Choi, Ruvim Izikson, Florian KrammerAbstract:ABSTRACT Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the Virus undergoes extensive antigenic drift. Antibodies that target the highly conserved Hemagglutinin stalk can protect against drifted Viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal Influenza Virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant Hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and Influenza B Virus Hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low Influenza Virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.) IMPORTANCE The present study provides evidence that titers of broadly neutralizing Hemagglutinin stalk-reactive antibodies increase with age, possibly due to repeated exposure to divergent Influenza Viruses. These relatively high levels of antistalk titers may be responsible for lower circulation rates of Influenza Viruses in older individuals. Our findings suggest that the level of antistalk antibodies is a good surrogate marker for protection against Influenza Virus infection. In addition, the levels of antistalk antibodies might determine the breadth of protection against different drifted strains.
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Age Dependence and Isotype Specificity of Influenza Virus Hemagglutinin Stalk-Reactive Antibodies in Humans
American Society for Microbiology, 2016Co-Authors: Raffael Nachbagauer, Peter Palese, Angela Choi, Ruvim Izikson, Manon M. Cox, Florian KrammerAbstract:Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the Virus undergoes extensive antigenic drift. Antibodies that target the highly conserved Hemagglutinin stalk can protect against drifted Viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal Influenza Virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant Hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and Influenza B Virus Hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low Influenza Virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.
Stephen C. Harrison - One of the best experts on this subject based on the ideXlab platform.
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a prevalent focused human antibody response to the Influenza Virus Hemagglutinin head interface
Mbio, 2021Co-Authors: Kevin R Mccarthy, Stephen C. Harrison, Jiwon Lee, Akiko Watanabe, Masayuki Kuraoka, Lindsey R Robinsonmccarthy, George Georgiou, Garnett KelsoeAbstract:Novel animal Influenza Viruses emerge, initiate pandemics, and become endemic seasonal variants that have evolved to escape from prevalent herd immunity. These processes often outpace vaccine-elicited protection. Focusing immune responses on conserved epitopes may impart durable immunity. We describe a focused, protective antibody response, abundant in memory and serum repertoires, to a conserved region at the Influenza Virus Hemagglutinin (HA) head interface. Structures of 11 examples, 8 reported here, from seven human donors demonstrate the convergence of responses on a single epitope. The 11 are genetically diverse, with one class having a common, IGκV1-39, light chain. All of the antibodies bind HAs from multiple serotypes. The lack of apparent genetic restriction and potential for elicitation by more than one serotype may explain their abundance. We define the head interface as a major target of broadly protective antibodies with the potential to influence the outcomes of Influenza Virus infection. IMPORTANCE The rapid appearance of mutations in circulating human Influenza Viruses and selection for escape from herd immunity require prediction of likely variants for an annual updating of Influenza vaccines. The identification of human antibodies that recognize conserved surfaces on the Influenza Virus Hemagglutinin (HA) has prompted efforts to design immunogens that might selectively elicit such antibodies. The recent discovery of a widely prevalent antibody response to the conserved interface between two HA "heads" (the globular, receptor-binding domains at the apex of the spike-like trimer) has added a new target for these efforts. We report structures of eight such antibodies, bound with HA heads, and compare them with each other and with three others previously described. Although genetically diverse, they all converge on a common binding site. The analysis here can guide immunogen design for preclinical trials.
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conserved epitope on Influenza Virus Hemagglutinin head defined by a vaccine induced antibody
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Donald D Raymond, Stephen C. Harrison, Goran Bajic, Jack Ferdman, Pirada Suphaphiphat, Ethan C Settembre, Anthony M Moody, Aaron G SchmidtAbstract:Circulating Influenza Viruses evade neutralization in their human hosts by acquiring escape mutations at epitopes of prevalent antibodies. A goal for next-generation Influenza vaccines is to reduce escape likelihood by selectively eliciting antibodies recognizing conserved surfaces on the viral Hemagglutinin (HA). The receptor-binding site (RBS) on the HA "head" and a region near the fusion peptide on the HA "stem" are two such sites. We describe here a human antibody clonal lineage, designated CL6649, members of which bind a third conserved site ("lateral patch") on the side of the H1-subtype, HA head. A crystal structure of HA with bound Fab6649 shows the conserved antibody footprint. The site was invariant in isolates from 1977 (seasonal) to 2012 (pdm2009); antibodies in CL6649 recognize HAs from the entire period. In 2013, human H1 Viruses acquired mutations in this epitope that were retained in subsequent seasons, prompting modification of the H1 vaccine component in 2017. The mutations inhibit Fab6649 binding. We infer from the rapid spread of these mutations in circulating H1 Influenza Viruses that the previously subdominant, conserved lateral patch had become immunodominant for individuals with B-cell memory imprinted by earlier H1 exposure. We suggest that introduction of the pdm2009 H1 Virus, to which most of the broadly prevalent, neutralizing antibodies did not bind, conferred a selective advantage in the immune systems of infected hosts to recall of memory B cells that recognized the lateral patch, the principal exposed epitope that did not change when pdm2009 displaced previous seasonal H1 Viruses.
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distinct functional determinants of Influenza Hemagglutinin mediated membrane fusion
eLife, 2015Co-Authors: Stephen C. Harrison, Tijana IvanovicAbstract:Membrane fusion is the critical step for infectious cell penetration by enveloped Viruses. We have previously used single-virion measurements of fusion kinetics to study the molecular mechanism of Influenza-Virus envelope fusion. Published data on fusion inhibition by antibodies to the 'stem' of Influenza Virus Hemagglutinin (HA) now allow us to incorporate into simulations the provision that some HAs are inactive. We find that more than half of the HAs are unproductive even for virions with no bound antibodies, but that the overall mechanism is extremely robust. Determining the fraction of competent HAs allows us to determine their rates of target-membrane engagement. Comparison of simulations with data from H3N2 and H1N1 Viruses reveals three independent functional variables of HA-mediated membrane fusion closely linked to neutralization susceptibility. Evidence for compensatory changes in the evolved mechanism sets the stage for studies aiming to define the molecular constraints on HA evolvability.
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viral membrane fusion
Nature Structural & Molecular Biology, 2008Co-Authors: Stephen C. HarrisonAbstract:Infection by Viruses having lipid-bilayer envelopes proceeds through fusion of the viral membrane with a membrane of the target cell. Viral 'fusion proteins' facilitate this process. They vary greatly in structure, but all seem to have a common mechanism of action, in which a ligand-triggered, large-scale conformational change in the fusion protein is coupled to apposition and merger of the two bilayers. We describe three examples--the Influenza Virus Hemagglutinin, the flaviVirus E protein and the vesicular stomatitis Virus G protein--in some detail, to illustrate the ways in which different structures have evolved to implement this common mechanism. Fusion inhibitors can be effective antiviral agents.
John K. Rose - One of the best experts on this subject based on the ideXlab platform.
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Hemagglutinin stalk immunity reduces Influenza Virus replication and transmission in ferrets
Journal of Virology, 2016Co-Authors: Raffael Nachbagauer, Peter Palese, Florian Krammer, Rong Hai, Alex B. Ryder, Matthew S. Miller, John K. Rose, Adolfo Garciasastre, Randy A AlbrechtAbstract:We assessed whether Influenza Virus Hemagglutinin stalk-based immunity protects ferrets against aerosol-transmitted H1N1 Influenza Virus infection. Immunization of ferrets by a universal Influenza Virus vaccine strategy based on viral vectors expressing chimeric Hemagglutinin constructs induced stalk-specific antibody responses. Stalk-immunized ferrets were cohoused with H1N1-infected ferrets under conditions that permitted Virus transmission. Hemagglutinin stalk-immunized ferrets had lower viral titers and delayed or no Virus replication at all following natural exposure to Influenza Virus.
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assessment of Influenza Virus Hemagglutinin stalk based immunity in ferrets
Journal of Virology, 2014Co-Authors: Florian Krammer, Peter Palese, Rong Hai, Mark A. Yondola, Gene S. Tan, Alex B. Ryder, Matthew S. Miller, John K. Rose, Victor H Leyvagrado, Adolfo GarciasastreAbstract:Therapeutic monoclonal antibodies that target the conserved stalk domain of the Influenza Virus Hemagglutinin as well as stalk-based universal Influenza Virus vaccine strategies are being developed as promising countermeasures for Influenza Virus infections. The pan-H1 reactive monoclonal antibody 6F12 has been extensively characterized and shows broad efficacy against divergent H1N1 strains in the mouse model. Here we demonstrate its efficacy against a pandemic H1N1 challenge Virus in the ferret model of Influenza disease. Furthermore, we recently developed a universal Influenza Virus vaccine strategy based on chimeric Hemagglutinin constructs that focuses the immune response towards the conserved stalk domain of the Hemagglutinin. Here we set out to test this vaccination strategy in the ferret model. Both strategies, pre-treatment of animals with stalk-reactive monoclonal antibody as well as vaccination with chimeric Hemagglutinin based constructs were able to significantly reduce viral titers in nasal turbinates, lungs and olfactory bulbs. In addition, vaccinated animals also showed reduced nasal wash viral titers. In summary both strategies showed efficacy in reducing viral loads after Influenza Virus challenge in the ferret model.
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Assessment of Influenza Virus Hemagglutinin stalk-based immunity in ferrets
Journal of Virology, 2014Co-Authors: Rong Hai, Mark A. Yondola, Gene S. Tan, Victor H. Leyva-grado, Alex B. Ryder, Matthew S. Miller, John K. Rose, Adolfo García-sastreAbstract:ABSTRACT Therapeutic monoclonal antibodies that target the conserved stalk domain of the Influenza Virus Hemagglutinin and stalk-based universal Influenza Virus vaccine strategies are being developed as promising countermeasures for Influenza Virus infections. The pan-H1-reactive monoclonal antibody 6F12 has been extensively characterized and shows broad efficacy against divergent H1N1 strains in the mouse model. Here we demonstrate its efficacy against a pandemic H1N1 challenge Virus in the ferret model of Influenza disease. Furthermore, we recently developed a universal Influenza Virus vaccine strategy based on chimeric Hemagglutinin constructs that focuses the immune response on the conserved stalk domain of the Hemagglutinin. Here we set out to test this vaccination strategy in the ferret model. Both strategies, pretreatment of animals with a stalk-reactive monoclonal antibody and vaccination with chimeric Hemagglutinin-based constructs, were able to significantly reduce viral titers in nasal turbinates, lungs, and olfactory bulbs. In addition, vaccinated animals also showed reduced nasal wash viral titers. In summary, both strategies showed efficacy in reducing viral loads after an Influenza Virus challenge in the ferret model. IMPORTANCE Influenza Virus Hemagglutinin stalk-reactive antibodies tend to be less potent yet are more broadly reactive and can neutralize seasonal and pandemic Influenza Virus strains. The ferret model was used to assess the potential of Hemagglutinin stalk-based immunity to provide protection against Influenza Virus infection. The novelty and significance of the findings described in this report support the development of vaccines stimulating stalk-specific antibody responses.
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vaccination with a recombinant vesicular stomatitis Virus expressing an Influenza Virus Hemagglutinin provides complete protection from Influenza Virus challenge
Journal of Virology, 1998Co-Authors: Anjeanette Roberts, Evelyne Kretzschmar, Archibald S Perkins, John P Forman, Ryan Price, Linda Buonocore, Yoshihiro Kawaoka, John K. RoseAbstract:Since the development of a system for generating vesicular stomatitis Virus (VSV) from plasmid DNAs, our laboratory has reported the expression of several different glycoproteins from recombinant VSVs. In one of these studies, high-level expression of an Influenza Virus Hemagglutinin (HA) from a recombinant VSV-HA and efficient incorporation of the HA protein into the virions was reported (E. Kretzschmar, L. Buonocore, M. J. Schnell, and J. K. Rose, J. Virol. 71:5982–5989, 1997). We report here that VSV-HA is an effective intranasal vaccine vector that raises high levels of neutralizing antibody to Influenza Virus and completely protects mice from bronchial pneumonia caused by challenge with a lethal dose of Influenza A Virus. Additionally, these recombinant VSVs are less pathogenic than wild-type VSV (serotype Indiana). This vector-associated pathogenicity was subsequently eliminated through introduction of specific attenuating deletions. These live attenuated recombinant VSVs have great potential as vaccine vectors.
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vaccination with a recombinant vesicular stomatitis Virus expressing an Influenza Virus Hemagglutinin provides complete protection from Influenza Virus challenge
Journal of Virology, 1998Co-Authors: Anjeanette Roberts, Evelyne Kretzschmar, Archibald S Perkins, John P Forman, Ryan Price, Linda Buonocore, Yoshihiro Kawaoka, John K. RoseAbstract:Since the development of a system for generating vesicular stomatitis Virus (VSV) from plasmid DNAs, our laboratory has reported the expression of several different glycoproteins from recombinant VSVs. In one of these studies, high-level expression of an Influenza Virus Hemagglutinin (HA) from a recombinant VSV-HA and efficient incorporation of the HA protein into the virions was reported (E. Kretzschmar, L. Buonocore, M. J. Schnell, and J. K. Rose, J. Virol. 71:5982–5989, 1997). We report here that VSV-HA is an effective intranasal vaccine vector that raises high levels of neutralizing antibody to Influenza Virus and completely protects mice from bronchial pneumonia caused by challenge with a lethal dose of Influenza A Virus. Additionally, these recombinant VSVs are less pathogenic than wild-type VSV (serotype Indiana). This vector-associated pathogenicity was subsequently eliminated through introduction of specific attenuating deletions. These live attenuated recombinant VSVs have great potential as vaccine vectors.
Adolfo Garciasastre - One of the best experts on this subject based on the ideXlab platform.
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Hemagglutinin stalk immunity reduces Influenza Virus replication and transmission in ferrets
Journal of Virology, 2016Co-Authors: Raffael Nachbagauer, Peter Palese, Florian Krammer, Rong Hai, Alex B. Ryder, Matthew S. Miller, John K. Rose, Adolfo Garciasastre, Randy A AlbrechtAbstract:We assessed whether Influenza Virus Hemagglutinin stalk-based immunity protects ferrets against aerosol-transmitted H1N1 Influenza Virus infection. Immunization of ferrets by a universal Influenza Virus vaccine strategy based on viral vectors expressing chimeric Hemagglutinin constructs induced stalk-specific antibody responses. Stalk-immunized ferrets were cohoused with H1N1-infected ferrets under conditions that permitted Virus transmission. Hemagglutinin stalk-immunized ferrets had lower viral titers and delayed or no Virus replication at all following natural exposure to Influenza Virus.
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assessment of Influenza Virus Hemagglutinin stalk based immunity in ferrets
Journal of Virology, 2014Co-Authors: Florian Krammer, Peter Palese, Rong Hai, Mark A. Yondola, Gene S. Tan, Alex B. Ryder, Matthew S. Miller, John K. Rose, Victor H Leyvagrado, Adolfo GarciasastreAbstract:Therapeutic monoclonal antibodies that target the conserved stalk domain of the Influenza Virus Hemagglutinin as well as stalk-based universal Influenza Virus vaccine strategies are being developed as promising countermeasures for Influenza Virus infections. The pan-H1 reactive monoclonal antibody 6F12 has been extensively characterized and shows broad efficacy against divergent H1N1 strains in the mouse model. Here we demonstrate its efficacy against a pandemic H1N1 challenge Virus in the ferret model of Influenza disease. Furthermore, we recently developed a universal Influenza Virus vaccine strategy based on chimeric Hemagglutinin constructs that focuses the immune response towards the conserved stalk domain of the Hemagglutinin. Here we set out to test this vaccination strategy in the ferret model. Both strategies, pre-treatment of animals with stalk-reactive monoclonal antibody as well as vaccination with chimeric Hemagglutinin based constructs were able to significantly reduce viral titers in nasal turbinates, lungs and olfactory bulbs. In addition, vaccinated animals also showed reduced nasal wash viral titers. In summary both strategies showed efficacy in reducing viral loads after Influenza Virus challenge in the ferret model.
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induction of cross reactive antibodies to novel h7n9 Influenza Virus by recombinant newcastle disease Virus expressing a north american lineage h7 subtype Hemagglutinin
Journal of Virology, 2013Co-Authors: Peter H Goff, Irina Margine, Florian Krammer, Adolfo Garciasastre, Christopher W Seibert, Peter PaleseAbstract:Severe human disease caused by the emerging H7N9 Influenza Virus in China warrants a rapid response. Here, we present a recombinant Newcastle disease Virus expressing a North American lineage H7 Influenza Virus Hemagglutinin. Sera from immunized mice were cross-reactive to a broad range of H7 subtype Viruses and inhibited hemagglutination by the novel H7 Hemagglutinin. Immunized mice were protected against a heterologous H7 subtype challenge, and genetic analysis suggested that cross-protective antibodies recognize conserved antigenic sites.
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a single amino acid substitution in 1918 Influenza Virus Hemagglutinin changes receptor binding specificity
Journal of Virology, 2005Co-Authors: Laurel Glaser, Ian A. Wilson, Terrence M Tumpey, Christopher F Basler, Adolfo Garciasastre, Jeffery K Taubenberger, James Stevens, Dmitriy Zamarin, Peter PaleseAbstract:The receptor binding specificity of Influenza Viruses may be important for host restriction of human and avian Viruses. Here, we show that the Hemagglutinin (HA) of the Virus that caused the 1918 Influenza pandemic has strain-specific differences in its receptor binding specificity. The A/South Carolina/1/18 HA preferentially binds the α2,6 sialic acid (human) cellular receptor, whereas the A/New York/1/18 HA, which differs by only one amino acid, binds both the α2,6 and the α2,3 sialic acid (avian) cellular receptors. Compared to the conserved consensus sequence in the receptor binding site of avian HAs, only a single amino acid at position 190 was changed in the A/New York/1/18 HA. Mutation of this single amino acid back to the avian consensus resulted in a preference for the avian receptor.
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mucosal immunization with attenuated shigella flexneri harboring an Influenza Hemagglutinin dna vaccine protects mice against a lethal Influenza challenge
Virology, 2004Co-Authors: William H Vecino, Adolfo Garciasastre, Luis Martinezsobrido, Natalie M Quanquin, Ana Fernandezsesma, William R Jacobs, Glenn J FennellyAbstract:Mucosal surfaces are important for the induction of immunity against Influenza Virus. In a murine intranasal immunization model, we demonstrated that the attenuated Shigella flexneri Δasd strain 15D, carrying a DNA construct encoding the Influenza Virus Hemagglutinin (HA), induces protective immunity against a lethal respiratory challenge with Influenza A/WSN/33. Influenza Virus-specific IFN-γ T cells were detected among splenocytes, and anti-HA IgG was detected in serum post-immunization, albeit at low levels. Following Influenza Virus challenge, an accelerated anti-HA IgA antibody response was detected in bronchoalveolar lavage (BAL) washings from mice vaccinated with attenuated shigella containing the HA construct. These results suggest that S. flexneri Δasd strain 15D is a promising vector for mucosal DNA vaccine immunization against Influenza Virus and other mucosal pathogens.