Giuseppe
Emeritus
[Source: PLoS ONE, full text: (LINK). Abstract, edited.]
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Designing and Testing Broadly-Protective Filoviral Vaccines Optimized for Cytotoxic T-Lymphocyte Epitope Coverage
Paul W. Fenimore<SUP>1</SUP><SUP>*</SUP>, Majidat A. Muhammad<SUP>2</SUP><SUP>#</SUP>, William M. Fischer<SUP>1</SUP><SUP>#</SUP>, Brian T. Foley<SUP>1</SUP>, Russell R. Bakken<SUP>2</SUP>, James R. Thurmond<SUP>3</SUP>, Karina Yusim<SUP>1</SUP>, Hyejin Yoon<SUP>1</SUP>, Michael Parker<SUP>2</SUP>, Mary Kate Hart<SUP>4</SUP>, John M. Dye<SUP>2</SUP>, Bette Korber<SUP>1</SUP>, Carla Kuiken<SUP>1</SUP>
<SUP></SUP>
1 Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America, 2 Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fredrick, Maryland, United States of America, 3 Fly Base, Indiana University, Bloomington, Indiana, United States of America, 4 DynPort Vaccine Company, Frederick, Maryland, United States of America
Abstract
We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1) but also appropriate for Hepatitis C virus (HCV) and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL) epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.
Citation: Fenimore PW, Muhammad MA, Fischer WM, Foley BT, Bakken RR, et al. (2012) Designing and Testing Broadly-Protective Filoviral Vaccines Optimized for Cytotoxic T-Lymphocyte Epitope Coverage. PLoS ONE 7(10): e44769. doi:10.1371/journal.pone.0044769
Editor: Jianqing Xu, Fudan University, China
Received: May 10, 2012; Accepted: August 7, 2012; Published: October 3, 2012
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: Funding was provided by the Defense Threat Reduction Agency, project #CBM.VAXPLAT.05.10.RD.005 and by USAMRIID subcontract TA2F06062 and Los Alamos National Laboratory Directed Research funds 20050155DR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal's policy and have the following conflicts. Co-author M.K. Hart is an employee of DynPort Vaccine Company, a private company engaged in vaccine production. P.W. Fenimore, W. Fischer, C. Kuiken, and B.T. Korber have a patent interest in the work described. The patent disclosure is DOE S129405 entitled ?Mosaic Protein Antigens for a Pan-Filoviral Vaccine?, US Patent Application Number 61/623,342 filed 4/12/2012. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. The authors' adherence is demonstrated by inclusion of patent-sensitive data in one supplementary information file, and the specification of all input data for the authors' analysis. This study is reproducible from the information in the manuscript, figures, and supporting information.
* E-mail: paulf@lanl.gov
# These authors contributed equally to this work.
-Paul W. Fenimore<SUP>1</SUP><SUP>*</SUP>, Majidat A. Muhammad<SUP>2</SUP><SUP>#</SUP>, William M. Fischer<SUP>1</SUP><SUP>#</SUP>, Brian T. Foley<SUP>1</SUP>, Russell R. Bakken<SUP>2</SUP>, James R. Thurmond<SUP>3</SUP>, Karina Yusim<SUP>1</SUP>, Hyejin Yoon<SUP>1</SUP>, Michael Parker<SUP>2</SUP>, Mary Kate Hart<SUP>4</SUP>, John M. Dye<SUP>2</SUP>, Bette Korber<SUP>1</SUP>, Carla Kuiken<SUP>1</SUP>
<SUP></SUP>
1 Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America, 2 Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fredrick, Maryland, United States of America, 3 Fly Base, Indiana University, Bloomington, Indiana, United States of America, 4 DynPort Vaccine Company, Frederick, Maryland, United States of America
Abstract
We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1) but also appropriate for Hepatitis C virus (HCV) and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL) epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.
Citation: Fenimore PW, Muhammad MA, Fischer WM, Foley BT, Bakken RR, et al. (2012) Designing and Testing Broadly-Protective Filoviral Vaccines Optimized for Cytotoxic T-Lymphocyte Epitope Coverage. PLoS ONE 7(10): e44769. doi:10.1371/journal.pone.0044769
Editor: Jianqing Xu, Fudan University, China
Received: May 10, 2012; Accepted: August 7, 2012; Published: October 3, 2012
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: Funding was provided by the Defense Threat Reduction Agency, project #CBM.VAXPLAT.05.10.RD.005 and by USAMRIID subcontract TA2F06062 and Los Alamos National Laboratory Directed Research funds 20050155DR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal's policy and have the following conflicts. Co-author M.K. Hart is an employee of DynPort Vaccine Company, a private company engaged in vaccine production. P.W. Fenimore, W. Fischer, C. Kuiken, and B.T. Korber have a patent interest in the work described. The patent disclosure is DOE S129405 entitled ?Mosaic Protein Antigens for a Pan-Filoviral Vaccine?, US Patent Application Number 61/623,342 filed 4/12/2012. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. The authors' adherence is demonstrated by inclusion of patent-sensitive data in one supplementary information file, and the specification of all input data for the authors' analysis. This study is reproducible from the information in the manuscript, figures, and supporting information.
* E-mail: paulf@lanl.gov
# These authors contributed equally to this work.
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