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Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses.
J Virol. 2016 May; 90(9):4720-4734.JV

Abstract

One of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates.

IMPORTANCE

Universal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a "subtype universal" vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates.

Links

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Authors+Show Affiliations

Carter DM
Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
Darby CA
Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
Lefoley BC
Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
Crevar CJ
Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA.
Alefantis T
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Oomen R
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Anderson SF
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Strugnell T
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Cortés-Garcia G
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Vogel TU
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Parrington M
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Kleanthous H
Sanofi Pasteur, Cambridge, Massachusetts, USA.
Ross TM
Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA tedross@uga.edu.

MeSH

AnimalsAntibodies, MonoclonalAntibodies, ViralAntigens, ViralCell LineDisease Models, AnimalHemagglutination Inhibition TestsHemagglutinin Glycoproteins, Influenza VirusHumansImmunizationInfluenza A Virus, H1N1 SubtypeInfluenza VaccinesInfluenza, HumanMiceModels, MolecularOrthomyxoviridae InfectionsPhylogenyProtein BindingProtein ConformationProtein Interaction Domains and MotifsVaccines, Virus-Like Particle

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26912624

Citation

Carter, Donald M., et al. "Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses." Journal of Virology, vol. 90, no. 9, 2016, pp. 4720-4734.
Carter DM, Darby CA, Lefoley BC, et al. Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses. J Virol. 2016;90(9):4720-4734.
Carter, D. M., Darby, C. A., Lefoley, B. C., Crevar, C. J., Alefantis, T., Oomen, R., Anderson, S. F., Strugnell, T., Cortés-Garcia, G., Vogel, T. U., Parrington, M., Kleanthous, H., & Ross, T. M. (2016). Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses. Journal of Virology, 90(9), 4720-4734. https://doi.org/10.1128/JVI.03152-15
Carter DM, et al. Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses. J Virol. 2016;90(9):4720-4734. PubMed PMID: 26912624.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses. AU - Carter,Donald M, AU - Darby,Christopher A, AU - Lefoley,Bradford C, AU - Crevar,Corey J, AU - Alefantis,Timothy, AU - Oomen,Raymond, AU - Anderson,Stephen F, AU - Strugnell,Tod, AU - Cortés-Garcia,Guadalupe, AU - Vogel,Thorsten U, AU - Parrington,Mark, AU - Kleanthous,Harold, AU - Ross,Ted M, Y1 - 2016/04/14/ PY - 2016/01/23/received PY - 2016/02/19/accepted PY - 2016/2/26/entrez PY - 2016/2/26/pubmed PY - 2016/8/26/medline SP - 4720 EP - 4734 JF - Journal of virology JO - J Virol VL - 90 IS - 9 N2 - UNLABELLED: One of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates. IMPORTANCE: Universal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a "subtype universal" vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/26912624/Design_and_Characterization_of_a_Computationally_Optimized_Broadly_Reactive_Hemagglutinin_Vaccine_for_H1N1_Influenza_Viruses_ DB - PRIME DP - Unbound Medicine ER -