Tweet
Accepted manuscript posted online 24 February 2016, doi: 10.1128/JVI.03152-15
Design and Characterization of a COBRA HA vaccine for H1N1 influenza viruses.
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 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 HAI activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that elicited the broadest hemagglutination-inhibition (HAI) response and protected mice against both 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.
Significance Statement: Universal influenza vaccine approaches have the potential to be paradigm-shifting for the influenza vaccine field, with the goal of replacing 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 drifted H1 strains 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.
Design and Characterization of a COBRA HA vaccine for H1N1 influenza viruses.
- Donald M. Carter1,
- Christopher A. Darby1,
- Bradford C. LeFoley1,
- Corey J. Crevar2,
- Timothy Alefantis3,
- Raymond Oomen3,
- Stephen F. Anderson3,
- Tod Strugnell3,
- Guadalupe Cort?s-Garcia3,
- Thorsten U. Vogel3,
- Mark Parrington3,
- Harold Kleanthous3 and
- Ted M. Ross1*
- 1University of Georgia, Center for Vaccines and Immunology, Department of Infectious Diseases, Athens, GA 30602
- 2Vaccine and Gene Therapy Institute of Florida, 9801 SW Discovery Way, Port St. Lucie, FL 34987, USA
- 3Sanofi Pasteur, 38 Sidney Street, Cambridge, MA 02139, USA
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 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 HAI activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that elicited the broadest hemagglutination-inhibition (HAI) response and protected mice against both 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.
Significance Statement: Universal influenza vaccine approaches have the potential to be paradigm-shifting for the influenza vaccine field, with the goal of replacing 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 drifted H1 strains 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.
