Recombinant Protein Vaccines Formulated with Enantio-Specific Cationic Lipid R-DOTAP Induce Protective Cellular and Antibody-Mediated Immune Responses in Mice
Siva K. Gandhapudi,
Hua Shi,
Martin R. Ward,
John Peyton Bush,
Margarita Avdiushko,
Karuna Sundarapandiyan,
Lauren V. Wood,
Mania Dorrani,
Afsheen Fatima,
Joe Dervan,
Frank Bedu-Addo,
Greg Conn,
Ted M. Ross,
Jerold G. Woodward
Affiliations
Siva K. Gandhapudi
Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
Hua Shi
Center for Influenza Vaccine Research for High Risk Populations, University of Georgia, Athens, GA 30602, USA
Martin R. Ward
Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
John Peyton Bush
Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
Margarita Avdiushko
Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
Karuna Sundarapandiyan
PDS Biotechnology Corporation, Florham Park, NJ 07932, USA
Lauren V. Wood
PDS Biotechnology Corporation, Florham Park, NJ 07932, USA
Mania Dorrani
PDS Biotechnology Corporation, Florham Park, NJ 07932, USA
Afsheen Fatima
PDS Biotechnology Corporation, Florham Park, NJ 07932, USA
Joe Dervan
PDS Biotechnology Corporation, Florham Park, NJ 07932, USA
Frank Bedu-Addo
PDS Biotechnology Corporation, Florham Park, NJ 07932, USA
Greg Conn
PDS Biotechnology Corporation, Florham Park, NJ 07932, USA
Ted M. Ross
Center for Influenza Vaccine Research for High Risk Populations, University of Georgia, Athens, GA 30602, USA
Jerold G. Woodward
Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
Adjuvants are essential components of subunit vaccines added to enhance immune responses to antigens through immunomodulation. Very few adjuvants have been approved for human use by regulatory agencies due to safety concerns. Current subunit vaccine adjuvants approved for human use are very effective in promoting humoral immune responses but are less effective at promoting T-cell immunity. In this study, we evaluated a novel pure enantio-specific cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (R-DOTAP) as an immunomodulator for subunit vaccines capable of inducing both humoral- and cellular-mediated immunity. Using recombinant protein antigens derived from SARS-CoV2 spike or novel computationally optimized broadly reactive influenza antigen (COBRA) proteins, we demonstrated that R-DOTAP nanoparticles promoted strong cellular- and antibody-mediated immune responses in both monovalent and bivalent vaccines. R-DOTAP-based vaccines induced antigen-specific and polyfunctional CD8+ and CD4+ effector T cells and memory T cells, respectively. Antibody responses induced by R-DOTAP showed a balanced Th1/Th2 type immunity, neutralizing activity and protection of mice from challenge with live SARS-CoV2 or influenza viruses. R-DOTAP also facilitated significant dose sparing of the vaccine antigens. These studies demonstrate that R-DOTAP is an excellent immune stimulator for the production of next-generation subunit vaccines containing multiple recombinant proteins.
