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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.<\/jats:p>","DOI":"10.3390\/v15020432","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T04:08:07Z","timestamp":1675656487000},"page":"432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Recombinant Protein Vaccines Formulated with Enantio-Specific Cationic Lipid R-DOTAP Induce Protective Cellular and Antibody-Mediated Immune Responses in Mice"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0764-1308","authenticated-orcid":false,"given":"Siva K.","family":"Gandhapudi","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Shi","sequence":"additional","affiliation":[{"name":"Center for Influenza Vaccine Research for High Risk Populations, University of Georgia, Athens, GA 30602, USA"},{"name":"Center for Vaccines and Immunology and Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin R.","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John Peyton","family":"Bush","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"Avdiushko","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karuna","family":"Sundarapandiyan","sequence":"additional","affiliation":[{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren V.","family":"Wood","sequence":"additional","affiliation":[{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mania","family":"Dorrani","sequence":"additional","affiliation":[{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afsheen","family":"Fatima","sequence":"additional","affiliation":[{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe","family":"Dervan","sequence":"additional","affiliation":[{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Bedu-Addo","sequence":"additional","affiliation":[{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greg","family":"Conn","sequence":"additional","affiliation":[{"name":"PDS Biotechnology Corporation, Florham Park, NJ 07932, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1947-7469","authenticated-orcid":false,"given":"Ted M.","family":"Ross","sequence":"additional","affiliation":[{"name":"Center for Influenza Vaccine Research for High Risk Populations, University of Georgia, Athens, GA 30602, USA"},{"name":"Center for Vaccines and Immunology and Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerold G.","family":"Woodward","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41573-021-00163-y","article-title":"Emerging concepts in the science of vaccine adjuvants","volume":"20","author":"Pulendran","year":"2021","journal-title":"Nat. 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