Vaxfectin™-Formulated Influenza DNA Vaccines Encoding NP and M2 Viral Proteins Protect Mice against Lethal Viral Challenge

Abstract

Next generation influenza vaccines containing conserved antigens may enhance immunity against seasonal or pandemic influenza virus strains. Using a plasmid DNA (pDNA)-based vaccine approach, we systematically tested combinations of NP, M1 and M2 antigens derived from consensus sequences for protection against lethal influenza challenge and compared formulations for adjuvanting low pDNA vaccine doses. The highest level of protection at the lowest pDNA doses was provided by Vaxfectin™-formulated NP + M2. Vaxfectin™ adjuvanticity was confirmed with a low dose of HA pDNA. These promising proof-of-concept data support the clinical development of Vaxfectin™-formulated pDNA encoding NP + M2 consensus proteins.

Use of Vaxfectin Adjuvant with DNA Vaccine Encoding the Measles Virus Hemagglutinin and Fusion Proteins Protects Juvenile and Infant Rhesus Macaques against Measles Virus

“…Vaxfectin is a recently introduced cationic lipid-based adjuvant for DNA vaccines that consists of an equimolar mixture of the cationic lipid GAP-DMORIE [(Ϯ)-N-(3-aminopropyl)-N,Ndimethyl-2,3-bis(cis-9-tetradecenyloxy)-1-propanaminium bromide)] and a neutral colipid, DPyPE (1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine) (15). Vaxfectin is dose sparing, enhances the production of antigen-specific antibody in small animals, including virus-neutralizing antibody, and can induce immunity to a variety of infections (13,15,16,18,24,29,41). However, the efficacy of Vaxfectin-formulated DNA vaccines has not been reported for humans, and there is only a single study of nonhuman primates (22).…”

New technologies for influenza vaccines

“…161 In rodent models, such T cell-based vaccines can protect from challenge. [155][156][157]159,162 In the more rigorous ferret model, they perform less well. 158 The recurrent nature of influenza infection, despite the presence of such conserved antigens in every circulating influenza virus strain, is an indication that immunity directed against these antigens is incomplete, although cell mediated responses appear to contribute to the clearance of infection in humans.…”

“…[155][156][157][158][159][160] Vaccines based solely on conserved internal antigens must rely on cell-mediated immunity, because the target antigens are not exposed on the surface of an influenza virion for antibody binding. 161 In rodent models, such T cell-based vaccines can protect from challenge.…”

The Signal Peptide Sequence Impacts the Immune Response Elicited by a DNA Epitope Vaccine

“…An advantage of DNA vaccines is the ease with which one can introduce changes to qualitatively and quantitatively affect their immunogenicity (13,23,35). A number of approaches have been employed to enhance the efficacy of DNA vaccines, which include optimizing antigen processing (24) and presentation (5, 9, 17, 27, 29-31, 33, 37), using epitope-carrier protein fusion molecules (41), employing different delivery methods (18,21,22,28,34), and introducing immunomodulatory sequences in the plasmid vaccines (3,8,10,13,19,22,23,40). In both full-length and minigene DNA vaccines, leader sequences have been used to directly target the encoded antigen/epitope to the endoplasmic reticulum (ER) for major histocompatibility complex class I (MHC I) presentation with mixed success (5,7,9,17,33).…”