title: A Tetravalent Sub-unit Dengue Vaccine Formulated with Ionizable Cationic Lipid Nanoparticle induces Significant Immune Responses in Rodents and Non-Human Primates.
abstract: Dengue virus has emerged as an important arboviral infection worldwide. As a complex pathogen, with four distinct serotypes, the development of a successful Dengue virus vaccine has proven to be challenging. Here, we describe a novel Dengue vaccine candidate that contains truncated, recombinant, Dengue virus envelope protein from all four Dengue virus serotypes (DEN-80E) formulated with ionizable cationic lipid nanoparticles (LNPs). Immunization studies in mice, Guinea pigs, and in Rhesus macaques, revealed that LNPs induced high titers of Dengue virus neutralizing antibodies, with or without co-administration or encapsulation of a Toll-Like Receptor 9 agonist. Importantly, LNPs were also able to boost DEN-80E specific CD4+ and CD8+ T cell responses. Cytokine and chemokine profiling revealed that LNPs induced strong chemokine responses without significant induction of inflammatory cytokines. In addition to being highly efficacious, the vaccine formulation proved to be well-tolerated, demonstrating no elevation in any of the safety parameters evaluated. Notably, reduction in cationic lipid content of the nanoparticle dramatically reduced the LNP's ability to boost DEN-80E specific immune responses, highlighting the crucial role for the charge of the LNP. Overall, our novel studies, across multiple species, reveal a promising tetravalent Dengue virus sub-unit vaccine candidate.
authors.affiliation: Infectious Diseases and Vaccines, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Gokul
authors.initials: G
authors.lastname: Swaminathan
authors.affiliation: Infectious Diseases and Vaccines, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thoryk
authors.affiliation: Infectious Diseases and Vaccines, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Kara S
authors.initials: KS
authors.lastname: Cox
authors.affiliation: Pharmaceutical Sciences, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Smith
authors.affiliation: Safety Assessment &Regulatory Affairs, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jayanthi J
authors.initials: JJ
authors.lastname: Wolf
authors.affiliation: Pharmaceutical Sciences, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Marian E
authors.initials: ME
authors.lastname: Gindy
authors.affiliation: Infectious Diseases and Vaccines, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.affiliation: Infectious Diseases and Vaccines, Merck Research Laboratories, Merck &Co., Inc., Kenilworth, NJ, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bett
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003715:Dengue / Q000276:immunology / Q000517:prevention & control; D053059:Dengue Vaccines / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007117:Immunization, Secondary; D008055:Lipids / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology
chemical_list: D053059:Dengue Vaccines; D008055:Lipids; D014759:Viral Envelope Proteins