Immunogenicity of a Psoralen-Inactivated Dengue Virus Type 1 Vaccine Candidate in Mice

摘要

Dengue viruses consist of four distinct RNA viruses of the genus Flaviviridae and are transmitted to humans primarily through the bite of the Aedes aegypti mosquito. Prior dengue virus infection is a major risk factor for the subsequent development of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) following reinfection with a heterotypic dengue virus serotype. Dengue virus vaccine development has thus been hindered by the competing needs to develop a vaccine that provides lasting and uniform protection against all four serotypes without predisposing recipients to an increased risk of DHF and DSS. Psoralens are photoreactive compounds that freely permeate phospholipid membranes and intercalate between nucleic acids. Following exposure to UV-A radiation, the intercalated psoralen covalently cross-links pyrimidine residues, leading to viral inactivation through the inhibition of genome replication. The interaction of psoralen with viral nucleic acids leaves immunogenic surface epitopes intact (4). In this study, we photoinactivated the dengue virus type 1 (DENV-1) Western Pacific 74 strain with three different psoralens: 4'- aminomethyltrioxsalen hydrochloride (AMT; product number A4330, CAS number 62442-61-9; Sigma-Aldrich), 8-methoxypsoralen (8-MOP; catalog number 214150010, CAS number 298-81-7; Acros Organics), and 4,5',8-trimethylpsoralen (TMP; catalog number 229881000, CAS number 3902- 71-4; Acros Organics). We then determined the immunogenicity of AMT-inactivated DENV-1 in Mus musculus mice.