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J. Virol. doi:10.1128/JVI.00512-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

An Immunogenic and Protective Alphavirus Replicon Particle-Based Dengue Vaccine Overcomes Maternal Antibody Interference in Weanling Mice

Carolina Vaccine Institute; and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

^* To whom correspondence should be addressed. Email: ljwhite{at}med.unc.edu.

	Abstract

A candidate pediatric dengue virus (DENV) vaccine based on non-propagating Venezuelan equine encephalitis virus (VEE) replicon particles (VRP) was tested for immunogenicity and protective efficacy in weanling mice in the presence and absence of potentially interfering maternal antibodies. A gene cassette encoding envelope proteins prM and E from mouse-adapted DENV2 strain NGC was cloned into a VEE replicon vector and packaged into VRP, which programmed proper in vitro expression and processing of DENV2 envelope proteins upon infection of Vero cells. Primary immunization of 3-week-old weanling BALB/c mice in the footpad with DENV2-VRP resulted in high levels of DENV-specific serum IgG antibodies and significant titers of neutralizing antibodies in all vaccinates. A booster immunization 12 weeks after the prime resulted in increased neutralizing antibodies that were sustained for at least 30 weeks. Immunization at a range of doses of DENV2-VRP protected mice from an otherwise lethal intracranial DENV2 challenge. To model vaccination in the presence of maternal antibodies, weanling pups born to DENV2-immune or DENV2-naïve dams were immunized with either DENV2-VRP or live DENV2 given peripherally. The DENV2-VRP vaccine induced neutralizing antibody responses in young mice, regardless of the maternal immune status. In contrast, live DENV2 vaccination performed poorly in the presence of pre-existing anti-DENV2 antibodies. This study demonstrates the feasibility of a VRP vaccine approach as an early life DENV vaccine in populations with high levels of circulating dengue antibodies, and suggests the utility of VRP-based vaccines in other instances where maternal antibodies make early vaccine problematic.