Recombinant Virus-Like Particle (VLP) and DNA Vaccines for Chikungunya Virus (CHIKV) and Other Alphaviruses
Posted Feb 27 2011 7:00pm
Description of Invention: Available for licensing and commercial development are compositions and methods of use as vaccines of virus-like particles (VLPs) expressing one or more Alphavirus capsid and envelope proteins, and in particular Chikungunya virus (CHIKV) core and envelope proteins. The invention also describes DNA, viral or other gene-based vector and VLP vaccines, methods of making and methods of their use in inducing immunity, for example to CHIKV infection.
Alphaviruses are RNA-containing viruses that cause a wide variety of mosquito-transmitted diseases, including equine encephalitis. CHIKV, an Alphavirus in the family Togaviridae, was first isolated in Tanzania in 1952 and is transmitted to humans by mosquitoes. The disease caused by CHIKV resembles infection by dengue virus, characterized by rash, high fever, and severe, sometimes persistent arthritis. By 2007, an estimated 1.4 - 6.5 million people in India, Southeast Asia, Africa and Europe had been infected. Vaccines or anti-viral therapies against CHIKV are not available, raising concerns about its continued evolution and spread in humans. There has been limited success to date in developing a safe and effective CHIKV vaccine. A live CHIKV vaccine candidate caused transient arthralagia in volunteers. Other efforts to develop a CHIKV vaccine include a live attenuated vaccine, a formalin-killed vaccine, a Venezuelan equine encephalitis/CHIKV chimeric live attenuated vaccine and a consensus-based DNA vaccine, but development of a safe and effective CHIKV vaccine will require additional evaluation in humans.
This invention provides CHIKV vaccines based on plasmid expression vectors encoding structural proteins of the virus, which gave rise to VLPs in transfected cells and also served as DNA vaccines. The VLPs consisted of the core, E1 and E2 proteins and were similar in buoyant density and morphology to replication-competent virus. To evaluate the potency and specificity of neutralizing antibodies, pseudotyped lentiviral vectors bearing the CHIKV glycoproteins E1/E2 were developed that showed pH-dependent entry and antibody inhibition similar to CHIKV. Mice were immunized with VLPs (West African strain, 37997) or with DNA vaccines encoding viral gene products from 37997 as well as the latest outbreak strain, OPY-1. Immunization with VLPs elicited high titer neutralizing antibodies against homologous and heterologous strain envelope at >100 fold higher titers than DNA vaccines. These vaccines also induced CD4 and CD8 T-cell responses by analysis with intracellular cytokine staining (ICS). These VLP vaccines are likely to confer protection against emerging CHIKV outbreaks and represent a strategy that could be applied to other pathogenic viruses to prevent their infection and spread.
Development of vaccines against CHIKV
Development of vaccines against other Alphavirus
Immunization of mice with VLPs plus adjuvant results in neutralizing antibodies against both homologous and heterologous strains with titers at least two orders of magnitude greater than immunization with a DNA vaccine.
VLPs induce innate immunity responses as well as CD8 T-cell responses.
VLPs closely resemble mature virions but they do not contain viral genomic material. Therefore, VLPs are non-replicative in nature, which make them safe for administration in the form of immunogenic compositions in vaccines.
Development Status: This technology is in the pre-clinical stage of development.