Abstract
Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever. The virus is endemic in over 120 countries, causing over 350 million infections per year. Dengue vaccine development is challenging because of the need to induce simultaneous protection against four antigenically distinct DENV serotypes and evidence that, under some conditions, vaccination can enhance disease due to specific immunity to the virus. While several live-attenuated tetravalent dengue virus vaccines display partial efficacy, it has been challenging to induce balanced protective immunity to all 4 serotypes. Instead of using whole-virus formulations, we are exploring the potentials for a particulate subunit vaccine, based on DENV E-protein displayed on nanoparticles that have been precisely molded using Particle Replication in Non-wetting Template (PRINT) technology. Here we describe immunization studies with a DENV2-nanoparticle vaccine candidate. The ectodomain of DENV2-E protein was expressed as a secreted recombinant protein (sRecE), purified and adsorbed to poly (lactic-co-glycolic acid) (PLGA) nanoparticles of different sizes and shape. We show that PRINT nanoparticle adsorbed sRecE without any adjuvant induces higher IgG titers and a more potent DENV2-specific neutralizing antibody response compared to the soluble sRecE protein alone. Antigen trafficking indicate that PRINT nanoparticle display of sRecE prolongs the bio-availability of the antigen in the draining lymph nodes by creating an antigen depot. Our results demonstrate that PRINT nanoparticles are a promising platform for delivering subunit vaccines against flaviviruses such as dengue and Zika.
Highlights
Dengue virus (DENV), a member of the flaviviridae family, is the causative agent of dengue fever and dengue hemorrhagic fever
DENV has 4 distinct serotypes and secondary DENV infections are associated with hemorrhagic fever and dengue shock syndrome
Regardless of nanoparticle shape or size, particulation of secreted recombinant protein (sRecE) enhances DENV specific IgG titers and induces a robust, long lasting neutralizing antibody response and by adsorbing sRecE to the nanoparticles, we prolong the exposure of sRecE to the immune system
Summary
Dengue virus (DENV), a member of the flaviviridae family, is the causative agent of dengue fever and dengue hemorrhagic fever. Mosquito vectors are widely distributed in tropical and subtropical regions and is the most prevalent arthropod borne viral pathogen worldwide. 1 million infections develop into severe disease of which nearly 2–5% is fatal [1,2]. More than 125 countries are endemic to DENV, but geographical expansion is expected to increase due to climate change, globalization of travel and trade and viral evolution [3,4,5,6]. Dengue is a complex disease resulting in a wide variety of clinical symptoms. The majority of infections are very mild or clinically in apparent. Infections are often misdiagnosed due to similarities between other prevalent tropical diseases. Most patients undergo a sudden onset of fever that remains for 2–7 days, accompanied by arthralgia, myalgia and skin rash [7]
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