Oct 242016
 
Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype-Specific Neutralizing Antibody Responses Stefan W. Metz Shaomin Tian Gabriel Hoekstra Xianwen Yi Michelle Stone Katie Horvath Michael J. Miley Joseph DeSimone Chris J. Luft Aravinda M. de Silva

Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype-Specific Neutralizing Antibody Responses
Stefan W. Metz Shaomin Tian Gabriel Hoekstra Xianwen Yi Michelle Stone Katie Horvath Michael J. Miley Joseph DeSimone Chris J. Luft Aravinda M. de Silva

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.

Author Summary

Dengue virus (DENV) is transmitted by mosquitoes and is endemic in over 120 countries, causing over 350 million infections yearly. Most infections are clinically unapparent, but under specific conditions, dengue can cause severe and lethal disease. DENV has 4 distinct serotypes and secondary DENV infections are associated with hemorrhagic fever and dengue shock syndrome. This enhancement of infection complicates vaccine development and makes it necessary to induce protective immunity against all 4 serotypes. Since whole virus vaccine candidates struggle to induce protective immunity, we are developing a nanoparticle display vaccine approach. We have expressed, purified and characterized a soluble recombinant E-protein (sRecE). Regardless of nanoparticle shape or size, particulation of 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.

Nanoparticle display shows great promise in dengue vaccine development and possibly other mosquito-borne viruses like zika virus.

Learn more: Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype-Specific Neutralizing Antibody Responses

 

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