Nanoparticle delivery of a tetravalent E protein subunit vaccine induces balanced, type-specific neutralizing antibodies to each dengue virus serotype.

Stefan W Metz,Michele Stone,Yi Xianwen,Katie Horvath,Alex Brackbill,Chris Luft,Ashlie Thomas,Shaomin Tian,Michael J Miley,Aravinda M De Silva,Joseph M Desimone

doi:10.1371/journal.pntd.0006793

Abstract

Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic shock syndrome. Dengue vaccine development is challenging because of the need to induce protection against four antigenically distinct DENV serotypes. Recent studies indicate that tetravalent DENV vaccines must induce balanced, serotype-specific neutralizing antibodies to achieve durable protective immunity against all 4 serotypes. With the leading live attenuated tetravalent DENV vaccines, it has been difficult to achieve balanced and type-specific responses to each serotype, most likely because of unbalanced replication of vaccine viral strains. Here we evaluate a tetravalent DENV protein subunit vaccine, based on recombinant envelope protein (rE) adsorbed to the surface of poly (lactic-co-glycolic acid) (PLGA) nanoparticles for immunogenicity in mice. In monovalent and tetravalent formulations, we show that particulate rE induced higher neutralizing antibody titers compared to the soluble rE antigen alone. Importantly, we show the trend that tetravalent rE adsorbed to nanoparticles stimulated a more balanced serotype specific antibody response to each DENV serotype compared to soluble antigens. Our results demonstrate that tetravalent DENV subunit vaccines displayed on nanoparticles have the potential to overcome unbalanced immunity observed for leading live-attenuated vaccine candidates.

Highlights

The four dengue virus (DENV) serotypes are the causative agent of dengue fever and dengue hemorrhagic fever
Dengue virus (DENV) type-specific human mAbs 1F4 (DENV1), 2D22 (DENV2) and 5J7 (DENV3) which bind to quaternary structure epitopes displayed on the E homodimer or higher order structures showed marginal binding to each cognate antigen indicating that the purified antigens were mainly present as monomers [38]
A safe and efficacious vaccine that protects against all 4 DENV serotypes is urgently needed, but so far, results with leading live-attenuated tetravalent vaccine candidates are mixed

Summary

Introduction

The four dengue virus (DENV) serotypes are the causative agent of dengue fever and dengue hemorrhagic fever. Mosquitoes and both virus and vector are widely distributed throughout all tropical and subtropical regions, resulting in an estimated 300 million new infections per year, and approximately 1 million cases of severe disease with a case fatality 2–5% [1]. People experiencing secondary heterotypic infections are at greater risk of developing severe disease. DENV serotype cross-reactive and poorly neutralizing antibodies induced after the primary infection, appear to enhance the second infection via the formation of virus-antibody complexes that promote infection of Fc-receptor bearing human myeloid cells [2,3]. It has been challenging to control the main mosquito vector of DENV. There are no effective antiviral or other therapies to treat DENV infections [4]

Methods

Results

Conclusion