Recombinant Dengue Virus 4 Envelope Glycoprotein Virus-Like Particles Derived from Pichia pastoris are Capable of Eliciting Homotypic Domain III-Directed Neutralizing Antibodies.

Dengue is a viral pandemic caused by four dengue virus serotypes (DENV-1, 2, 3, and 4) transmitted by Aedes mosquitoes. Reportedly, there has been a 2-fold increase in dengue cases every decade. An efficacious tetravalent vaccine, which can provide long-term immunity against all four serotypes in all target populations, is still unavailable. Despite the progress being made in the live virus-based dengue vaccines, the World Health Organization strongly recommends the development of alternative approaches for safe, affordable, and efficacious dengue vaccine candidates. We have explored virus-like particles (VLPs)-based nonreplicating subunit vaccine approach and have developed recombinant envelope ectodomains of DENV-1, 2, and 3 expressed in Pichia pastoris These self-assembled into VLPs without pre-membrane (prM) protein, which limits the generation of enhancing antibodies, and elicited type-specific neutralizing antibodies against the respective serotype. Encouraged by these results, we have extended this work further by developing P. pastoris-expressed DENV-4 ectodomain (DENV-4 E) in this study, which was found to be glycosylated and assembled into spherical VLPs without prM, and displayed critical neutralizing epitopes on its surface. These VLPs were found to be immunogenic in mice and elicited DENV-4-specific neutralizing antibodies, which were predominantly directed against envelope domain III, implicated in host-receptor recognition and virus entry. These observations underscore the potential of VLP-based nonreplicative vaccine approach as a means to develop a safe, efficacious, and tetravalent dengue subunit vaccine. This work paves the way for the evaluation of a DENV E-based tetravalent dengue vaccine candidate, as an alternative to live virus-based dengue vaccines.

Khetarpal N ，Shukla R ，Rajpoot RK ，Poddar A ，Pal M ，Swaminathan S ，Arora U ，Khanna N ... -  《-》

Virus-like particles derived from Pichia pastoris-expressed dengue virus type 1 glycoprotein elicit homotypic virus-neutralizing envelope domain III-directed antibodies.

Poddar A ，Ramasamy V ，Shukla R ，Rajpoot RK ，Arora U ，Jain SK ，Swaminathan S ，Khanna N ... -  《BMC BIOTECHNOLOGY》

A tetravalent virus-like particle vaccine designed to display domain III of dengue envelope proteins induces multi-serotype neutralizing antibodies in mice and macaques which confer protection against antibody dependent enhancement in AG129 mice.

Ramasamy V ，Arora U ，Shukla R ，Poddar A ，Shanmugam RK ，White LJ ，Mattocks MM ，Raut R ，Perween A ，Tyagi P ，de Silva AM ，Bhaumik SK ，Kaja MK ，Villinger F ，Ahmed R ，Johnston RE ，Swaminathan S ，Khanna N ... -  《PLoS Neglected Tropical Diseases》

Tetravalent recombinant dengue virus-like particles as potential vaccine candidates: immunological properties.

Liu Y ，Zhou J ，Yu Z ，Fang D ，Fu C ，Zhu X ，He Z ，Yan H ，Jiang L ... -  《BMC MICROBIOLOGY》

Pichia pastoris-expressed dengue 2 envelope forms virus-like particles without pre-membrane protein and induces high titer neutralizing antibodies.

Mani S ，Tripathi L ，Raut R ，Tyagi P ，Arora U ，Barman T ，Sood R ，Galav A ，Wahala W ，de Silva A ，Swaminathan S ，Khanna N ... -  《PLoS One》