Developing Vertebrate-Specific Replication-Defective Dengue Virus as Novel Single-CycleDengue Vaccine Candidate

Developing Vertebrate-Specific Replication-Defective Dengue Virus asa Novel Single-Cycle Dengue Vaccine Candidate
Abstract
With an estimated minimum of 390 million dengue virus (DENV) infections per year, the
DENV epidemic was listed as one of the worldandapos;s top 10 public health threats by WHO in
2019. At present, there is no specific treatment. A universal vaccine is urgently needed.
DENV vaccine developmentandapos;s unique challenge is that a dengue vaccine must induce
long-term protection against all four serotypes simultaneously. Historically, tetravalent
live attenuated viral vaccines have shown that it is difficult to achieve balanced immunity
to all four serotypes. Also, inactivated virus vaccines canandapos;t confer long-term immunity to
prevent potential antibody-dependent enhancement (ADE). Mindful of these obstacles,
we have investigated single-cycle, pseudoinfectious DENVs as vaccine candidates to
induce balanced long-term immunity against all four serotypes. A significant impediment
to this approach is that replicating pseudoinfecious DENVs usually require complicated
and low-efficient packaging cells, making the scale-up production difficult and costly.
Thus, towards the overall goal of developing a safe, effective, and affordable DENV
vaccine, we converted dual-tropic DENVs into artificial insect-specific viruses to
overcome the dependence on packaging cells to produce a single-cycle virus vaccine.
These vertebrate-specific replication-defective DENVs (VSRD-DENV) were generated
by optimizing the furin cleavage site in viral pre-membrane protein (prM). Preliminary
animal experiments with VSRD-DENV1 and VSRD-DENV2 demonstrated that the
VSRD-DENVs induced robust protective immunity with inherent high safety levels in
mice. Based on these highly promising preliminary results and considering the urgent
need for an effective dengue vaccine, Tengen Biomedical Co. and Howard University
have teamed up to accelerate the evaluation of the VSRD-DENVs-based dengue
vaccine. To achieve this goal, we propose to generate and characterize VSRD-DENV3
and VSRD-DENV4 vaccine candidate viruses. We will then perform a comprehensive
analysis of the immunogenicity and protective efficacy of tetravalent VSRD-DENVs in a
sensitive AG129 mouse model. Successful completion of these proposed studies will
enable the dengue vaccine candidate into non-human primate testing and establish a
platform for developing vaccines for other important flaviviruses.Narrative:
The proposal addresses the urgent need for a safe, effective, and affordable tetravalent dengue
vaccine. We have developed unique means to convert dual-tropic dengue virus (DENV) into
vertebrate-specific replication defective DENVs (VSRD-DENV) as a novel single-cycle DENV
vaccine, which potentially induces balanced long-term immunity against four serotypes in
tetravalent formulation. In the proposed project, a tetravalent VSRD-DENV-based dengue
vaccine will be developed and comprehensively investigated in AG129 mice model.