# Development of a Flavivirus Vaccine to Reduce Antibody-Dependent Enhancement of Infection

> **NIH NIH R21** · LOYOLA UNIVERSITY CHICAGO · 2020 · $184,560

## Abstract

Abstract
Zika virus (ZIKV) causes an increase of Guillain Barre syndrome and microcephaly. ZIKV is transmitted via
Aedes mosquitos, which also spreads dengue virus (DENV). DENV has four serotypes that differ by 30-35%
and DENV envelop protein differs from ZIKV envelop protein by 41-46%. Primary infection by DENV leads to
life-long immunity to the infecting serotype but not to the other serotypes. Secondary infection by other
serotypes is often associated with life-threatening complications. It is believed that the antibodies generated in
the primary infection opsonize the secondary virus in the secondary infection to target monocytes and
macrophages via Fc-receptor-mediated endocytosis leading to higher viral loads and severe diseases, i.e.
antibody-dependent enhancement (ADE) of infection. It was shown that human monoclonal antibodies
generated from DENV-infected subjects cross-reacted with ZIKV. Importantly they greatly enhanced ZIKV
infection, potentially ADE in humans. To develop a vaccine that prevents ADE, we propose to develop a
unique vaccine which will induce ZIKV and DENV1-4-specific cytotoxic T lympgocytes (CTLs) but no specific
antibodies. CTLs alone are shown to effectively control infection in DENV mouse model. We hypothesize that a
vaccine inducing CTLs specific for ZIKV and DENV1-4 NS3,4b and 5 will prevent ADE by reducing the
secondary infection. We plan to use papillomavirus-like particles (PV VLPs) as a delivery vector and an
adjuvant: PV VLPs are highly immunogenic and are the major components for the HPV vaccines approved by
the FDA. The VLPs can also be used to package DNA plasmids that carry genes of interest to form
papillomavirus pseudoviruses. The pseudoviruses can enter dendritic cells and macrophages for antigen
presentation. The VLPs as well as DNA itself can activate the NLRP3 and AIM2 inflammasomes, respectively,
to help mount effective adaptive immune responses. Notably, the pseudoviruses are able to elicit strong
immune responses via systemic immunization route. We plan to use the VLPs to make pseudoviruses
encoding ZIKV and DENV1-4 NS3/4b/5 proteins to induce specific CTLs and effector memory T cells. In Aim 1
we will develop papillomaviruses pseudoviruses carrying plasmids expressing NS3/4b/5 protein fragments
unique to ZIKV and DENV1-4. We will make the proteins unstable and degraded in proteasomes to avoid
antibody induction and to enhance CTL generation by rearranging the gene sequences and adding ubiquitin at
its 5's end; We plan to use bovine papillomavirus and cottontail rabbit papillomavirus VLPs to package
plasmids encoding the unstable and ubiquinated ZIKV and DENV1-4 NS3/4b/5 proteins to make the
pseudoviruses. In Aim 2, we will test if systemic immunization with the pseudoviruses induces strong
NS3/4b/5-specific CTL and effector memory T cell responses. Further we plan to test if the vaccine will reduce
ADE of infection in the animal models.

## Key facts

- **NIH application ID:** 9867645
- **Project number:** 5R21AI140210-02
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** LIANG QIAO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,560
- **Award type:** 5
- **Project period:** 2019-02-06 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867645

## Citation

> US National Institutes of Health, RePORTER application 9867645, Development of a Flavivirus Vaccine to Reduce Antibody-Dependent Enhancement of Infection (5R21AI140210-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867645. Licensed CC0.

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