Date of Award

2020

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

Abstract

Zika virus (ZIKV) and Dengue virus (DENV) are flaviviruses that circulate in the same endemic regions and can co-infect the same individual. While primary infection by DENV leads to life-long immunity to the infecting serotype, it does not provide immunity to other serotypes. Moreover, ZIKV and DENV antibodies can be cross-reactive and potentially enhance infection of the other virus through a process known as antibody-dependent enhancement (ADE). In this mechanism, antibodies weakly bind the infecting virus and direct virions to immunoglobulin Fc receptors on macrophages. This promotes viral uptake and infection rather than neutralize the virus. Due to this mechanism, the typical Ab-based vaccines may not be an appropriate vaccine design strategy in this context. However, cytotoxic T lymphocyte (CTL) -based vaccines can protect against infecting viruses without inducing an antibody response. Previously, our lab designed and tested a ZIKV CTL vaccine. This DNA-based vaccine contained the ubiquitinated, rearranged sequence for non-structural protein 3 (NS3) of ZIKV and was expressed in pVAX1, a vector that is FDA-approved for human use. This vaccine induced ZIKV-specific CTLs in mice, protected mice from viral challenge, and did not significantly induce anti-ZIKV antibodies. Additionally, this vaccine partially protected against DENV2 infection. To expand this vaccine, we added ubiquitinated, rearranged NS3 DNA sequences of all 4 DENV serotypes (DENV1-4) to the existing ZIKV vaccine and immunized mice with our ZIKV-DENV Ub/NS3 constructs. We hypothesize that our combined ZIKV-DENV Ub/NS3 construct will induce a protective (non-Ab-mediated) response against both ZIKV and DENV and will expand ZIKV- and DENV- specific CTL populations to provide immunity against these viruses.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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