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Pre-vaccination microenvironment impact Dengue vaccine response
Dissertation   Open access

Pre-vaccination microenvironment impact Dengue vaccine response

Abdullah Muhammed Izmirly
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2021
DOI:
https://doi.org/10.17918/00000863
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Abstract

Dengue viruses
It has been estimated that more than 390 million people are infected with Dengue virus every year; around 96 million of these infections result in clinical pathologies. To date, there is only one licensed viral vector-based Dengue virus vaccine (DENGVAXIATM) approved for use in some parts of the world. While initially approved for administration independent of serostatus, the current guidance only recommends the use of this vaccine to seropositive individuals. Therefore, there is a critical need for investigating the influence of Dengue virus serostatus and immunological mechanisms that influence vaccine outcome. Here, we provide comprehensive evaluation of serostatus and host immune factors that correlate with robust immune responses to a Dengue virus vector based tetravalent vaccine (TV003) in a clinical cohort of human subjects. As expected, seropositive individuals demonstrate a much stronger immune response to TV003 vaccine. However, our multi-layered immune profiling revealed that seropositive subjects have increased baseline/pre-vaccination frequencies of total circulating T follicular helper (cTfh) cells and the Tfh centric chemokine CXCL13/BLC. Importantly, this baseline/pre- vaccination cTfh profile correlated with the vaccinees' ability to induce neutralizing antibody titers against all four serotypes of Dengue virus, an important endpoint for Dengue vaccine clinical trials. Furthermore, we interrogated antigen specific circulating T follicular helper cells (cTfh) differences between subjects that are, seropositive, with existing antibodies to any of the four Dengue virus serotypes due to prior infection before vaccination (referred to as "Immune"), or seronegative, subjects with no existing antibodies to any of the four Dengue virus serotypes (referred to as "naïve"). We found seropositive and seronegative subjects have increased frequencies of total dengue specific circulating T follicular helper (cTfh) cells along with increase in anti- and pro- inflammatory cytokines at Day 12-15 after vaccination. Importantly, we found that Dengue-specific cTfh cells are induced at significantly higher frequency in immunized when compared to naïve subjects. Overall, we provide novel insights into the favorable cTfh centric immune status that persists in Dengue virus seropositive individuals that correlate with their ability to mount robust vaccine specific immune responses. Such detailed interrogation of cTfh cell biology in the context of clinical vaccinology will help uncover mechanisms and targets for favorable immuno-modulatory agents. Furthermore, due to the current pandemic and the similarities between Dengue virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) we included a detailed review on SARS-CoV-2. This review summarized the background and pathogenesis of SARS-CoV- 2 and the front-runners in the race of SARS-COV-2 vaccine development.

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