Development of vaccine conjugates based on Dengue virus using a staphylococcal immune evasion protein

Abstract

Dengue viruses (DENV) are members of the Flavivirus family and are thought to infect up to 400 million people per annum and have the potential to lead to large epidemics with subsequent human and economic consequences. The 2 current vaccines being developed are at the clinical trial stage and focus on the induction of neutralising antibodies but there are at least 5 different serotypes of the virus and it appears that induction of immunity to any one serotype will not subsequently provide cross protection to the others. The purpose of this project is to develop an immunisation strategy that will provide protection across all serotypes. A common antigen expressed by all serotypes is designated NS1 which is a non-structural protein expressed on the surface of infected cells. However, on its own NS1 is poorly immunogenic so the intention here is to develop a vector system that combines the expression of NS1 epitopes with those of a highly immunogenic protein derived from Staphylococcus aureus the Staphylococcal immunoglobulin-binding protein, Sbi. Sbi is composed of a number of separate domains each of which has characteristic interactive properties with C3. Previous studies have shown that Sbi N-terminal domain IV (Sbi-IV) binds to C3 and its proteolytic fragments, however, the Sbi domains III and IV are essential for fluid phase consumption of C3 activating via the alternative complement pathway. In this project the domains III and IV of Sbi have been cloned and expressed in E. coli and conjugated to NS1. These can bind to complement C3, causing cleavage, and lead to the generation of C3d which is able to crosslink binding between the NS1 antigen and complement receptor 2 (CR2) present on phagocytic cells and B cells to greatly enhance a TH2 (antibody) mediated response and ultimately, the generation of memory TH2 cells to provide expansion of B cells (plasma cells) producing DENV specific neutralising antibodies.

Date of Award	6 Sept 2017
Original language	English
Awarding Institution	University of Bath
Supervisor	Jean Van Den Elsen (Supervisor)