The INVADE team holds the largest and most unique sample bank of acute ZIKV human sera to date and will definitively assess ZIKV antibody dependent enhancement (ADE) occurring in humans and further identify the T-cell epitope responses.
ADE is a phenomenon in which preexisting poorly neutralizing antibodies, which provide low protection, lead to more serious and, in some cases, life-threatening infection. It is a serious concern with mosquito-borne flaviviruses such as Dengue virus (DENV) and ZIKV.
The information generated by INVADE is critical to developing vaccines, serological diagnostic assays as well as understanding the potential mechanisms of immune pathogenesis responsible for severe neurological and fatal defects.
The INVADE research group is identifying the major T-cell epitopes and cross reactive B-cell epitopes on ZIKV and assessing the role of flavivirus antibodies in protective and pathogenic immunity following ZIKV through antibody dependent enhancement (ADE).
- Define the epitope breadth/repertoire and the targets of CD4 and CD8 responses,
- Derive sets of HLA class I and class II predicted epitopes covering the entire ZIKV proteome,
- Define phenotypes and T cell subsets associated with CD4 and CD8 specific T cells,
- Manufacture a representative library of about 2,000 peptides derived from Zika,
- Identify the major type-specific and cross reactive B-cell epitopes on ZIKV,
- Assess the role of flavivirus antibodies in protective and pathogenic immunity (e.g. related to prior dengue infections, dengue and yellow fever vaccines),
- Assess putative in vivo mutations within ADE associated proteins using protein modelling and monoclonal antibody (mAb) mapping.
Results and Achievements
Even though ADE from a prior ZIKV infection followed by a DENV infection has been demonstrated (George et al. 2017) this does not infer that ADE from a prior DENV infection followed by ZIKV infection will occur. Macaque monkey models to date, despite their low sample size, failed to generate ZIKV after a previous DENV infection (McCracken, et al., 2017; Pantoja et al. 2017).
The preliminary results of the ZikaPLAN INVADE group suggest human sera previously exposed to dengue virus infections generate a great diversity in ZIKV ADE responses. This distinguishes ADE in situ from previous primate in vivo models. It has been identified that ZIKV has a new mechanism of T-cell immunoevasion and an extensive ZIKV T-cell epitope map, which is notably distinct from related flavivirus species, has been completed.
By associating the ZIKV ADE response per patient with their epidemiological history, a clear correlation would infer ZIKV ADE is a population phenomenon. Both the sample size, biological realism of the assay and putative epidemiological associations will set this investigation apart from all its predecessors. A ZIKV reverse genetics system will establish the prototype molecular mechanism of ADE because it is directed by extensive, sophisticated bioinformatics analysis, and undergirded by a robust in vitro assay. Whether ZIKV can evolve to exploit DENV antibody immunity and select for ADE will be established. Finally, important cross-species T-cell epitope mapping will also be performed.
Group leader: Prof. Andrew Falconar, Fundación Universidad del Norte
- London School of Hygiene & Tropical Medicine
- La Jolla Institute for Allergy and Immunology
- The University of North Carolina at Chapel Hill