An estimated 2.3 billion people live at risk of infection by the Zika virus (ZIKV), a mosquito-borne flavivirus that causes microcephaly in newborns, as well as eye- and neurological defects, and Guillain-Barre syndrome in adults. Zika co-circulates in the same geographical region with the four serotypes of Dengue virus, which is of concern for both Dengue and Zika vaccine development. Antibodies that develop in response to Dengue can enhance Zika infection, and vice versa (Antibody-Dependent Enhancement, ADE). A recently discovered class of antibodies has been found to exhibit less ADE; these antibodies broadly and potently neutralize Zika and all four Dengue serotypes, and do so by binding to a quaternary epitope at the interface between adjacent E glycoprotein subunits on the viral envelope. This envelope dimer epitope (EDE) is a promising target for vaccine development. The goal of this exploratory R21 project is to discover glycopeptides that are good structural mimics of the EDE on ZIKV. Such molecules, when used as vaccine immunogens, should stimulate a broadly neutralizing antibody response that is protective against ZIKV, while avoiding ADE effects. The Krauss lab will use its directed evolution technology to scaffold the carbohydrate and peptide components of the EDE into arrangements that enable strong recognition by EDE antibodies, producing EDE mimics. Two further types of studies will then determine which among these glycopeptide ?hits? are best for future immunogenicity studies. The Sarathy and Barrett labs with determine whether selected glycopeptides compete with ZIKV for binding to the EDE antibodies, whereas the Wilson lab will determine structures of glycopeptide-antibody complexes to determine whether glycopeptides bind to the antibodies through ZIKV-like contacts.

Public Health Relevance

to Public Health: The Zika virus causes microcephaly and other birth defects in newborns, and is associated with Guillain-Barre syndrome in adults. The virus has recently spread worldwide, with 2.3 billion people now at risk of infection and no vaccine is yet available. This project will explore the development of novel vaccines to combat Zika.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI140030-02
Application #
9698290
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Woodson, Sara Elaine
Project Start
2018-05-15
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brandeis University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02453