! Dengue viruses are mosquito-borne flaviviruses of immense public health impact that cause a spectrum of disease in humans ranging from mild to fatal. Progression to severe dengue disease is promoted by the presence of non-neutralizing anti-dengue IgGs that modulate virus and cytokine production in Fc receptor- bearing cells. We have shown that progression to severe dengue disease is promoted by the presence of anti- dengue antibodies with abundant afucosylated Fc glycoforms, a modification that enhances affinity of the Fc for a specific activating Fc receptor, Fc?RIIIa. Thus, our data point to a role for Fc?RIIIa in the pathogenesis of dengue disease. In this proposal we will study samples from Phase III trials of a live, attenuated tetravalent dengue virus vaccine, CYD-TDV (Dengvaxia, Sanofi Pasteur), to define mechanism involved in human immunity to dengue viruses. Recent analyses of data from the Phase III trials of CYD-TDV showed that risk for disease was increased in some study cohorts by vaccination. This finding highlights the importance of understanding how antibody responses to dengue vaccination are regulated and molecular mechanisms by which antibodies can enhance dengue infections.
Aims i n this proposal will: a) define regulators of Fc fucosylation on antibodies elicited by CYD-TDV vaccination or by natural dengue infection in humans; b) define associations between post- vaccination/pre-infection anti-dengue antibody repertoires and susceptibility to dengue disease during a 5-year follow-up period after vaccination; c) define mechanisms by which Fc?RIIIa impacts dengue infections and disease pathogenesis. Collectively, these aims will advance our fundamental understanding of mechanisms regulating human immunity to dengue viruses and guide the design of safe, effective dengue virus vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI111825-06
Application #
9674741
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Keeffe, Jennifer R; Van Rompay, Koen K A; Olsen, Priscilla C et al. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25:1385-1394.e7
Wu, Xianfang; Dao Thi, Viet Loan; Huang, Yumin et al. (2018) Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell 172:423-438.e25
Hernandez, Nicholas; Melki, Isabelle; Jing, Huie et al. (2018) Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 215:2567-2585
Rosenberg, Brad R; Freije, Catherine A; Imanaka, Naoko et al. (2018) Genetic Variation at IFNL4 Influences Extrahepatic Interferon-Stimulated Gene Expression in Chronic HCV Patients. J Infect Dis 217:650-655
Wang, Taia T; Bournazos, Stylianos; Ravetch, Jeffrey V (2018) Immunological responses to influenza vaccination: lessons for improving vaccine efficacy. Curr Opin Immunol 53:124-129
Kenney, Adam D; Dowdle, James A; Bozzacco, Leonia et al. (2017) Human Genetic Determinants of Viral Diseases. Annu Rev Genet 51:241-263
Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233
Robbiani, Davide F; Bozzacco, Leonia; Keeffe, Jennifer R et al. (2017) Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico. Cell 169:597-609.e11
Wang, Taia T; Sewatanon, Jaturong; Memoli, Matthew J et al. (2017) IgG antibodies to dengue enhanced for Fc?RIIIA binding determine disease severity. Science 355:395-398
Maamary, Jad; Wang, Taia T; Tan, Gene S et al. (2017) Increasing the breadth and potency of response to the seasonal influenza virus vaccine by immune complex immunization. Proc Natl Acad Sci U S A 114:10172-10177

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