Molecular analysis of antibody repertoire elicited after yellow fever vaccination Even though an effective vaccine against the yellow fever virus (YFV) exist a high frequency of global YFV outbreaks represent an imminent threat to human health. Health authorities have confirmed more than 500 deaths just in Brazil in the last two years, and more than 150 incidents of YFV outbreaks in 26 African countries were reported to the WHO in the last 30 years. YFV infection causes a febrile flu-like illness, and about 10-25% of patients develop hemorrhagic manifestations, kidney and liver damage that can result in death. YFV show similarities compared to other medical important flavivirus as dengue virus (DENV) and zika virus (ZIKV). The central hypothesis underlying the proposed work is that in geographic regions where YFV co-circulates with DENV and ZIKV endemic flaviviruses, cohorts vaccinated for YFV will exhibit a statistically different pattern of incidence of DENV and ZIKV infections (significantly lower or greater) compared to unvaccinated controls, due to vaccine elicitation of serum IgG antibodies cross-reactive between YFV and DENV and/or ZIKV. In view of this, the aims of this collaborative project are to: (i) inform on the complexity and molecular features of the antibody repertoire elicited by YFV vaccination that are specific to YFV and those that cross-react with DENV-2 and/or ZIKV, (ii) isolate YFV-specific monoclonal antibodies (mAbs) with therapeutic potential, (iii) evaluate the ability of these mAbs to protect against YFV, DENV and ZIKV infections or to increase the infection through antibody dependent enhancement (ADE), and (iv) identify the epitopes targeted by the neutralizing and cross-reactive mAbs. Our multidisciplinary approach will include a set of original tools for analyzing adaptive immune responses? developed, published, and protected by two issued US patents and currently available only at UT Austin?to comprehensively identify, at high throughput, high-affinity human cross-reactive serum antibodies and delineate the molecular nature of cross-reactive antibody generation. Collectively, this work will be important to determine the existence of ADE-induced by YFV vaccination and to open up the perspectives to develop vaccination strategies that minimize ADE responses between YFV, ZIKV and DENV and also the development of effective mAb therapeutics against Yellow Fever.

Public Health Relevance

Yellow fever virus (YFV), a member of the dengue (DENV) and zika virus (ZIKV) family, infects thousands of people each year. By analyzing vaccine recipients for YFV, the aim of this work it to characterize specific and protective antibodies, as well as cross-reactive antibodies (against ZIKV and DENV). This could lead to the rapid development of therapeutics for YFV and aid the design of a future vaccine protective for multiple flaviviruses including DENV and ZIKV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI143552-01
Application #
9701699
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Challberg, Mark D
Project Start
2019-03-01
Project End
2024-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Foundation for Research Development
Department
Type
DUNS #
898723903
City
Belo Horizonte
State
Country
Brazil
Zip Code
31270901