Yellow fever virus (YFV) is a clinically relevant flavivirus and an NIAID Category C Priority Pathogen. YFV is typically spread by mosquitoes and the World Health Organization has estimated that urban yellow fever causes 200,000 cases and 30,000 deaths annually. The current live YFV vaccine used in the United States, YF-VAX?, has provided significant protection against YFV infection but the risks of vaccination may in some circumstances outweigh the benefits. For instance, immunization with YF-VAX? results in 1 to 2 vaccineassociated deaths per million doses administered - including fatalities in young, otherwise healthy adults. Adverse events occur at much higher rates in vulnerable populations such as the elderly, and the live vaccine is formally contraindicated in other vulnerable populations such as infants or individuals with immune disorders such as a history of thymectomy or thymic dysfunction. In this project, we present evidence demonstrating that we have developed a novel vaccine platform that provides an effective and safe alternative to live virus vaccines. We show that virus inactivation using hydrogen peroxide enhances antigenicity and immunogenicity in comparison with other approaches such as formaldehyde-based inactivation techniques. Using this vaccine platform, we propose the development of a new YFV vaccine for use in both healthy individuals and vulnerable populations that have contraindications for immunization with live viral vaccines. This work will involve 1) development of an appropriately rigorous YFV infection model, 2) analysis and optimization of an inactivated YFV vaccine formulation, and 3) characterization of vaccinemediated immune responses and protection against lethal challenge with clinically relevant strains of virulent YFV. the establishment of this second-generation YFV vaccine will represent the first advance in YFV vaccination in >50 years and provide a much needed vaccine alternative for immunologically vulnerable populations.

Public Health Relevance

The goal of this Project is to develop a model of viscerotropic yellow fever in non-human primates and to test the efficacy of a novel inactivated yellow fever vaccine in both aged and immunologically vulnerable animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54AI081680-01
Application #
7676346
Study Section
Special Emphasis Panel (ZAI1-DDS-M (J2))
Project Start
2009-04-20
Project End
2014-02-28
Budget Start
2009-04-20
Budget End
2010-02-28
Support Year
1
Fiscal Year
2009
Total Cost
$266,275
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Smithey, Megan J; Venturi, Vanessa; Davenport, Miles P et al. (2018) Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection. Proc Natl Acad Sci U S A 115:E6817-E6825
Maurizio, Paul L; Ferris, Martin T; Keele, Gregory R et al. (2018) Bayesian Diallel Analysis Reveals Mx1-Dependent and Mx1-Independent Effects on Response to Influenza A Virus in Mice. G3 (Bethesda) 8:427-445
Uhrlaub, Jennifer L; Smithey, Megan J; Nikolich-Žugich, Janko (2017) Cutting Edge: The Aging Immune System Reveals the Biological Impact of Direct Antigen Presentation on CD8 T Cell Responses. J Immunol 199:403-407
Pryke, Kara M; Abraham, Jinu; Sali, Tina M et al. (2017) A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses. MBio 8:
Bottomly, Daniel; Wilmot, Beth; McWeeney, Shannon K (2015) plethy: management of whole body plethysmography data in R. BMC Bioinformatics 16:134
Gralinski, Lisa E; Ferris, Martin T; Aylor, David L et al. (2015) Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross. PLoS Genet 11:e1005504
Okumura, Atsushi; Rasmussen, Angela L; Halfmann, Peter et al. (2015) Suppressor of Cytokine Signaling 3 Is an Inducible Host Factor That Regulates Virus Egress during Ebola Virus Infection. J Virol 89:10399-406
LaBeaud, A Desiree; Banda, Tamara; Brichard, Julie et al. (2015) High rates of o'nyong nyong and Chikungunya virus transmission in coastal Kenya. PLoS Negl Trop Dis 9:e0003436
Mirrashidi, Kathleen M; Elwell, Cherilyn A; Verschueren, Erik et al. (2015) Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection. Cell Host Microbe 18:109-21
Davis, Zoe H; Verschueren, Erik; Jang, Gwendolyn M et al. (2015) Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Mol Cell 57:349-60

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