Of the arboviruses that are NIAID Category A, B and C Priority Pathogens, approved vaccines are available only for Japanese encephalitis virus, tick-borne encephalitis virus, and yellow fever virus (YFV). Additionally, use of even the highly effective YFV17D vaccine is now being re-evaluated due to increasing reports of severe adverse events following vaccination, particularly in immunocompromised patients. There are currently no other prophylactic or therapeutic strategies approved for arbovirus diseases. Thus, we propose to investigate the utility of human (Hu) and humanized murine (MuHu) arbovirus-specific monoclonal antibodies (MAbs) as antiviral prophylactic or therapeutic reagents. Initial studies, including those in our Progress Report below, indicate that MAbs can be effective prophylactic and therapeutic agents for the encephalitic West Nile and Venezuelan equine encephalitis viruses (VEEV) in mouse models of infection. Based on these results we hypothesize that antiviral MAb prophylaxis and/or therapy using Hu- or MuHuMAbs will also be successful for the viscerotropic, Category A and C arboviruses dengue (DENV) and yellow fever (YFV). We will continue to assess the protective and therapeutic capacities of HuMAb for VEEV developed during our first grant period and will use two approaches to develop YFV and DENV2-reactive HuMAb or MuHuMAb. 1) Use new cell fusion partners, MFP2 or MFP2D cells, to prepare human hybridomas using either human peripheral blood B-cells from infection-immune persons, or human B-cells from virus-immunized, humanized mice. 2) Genetically recombine the variable regions of protective murine MAbs with the constant regions of human immunoglobulin. Protective and therapeutic capacity of these MAbs will be tested by peripheral virus challenge of outbred mice (VEEV) or inbred mice deficient in their interferon response (YFV and DENV2).
Specific aims are as follows: 1. Continue characterization and assessment of protective and therapeutic capacities of human or humanized VEEV-reactive MAbs and map the human anti-VEEV repertoire. 2. Develop HuMAbs and MuHuMAbs specific for YFV and DENV2 Eproteins. 3. Develop a new peripheral challenge animal model for YF using YFV17D vaccine in interferondeficient AG129 mice. 4. Characterize the ability of the YFV- and DENV2-reactive MuHuMAbs and HuMAbs to protect from or treat YFV and DENV2 infections in the AG129 mouse model and use the HuMAbs to map the human anti-E protein antibody repertoire. This project fits within the RMRCE Integrated Research Focus on Viral Therapeutics and will interact directly with RPs 3.1 and 1.7 and Core C.

Public Health Relevance

There are few vaccines and no antiviral therapeutics available for use in human infections with the emerging, medically important arboviruses Venezuelan equine encephalitis (VEEV), yellow fever (YFV) or dengue (DENV) viruses. This project will develop safe and effective human antibodies that can be used in preventing or curing human VEEV, YFV or DENV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065357-08
Application #
8375712
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$204,921
Indirect Cost
$43,117
Name
Colorado State University-Fort Collins
Department
Type
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Webb, Jessica R; Price, Erin P; Somprasong, Nawarat et al. (2018) Development and validation of a triplex quantitative real-time PCR assay to detect efflux pump-mediated antibiotic resistance in Burkholderia pseudomallei. Future Microbiol 13:1403-1418
York, Joanne; Nunberg, Jack H (2018) A Cell-Cell Fusion Assay to Assess Arenavirus Envelope Glycoprotein Membrane-Fusion Activity. Methods Mol Biol 1604:157-167
Rhodes, Katherine A; Somprasong, Nawarat; Podnecky, Nicole L et al. (2018) Molecular determinants of Burkholderia pseudomallei BpeEF-OprC efflux pump expression. Microbiology 164:1156-1167
Cummings, Jason E; Slayden, Richard A (2017) Transient In Vivo Resistance Mechanisms of Burkholderia pseudomallei to Ceftazidime and Molecular Markers for Monitoring Treatment Response. PLoS Negl Trop Dis 11:e0005209
Pettey, W B P; Carter, M E; Toth, D J A et al. (2017) Constructing Ebola transmission chains from West Africa and estimating model parameters using internet sources. Epidemiol Infect 145:1993-2002
Furuta, Yousuke; Komeno, Takashi; Nakamura, Takaaki (2017) Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 93:449-463
Skyberg, Jerod A; Lacey, Carolyn A (2017) Hematopoietic MyD88 and IL-18 are essential for IFN-?-dependent restriction of type A Francisella tularensis infection. J Leukoc Biol 102:1441-1450
Plumley, Brooke A; Martin, Kevin H; Borlee, Grace I et al. (2017) Thermoregulation of Biofilm Formation in Burkholderia pseudomallei Is Disrupted by Mutation of a Putative Diguanylate Cyclase. J Bacteriol 199:
Randall, Linnell B; Georgi, Enrico; Genzel, Gelimer H et al. (2017) Finafloxacin overcomes Burkholderia pseudomallei efflux-mediated fluoroquinolone resistance. J Antimicrob Chemother 72:1258-1260
Podnecky, Nicole L; Rhodes, Katherine A; Mima, Takehiko et al. (2017) Mechanisms of Resistance to Folate Pathway Inhibitors in Burkholderia pseudomallei: Deviation from the Norm. MBio 8:

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