The filoviruses Ebola (EBOV) and Marburg (MARV) cause the most severe hemorrhagic fevers in humans with the mortality rates up to 90% and are considered potential weapons for bioterrorism and biological warfare. Recently published studies demonstrated a successful protection of rodents and nonhuman primates (NHP) against filoviruses by passively transferred polyclonal antibodies (Abs) and mouse monoclonal antibodies (mAbs). However, fully human mAbs have important advantages over murine, chimeric, or humanized mAbs that include their safety and greater potency. The central hypothesis of this proposal is that survivors of EBOV and MARV Infections likely possess circulating B cells encoding naturally-occurring human Abs that neutralize virus and protect against disease. This hypothesis is supported by a recent progress of the research team included in the application in isolation of human mAbs from a survivor of MARV infection. The key requirements for successful treatment of filovirus infections with mAbs may include (A) use of high-affinity mAbs, and (B) administration of a cocktail of mAbs binding to the diverse viral epitopes, rather than an individual mAb. This possibility will be tested by generation of comprehensive reagents for study of filovirus recognition by human Abs which will be used for pursuing the following Specific Aims: 1) To isolate large panels of human mAbs to EBOV and MARV from the B cells of humans following natural infection; 2) To identify and characterize the most potent neutralizing and cross neutralizing human mAbs; 3) To test and optimize protection of human mAbs in rodents and NHP; 4) To test post-exposure treatment of NHPs with human mAbs in combination with recombinant VSV-vectored vaccines from RPI and anti-filovirus small interfering RNA (siRNA) from RP2. This proposal incorporates experts in molecular immunology, molecular virology, viral pathogenesis and public health, with access to BSL-4 facilities. We have access to blood of survivors of all five filovirus species highly pathogenic for humans {Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus, Ivory Coast ebolavirus, and MARV) in Gabon, Democratic Republic of Congo and Uganda, that is important due to the significant antigenic diversity between the individual species of filoviruses, and blood of individuals seropositive for EBOV infection who did not experience disease. The proposed research Is significant because it will result in generation of large panels of human mAbs that neutralize EBOV or MARV, identify the most potent mAbs and test them in rodents and NHPs on their own and in combination with the other post-exposure treatments included in the CETR.

Public Health Relevance

): The proposed research Is relevant for public health because it is aimed at development of therapeutic antibodies against the filoviruses, Ebola and Marburg, which cause the most severe hemorrhagic fevers in humans with the mortality rates up to 90%. It is also aimed at understanding the rules and principles underlying molecular recognition of filoviruses by antibodies. Thus, the proposed research is relevant to the part of NIH's mission that pertains to reduce vulnerability of the population to biothreat agents

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI109711-04
Application #
9235247
Study Section
Special Emphasis Panel (ZAI1-LR-M)
Project Start
Project End
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
4
Fiscal Year
2017
Total Cost
$1,004,465
Indirect Cost
$193,084
Name
University of Texas Medical Br Galveston
Department
Type
Domestic Higher Education
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Gilchuk, Pavlo; Mire, Chad E; Geisbert, Joan B et al. (2018) Efficacy of Human Monoclonal Antibody Monotherapy Against Bundibugyo Virus Infection in Nonhuman Primates. J Infect Dis 218:S565-S573
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Ilinykh, Philipp A; Santos, Rodrigo I; Gunn, Bronwyn M et al. (2018) Asymmetric antiviral effects of ebolavirus antibodies targeting glycoprotein stem and glycan cap. PLoS Pathog 14:e1007204
King, Liam B; Fusco, Marnie L; Flyak, Andrew I et al. (2018) The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding. Cell Host Microbe 23:101-109.e4
Mire, Chad E; Geisbert, Joan B; Borisevich, Viktoriya et al. (2017) Therapeutic treatment of Marburg and Ravn virus infection in nonhuman primates with a human monoclonal antibody. Sci Transl Med 9:
Mire, Chad E; Geisbert, Thomas W (2017) Neutralizing the Threat: Pan-Ebolavirus Antibodies Close the Loop. Trends Mol Med 23:669-671

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