The major accomplishments for this year are summarized below. 1) Middle East Respiratory Syndrome coronavirus (MERS-CoV) has repeatedly caused outbreaks in the Arabian Peninsula. To date, no approved medical countermeasures (MCM) are available to combat MERS-CoV infections. Several neutralizing human monoclonal antibodies (mAbs), including m336, a germline-like human mAb, have been chosen as promising MCM for MERS-CoV. However, their clinical development has been hindered by the lack of a robust animal model that recapitulate the morbidity and mortality of human infections. We assessed the prophylactic and therapeutic efficacy of m336 by using well-characterized transgenic mice shown to be highly sensitive to MERS-CoV infection and disease. We found that mice treated with m336 prior to or post lethal MERS-CoV challenging were fully protected, compared to control mice which sufferered from profound weight loss and uniform death within days after infection. Taken together, these results support further development of m336 and other human monoclonal antibodies as potential therapeutics for MERS-CoV infection. 2) Passive immunotherapy via either convalescent plasma or mAbs has proven to be effective for other infectious agents. Following infection with MERS-CoV, common marmosets were treated with high titer hyperimmune plasma or the mAb m336, at 6 and 48 h post inoculation. Both treatments reduced signs of clinical disease, but reduction in viral loads in the respiratory tract were only found in the hyperimmune plasma group. A decrease in gross pathology was found only in the mAb-treated group, but no histological differences were observed between treated and control animals. While both hyperimmune plasma and the m336 treatments reduced the severity of disease in the common marmoset, neither treatment resulted in full protection against disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011156-09
Application #
9556475
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
van Doremalen, Neeltje; Falzarano, Darryl; Ying, Tianlei et al. (2017) Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets. Antiviral Res 143:30-37
Agrawal, Anurodh Shankar; Ying, Tianlei; Tao, Xinrong et al. (2016) Passive Transfer of A Germline-like Neutralizing Human Monoclonal Antibody Protects Transgenic Mice Against Lethal Middle East Respiratory Syndrome Coronavirus Infection. Sci Rep 6:31629
Ying, Tianlei; Li, Wei; Dimitrov, Dimiter S (2016) Discovery of T-Cell Infection and Apoptosis by Middle East Respiratory Syndrome Coronavirus. J Infect Dis 213:877-9
Houser, Katherine V; Gretebeck, Lisa; Ying, Tianlei et al. (2016) Prophylaxis With a Middle East Respiratory Syndrome Coronavirus (MERS-CoV)-Specific Human Monoclonal Antibody Protects Rabbits From MERS-CoV Infection. J Infect Dis 213:1557-61
Dimitrov, Dimiter S; Jiang, Shibo; Ying, Tianlei et al. (2015) No evidence for a superior platform to develop therapeutic antibodies rapidly in response to MERS-CoV and other emerging viruses. Proc Natl Acad Sci U S A 112:E5115
Ying, Tianlei; Li, Haoyang; Lu, Lu et al. (2015) Development of human neutralizing monoclonal antibodies for prevention and therapy of MERS-CoV infections. Microbes Infect 17:142-8
Ying, Tianlei; Prabakaran, Ponraj; Du, Lanying et al. (2015) Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody. Nat Commun 6:8223
Ying, Tianlei; Du, Lanying; Ju, Tina W et al. (2014) Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J Virol 88:7796-805
Geisbert, Thomas W; Mire, Chad E; Geisbert, Joan B et al. (2014) Therapeutic treatment of Nipah virus infection in nonhuman primates with a neutralizing human monoclonal antibody. Sci Transl Med 6:242ra82
Zhu, Zhongyu; Prabakaran, Ponraj; Chen, Weizao et al. (2013) Human monoclonal antibodies as candidate therapeutics against emerging viruses and HIV-1. Virol Sin 28:71-80

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