A Neutralizing Human Monoclonal Antibody Protects African Green Monkeys from Hendra Virus Challenge

Abstract

Hendra virus (HeV) is a recently emerged zoonotic paramyxovirus that can cause a severe and often fatal disease in horses and humans. HeV is categorized as a biosafety level 4 agent, which has made the development of animal models and testing of potential therapeutics and vaccines challenging. Infection of African Green monkeys (AGMs) with HeV was recently demonstrated and disease mirrored fatal HeV infection in humans, manifesting as a multisystemic vasculitis with widespread virus replication in vascular tissues and severe pathologic manifestations in the lung, spleen and brain. Here, we demonstrate that m102.4, a potent HeV neutralizing human monoclonal antibody (hmAb), can protect AGMs from disease post infection (p.i.) with HeV. Fourteen AGMs were challenged intratracheally with a lethal dose of HeV and twelve subjects were infused twice with a 100 mg dose of m102.4 beginning at either 10 hr, 24 hr or 72 hr p.i. and again approximately 48 hrs later. The presence of viral RNA, infectious virus and HeV-specific immune responses demonstrated that all subjects were infected following challenge. All twelve AGMs that received m102.4 survived infection; whereas the untreated control subjects succumbed to disease on day 8 p.i.. Animals in the 72 hr treatment group exhibited neurological signs of disease but all animals started to recover by day 16 p.i.. These results represent successful post-exposure in vivo efficacy by an investigational drug against HeV and highlight the potential impact a hmAb can have on human disease.

A Recombinant Hendra Virus G Glycoprotein Subunit Vaccine Protects Nonhuman Primates against Hendra Virus Challenge

“…Histopathologic analysis of samples from the three control animals that succumbed to a HeV challenge was mostly consistent with previous findings on henipavirus-infected AGMs (11,20,26,30), and lesions from control animals R335 and O7521 were more prominent than those from control animal R372. Noteworthy lesions included interstitial pneumonia, necrosis and hemorrhage of the splenic white pulp, and variable syncytial cell formation in lymphoid tissues.…”

“…This MAb, m102.4, targets the ephrin-B2 and -B3 receptor binding domain of the henipavirus envelope attachment (G) glycoprotein (12)(13)(14)(15)(16). m102.4 is a potent cross-reactive neutralizing antibody in vitro (17,18) and had been shown to protect ferrets from a lethal NiV challenge (19) and AGMs from a lethal HeV challenge (20 In addition to the postexposure treatments, two experimental preventive vaccines against henipaviruses have been evaluated in animal models. A recombinant adeno-associated virus vaccine expressing the NiV G protein completely protected hamsters against a homologous NiV challenge and protected 50% of the animals against a heterologous HeV infection (21).…”

Successful Treatment of Ebola Virus–Infected Cynomolgus Macaques with Monoclonal Antibodies

“…Consistently, successful strategies using a mAb after infection were recently reported against Nipah and Hendra viruses (35). This fresh wave of treatment options against some of the most feared viral hemorrhagic fever viruses may provide concrete solutions to both the public health and the biosafety/biosecurity sectors.…”

Animal Challenge Models of Henipavirus Infection and Pathogenesis

“…NiV infection of pigs is frequently asymptomatic, this was especially noted following natural infections but also later during experimental challenge of pigs with NiV by the ocular and oronasal route (Mohd Nor et al 2000;Middleton et al 2002; Human infection and pathogenesis (Chadha et al, 2006;Goh et al, 2000;Hsu et al, 2004;Wong et al, 2002) c HeV-infected guinea pig (Hooper et al, 1997b;Torres-Velez et al, 2008;Westbury et al, 1995;Williamson et al, 2000Williamson et al, , 2001; NiV-infected guinea pig Wong et al, 2003) HeV-infected African green monkey (Bossart et al, 2011;Rockx et al, 2010); NiV-infected African green monkey l NiV-infected squirrel monkey (Marianneau et al, 2010) m HeV-infected horse (Hooper et al, 1997a;Marsh et al, 2011;Murray et al, 1995aMurray et al, , 1995bWilliamson et al, 1998) n Model developed for equine and/or livestock vaccine development Weingartl et al 2006;Berhane et al 2008; also refer to the chapter on Henipaviruses in their natural host (Middleton and Weingartl, this issue). When symptoms were appare...…”