Humanized Monoclonal Antibody against West Nile Virus Envelope Protein Administered after Neuronal Infection Protects against Lethal Encephalitis in Hamsters

Abstract

Humans infected with West Nile virus (WNV) may clinically present with symptoms that are suggestive of neurological infection. Nearly all treatments of WNV disease have been effective in animal models only if administered before or soon after viral challenge. Here, we evaluated whether a potent neutralizing anti-WNV humanized monoclonal antibody (MAb), hE16, could improve the course of disease in a hamster model when administered after the virus had infected neurons in the brain. Five days after viral injection, WNV was detected in the brains of hamsters by cytopathic assay, quantitative reverse-transcription polymerase chain reaction, and immunohistochemical staining of WNV envelope in neurons. Notably, 80%-90% of the hamsters treated 5 days after viral injection by intraperitoneal injection with hE16 survived the disease, compared with 37% of the placebo-treated hamsters (P< or =.001). The hamsters that received hE16 directly in the brain also exhibited markedly improved survival rates, compared with those in the placebo-treated hamsters. In prospective experiments, hamsters with high levels of infectious WNV in their cerebrospinal fluid were also protected by hE16 when administered 5 days after viral injection. These experiments suggest that humanized MAbs with potent neutralizing activity are a possible treatment for human patients after WNV has infected neurons in the central nervous system.

Anti-inflammatory activity of intravenous immunoglobulins protects against West Nile virus encephalitis

“…Studies in murine models using low doses of IVIG preparations that contained high titres of WNV neutralizing antibodies confirmed robust protection from WNV encephalitis (Ben-Nathan et al, 2003. Passive transfer of WNV-specific monoclonal or murine polyclonal antibodies aborted or limited WNV infections in rodent models in a dose-, time-and complementdependent manner (Agrawal & Petersen, 2003;Mehlhop et al, 2005;Morrey et al, 2006). Our earlier investigation of the protective mechanisms of IVIG in a model of herpes simplex virus type 1 (HSV1) encephalitis demonstrated that IVIG's potent anti-inflammatory and immunomodulatory activities, rather than its neutralizing activity, were essential for protection.…”

The relative contribution of antibody and CD8+ T cells to vaccine immunity against West Nile encephalitis virus

“…Passive transfer of monoclonal or polyclonal antibodies protect mice and hamsters from lethal subcutaneous or intraperitoneal WNV challenge [5][6][7][8]10,11,15,40,56]. To address the relative potency of the WNV-specific antibody response generated by the vaccines, we passively transferred serum from immunized to younger naïve mice before lethal peripheral challenge.…”

Monoclonal antibody produced in plants efficiently treats West Nile virus infection in mice

“…This mAb is highly inhibitory because it blocks viral fusion at concentrations that result in low occupancy of accessible sites on the virion (10,11). Hu-E16 has therapeutic activity in rodents even after WNV has entered the central nervous system (9,12), in part because it can directly disrupt virus transmission between neurons (13). Despite the promise that Hu-E16 and other mAbs have as prophylactics and therapeutics for WNV or other infectious diseases, their application may be limited by the high production costs and scalability associated with the mammalian-cell culture production system.…”