Alphavirus Antiviral Drug Development: Scientific Gap Analysis and Prospective Research Areas

Abstract

The New World alphaviruses Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV) pose a significant threat to human health as the etiological agents of serious viral encephalitis through natural infection as well as through their potential use as a biological weapon. At present, there is no FDA-approved medical treatment for infection with these viruses. The Defense Threat Reduction Agency, Joint Science and Technology Office for Chemical and Biological Defense (DTRA/JSTO), is currently funding research aimed at developing antiviral drugs and vaccines against VEEV, EEEV, and WEEV. A review of antiviral drug discovery efforts for these viruses revealed significant gaps in the data, assays, and models required for successful drug development. This review provides a description of these gaps and highlights specific critical research areas for the development of a target-based drug discovery program for the VEEV, EEEV, and WEEV nonstructural proteins. These efforts will increase the probability of the successful development of a pharmaceutical intervention against these viral threat agents.

Host responses to live-attenuated Venezuelan equine encephalitis virus (TC-83)

“…These public health concerns have fostered a renewed interest in understanding VEEV infection, the ensuing human disease and mechanisms of immune development. 15,16 Several studies have evaluated VEEV infection and disease; although the molecular responses occurring during human infection remain largely unknown. 12,[17][18][19][20][21] The present study assessed the molecular components of an effective immune response to VEEV by studying the in vitro responses of naïve human PBMCs to infection with the live-attenuated TC-83 vaccine strain and comparing these responses to those from vaccine responder and nonresponder PBMCs exposed to TC-83.…”

State-of-the-Art Therapeutic Medical Countermeasures for Viral Threat Agents

“…47 Specifically, the development of high-throughput screening assays, the THERAPEUTIC MCMs FOR VIRAL THREAT AGENTS resolution of the crystal structure of the nonstructural proteins, and the development of animal models to support therapeutic evaluation were cited as missing prerequisites to a successful target-based drug development program. The products discussed in this section are early in development and are summarized in Table 3.…”

Development of Human and Macaque Antibodies Using Antibody Phage Display for the Detection of Equine Encephalitis Viruses

“…"At present there is no FDA-approved medical treatment for infection with these viruses." (Reichert et al, 2009). However, antibody phage display and other techniques have already delivered human or human-like antibodies as leads for the treatment or prophylaxis of equine encephalitis.…”