Antibody Prophylaxis and Therapy for Flavivirus Encephalitis Infections

Abstract

The outbreak of West Nile (WN) encephalitis in the United States has rekindled interest in developing direct methods for prevention and control of human flaviviral infections. Although equine WN vaccines are currently being developed, a WN vaccine for humans is years away. There is also no specific therapeutic agent for flaviviral infections. The incidence of human WN virus infection is very low, which makes it difficult to target the human populations in need of vaccination and to assess the vaccine's economic feasibility. It has been shown, however, that prophylactic application of antiflaviviral antibody can protect mice from subsequent virus challenge. This model of antibody prophylaxis using murine monoclonal antibodies (MAbs) has been used to determine the timing of antibody application and specificity of applied antibody necessary for successful prophylaxis. The major flaviviral antigen is the envelope (E) glycoprotein that binds cellular receptors, mediates cell membrane fusion, and contains an array of epitopes that elicit virus‐neutralizing and nonneutralizing antibodies. The protective efficacy of an E‐glycoprotein‐specific MAb is directly related to its ability to neutralize virus infectivity. The window for successful application of prophylactic antibody to prevent flaviviral encephalitis closes at about 4 to 6 days postinfection concomitant with viral invasion of the brain. Using murine MAbs to modify human disease results in a human antimouse antibody (HAMA) response that eventually limits the effectiveness of subsequent murine antibody applications. To reduce the HAMA response and make these MAbs more generally useful for humans, murine MAbs can be “humanized” or human MAbs with analogous reactivities can be developed. Antiflaviviral human or humanized MAbs might be practical and cost‐effective reagents for preventing or modifying flaviviral diseases.

Type- and Subcomplex-Specific Neutralizing Antibodies against Domain III of Dengue Virus Type 2 Envelope Protein Recognize Adjacent Epitopes

“…In our study, we found six different strongly neutralizing MAbs against DENV-2 that localized to two overlapping structural epitopes on the lateral ridge and adjacent A strand of DIII. For flaviviruses, virus type-specific epitopes generally elicit the most potent neutralizing antibodies (2,28,42,53,56,63,64). Of the DIII-specific MAbs against DENV-2 in our panel, in general, the ones with the strongest neutralizing activities were type specific and localized to the lateral ridge of DIII centered at the FG loop, near residues E383 and P384.…”

“…Serotype-specific epitopes elicit antibodies with the strongest neutralizing activities (62,63), and protection in animals by antibodies correlates with neutralizing activity in vitro (6,20,25,43,53,63). Based on epitope mapping data, many type-specific neutralizing antibodies against individual flaviviruses localize to DIII (1,2,10,18,39,53,61,65,66,76), whereas neutralizing monoclonal antibodies (MAbs) that cross-react with other flaviviruses localize primarily to DII, near the fusion peptide (17,23,24,54,61,68).…”

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…Mice deficient for B cells and antibody production demonstrated higher viral loads in CNS and increased vulnerability to lethal WNV infection than wild-type mice [221]. Similarly, adoptive transfer of monoclonal antibodies protected mice from lethal encephalitis caused by other flaviviruses, namely JEV [223], SLEV [224], and yellow fever virus [225]. Further, high levels of JEV-specific IgM and IgG in the CSF was linked to virus clearance from the CNS and a better clinical outcome in patients [226,227].…”

Japanese encephalitis virus produces a CD4+ Th2 response and associated immunoprotection in an adoptive-transfer murine model

“…However, recurring outbreaks in countries like India underline the need for a more effective vaccine (Kabilan et al, 2004;Parida et al, 2006). Studies carried out in humans and in animal models of the disease have indicated the importance of an effective humoral response in preventing flavivirus infection both in the periphery and within the central nervous system (CNS) (Burke et al, 1985;Roehrig et al, 2001;Ben-Nathan et al, 2003;Diamond et al, 2003).…”