GENERATION AND CHARACTERIZATION OF HUMAN MONOCLONAL ANTIBODIES WITH NEUTRALIZING ACTIVITY FOR DENGUE VIRUS

Abstract

Dengue virus (DENV) is a member of the family Flaviviridae and the genus Flavivirus. DENV is the etiological agent of dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the most common arthropod-borne viral diseases of global importance. DENV includes four related although antigenically-distinct serotypes (DENV1, 2, 3 and 4). All four DENV serotypes can be found throughout the tropical and sub-tropical regions of the world and transmission of DENV takes place in more than 100 countries in the Americas, Middle East, Africa and Asia-Pacific region. Latest estimate puts the number of people in 2012 living in dengue endemic areas at 3.6 billion, which constitutes more than half the world¿s population. A recent study using new modeling techniques estimated 96 million apparent and 294 million inapparent dengue infections worldwide in 2010. Infection with one DENV serotype confers lifetime immunity to that serotype although not the remaining serotypes. There are presently no licensed vaccines nor specific treatments for dengue and therapy is mainly supportive in nature. Natural long term immunity to DENV is mediated by serotype-specific antibodies. Specifically, antibodies generated as part of a natural human immune response against DENV have been postulated to decrease viremia and disease severity. In this regard, they represent a possible therapeutic modality that has not been exploited. In this study, we have generated and characterized two fully human monoclonal antibodies, one specific for DENV1 and the other DENV2 from convalescent patients. We demonstrate that they have good neutralizing activity both in vitro and in vivo, making them potential therapeutic candidates for the future treatment of DENV infections.