The generation of native human monoclonal antibodies with neutralising activity for dengue virus

Abstract

Dengue is the most significant mosquito-borne viral disease affecting humans. At present close to 2.5 billion people living in more than 100 dengue endemic countries in the tropical/sub-tropical belt are considered to be at risk of dengue infection. Dengue diseases affect 50 million people yearly, with frequent and recurrent epidemics (Stephenson 2005). The 1990?s saw a return of dengue diseases in Singapore despite stringent mosquito controls, peaking with the largest ever outbreak in 2005. Over 80% of the reported cases were young adults. In addition to the mortality and morbidity associated with infection, dengue also imposes a considerable burden on the finances and infrastructure of the health-care systems in Singapore and developing countries. Hence, alternatives to dengue vaccines, such as passive antibody therapies and/or antivirals are needed urgently to help control dengue-associated diseases in the immediate term. These proposed therapeutics have the potential to help large numbers of infected individuals in Singapore and elsewhere until such time that safe vaccines become available and can achieve a decent coverage in target populations in endemic countries in approximately 10-20 years. As part of the project, we have isolated a first ever fully human antibody with potential clinical utility using a clone of an immortalized human B memory lymphocyte capable of producing a human antibody with remarkable neutralizing activity to Dengue Virus Type 1in vitro and in vivo. We have isolated the genes that form the template for this antibody and successfully generated a Fab (for X-ray crystallography) and various human IgG subclasses (IgG1, IgG2, IgG3 and IgG4) of recombinant monoclonal antibody. Our study provided greater insights to the ADE hypothesis and demonstrated that this antibody can be a good prophylactic and therapeutic candidate in the treatment of dengue.