Dengue is the most significant arthropod-transmitted viral infection of humans. Both in the context of natural infection and vaccination, human antibodies are necessary for clearing dengue virus (DENV). Paradoxically, under some conditions antibodies can also enhance the ability of DENV to infect cells and antibodies have been demonstrated to exacerbate disease in animal models of dengue. Despite the evidence that antibodies are important in dengue pathogenesis, very little is known about the binding and functional properties of the human antibody response to DENV. This is a remarkable gap in our knowledge given the scale of the global dengue problem. Based on preliminary studies from our group, here we propose to test the hypothesis that new epitopes created by the assembly and close packing of viral proteins on the surface of the virus are the main targets of the functionall important human antibody response. The impact of this work will be far ranging as it will redirect a field that has mainly focused on B-cell epitopes on subunits of E protein to consider new structural features and epitopes created following viral assembly. Our studies are divided into the following aims.
In aim 1 we will define the main antigens and epitopes recognized by neutralizing antibodies in human immune serum.
In aim 2 we will test the hypothesis that DENV enhancing antibodies in human immune serum mainly target the viral pre-membrane protein. The significance of the work is high because the studies are directly relevant to developing new vaccines and for evaluating current vaccines entering clinical trials.
Dengue viruses are endemic in over 100 countries and the World Health Organization estimates that approximately 50 million new infections occur each year. Vaccination is a feasible solution to prevent and control dengue. However, dengue vaccines need to be developed with caution because of evidence that antibodies against dengue virus can prevent or enhance disease. We propose to study the human antibody response to dengue virus and describe the difference between dengue antibodies that are beneficial or harmful. The studies are relevant to developing a safe and effective vaccine against dengue.
| Messer, William B; de Alwis, Ruklanthi; Yount, Boyd L et al. (2014) Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity. Proc Natl Acad Sci U S A 111:1939-44 |
| Zhou, Yang; Austin, S Kyle; Fremont, Daved H et al. (2013) The mechanism of differential neutralization of dengue serotype 3 strains by monoclonal antibody 8A1. Virology 439:57-64 |
| Smith, Scott A; de Alwis, A Ruklanthi; Kose, Nurgun et al. (2013) The potent and broadly neutralizing human dengue virus-specific monoclonal antibody 1C19 reveals a unique cross-reactive epitope on the bc loop of domain II of the envelope protein. MBio 4:e00873-13 |
| Wahala, Wahala M P B; Huang, Claire; Butrapet, Siritorn et al. (2012) Recombinant dengue type 2 viruses with altered e protein domain III epitopes are efficiently neutralized by human immune sera. J Virol 86:4019-23 |
