Structure-Guided Design of Dengue and Zika Virus Protein Subunit Vaccines
Abstract
Dengue and Zika are closely related viruses that are transmitted by mosquitoes to people living in tropical and subtropical regions of the world. Dengue viruses (DENV) infect over 400 million people each year, and many infected individuals develop dengue fever or severe dengue hemorrhagic fever. Zika virus (ZIKV) has recently emerged in the American Hemisphere and caused large epidemics in nearly all countries in the Caribbean and Latin America. ZIKV infections can cause severe fetal defects in pregnant women and neurological disease in adults. The US Military has a long history of research to develop live, attenuated vaccines against DENVs because troops deployed in tropical regions of the world are at risk of infection by these viruses. However, it has been difficult to develop safe and effective live dengue vaccines because the disease is caused by four closely related but distinct (serotypes) viruses and the vaccine has to protect people from all four viruses. A long collaborative effort between the US military and Glaxo-Smith Kline to develop a DENV vaccine was abandoned because of the difficulty of balancing the replication of four vaccine viruses. Recently, a live DENV vaccine developed by Sanofi Pasture (Dengvaxia) has been approved for use in some countries. However, this vaccine is not suitable for use by the US military or US civilians because it mainly works by boosting the immune response of people who have already been naturally infected by DENVs. Furthermore, this vaccine is administered as 3 doses over 12 months, which is not practical for troops deployed at short notice or for casual travelers visiting countries with ongoing dengue transmission. We need to invest in alternative strategies to live virus vaccines to protect people from DENVs and other closely related viruses. This proposal is a collaborative effort between the laboratories of Drs. Aravinda de Silva and Brian Kuhlman at the University of North Carolina (UNC) School of Medicine and Drs. Richard Jarman and Gregory Gromowski at the Walter Reed Army Institute for Research (WRAIR). Dr. de Silva and other investigators have recently identified major sites (epitopes) on the protein envelope of DENVs targeted by human antibodies that neutralize dengue infections. Dr. Kuhlman is a biochemist with particular expertise in protein engineering. Together, the laboratories of Drs. de Silva and Kuhlman have started to collaborate to design and produce novel proteins that efficiently display the sites on DENVs and ZIKV targeted by human neutralizing antibodies. The UNC investigators will provide these new proteins to Drs. Jarman and Gromowski at WRAIR for testing as protein subunit vaccines in mice. The new protein subunit vaccines from UNC will be evaluated for their ability protect animals from single virus as well as provide broad protection against multiple viruses. While live virus vaccines have a strong track record, they are not ideal for simultaneous induction of balanced responses to multiple related viruses. Moreover, live virus vaccines are contraindicated during pregnancy, in the elderly, and in immune-compromised individuals. The protein subunit vaccines evaluated in this project may lead to a new platform technology for protecting the military and civilians at high risk of infection by DENVs, ZIKV, and other related viruses. Our proposal is responsive to the Fiscal Year 2017 Peer Reviewed Medical Research Program Area of Encouragement Vaccine Development for Infectious Disease, which specifically mentions the arthropod-borne flaviviruses DENV, ZIKV, and West Nile virus as priorities for the military.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1820035
Entities
People
- Brian Kuhlman
Organizations
- United States Army
- University of North Carolina at Chapel Hill