Despite being the most important mosquito-transmitted viral disease, there is currently no vaccine for dengue. There are four distinct serotypes of dengue virus (DENV) and cross reactive antibodies to one serotype can enhance infection of other serotypes into Fc receptor-bearing cells such as macrophages correlating with severe disease in humans. A safe and effective vaccine should induce strong, cross protective neutralizing antibodies against all four DENV serotypes, while minimizing non-neutralizing cross reactive antibodies that will only serve to enhance infection and disease severity. Therefore, an optimal vaccine should include only those antigenic regions that will induce strongly neutralizing antibodies and none of the antigenic regions that induce non-neutralizing antibodies. The central aim of this project is to investigate the hypothesis that a vaccine containing only those epitopes that will induce a strong, broadly neutralizing DENV antibody response will be safe and effective. To accomplish this central aim, this project proposes to shift the current paradigm of DENV vaccine research by using insights derived from the study of unique human monoclonal anti-DENV antibodies against the surface E protein to design, characterize, and test a chimeric vaccine in a mouse model. The first specific aim is to design flavivirus E protein chimeras containing DENV epitopes, and characterize their folding, assembly, and functionality. As our results with human MAbs indicate that the important neutralizing DENV epitopes are conformationally sensitive, a related flavivirus, yellow fever will be used as a scaffold for constructing the chimeras. We will introduce specific DENV epitopes into the yellow fever 17D vaccine strain E protein, generate chimeric E protein, virus- like particles, and infectious virus and determine whether these E protein chimeras are still recognized by our human anti-DENV monoclonal antibodies. The second specific aim is to evaluate the antigenicity of flavivirus E protein chimeras containing DENV epitopes in a mouse model and assay serum for the presence of binding, neutralizing, and enhancing anti-DENV antibodies in vitro. The third specific aim is to determine if flavivirus E protein chimeras containing DENV epitopes will produce a protective immunological response in a mouse DENV challenge model. Infectious challenge with DENV is proposed using a widely accepted murine model of DENV infection. Successful completion of the aims will create a DENV vaccine that will induce a broadly neutralizing antibody response, while minimizing the induction of a non-neutralizing, enhancing antibody response, minimizing the risk of more severe disease in vaccine recipients.

Public Health Relevance

As there are none currently available, the development of a vaccine against dengue virus is a high priority. Since primary infection with any of the four dengue virus serotypes produces an antibody response that protects against re-infection with that same serotype, but can increase the disease severity of a secondary infection with one of the other serotypes, a safe and effective dengue vaccine will need to induce broad protection against all four dengue virus serotypes. Using insights derived from the study of unique human monoclonal antibodies, this project will design and characterize a vaccine that contains only those epitopes that induce a strong, broadly neutralizing dengue antibody response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI099210-04
Application #
9047232
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Challberg, Mark D
Project Start
2013-05-10
Project End
2017-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Florida Gulf Coast University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
834477051
City
Fort Myers
State
FL
Country
United States
Zip Code
33965
Myhrvold, Cameron; Freije, Catherine A; Gootenberg, Jonathan S et al. (2018) Field-deployable viral diagnostics using CRISPR-Cas13. Science 360:444-448
Schultz, M J; Tan, A L; Gray, C N et al. (2018) Wolbachia wStri Blocks Zika Virus Growth at Two Independent Stages of Viral Replication. MBio 9:
Grubaugh, Nathan D; Ladner, Jason T; Kraemer, Moritz U G et al. (2017) Genomic epidemiology reveals multiple introductions of Zika virus into the United States. Nature 546:401-405
Gaitor, Jamie C; Paul, Lauren M; Reardon, Melissa M et al. (2017) Ionic liquids with thioether motifs as synthetic cationic lipids for gene delivery. Chem Commun (Camb) 53:8328-8331
Schultz, Michaela J; Isern, Sharon; Michael, Scott F et al. (2017) Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures. J Virol 91:
Metsky, Hayden C; Matranga, Christian B; Wohl, Shirlee et al. (2017) Zika virus evolution and spread in the Americas. Nature 546:411-415
Paul, Lauren M; Carlin, Eric R; Jenkins, Meagan M et al. (2016) Dengue virus antibodies enhance Zika virus infection. Clin Transl Immunology 5:e117
Muyanja, Enoch; Ssemaganda, Aloysius; Ngauv, Pearline et al. (2014) Immune activation alters cellular and humoral responses to yellow fever 17D vaccine. J Clin Invest 124:3147-58
Teets, Frank D; Ramgopal, Moti N; Sweeney, Kristen D et al. (2014) Origin of the dengue virus outbreak in Martin County, Florida, USA 2013. Virol Rep 1-2:2-8
Costin, Joshua M; Zaitseva, Elena; Kahle, Kristen M et al. (2013) Mechanistic study of broadly neutralizing human monoclonal antibodies against dengue virus that target the fusion loop. J Virol 87:52-66