Dengue virus (DENV) causes dengue fever, the most prevalent arthropod-borne viral illness in humans (NIAID Category A pathogen). Globally, the four serotypes of DENV cause an estimated 100 million new cases of dengue fever and 250,000 cases of dengue hemorrhagic fever (DHF) per year. Currently, no specific therapy is available, and vaccines are still in early stages of development. Given that the most advanced tetravalent live attenuated DENV vaccine candidate showed a poor 30% overall efficacy rate in a recently published phase 2b clinical trial, there remains a pressing need for new approaches for safe, effective vaccines. In the first cycle of this R01 we developed a large panel of ~500 novel monoclonal antibodies (MAbs) against all four DENV serotypes and analyzed the structural, biophysical, and cellular mechanisms of Ab-mediated neutralization of several of them. These studies defined novel epitopes on DENV E proteins recognized by inhibitory antibodies (Abs), many of which are not solvent-accessible according to existing atomic models of the virus particle. Our studies revealed that the structure of DENV was more complex than anticipated and is likely a heterogeneous and structurally dynamic ensemble of different states, each of which may interact differentially with Ab. In this renewal application, we propose to define the spectrum of structural states sampled by the DENV virion, determine the structural basis of differential neutralization of individual DENV serotype by cross-reactive, fusion-loop specific Abs, and assess the role of anti-prM Abs in recognition and neutralization of DENV. This information will be translated into developing a novel inactivated vaccine strategy that traps DENV particles in structural states that preferentially elicit highly neutralizing Abs.
The goal of this application is to define new states of DENV particle structure and determine how these interact with specific MAbs. This information will be translated into developing a novel DENV vaccine strategy that traps virions in states that preferentially elicit highly neutralizing Abs.
| Sevvana, Madhumati; Long, Feng; Miller, Andrew S et al. (2018) Refinement and Analysis of the Mature Zika Virus Cryo-EM Structure at 3.1 Å Resolution. Structure 26:1169-1177.e3 |
| Pierson, Theodore C; Diamond, Michael S (2018) The emergence of Zika virus and its new clinical syndromes. Nature 560:573-581 |
| Thawani, Ankita; Sirohi, Devika; Kuhn, Richard J et al. (2018) Zika Virus Can Strongly Infect and Disrupt Secondary Organizers in the Ventricular Zone of the Embryonic Chicken Brain. Cell Rep 23:692-700 |
| Scott, Jason M; Lebratti, Tania J; Richner, Justin M et al. (2018) Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice. J Virol : |
| Regla-Nava, Jose Angel; Elong Ngono, Annie; Viramontes, Karla M et al. (2018) Cross-reactive Dengue virus-specific CD8+ T cells protect against Zika virus during pregnancy. Nat Commun 9:3042 |
| Bullard, Brianna L; Corder, Brigette N; Gorman, Matthew J et al. (2018) Efficacy of a T Cell-Biased Adenovirus Vector as a Zika Virus Vaccine. Sci Rep 8:18017 |
| Therkelsen, Matthew D; Klose, Thomas; Vago, Frank et al. (2018) Flaviviruses have imperfect icosahedral symmetry. Proc Natl Acad Sci U S A 115:11608-11612 |
| Caine, Elizabeth A; Jagger, Brett W; Diamond, Michael S (2018) Animal Models of Zika Virus Infection during Pregnancy. Viruses 10: |
| Gorman, Matthew J; Caine, Elizabeth A; Zaitsev, Konstantin et al. (2018) An Immunocompetent Mouse Model of Zika Virus Infection. Cell Host Microbe 23:672-685.e6 |
| Richner, Justin M; Diamond, Michael S (2018) Zika virus vaccines: immune response, current status, and future challenges. Curr Opin Immunol 53:130-136 |
Showing the most recent 10 out of 69 publications
