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"Structure-based design of broad flavivirus immunogens based on glycoprotein E domain III (EDIII)"

Dengue virus (DENV) is a mosquito-spread flavivirus that causes millions of infections worldwide every year. There are four serotypes of DENV (DENV1-4); primary infection by one serotype leads to a self-limiting febrile illness and subsequent lifelong immunity against that serotype. However, secondary infection by a heterologous serotype can lead to severe disease (Severe Dengue) that is characterized by immunologic dysfunction. Severe Dengue is thought to be induced by antibody-dependent enhancement (ADE), a phenomenon whereby serotype-specific and non-neutralizing antibodies elicited during primary infection are re-elicited during secondary infection, but fail to neutralize the heterologous serotype and instead enhance viremia by recruiting susceptible cells to the viral particle. Recent studies have reported the potential for ADE of DENV caused by primary ZIKV infection. Therefore, a critical goal for flavivirus vaccine design is to induce potently cross-neutralizing antibodies, but avoid induction of non-neutralizing antibody. We have taken a structure based design and phage display approach to develop “resurfaced” variants of DENV and ZIKV E glycoprotein domain III (EDIII) that maintain epitopes that are targeted by critical neutralizing antibody, but where regions bound by non-neutralizing antibodies are masked by mutation. We have biochemically characterized these resurfaced EDIIIs (rsDIIIs) for their reactivity toward antibodies, and for their structural features. Finally we generated immunogenic nanoparticle utilizing Spycatcher/Spytag conjugation technology and tested those nanoparticle for their capacity to induce neutralizing and protective response in mice. These studies provide insight into next-generation vaccine design strategies for globally significant flaviviruses.

Meeting ID: 945 6630 0461 Passcode: 088953

from Chemistry