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Principal Investigator: WALTHER H MOTHES
Organization: YALE UNIVERSITY
Fiscal Year: 2022
Award: $828,211
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
The COVID19 pandemic may take 1-3 years and only fully subside once we reach herd immunity. Given
the high mortality of COVID19, it is of critical importance to reach herd immunity through a vaccine. The
viral spike glycoprotein (S) is central to our efforts for developing an effective vaccine immunogen. The S
protein mediates viral entry into susceptible cells, is the primary target for antibodies, and is a widely
used antigen in diagnostic kits. As such understanding the structure and dynamics of the S protein, and
how antibodies engage it, is important to our response to COVID19. S consists of a trimer of S1/S2
dimers. S1 contains the receptor-binding domain (RBD) that interacts with receptor ACE2. S2 is further
processed by proteases into S2' that mediates fusion. Structural insights into the S protein have been
gained by single particle cryo electron microscopy (SP cryoEM) of a soluble trimer comprising most of the
ectodomain, as well as by cryo electron tomography (cryoET) and SP cryoEM of native virus particles.
These structural studies have revealed several distinct conformational prefusion states wherein the RBD
domain points either up or down. Receptor ACE2 binds the RBD in the up conformation and stabilizes S
in the `two-RBD-up' or `three-RBD-up' conformations. The observations of several distinct conformations
at the EM level suggest that the S trimer exists in a conformational equilibrium. Real-time measurements
of conformational dynamics of the S protein have not been performed. Many antibodies that bind and
neutralize the S protein are being isolated from single B cells from recovered patients, or generated in
mice, and their epitopes are being structurally characterized. Surprisingly, even though many antibodies
clearly bind SARS-CoV-2 S, many do not neutralize the virus. Vaccine studies and clinical trials based on
soluble RBD and S immunogens are under way. In general, they elicit antibodies and can protect from
challenge in non-human primates and underscore our hope that a vaccine that develops antibodies
against the S protein will be successful. However, the observation of non-neutralizing antibodies, a
decline of antibodies in patients and worrisome evidence that antibody-bound coronavirus particles are
responsible for the tissue-damaging inflammatory response seen in patients indicate that we need to
know more about antibody mediated immunity against SARS-CoV-2. To address these challenges, the
Mothes, Liu, Xiong and Blanchard laboratories will employ single molecule and in vivo imaging
techniques to determine the structure and dynamics of ligand-free and antibody-bound SARS-CoV-2 S
protein in the context of virus particles, and determine the fate of antibody-bound virus in vivo. Our work
will inform active and passive immunization strategies against the COVID19 pandemic.
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