R01AI163395

Structure and Dynamics of the SARS-CoV-2 Spike Protein - Summary

The COVID-19 pandemic may take 1-3 years and only fully subside once we reach herd immunity. Given the high mortality of COVID-19, 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 COVID-19.

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 underway. 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 COVID-19 pandemic.

Yale Univ

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93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New Haven, Connecticut 065191418 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 388% from $848,007 to $4,142,443.