COVID-19 / Medicine / Health

An Old Antibody Provides a New Clue Against Covid-19

The mobility of the coronavirus spike protein reveals a binding site for antibodies

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An antibody isolated from a patient who recovered from the 2003 SARS outbreak has lead researchers to better understand the nature of how coronaviruses invade the human body, and how our immune systems attack it.

The 2003 outbreak of SARS in Asia spurred a fury of activity to try and find both treatments and preventative vaccines against coronavirus. That outbreak, now 17 years in the past, is still providing clues for researchers in their search for the current Covid-19 outbreak. One research group out of the Scripps Research Institute in California is looking into whether an antibody isolated from a 2003 SARS patient is capable of neutralizing the current SARS-Cov-2 strain.

The current strain of coronavirus — SARS-CoV-2 — shares noticeable similarity to the 2003 SARS-causing strain — SARS-CoV. Both viruses utilize a similar mechanism of attaching to and invading human tissue. Both of the strains rely on a surface protein known as the S-protein, or spike protein to attach to a specific receptor on the human host cell. The receptor, called angiotensin converting enzyme-2 (ACE2) serves as a sort of landing pad for the virus, whose spike protein’s structure closely matches the receptor domain of ACE2. Before binding, spike proteins need to be cleaved by enzymes called protease, which activates them prior to binding to ACE2. The enzyme responsible for cleaving spike proteins is TMPRSS2. These steps are required in the viruses life cycle.

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The Many Shapes of Spike

The process of activating spike proteins is far more complex. These proteins, while images may depict them as static structures, are highly mobile. Spike proteins expand, contract and rotate to assume different configurations. This movement is accentuated by protease activation — the cleavage of the inactive spike protein reconfigures it to allow for binding to ACE2. The Scripps group believes that the key to antibody targeting of spike proteins has more to do with the configuration they are in, than their overall amino acid sequence.

By using X-ray crystallography, this research team was able to model the configuration of the spike protein in its bound and unbound state. By studying the antibody that targets the SARS-CoV strain, they were able to determine that the spike protein assumes a specific configuration when binding to host cells, and in this configuration it is targeted by host antibodies.

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To visualize the configurations of the spike protein, picture an umbrella. An umbrella can assume two basic configurations — open and closed. Spike proteins are crudely shaped in this way, and similarly can configure themselves in an open — or “up” — configuration or an closed — “down” — configuration. The only difference between spike proteins and an umbrella is that spike proteins have three different regions of its outer receptor binding domain that can each assume an up or down configuration independently. In assuming these different configuration, the protein expose different regions of itself to the human immune system — just as the handle of an umbrella is exposed in the open position, but hidden away when closed.

The human immune system will use whatever information it can obtain from a pathogen to try to develop antibodies against it. The most obvious region that researchers believed would be the target for the human adaptive immune response is the receptor binding domain (RBD) on the outer surface of the spike protein. It is true that this region is targeted by the immune system and current patients infected with Covid-19 are likely generating antibodies against this region. But, the RBD is also the region with the highest mutation rate, making antibodies against previous coronavirus infections potentially ineffective against modern strains. Such is the case with influenza, which is why we don’t naturally develop immunity to new strains and why a new vaccine must be developed every year to keep up with mutation on the viruses outer surface proteins.

The antibody currently being investigated by Ian Wilson and his team at Scripps works a little differently. This antibody seems to take advantage of the proteins “up” configuration and targets regions of the spike protein that are less apt to undergo change — those located down on the stalk of the protein. This has lead his team to question whether those antibodies proven to neutralize SARS-CoV may be effective against the novel SARS-CoV-2 strain. If so, they could prove a valuable tool in treating current infections or in developing vaccines to protect against future infection.

Targeting more conserved regions of the coronavirus spike protein also holds the promise for a universal vaccine capable of protecting against multiple coronavirus strains. The prospect of a universal vaccine relies on regions of viral antigens that are shared between multiple strains. There is currently a broad hunt for a universal vaccine against influenza that would eliminate the need for annual immunizations against the virus. As of yet, this has not been accomplished for either virus.

Wilson’s team has determined that the antibody isolated from the 2003 SARS outbreak by itself is not enough to neutralize SARS-CoV-2 in vitro. This could be seen as a setback, but there is evidence that antibodies that fail to neutralize viruses in vitro do in fact impart immunity in living models — hinting at some extra mechanism or possible synergy with other proteins or antibodies in the living host. Due to this evidence, proven in a wide range of other viruses with similar surface antigens, Wilson’s team is hopeful that this old antibody may provide some level of immunity against Covid-19. Further studies in animal models will provide valuable insight into this antibody’s potential as a treatment for Covid-19.

Reference

Hoffmann M, 2020:https://doi.org/10.1016/j.cell.2020.02.052

NIH Director’s Blog: https://directorsblog.nih.gov/2020/04/14/antibody-points-to-possible-weak-spot-on-novel-coronavirus/

Wilson I, 2020: https://science.sciencemag.org/content/early/2020/04/02/science.abb7269.long

Medical student, molecular biologist and educator. I write about science and medicine.

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