What Is the Spike Protein in COVID-19?

By Nidhi Parekh of The Shared Microscope

The SARS-CoV-2 spike protein plays a crucial role in COVID-19 infection. Learn about the spike protein and its importance as a therapeutic target in COVID-19 vaccines.

image of a stethoscope, mask, and person holding a cutout of a heart shape
Photo by Karolina Grabowska on Pexels.com

Learn about the coronavirus spike protein and its importance as a therapeutic target to beat COVID-19.

Here’s Everything You Need to Know about the Coronavirus Spike Protein and COVID-19

Table of Contents:


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Shortly after people in Wuhan, China came down with a mysterious respiratory illness in December 2020, scientists got to work figuring out what was going on. In January 2020, Chinese researchers worked to rapidly identify and make available the genome of a novel coronavirus underlying the new disease. The virus gained the name SARS-CoV-2 because of its structural similarity to SARS-CoV (SARS), which broke out in 2003 and was swiftly contained by 2004.

The novel coronavirus, SARS-CoV-2, caused a syndrome which began to be called “coronavirus disease 2019,” or COVID-19 for short. COVID-19 was declared a global pandemic by the World Health Organization on March 11, 2020.

While scientists did not have all the answers at the outset of the pandemic, they worked hard to understand the disease. As time progressed, answers emerged. Scientists learned that the virus’s structure helped COVID-19 spread. Namely, a protein on the surface of the virus proved to be important in the COVID-19 infection mechanism. This protein is known as the spike protein or S protein.

Just what is this spike protein? By now, you’ve seen the ubiquitous image of the SARS-CoV-2 virus which causes COVID-19. The virus resembles a sphere with some spiky protrusions.  These spikes are, aptly, known as spike proteins.

Over time, researchers have unveiled the molecular structure of the coronavirus spike protein, and have figured out how the spike protein causes COVID-19. Namely, we’ve learned that the spike protein plays an important role in invading human cells. This insight has also illuminated the importance of spike proteins as a therapeutic target.  

Knowing about the spike proteins and overall molecular structure of the pandemic virus has helped develop novel treatments and vaccines against COVID-19. Several vaccines developed against COVID-19 work to foster immunity to this spike protein to prevent an infection from taking hold.

Understanding the structure and function of the coronavirus spike protein can go a long way in improving one’s understanding of how COVID-19 vaccines work. So let’s just get to it.

The Structure of the Coronavirus Spike Protein

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sars-cov-2 virus structure -- fancy comma blog
Structure of SARS-CoV-2, the virus that causes COVID-19. Spike proteins are depicted in red.

As you can see from the image above, several spike proteins are found on the surface of the SARS-CoV-2 virus. The spike proteins of the SARS-CoV-2 virus bind to Angiotensin-Converting Enzyme 2 (ACE2) receptors that are found on the surface of the host cell (i.e. the cells in our body that become infected by the coronavirus).

As I mentioned, the spike proteins are also known as S proteins. Each S protein on the coronavirus consists of three components that combine to form a ‘trimer.’ Two of the three components of the trimer are subunits of the S protein. These two subunits are called Subunit 1 (S1) and Subunit 2 (S2). Both S1 and S2 play an important role in disease progression. Together, S1 and S2 enable the virus to communicate with the host to rapidly take over host cells — that is, our human cells — to help the virus make more copies of itself. This is what causes COVID-19 infection.

Let’s talk more about how S1 and S2 promote COVID-19 infection next.

The S1 Subunit

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S1 plays an important role in initiating viral infection – it interacts with the cell receptors present on the surface of the host cell. Some mutations in S1 can play an important role in enhancing the interaction with ACE2 receptors found on the surface of our cells. Other research suggests that S1 is not the ideal drug target because it is highly mutable. S1, therefore, is not the ideal candidate for a drug or vaccine against COVID-19. However, it acts as a “wingman” to promote COVID-19 along with S2, as I’ll explain next.

The S2 Subunit

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As I’ve just mentioned, S1’s role is to set the stage for a COVID-19 infection. The S2 subunit, on the other hand, is important for viral fusion and entry that actually causes COVID-19. What does this mean?

Well, for the coronavirus to affect the cells in our body, it must first get into our cells somehow. This is accomplished via teamwork of S1 and S2. S1 binds to our cell’s ACE2 receptor. Then, a little rift forms in a small area between the S1 and S2 subunits. This rift causes the S2 subunit to change shape, which sets up the virus to transmit its contents into the host cell. Once the virus opens and spill its contents into the host cell, a COVID-19 infection can occur. The novel coronavirus hijacks the cell and forces it to make copies of itself, which is what causes COVID-19.

Unlike the S1 subunit which often undergoes genetic mutations, the S2 subunit is fairly conserved (that is, it does not undergo mutation). This makes the S2 subunit an ideal target for therapeutics.

illustration showing the s1/s2 cleavage site on the viral spike protein, which helps the SARS-CoV-2 virus fuse with host cells
Illustration by Nidhi Parekh of The Shared Microscope

The Function of the Spike Protein

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As you’ve learned, the spike or S protein plays a pivotal role in viral infection. Working together, the S1 and S2 subunits facilitate the steps necessary for the novel coronavirus to enter our cells and multiply rapidly to cause COVID-19. 

More specifically:

  • The S1 subunit plays an important role in communicating with and binding to cell receptors of the host cell.
  • The S2 subunit plays an important role in viral fusion and entry. 

In theory, if you can prevent the attachment of the spike protein to the host cell, you can prevent infection. Without the spike protein attaching to a host cell (for instance, human cells), the coronavirus has no way to cause an infection. It cannot get into our cells to deposit its genome and take over our cellular machinery to replicate. 

So, there’s no path to viral entry without the spike protein, which is why developing immunity to spike proteins has been the main therapeutic target in the COVID-19 vaccine race.

The coronavirus spike protein changes shape after binding to our cells

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Beyond its subunit makeup, another important aspect of the spike protein is its shape. The protein changes shape after binding to host cells (for example, our human cells). 

Before it can cause infection, the spike protein exists in a stable pre-fusion conformation. When the virus interacts with the host cell, it undergoes a rearrangement into the post-fusion form which allows the virus to fuse into the host cell. Once the spike protein changes conformation, it is too late — the infection stages have already begun. 

illustration showing that, after fusing to a human cell, the novel coronavirus spike protein changes shape
Illustration by Nidhi Parekh of The Shared Microscope

To prevent COVID-19, it was, therefore, important to determine and target the pre-fusion shape of the spike protein. Scientists understood this principle early on and have exploited it for the production of vaccines, therapies, diagnostic tests, and antiviral drugs. 

Top COVID-19 Vaccines Target the Spike Protein

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The top COVID-19 vaccines target the disease-causing coronavirus’s spike protein.

Understanding how the spike protein and ACE2 receptors on our cells interact has been critical to planning an approach to the development of effective vaccines against infection by the SARS-CoV2 virus. 

Most of the top COVID-19 vaccines target the viral spike protein to develop immunity.

mRNA vaccines include Moderna and Pfizer/BioNTech. They contain a blueprint of the spike protein in the form of an mRNA message. The mRNA tells our body to produce the pre-fusion conformation of the spike protein. Once our body produces the spike protein, this trains our immune system to learn about and destroy the spike protein.

Viral vector vaccines are the Oxford/AstraZeneca and Johnson & Johnson vaccine. In these vaccines, another virus serves as a vehicle for essential genetic information encoding for the spike protein. The viral vector is then injected into our bodies, which causes our body to make the spike protein. The spike protein teaches our body how to fight the spike protein to prevent future infection. 

Protein subunit vaccines include Novavax. In a protein subunit vaccine, only the spike proteins are produced in a laboratory. Then, the spike proteins are injected into our bodies. Our body works on understanding the structure of this protein and neutralizing it. Learning the structure of the protein will ensure that our body can recognize it when exposed to the SARS-CoV-2 virus.

The above vaccines have all undergone crucial testing in clinical trials. They are currently going through the approval process for use in the US and worldwide. 

Read More about the Science of COVID-19

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The COVID-19 vaccines are the light at the end of the long and turbulent COVID-19 pandemic tunnel. Final results from Phase 3 clinical trials have shown that these vaccines are highly effective in preventing COVID-19 infection, even in high-risk individuals. 
To read more about the science of COVID-19, including how COVID-19 vaccines work, check out our COVID-19 resource page.

Nidhi Parekh is a science writer and illustrator blogging at The Shared Microscope. Visit them on Twitter, Facebook, or Instagram for informative, effective illustrations of concepts in biology.


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