Pfizer and BioNTech’s mRNA Vaccine Against COVID-19: How Does It Work?

This article was written for Fancy Comma, LLC and the original version of this article was published on their blogsite.

In this post, The Shared Microscope discusses the vaccine in development by Pfizer and BioNTech — one that is seen as a “dark horse” in the COVID-19 vaccine race. What is the road ahead for a potential COVID-19 vaccine from United States’ Pfizer and Germany’s BioNTech? Read on to learn about how the Pfizer/BioNTech vaccine works, the clinical trials process more generally, and when this vaccine could be commercially available.

The Vaccine Development Process

Vaccines are considered one of the greatest medical inventions in the world and have helped to wipe out a number of deadly infections such as smallpox. Vaccination has a number of advantages although creating a vaccine can be a long and complex process. Vaccines need to go through a plethora of checks to ensure they are safe and effective – if vaccines don’t pass this test, they do not get FDA approval to be used or sold commercially.

Vaccines need to go through a plethora of checks to ensure they are safe and effective – if vaccines don’t pass this test, they do not get FDA approval to be used or sold commercially.

To know more about the process of vaccine development, check out our post on the subject. Please also check out the illustration below: 

Vaccine development timeline, from preclinical laboratory research to clinical trials with human subjects.

The Pfizer/BioNTech COVID-19 Vaccine: Focused on Speed

Pfizer is collaborating with German company BioNTech to develop a COVID-19 vaccine in a timely manner. This vaccine, like the Moderna vaccine, the Oxford University/AstraZeneca vaccine, the vaccines in development by Novavax and Sinovac, is another frontrunner in this race against the pandemic. 

In July 2020, the U.S. government engaged Pfizer and BioNTech for $1.95 billion if they are able to help the Americans procure 100 million doses of the COVID-19 vaccine currently in development by Pfizer and BioNTech. As per this deal, the U.S. may acquire up to 500 million additional doses from Pfizer. Earlier this month, the two companies released a press release which suggests they will “potentially supply the EU with 200 million doses of mRNA based vaccine candidate against SARS-CoV-2.”

It is of note that the Pfizer/BioNTech vaccine is “late” to the race – clinical trials on this vaccine starting in July, at which point vaccines by Moderna and Oxford/AstraZeneca were in Phase 3 trials. Despite this, Pfizer’s CEO Albert Bourla believes the vaccine will receive FDA approval as early as October. 

Pfizer/BioNTech’s COVID-19 vaccine was late to enter Phase 3 clinical trials. Despite this, Pfizer’s CEO Albert Bourla believes the vaccine will receive FDA approval as early as October. @Pfizer @BioNTech_Group

The Pfizer/BioNTech COVID-19 Vaccine is of the mRNA Vaccine Type

Just like Moderna’s COVID-19 mRNA vaccine, the Pfizer/BioNTech COVID-19 vaccine uses messenger RNA or mRNA, making it an mRNA vaccine.  

As we have explained in our previous post explaining the vaccine in development by Moderna, the mRNA-1273 (and now Pfizer’s COVID-19 vaccine) is developed by the most cutting-edge of technologies – mRNA developed for use as a vaccine. Published scientific papers highlight that mRNA vaccines are a promising alternative to conventional vaccine approaches as they can be rapidly developed. They are also comparatively cheaper to manufacture and safe to administer. 

mRNA vaccines are developed using the most cutting-edge of technologies, which come with numerous benefits: quicker to develop, cheaper to manufacture in bulk, and safe to administer.

An mRNA vaccine uses mRNA, a messenger commonly found in the cells of our body. Traditional vaccines, on the other hand, use parts of the pathogen (perhaps a sugar, or protein) or whole inactivated pathogens. These mRNA “messages” are instructions to the body for the production of various types of proteins important for survival. 

Following the Central Dogma of Biology, messenger RNA (mRNA) are translated to proteins important to our body’s cells.

An Overview on How mRNA Vaccines Work

mRNA vaccines currently in development deliver mRNA to the body via injection. Studies are always ongoing to produce preventative nasal spray treatments against the SARS-CoV-2 virus, which causes COVID-19. Once injected, the mRNA enters cells to create the spike proteins needed to eventually build immunity against the SARS-CoV-2 virus. In the fight against COVID-19, the two most notable mRNA-based vaccines are the Pfizer/BioNTech vaccine and the Moderna vaccine.

Both these mRNA vaccines carry the instructions vital for the production of spike proteins that are normally found on the surface of the virus. These spike proteins are vital for infection, and therefore neutralising them in any way, neutralises the infection that SARS-CoV-2 viruses can cause, thereby preventing COVID-19 infection. They are therefore the most common therapeutic target for many drug companies. 

SARS-CoV-2 -- fancy comma blog
SARS-CoV-2, the virus that causes COVID-19. Spike proteins are in red.

There are a number of vaccines in development against the SARS-CoV-2 virus. Of these many vaccines, are two mRNA vaccines that have reached Phase 3 clinical trials: the vaccine developed by Moderna, and Pfizer and BioNTech’s BNT162.

On completion of currently ongoing Phase 3 clinical trials, we will know more on the safety and efficacy of both the mRNA vaccines, and if proven safe and effective, the companies developing the vaccines will receive FDA approval to commercialise them both in the United States and worldwide.

Pfizer and BioNTech’s mRNA Vaccine Against COVID-19: BNT162

As we have already mentioned, the BNT162 is another mRNA vaccine in development against the SARS-CoV-2 virus, which causes COVID-19. This vaccine would require a booster shot i.e. a total of two doses, to elicit a robust protective immune response against the SARS-CoV-2 virus. Pfizer, BioNTech and Chinese drugmaker Fosun Pharma developed two versions of the BNT162 vaccine: BNT162b1 and BNT162b2. 

In May 2020, the two versions of the vaccine were developed and ready for Phase 1 clinical trials. According to a preprint publication, the results showed that both the versions of the vaccine were able to elicit an immune response that was dose-dependent. The immune response invoked was directly proportional to the dose of the vaccine the participants received – the higher the dose, the stronger the immune response. 

A vaccine must take into consideration both vaccine effectiveness and safety. Considering both versions of the vaccine evoke strong robust immune responses, it was clear that they were both effective. However, the preprint of Phase 1 trials and the New York Times report that BNT162b2 produced significantly fewer mild side effects (such as fever and fatigue) in comparison to BNT162b1. For this reason, BNT162b2 was chosen for Phase 2 and Phase 3 trials instead. 

An Introduction to The BNT162b2 Vaccine

The BNT162b2 vaccine encodes a pre-fusion stabilised membrane-anchored SARS-CoV-2 full-length spike protein. In theory, it is the entirety of the spike protein (which is vital for infection mechanism), which has been glued in such a way that it cannot change shape. 

The COVID-19 vaccine in development by @Pfizer and @BioNTech_Group encodes a pre-fusion stabilised membrane-anchored SARS-CoV-2 full-length spike protein. Check out this post to learn more on the topic.

To understand this further, it is vital to know more about the structure of the SARS-CoV-2 viral spike (S) protein. I promise it will all make sense in a moment! 

The Structure of The SARS-CoV-2 Viral Spike Protein

By now, you’ve likely become accustomed to the iconic image of the SARS-CoV-2 virus – a round sphere with several spiky protrusions on the surface. The spike protein of the novel coronavirus is anchored into the membrane of the viral particle – like an iceberg – the top sticks out, while the rest of it is anchored into the membrane. This spike protein is vital for the mediation of the novel coronavirus’s entry into host cells. 

Each spike protein on the surface of the SARS-CoV-2 virus is made up of 2 subunits: the S1 subunit and the S2 subunit. Both these subunits have unique functions that enable the SARS-CoV-2 virus to infect endothelial cells of the lungs, the heart, the blood vessels, the brain etc. The S1 and S2 subunits are loosely bound at the “S1-S2 subunit cleavage site” – this is important for the mechanism in which the virus can cause disease, which will be explained further shortly. 

The Mechanism of Infection

The novel coronavirus uses the spike protein to bind to ACE2 receptors found on human cells of the heart, lungs, blood vessels, brain and so on. The S1 subunit (of the spike protein) is essential for initial binding of the virus to the ACE2 (angiotensin converting enzyme 2) receptor on the surface of the host cell. The S2 subunit, on the other hand, helps the virus fuse with the host cell (i.e. the cell it infects in the human body), thereby emptying the viral genome from the virus into the cells of our lungs, heart, brain, etc.

It is clear that the S1 and S2 subunits are both vital for infection mechanisms. However, for infection to convert from initial binding to ACE2 receptors on endothelial cells to fusion with these cells – an important intermediary step is essential. The S1 and S2 subunits must be “separated” by cleavage at the S1-S2 cleavage site. This cleavage is carried out by certain protease enzymes, which are outside of the scope of this article.

The S1/S2 cleavage site on the viral spike protein undergoes cleavage. It is only after this cleavage that the virus can fuse with host cells to cause infection.

 As you can imagine, after cleavage, the confirmation of the viral spike proteins change – much like cutting a piece of paper, it will look different after you cut it. Maybe a portion of it is separated, or it’s just ripped through.

The Spike Protein Exists in Two Distinct Conformations: Pre-Fusion and Post-Fusion

The fusion of the spike protein with human cells, leads to a change in shape (called a conformation) of the spike protein. 

To best explain these distinct conformations, check out the following illustration:

The viral spike protein undergoes conformational changes post fusion with host cells.

As you can see from the image above, these conformations are quite distinct from each other. The pre-fusion confirmation is what the virus has before it infects our cells – when it is at the point of “starting communication” with our body’s cells. Once the virus’s spike protein connects with and binds to ACE2 receptors on the surface of our cells, it undergoes cleavage at the S1-S2 cleavage site. This cleavage enables it to fuse with our cells thereby emptying the viral genetic contents into our cells. The fusion causes a change in the conformation of the spike protein – from a pre-fusion state to a post-fusion state. 

Once the virus fuses with our cells, it machinates the process of viral production to ensure the cells are only making more copies of the virus. Unstoppable viral replication therefore spawns. To prevent this coup, our cells should be able to identify the virus and stop it in its tracks before it is able to infect our cells. The vaccine teaches our body how to do this thereby preventing infection.

What’s the Conformation of the Spike Protein in the BNT162b2 vaccine?

The BNT162b2 vaccine for COVID-19 relies on the pre-fusion conformation of the spike protein. This is perhaps because when naturally infected, our bodies will be exposed to the pre-fusion conformation of the vaccine. It is after initial contact (i.e. during fusion) with the virus that the conformation of the spike proteins changes to the post-fusion conformation. 

Developing immunity against the pre-fusion conformation of the spike protein will ensure that our body is able to leverage knowing the properties of the virus (like the shape of the spike protein) to then evoke a strong immune response against the SARS-CoV-2 virus, which causes COVID-19. 

The pre-fusion spike protein is stabilised so that it cannot change its “structure”. This can be thought of as a safety feature of sorts. This vaccine also ensures that we build immunity to the entirety of the spike protein, thereby building immunity against infection by the virus. 

The mRNA that code for the spike protein are enclosed in a lipid nanoparticle, which makes it more efficient for delivery into cells. A lipid nanoparticle is used as a vehicle of delivery in both the Moderna vaccine and Pfizer/BioNTech’s vaccine. 

How Does Pfizer’s BNT1262b2 Vaccine Against COVID-19 Work?

Like the Moderna vaccine, the BNT1262b2 contains instructions for our bodies to create the pre-fusion conformation of SARS-CoV-2 viral spike proteins. As we have mentioned earlier, this protein is very important to the virus’s infection mechanism – the virus cannot infect any cells in the human body without the spike protein. 

The spike proteins on the surface of the virus act as a special key to the door that is our body. If we are able to make several copies of the key to study the key and understand how it destroys us, we can set up alarm systems and traps to keep the intruder (the virus) out. 

This is what the vaccine aims to do – it teaches the cells in our body the shape of the “special key” so we can quickly, effectively and easily identify it in the future. Once we are aware of this key that harms us, we then respond to it by ensuring those keys are blocked using traps. These “traps” are what we call antibodies and they neutralise these “special keys” so they are unable to intrude into our cells.

If we block the intruder (i.e. the virus) before it is able to enter our cells and do any harm, we can prevent infection by the SARS-CoV-2 virus and therefore also eliminate our risk of COVID-19 infection. 

Once the mRNA vaccine BNT162b2 is administered, the mRNA instructs our body to produce copies of the “special keys” so that our body can study them. These keys are flagged up in our body as they are different, even though they are replicas – like a badly cut key. Our immune system can then sense that something isn’t right and will throw out/eliminate these “keys”.

With the help of the vaccine, our body is able to learn to identify these spike proteins (keys) found on the SARS-CoV-2 vaccine and make antibodies (traps) to neutralise the effect of the spike proteins. This, in turn, prevents future COVID-19 infection – evoking immunity against the virus.

Current situation

The vaccine in development by Pfizer, in collaboration with BioNTech and Fosun Pharma has recently been in the spotlight almost on a daily basis. The Chief Executive of Pfizer has repeatedly said he hopes to answer questions on the safety and efficacy of the vaccine as early as October. 

In July, the companies launched Phase 2/3 trials with 30,000 volunteers in the US, Argentina, Brazil and Germany. The results of these are awaited. However, interim results suggest that volunteers see ‘mostly mild to moderate’ symptoms (like fatigue and headache) on receiving the vaccine – which is very promising. Earlier this month, the companies announced that they are seeking to expand their trial in the U.S. to 44,000 patients. 

Will this vaccine be our dark horse? Our knight in shining armour? Will it take a step closer to normal? There are a number of unanswered questions on all the vaccines, but if this vaccine is successful, the companies are to manufacture 1.3 billion doses of their vaccine by the end of 2021. Feel free to let us know your thoughts in the comment section below.

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