How the Novavax Vaccine for COVID-19, A Protein Subunit Vaccine, Works

Updated October 30, 2020

By Nidhi Parekh of The Shared Microscope

The current post will introduce you to NVX-CoV2373, the vaccine under development by Novavax. This vaccine candidate has been developed as a protein subunit vaccine. The Novavax vaccine contains a small piece of one of the proteins in the SARS-CoV-2 virus — the virus that causes COVID-19. The idea behind the Novavax vaccine is that we can develop immunity to the virus and avoid COVID-19 infection by exposing our immune systems to only this small subsection of the virus. Read on to learn more about Novavax and the science behind this COVID-19 vaccine.

Novavax: A SARS-CoV-2 “Protein Factory” to Beat COVID-19 $NVAX @TheSharedScope

Check out other posts in our COVID-19 vaccine series:
[Moderna | Oxford/AstraZeneca | Pfizer/BioNTech | Johnson & Johnson | Novavax | Sinovac]

Table of Contents:

What is a Subunit Vaccine?

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Simply put, a subunit vaccine uses a single component of a pathogen (that is, a bacterium or virus) to establish immunity. In other words, the vaccine is made from a single part of the pathogen — a subunit — rather than the whole pathogen itself. 

A subunit #vaccine uses a single component of a virus to establish immunity. In other words, the vaccine is made form a single part of the pathogen — a subunit — rather than the whole pathogen itself. @TheSharedScope #Novavax #COVID19

In the image below, our hypothetical vaccine would be made from the subunit which corresponds to the head of the vaccine, for example. The “head” would be extracted from the virus to make a vaccine using that particular subunit.

subunit vaccines
Source: The Shared Microscope on Instagram

Typically, a subunit vaccine is made up of components crucial to the pathogen’s infection mechanism. This is so that the human body can establish immunity and be able to defend against these components vital to the pathogens infection mechanism.

Accordingly, Novavax focuses on the spike proteins of SARS-CoV-2, which is the virus that causes COVID-19.  This is because the spike proteins on SARS-CoV-2 are crucial for the virus to gain entry to human cells.  Once the virus can gain entry to the cell, SARS-CoV-2 replicates and spreads, which causes COVID-19 infection.  

Therefore, in the case of COVID-19, the component of interest is the viral spike protein found on the surface of the SARS-CoV-2 virus. Since NVX-CoV2373 uses a protein subunit (the virus’s spike protein), it can be classed as a protein subunit vaccine. Other common subunits used in the development of these types of vaccines besides proteins include sugars.

cartoon structure of sars-cov-2

This illustration was created by Nidhi Parekh of The Shared Microscope. Visit The Shared Microscope on Instagram.

An illustration of the structure of the SARS-CoV-2 virus. The RNA of the virus is enveloped in a lipid membrane. The green spikes on the surface of the virus are spike proteins that are crucial to the SARS-CoV-2 virus to cause infection in humans.

An advantage to using subunit vaccines of any kind is that it is capable of eliciting a very robust immune response. The strong response is due to the fact that they contain crucial parts of the pathogen to which we build immunity.  However, in some cases, these vaccines could require booster shots to ensure ongoing immunity from the disease they protect against.

How Does Novavax’s COVID-19 Vaccine Work?

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As we have mentioned, the component of interest in a COVID-19 vaccine is the viral spike protein found on the surface of the SARS-CoV-2 virus. This is because the SARS-CoV-2 virus is unable to cause infection without the spike proteins on its surface. Because of the spike protein’s importance in the infection mechanism, it is a promising therapeutic target.  

Almost all the COVID-19 vaccines in development aim to exploit the spike protein, by either introducing information about the spike protein or the spike protein itself, to our bodies. Once our body is exposed to the spike protein, our immune systems can recognize it as an “invader” and launch an immune attack to neutralize and destroy it. 

Novavax’s NVX-CoV2373 vaccine is no different from the other COVID-19 vaccines in development — it, too, exploits the viral spike protein. In the case of Novavax, the spike proteins are cultured in a laboratory using a complicated mechanism which is beyond the scope of this article due to its complexity, so we will not discuss it here. These spike proteins are then purified to remove all other molecules. 

The purified spike proteins are then injected into our bodies.  Once introduced, they will be recognized as “invaders” and attacked and neutralized.  The introduction of spike proteins into our bodies teaches our immune cells how to attack the SARS-CoV-2 spike protein. When naturally exposed to the virus, our body will therefore have prepared its battleground and sent their best soldiers to conquer the SARS-CoV-2 virus as best as possible.  Next time the body has to deal with SARS-CoV-2, these trained soldiers will be at the ready to neutralize any virus as quickly as possible to help the body avoid a COVID-19 infection.

how novavax works
This illustration was created by Nidhi Parekh of The Shared Microscope. Visit The Shared Microscope on Instagram.

The main component of the Novavax vaccine is the spike proteins on SARS-CoV-2, the virus that causes COVID-19. The spike proteins are crucial for the virus to gain entry to human cells, so developing immunity to the spike proteins prevents COVID-19 infection.

Making the NovaVax Vaccine Requires a “Protein Factory”

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To produce the spike proteins, Novavax uses a unique mechanism.  This method has proven to work for the production of NanoFlu, which was fast-tracked for use against influenza. We will discuss this method using the following series of images.  These infographics endeavor to simplify and explain the methods behind the NovaVax  “protein factory” as best as possible.

A biological “protein factory” is used to create large amounts of the SARS-CoV-2 spike protein, which are harvested and used in the Novavax COVID-19 vaccine. @TheSharedScope #COVID19

Please note: The following schematic aims to explain concepts of biology and is therefore simplified to aid understanding.

how is novavax made?
This illustration was created by Nidhi Parekh of The Shared Microscope. Visit The Shared Microscope on Instagram.

The RNA coding for the SARS-CoV-2 spike protein is converted into DNA, which is added to a baculovirus. This forms a recombinant virus, containing baculovirus DNA and DNA translated from SARS-CoV-2 virus. The recombinant virus expresses the SARS-CoV-2 spike proteins when they infect cells.

As can be seen from the image above, the SARS-CoV-2 virus takes the form of an RNA molecule, a single-stranded molecule of nucleic acids. The virus is genetically engineered and chemically converted to double stranded DNA so that it can be added to another virus to facilitate mass production of the spike proteins. 

The DNA engineered from the SARS-CoV-2 virus is then added to a type of virus called a baculovirus, a virus which has unique properties that make it ideal for mass producing spike proteins for use in the Novavax COVID-19 vaccine.  Baculoviruses are a group of insect viruses that have a larger genome and can therefore accommodate additional “foreign” genes such as the SARS-CoV-2 virus.  

The mishmash of the SARS-CoV-2 and the baculovirus is called a recombinant virus, and it contains both DNA from the baculovirus and converted DNA from the SARS-CoV-2 virus. The recombinant baculovirus can now express the SARS-CoV-2 spike protein when it infects an insect cell. 

To cause infection, baculoviruses must typically be ingested by the insect. When the insect eats the recombinant virus, the virus gains entry into the insect’s cells.  Next, the recombinant virus will take over the cellular machinery of the insect. The takeover means that the insect cells produce viruses and viral particles in bulk, including increased production of the SARS-CoV-2 spike proteins that are synthesized by the baculoviruses. The spike proteins can then be harvested, purified, and used as a vaccine candidate.

Now that we know how the recombinant virus is made, let us look into some more detail on how Novavax manufactures NVX-CoV2373, their COVID-19 vaccine.

How is Novavax’s COVID-19 Vaccine Made?

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The way in which Novavax’s vaccine is made is slightly more complicated than the other COVID-19 vaccines we have discussed so far.  As we have mentioned earlier, the baculoviruses must infect the insect cells so as to take over its machinery and mass produce the SARS-CoV-2 spike proteins.  For this process, Novavax uses the baculoviruses to cause infection in Sf9 insect cells. The Sf9 insect cells are a cell line that are established from the ovarian tissue of the Spodoptera frugiperda (fall armyworm moth).

This Sf9 insect cell/baculovirus system has been widely used for the bulk production, isolation and purification of proteins. It has also been used to develop a flu vaccine. This system was utilized for the production of NanoFlu, a vaccine produced for older adults, which was fast-tracked for use against the seasonal influenza virus.

Please see below for a helpful illustration and step-by-step outline of Novavax’s manufacturing process.

Please note: The following schematics aim to explain concepts of biology and are therefore simplified to aid understanding.

novavax manufacturing process
This illustration was created by Nidhi Parekh of The Shared Microscope using information from a published, peer-reviewed scientific paper and Biorender. Visit The Shared Microscope on Instagram.
  1. The Sf9 insect cell is a type of cell found in insects. The Sf9 cells are infected with the recombinant baculovirus.
  2. Once the Sf9 cells are infected with the baculovirus, the virus takes over the cell and uses it to produce its own proteins. This means that complex viral proteins, including the SARS-CoV-2 spike proteins, are now produced in the Sf9 cell. Using the cellular machinery, proteins are able to fold into their correct structures.
  3. The viral spike proteins made in Step 2 undergo further modifications using the Sf9 cellular machinery. These modifications result in the production of SARS-CoV-2 spike proteins that can be transported to the surface of the cell and then be used to evoke a strong immune response.
  4. The spike proteins are transported to the surface of the insect cells (i.e. the cell membrane).
  5. Novavax extracts the correctly folded and modified spike proteins from the cell membrane and purifies them to ensure no unwanted molecules are present. The spike proteins can now be used as the major component of the Novavax vaccine. 

Once these steps are complete, Novavax harvests the extracted spike proteins and inserts them into “micelles,” which are small artificial capsules the size of viruses. These micelles are what is injected into our bodies via the Novavax COVID-19 vaccine. On injection, the micelles float freely in the human body. However, these micelles with the spike proteins do not get very far. Our immune system recognizes them as “foreign” and presents them to key immune cells. This process evokes the biological responses for immunity, and optimizes our chances to fight off SARS-CoV-2 viruses before they can cause COVID-19. 

Watch this video from Novavax for more information about the manufacturing process.

Unlike the other COVID-19 vaccines in development, Novavax’s NVX-CoV2373 vaccine is one of the few candidates that produces the viral spike proteins outside of the human body. @TheSharedScope

Unlike the other COVID-19 vaccines in development, the NVX-CoV2373 vaccine is one of the few vaccine candidates that produces the viral spike proteins outside of the human body. The proteins are manufactured using the methods discussed above, purified, and then injected into our bodies. Other vaccine developers, such as Oxford/AstraZeneca and Moderna,  are using technologies in which the genetic information relating to the SARS-CoV-2 spike protein is injected into the body, for us to then produce the spike protein ourselves to develop immunity to it.

Novavax Clinical Trials

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Although Novavax is far behind in the clinical trials compared to Moderna, Oxford/AstraZeneca and Sinovac, the vaccine shows a lot of promise. On May 25, 2020, Novavax announced the start of a Phase I study of NVX-CoV2373 in Australia.

Novavax’s Phase I/II clinical trials included 130 participants with an age range of 18 to 59 years. The company is due to announce their preliminary immunogenicity and safety results for the vaccine in the first week of August. Phase II trials will begin following successful Phase I results. 

Novavax has received $1.6 billion in funding from Operation Warp Speed to develop and distribute 100 million vaccines as early as the end of 2020. This money will be put towards completing late-stage clinical trials with up to 30,000 participants, and will also go toward the establishment of large-scale manufacturing for the vaccine. Novavax will also receive $388 million from the Coalition for Epidemic Preparedness (CEPI) to aid in development and manufacturing of the vaccine. However, this is dependent on the results of the Phase I clinical trials. Will Novavax show positive Phase I results? Keep your eyes peeled on the news for the latest on this vaccine. 

This post was written by Nidhi Parekh of The Shared Microscope. Check out The Shared Microscope on TwitterFacebook, or Instagram for more informative illustrations and blog posts on different scientific concepts. 

18 thoughts on “How the Novavax Vaccine for COVID-19, A Protein Subunit Vaccine, Works

    1. Yes, unlike the Moderna and Oxford vaccines, this one is more of a tried-and-true approach. Exciting about the clinical trials results – we will keep our eyes peeled to see if we can provide an update to this article!

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