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COVID-19

How vaccines work against SARS-CoV-2 (and its variants)

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The pandemic has created a sense of urgency, pushing science to achieve what was once thought as impossible. Within less than a year, the first vaccines were approved and dozens more are being developed around the world. They rely on different technologies, but all have a common enemy: the coronavirus.

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The spikes on the surface of SARS-CoV-2 make it look like a crown (hence why it is called a coronavirus).

These spikes act like binding receptors, which allows them to attach to human cells and trigger an infection.

The virus’ genetic material, located under the membrane, contains the genes that produce spike proteins.

This is what researchers need in order to develop vaccines.

Canada has signed supply agreements with seven vaccine manufacturers. No matter how they work, whether they are mRNA, non-replicating vectors or protein subunit vaccines, the spike protein always plays a critical role. And to understand the impact variants have on the effectiveness of vaccines, one must first understand how they work.

mRNA

The first two vaccines approved in Canada – Pfizer-BioNTech and Moderna – utilize a recent technology: messenger RNA. It is the first time it is being used to immunise people.

This type of vaccine has the advantage of being very quick to develop and produce in a laboratory. Its goal is to teach the body, by means of a copy of the coronavirus’ genetic material, to make on its own what it needs to fight the virus.

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Before being injected into the human body, mRNA must be encapsulated in a spherical bubble of lipid – generally a bilayer.

This protective envelope allows it to penetrate human cells without being destroyed.

mRNA can then deliver to cells the genetic instructions needed to produce the coronavirus spike protein.

Ribosomes receive the instructions, and just like a recipe, they read them and begin the production of proteins.

mRNA never reaches a cell’s nucleus, where our DNA is located, and therefore cannot in any way modify it.

Once protein production has begun, the instructions delivered by the mRNA molecule are destroyed; no trace is left behind.

The cell, which now has the ability to reproduce a harmless version of the spike protein, expresses it on its surface, in whole or in part, and also expels fragments.

Non-replicating viral vector

Two other vaccines have been approved by Health Canada, those from AstraZeneca and Johnson & Johnson, which were already in use in some countries. They both employ non-replicating viral vector technology.

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Unlike mRNA, the coronavirus’ genetic material is translated into DNA, added to a harmless virus (vector) that is then injected into the arm.

The virus is absorbed by the human cell, but it cannot reproduce or provoke an infection.

Once inside, the adenovirus transfers the DNA it contains into the nucleus of the cell, giving it access to the genes that produce the spikes.

The cell transcribes it into an mRNA molecule that allows ribosomes to produce the S protein.

The proteins are presented to the immune system by the vaccinated cell.

Protein subunit

In the case of protein subunit vaccines, such as the one by Novavax, which is under review by Health Canada, and Sanofi and GlaxoSmithKline, which is still in clinical development, most of the work takes place before the injection.

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The coronavirus genetic material is inserted into a virus that is then used to infect insect cells.

The goal is the same: to get the infected cell to produce the spike protein. But this time, it happens in a laboratory.

The cultured proteins are then harvested and assembled into nanoparticles that look like the surface of the coronavirus (but cannot reproduce or cause COVID-19).

Those nanoparticles are mixed with an adjuvant, a substance that will boost the immune response to the spike protein. This substance is then injected as a vaccine in order to come into contact with human cells.

Canada also has an agreement with the Quebec pharmaceutical company , whose virus-like particles vaccine uses a technology similar to the protein subunit vaccine. Spike proteins, however, are produced using plants, before being harvested and then assembled to make them look like coronavirus. This vaccine, currently under review by Health Canada, also uses an adjuvant from GlaxoSmithKline.

The immune response

No matter how they work, all these vaccines have the same goal: prepare the immune system to defend itself from the coronavirus, without being directly exposed to it.

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The vaccinated cell, which looks like the coronavirus, presents itself as an intruder in the human body.

This antigen forces the immune system to recognize the intruder and trigger an immune response.

The immune cells then come into play. They multiply themselves and trigger the production of antibodies that will target the S (spike) protein.

These antibodies prevent the coronavirus spikes from attaching to cells and can therefore prevent an infection.

Antigens also alert cells that can detect and kill other cells that may have been infected with the virus before they multiply.

If the body comes into contact with SARS-CoV-2 after being vaccinated, these cells will be ready to deal with it. This is called immunological memory.

The impact of variants

The vaccine race produced its first winners at the end of 2020. But concurrently, the emergence of new variants was also a cause for concern.

Every time the coronavirus replicates in human cells, it acquires mutations: random reproduction errors that modify its genetic code.

"It is something very natural", says Dr. Guillaume Poliquin, Acting Scientific Director General of the National Microbiology Laboratory for the Public Health Agency of Canada. And that's what happens to viruses each time they spread and multiply.

Most of those mutations are not significant. Some will render the virus ineffective or even kill it. But sometimes, it manages to benefit from these transformations.

"A variant is of concern when its mutations affect the transmission, virulence or severity of the infection, or even the response of diagnostic tests or vaccines."

— Dr. Guillaume Poliquin, Public Health Agency of Canada

This is the case of the variants originally detected in the U.K. (Alpha), South Africa (Beta) and Brazil (Gamma), for example.

At the heart of the spike

Some of the mutations in SARS-CoV-2’s genetic code affect the spike protein, the same protein that targets all of the vaccines previously mentioned.

A change in the S protein could therefore make it easier for the virus to infect human cells, and also reduce the effectiveness of vaccines.

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Each spike is made up of three identical proteins that fit together.

They are made up of hundreds of amino acids, some of which may have been modified or suppressed during replication.

The most concerning mutations are found at the top of the spike protein, where it connects with a human cell.

The affected areas allow the virus to attach more firmly to the cell (and therefore increase its chances of infecting it).

This mutation has been found in all three variants originally detected in the U.K. (B.1.1.7), South Africa (B.1.351) and Brazil (P.1), which explains why they seem to be more contagious.

The B.1.1.7 variant also presents mutations that could negatively impact the ability of antibodies generated by vaccines to attach to spikes and inactivate the virus.

The B.1.351 and P.1 variants have additional mutations that facilitate their adhesion to human cells and interfere with antibodies.

However, Dr. Poliquin of the Public Health Agency of Canada offers some reassurance.

"The immune response triggered by a vaccine is not against one single target, but against several elements of the spike protein", he explains. This is why the neutralisation rate can decrease, but not completely."

"Yes, there is a potential reduction in efficiency, but you don't go from 100% to 0%."

— Dr. Guillaume Poliquin, Public Health Agency of Canada

Dr. André Veillette, from the COVID-19 Vaccine Task Force, agrees.

"What is often overlooked is the second component of the immune system response: Cytotoxic T cells, which are also very important in fighting viruses. It is quite possible that this element of a vaccine-induced immune response remains intact even with the variants”, he says, although this remains to be proven.

Vaccines also provide very high levels of antibodies, which can partially compensate for the loss of efficiency against the spike.

If not, other solutions already exist. Messenger RNA vaccines can be adjusted fairly quickly to the new genetic profile of variants. "Pharmaceutical companies have already started to do this", reminds the immunologist.

A booster dose may therefore be enough to restore immunity.

Other vaccines to consider

Dr. Veillette believes that we must also consider virus-based vaccines in the fight against COVID-19. This is what China is doing.

This is the most traditional type of vaccine and has long been used. However, they are longer to develop. With this type of vaccine, weakened or inactivated viruses are used to trigger an immune response.

"If we decided to take a broader approach, with the help of inactivated virus vaccines, we could perhaps also generate protection mechanisms that will target other elements of the virus", he explains. This is a type of vaccine to consider if you have an increasing number of problems with spike protein variants."

So far, more rapid technologies have been prioritized, and only a few players have yet to develop virus vaccines against COVID-19.

"But this is an approach that could be part of the second or third generation of vaccines," suggests André Veillette. We may not be done vaccinating everyone against COVID-19."

"We are married to the coronavirus. It will stick around for a while."

— Dr. André Veillette, COVID-19 Vaccine Task Force

"We might need to get vaccinated with different vaccines from time to time", adds the immunologist from the Montreal Clinical Research Institute. An approach we are already familiar with. For example, the influenza vaccine is adjusted every year in anticipation of the dominant strain.

Flattening the curve

Meanwhile, experts stress the importance of slowing the spread of the virus.

"The more people are infected, the more the virus reproduces itself, and the more likely it is to make mistakes,” which causes the emergence of variants, warns Dr. Veillette.

"We must not let our guard down. If we let our guard down, the virus, especially with the presence of variants, will take over."

— Dr. André Veillette, COVID-19 Vaccine Task Force

"There will probably be other variants. But we want to avoid much more dangerous ones, that impact the severity of the disease or become completely resistant to vaccines", he says.

What protects us best against variants is also what protects us best against the virus, says Dr. Guillaume Poliquin from the Public Health Agency of Canada.

Physical distancing, masks and hand washing must therefore continue. "Deploying the vaccine is a priority", he says, "but it's important to remember that everyday measures continue to protect us."

No matter what variant is at play, the coronavirus is transmitted in the same manner.

The illustrations of SARS-CoV-2, the different types of vaccine and the immune response have been simplified for easier understanding.

The design of the spike protein was obtained from a homology model constructed from the experimental 3D coordinates of the Protein Data Bank (code 6VXX). The positions of the mutation sites are illustrated on the structure of the native spike protein. To our knowledge, there is currently no experimental structure of the different variants. The positions of the mutation sites were identified based on the homology model of the native spike structure, and therefore do not represent the exact shape of the mutated spikes.

With the collaboration of:

Olivier Julien, assistant professor in the Department of Biochemistry at the University of Alberta, for the scientific validation of illustrations of the different types of vaccines, André Veillette, immunologist at the Montreal Clinical Research Institute, for the validation of illustrations on the immune response and Nicolas Doucet, biochemist at the Institut national de la recherche scientifique, specializing in proteins and structural biology, for representations of the spike and the location of affected areas by the variants of SARS-CoV-2.

Daniel Blanchette Pelletier journalist, Melanie Julien desk-editor, Charlie Debons illustrator, Francis Lamontagne designer, André Guimaraes developer and Martine Roy coordinator. With the help of Mélanie Meloche-Holubowski for the translation.