How the viral vector vaccine puzzle was solved, leading to today’s COVID-19 injections

How would you go about solving a puzzle if you didn’t know which pieces to use, how many you would need, what it was supposed to look like when finished, or what function it could serve?

Such a challenge was taken up by Frank Graham in 1969 when he was a Canadian postdoctoral researcher in the laboratory of molecular biologist Alex Van der Eb in the Netherlands, working with human adenovirus 5 (Ad5). Upon his return to Canada in 1973, he continued his work on Ad5 in the Cancer Research Group of the Departments of Biology and Pathology at McMaster University.


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The sustainable technology he developed would serve humanity in several ways. Some of these are still emerging today, but one stands out from the rest: Graham’s Ad5 vector reportedly serves as a global platform for COVID-19 vaccines, including AstraZeneca vaccines and Johnson & Johnson approved in Canada.

Viral vectors

The puzzle Graham solved was to create a valuable viral vector: a microscopic Trojan horse that can be easily assembled, made in bulk inexpensively, and remains stable at normal refrigerator temperatures. More importantly, it is effective in transferring foreign DNA into mammalian cells, including human cells.

Viral vectors are modified viruses that can cause the body to generate protective responses without causing infections. These virus-like entities, which are generally rendered incapable of replicating, can achieve what intact natural viruses can, but without infectious destruction. They can enter human cells and instruct the machinery of those cells to express the genes carried by the vector, causing the cell to make and export the proteins encoded by those genes, all without permanently altering the host cell. .

Illustration of how a viral vector vaccine works by inserting genetic material from a target virus into an adenovirus.
Viral vector vaccines use a safe virus to insert pathogenic genes into the cell to produce an immune response.
(Shutterstock)

This means that once a viral vector vaccine for COVID-19 is administered, it can express the COVID-19 spike protein that is engineered into the vector genome. This allows the affected cells to present the COVID-19 protein antigen to the human immune system and to stimulate the immune defenses against infection with COVID-19.

Viral vectors induce a very powerful immune response. They generate both a neutralizing antibody to prevent infection and killer T cells (cytotoxic T cells or CTLs) to destroy cells infected with COVID-19.



Read more: Revealed: the protein “spike” that allows the 2019-nCoV coronavirus to penetrate and invade human cells


Several recognized non-replicating viral vectors have been developed for vaccines. These include those based on adenovirus, adeno-associated virus, herpes virus (such as cytomegalovirus) and vaccinia virus, as well as vectors based on retroviruses, including Moloney murine leukemia and others based on the modified lentivirus (HIV). All have been used in gene therapy and vaccine delivery clinical trials with varying success.

However, for large scale effective use as safe vaccines, viral vectors based on adenovirus (infamous for causing the common cold) or vaccinia virus are preferred. In the field of COVID-19 vaccines, the ones that stand out the most are based on adenoviral vectors. This is where Graham’s discoveries come into play.

The pieces of the puzzle

Black and white illustration of an adenovirus
Frank Graham developed a vector from human adenovirus 5 which now serves as the global platform for COVID-19 vaccines.
(Pixabay)

As the first piece of the puzzle, Graham developed a method to transfer foreign DNA (in this case, pieces of the human adenovirus subtype 5 genome) into a cell.

The article describing this technique has been cited by more than 10,000 researchers since its publication, making it one of the greatest successes in modern science.

Since viral vectors generally do not replicate, expanding (replicating) the vector for vaccine manufacture and production has presented a challenge. Vectors need living cells to house them and auction vectors, allowing them to reproduce. What was needed was a self-sustaining cell line implanted with a virus or modifiable vector.

Two people inspecting a large crate covered with netting, with an airplane in the background.
UNICEF employees check a shipment of 1.4 million doses of Johnson & Johnson COVID-19 vaccine donated by the United States at Hamid Karzai International Airport in Kabul, Afghanistan. Viral vector vaccines only require regular refrigeration, not ultra-cold storage like some mRNA vaccines.
(AP Photo / Mariam Zuhaib)

This was solved by Graham’s second approach. At McMaster University, he used his DNA transfer technique to establish a stable, easy-to-grow and easily manipulated human cell line called HEK293 cells, which permanently contained the genes necessary for the growth of a deficient vector. replication. Another classic is Graham’s article on this cell line, with over 6,000 citations.

The HEK293 cell line and its derivatives are now used worldwide, in industry and in academic and government research laboratories, to make vaccines and many other biologicals.

As a third approach, Graham prepared stable and robust molecular biology tools to allow the easy creation of stable adenovirus vectors with foreign gene insertions of up to 8,000 base pairs (individual units of genetic code) d foreign genetic information – this is enough data to produce the most useful proteins. This is used both for gene transfer and expression (in gene therapy) and for vaccine delivery, as we have seen with COVID-19 vaccines.

For vaccines, the process has taken a virus that causes cold symptoms, removed the genes that allow it to reproduce, and replaced them with genes from an infectious agent, such as a different virus, which is the ultimate target of a vaccine. These added genes trigger the production of a harmless part of the target virus. The body then recognizes and attacks this element, generating immunity. In the case of the COVID-19 virus, this element is the protein peak.

Assemble the puzzle

A woman climbs a curved staircase with an ornamental handrail.  In the background is a vaccination clinic in a large open space with arches on the sides.
A woman walks up the stairs to queue for the Sputnik V COVID-19 vaccine at a vaccination center in Gostiny Dvor, a huge exhibition center in Moscow, Russia. The banner reads “We will beat COVID-19 together!” “
(AP Photo / Alexander Zemlianichenko)

These advances were made with human adenovirus 5 and have been applied directly in COVID-19 vaccines developed by CanSino in China and the Sputnik V vaccine in Russia. The process has also been adapted to other adenovirus subtypes for COVID-19 vaccines. These include the chimpanzee adenovirus vector vaccine developed by the University of Oxford and AstraZeneca, and the human adenovirus 26 vector vaccine developed by Johnson & Johnson.

Graham, now retired and living in Italy, certainly knew how to put a puzzle together. Today, half a century after his early success in building viral vectors, billions of people around the world owe him thanks for protecting them from the pandemic virus.

Have a question about COVID-19 vaccines? Email us at ca‑[email protected] and vaccine experts will answer questions in future articles.

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About Hector Hedgepeth

Hector Hedgepeth

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