How are the different types of COVID-19 vaccines working?

The new generation genetic vaccines are sending their instructions to the human body in an unprecedented way.

Charles A. Rouyer
46 min readFeb 6, 2021

Vaccines provide information to the immune system to prime it ahead of an infection. Yet all the COVID-19 vaccines are not sending their training manual to the human body the same way. In the long run, scientists don’t seem to agree on some of the potential biosafety risks at the population level of the new genetic vaccines. (LONG READ — Updated March 4, 2021)

How different COVID-19 vaccine technologies are send information (antigen) for the immune system to produce antibodies. (Click on diagram to enlarge.)

To stop the COVID-19 pandemic, vaccination programs are frantically being rolled out around the world, triggering both hope and concern in the general population. Faced with not one vaccine, but many different kinds of technologies — some never used before on humans on such a large scale — a new breed of citizen and scientist is surfacing: the vaccine prudents, definitely pro-vaccine yet also staunchly pro-precautionary principle.

Even French President Emmanuel Macron expressed reservations recently. “I will be very cautious,” said President Macron when asked about the Pfizer-BioNTech COVID-19 vaccine, the first of the new generation immunizations to be rolled out. “We do not know everything about this vaccine, very much the same way as we don’t know everything about this virus”, acknowledged Macron early December 2020.

More importantly, Macron underlined how there are different kinds of COVID-19 vaccines. “Several vaccines are coming down the pipe. There isn’t just one,” then adding: “The April vaccine will not be the January one. Some vaccines will land in spring-summer, while being manufactured using different techniques.”

Indeed, many questions seem lost or overlooked in the current dominant narrative about how fast the immunization efforts can be scaled up or the impact of delayed deliveries of vaccine doses.

The key underlying questions are simply: What is the difference between an mRNA vaccine (Pfizer-BioNTech, Moderna), a DNA vaccine (AstraZenaca, Johnson & Johnson/Janssen, Sputnik 5) or a recombinant protein vaccine (Novavax)? What do these vaccines do inside the human body? Are all the different new generation genetic vaccines safe? Ultimately, to better grasp these many complex issues simply begs another basic question: what is a vaccine, after all, and how do vaccines trigger an immune response?

Components of a smallpox vaccination kit (Source: James Gathany, CDC)

“Vaccines are the best tool in medicine. They have saved more lives than any other therapy in medicine,” says Earl Brown, a viral geneticist. “But they are strong medicine,” adds the University of Ottawa Emeritus Professor, “and depending on how they are used, there have been problems.” The multidisciplinary Canadian scientist whose whole career has been about viruses and evolution, including making viruses from cloned genes, acknowledges: “To judge the safety is not so simple.”

Especially when the safety of the new COVID-19 vaccines is still being evaluated while some shots are already being rolled out, argue molecular geneticist Christian Vélot, a self-proclaimed vaccine prudent himself: “Personally, I have all my vaccines and booster shots, I am not antivaccine,” says the associate professor and researcher in molecular genetics at the University of Paris-Sarclay. “Yet, it doesn’t keep me from being mindful and wondering about the biosafety of the vaccines that are currently offered, especially considering the urgency with which they are being manufactured,” adds Christian Vélot, the president of the scientific board of CRIIGEN, a non-for-profit organization focusing on genetically-modified organisms (GMOs) and their potential impact on human or ecosystem health.

­­­“I like this term of ‘vaccine prudent’,” continues Christian Vélot, “because nowadays as soon as you are critical about a vaccine, you get automatically labelled as antivaccine,” says the former Green Party candidate to the European Parliament, who simply does not want to have to choose between being pro-vaccine or pro-precautionary principle: “One does not exclude the other,” continues the French molecular geneticist, who published in September 2020 a controversial expertise notice on the many different COVID-19 vaccines. The French molecular geneticist flags potential biosafety risks in his opinion, some at the population-scale such as recombinant viruses with mRNA vaccines.

The current new mRNA vaccine technology is safe, offers a Canadian molecular biologist specializing in RNA processes. “Perhaps a good way to think about this,” says Mark Bayfield, an associate professor and researcher at York University in Toronto, “is there may have always been an unknown, hypothetical risk that something from a virus that is used in a vaccine — the DNA or the RNA from a killed or attenuated virus in any of the vaccines we have used for decades — could always have mixed with an unrelated virus from an active infection, to make something unexpected, and so this type of thing could always have happened.”

Yet the Canadian molecular biologist acknowledges that “it is impossible for a scientist to say there is zero risk, because we cannot prove it is impossible.”

Considering how innovative some of the new generation COVID-19 vaccines are, is there enough hindsight, especially when dealing with genetic material, is the question that advocates of vaccine prudency are simply asking.

Indeed, leading edge biotechnology innovations allow now to print or edit very specific genetic strings to stimulate the human immune response, while the old school techniques are photocopying the whole book after toning it down (using weakened or inactivated viruses).

Ultimately, in the current new era of synthetic biology in the 21st century, are all the different COVID-19 vaccines equal when considering all the potential risks, from one’s individual health all the way to biosafety at the whole population-scale?

Title page of Edward Jenner book on vaccination (Source: WikiMedia)

Vaccines have been an incredible technological innovation since the very first immunization in the late 1700s by English physician Edward Jenner, using cowpox to protect a young boy from smallpox (thus the word ‘vaccine’, from the Latin vacca, for ‘cow’, referring to the cowpox disease.)

The vaccination process is then perfected in the 1880s by French biologist Louis Pasteur (who also invented pasteurization), with a vaccine against rabies.

In the tool kit of modern public health, vaccines basically rank a close second behind the first great advance to protect humankind from ill-health: garbage collection and the building of sewers and clean drinking water systems, in the fast-growing cities of the 1850s during the early industrial revolution. (At the same time, major contributors to better health in the last two hundred years or so have also come from improved socioeconomic conditions and possibly more so than from medical or public health interventions, has argued Thomas McKeown, a British physician. Indeed better nutrition and living conditions, including lower stress from making ends meet, can go a long way to keep populations healthy when considering all the determinants of health.)

This being said, simply put, vaccines are nothing else, but a boot camp designed to whip up the human body’s acquired defence mechanism into shape to get it ready if and when a new attacker shows up armed with a brand new weapon never fought against previously.

When faced with any unknown intruder, the human body quickly rolls out a defence program in several stages. The body reacts immediately with generic antiviral and inflammatory mechanisms (innate immune response) while designing and building an original counter weapon specific to the new enemy. This second phase arms race usually takes 7 to 8 days and is called the adaptive immune response. It allows the immune system to equip its foot soldiers, the white blood cells or lymphocytes, with the brand new counter-weapon, the antibody, to be deployed to the infection site and start fighting off the infection.

If the first line of defence has failed to nip the attack in the bud, the week-long delay for the second phase can unfortunately mean the immune system soldiers, the lymphocytes, are armed and deployed too late. The intruder, the virus, has time to establish a beachhead, assemble its invasion forces and overtake the host before the natural defenses can react with the adequate new specific counter-weapon. The infection spreads and the virus can win the battle.

Vaccines, in a nutshell, are designed to show what the new enemy looks like, ahead of time, in order to trigger the adaptive immune response, to prime the body, so it can later react right away in case of an infection, instead of waiting the 7 or 8 days.

Some recent research has actually shown how the novel coronavirus (SARS-CoV-2 or severe acute respiratory syndrome coronavirus 2) responsible for the COVID-19 can actually disable the alarm system of some hosts (reduced interferon production), as part of the innate immune response, who then cannot even trigger the adaptive immune response .

The enemy can quietly invade the human body, as if climbing the walls of a fortified city at night while everyone is asleep. The opponent forces can thus enjoy a stronghold in the morning when the city wakes up, to realize too late it is under attack and is now occupied by the enemy with little chance of fighting back and recovery. This could explain, for instance, how some younger individuals can experience a very strong COVID-19 infection.

Yet, all vaccines are not equal.

With the advent of the current synthetic biology era, there are now multiple ways to provide the body with the information to prime the immune system. The newer generation of genetic COVID-19 vaccines are utilizing technologies never used before on humans on a very large scale, to bring in the information to train the immune system.

This includes the Pfizer-BioNTech mRNA vaccine, the first to be approved on an emergency basis and now deployed full scale, in the United Kingdom, in Canada, in the United States and in continental Europe, as well as the Moderna mRNA vaccine, also recently approved in the U.S., Canada, the European Union, Israel and Switzerland. (The AstraZeneca vaccine, using a different DNA-based technology, was recently approved in the U.K., India and by the European Union.)

The two front runners are called ‘mRNA vaccines’ for the one specific technology they both use to bring the information about the novel coronavirus (the SARS-CoV-2) into the human body.

In these new generation vaccines, the training instructions for the immunization boot camp is completely different and has never been used with billions of “trainees”, that is: humans.

“Everything is so new right now. This group of vaccines just sprang out in months,” says Earl Brown. “This is synthetic biology,” summarizes the Canadian viral geneticist. “Biology is the proteins, the organisms, the tissues of the living organisms. Now in the laboratory we can make each of the components of those tissues quite readily. So, as we all know our genes are in DNA, that is the recipe book to make the soup. […] DNA makes RNA makes proteins. This is how life works.”

Simplified overview of the processes involved in the primary immune response (Source: Sciencia58 and the makers of the single images Domdomegg, [1], Fæ, Petr94, Manu5, CC BY-SA 4.0, via Wikimedia.)

Traditional vaccines technology ever since Pasteur’s innovation, is based on weakening or deactivating a specific virus in the lab, to then inject it into the human arm. The host’s immune system is thus exposed to a harmless version of the virus and learns to recognize it. Then it builds an antibody specifically against the virus to be vaccinated against, in order to be ready in the future to mount any counterattack if needed.

At this point, the body’s fully operational new defence program is ready to deploy an army of trained killer T- white blood cells (lymphocytes) right away in case of exposure to the actual living virus.

Imagine vaccination as stockpiling weapons specific to an enemy ahead of time, to shoot down the intruder as soon as it climbs over the city walls. Or more accurately, making a prisoner, disassembling its assault weaponry (antigen) to identify its key features and designing a new counter-weapon (antibody) to neutralize it.

The body then stores the assembly manual to build this anti-intruder specific arsenal quickly, to deploy it swiftly in case of an invasion by this attacker. Instead of waiting the 7 to 8 days to figure out how to neutralize the new enemy, which would afford it ample time to invade and take over the fortified city: our human body.

The trick in this training boot camp for our immune system, is to make sure the “prisoner” is not too strong (virulent) when brought in within the city walls and that it is not able bodied enough to go on the loose and take a strong hold, like a Trojan horse.

This is actually what happened in the 1950s, when a Polio vaccine manufactured in the U.S. by the Cutter pharmaceutical company actually triggered the disease because the virus had not been properly inactivated. Yet other Polio vaccines at the time containing the properly inactivated virus were safe and effective, such as the Canadian Connaught vaccine. This type of traditional vaccine is referred to as a “whole-pathogen vaccine.”

“There have been problems. There have been horror stories with vaccine roll outs,” confirms Earl Brown, definitely pro-vaccine yet not shying away from looking into the horse’s mouth. “You have to make sure your system works and that it is safe. It is quite simple in that regard.”

At the person’s level, new generation vaccines such as mRNA immunization may have an advantage over the more traditional vaccines based on inactivated viruses, suggests mRNA processes expert, Mark Bayfield “If anything these [mRNA] vaccines pose less risk. They are very minimalist. They do not have the ability to form a proper virus in any way. They have no risks of actually forming an infection by the virus.”

Diagram of the structure of the coronavirus SARS-CoV-2, including the spike glycoprotein S and the RNA-based genome (Source: SPQR10, CC BY-SA 4.0 , via Wikimedia)

2. The mRNA vaccines, such as the Pfizer-BioNTech and Moderna shots, inject the ‘instruction manual’ to build the actual enemy weapon.

Indeed, this type of new generation vaccine injects the genetic code for the spikes around the SARS-CoV-2 (giving the virus its now familiar crown-like appearance and thus its name of coronavirus; corona meaning ‘crown’ in Latin.)

These spikes are the new powerful weapon making the novel coronavirus highly contagious. Like a sophisticated attack machinery on an alien spacecraft, the spikes allow the SARS-CoV-2 to dock onto human lung cells, to open easily the secure hatch and to discharge its own foreign material inside the host’s vessel, the human body, to beef up the invasion.

Or more simply, imagine these spikes as a key fitting perfectly into the lock of the massive wooden doors to our fortified city, allowing the enemy to lower the drawbridge and to enter easily in droves.

And so, what if this instruction manual to build the fancy docking weapon or the key to the city, was to fall into the hands of a different rogue group? In scientific terms, this describes the ability of different viruses to recombine. It essentially means that viruses can share and swap some of their RNA (or their DNA).

In the end, the key question vaccine prudent voices are asking is: what if the genetic code for the SARS-CoV-2 spikes were to recombine with another virus also present at the same time, at the injection site of the COVID-19 mRNA vaccine?

The odds are extremely low. Yet, given the hundreds of millions of doses potentially administered throughout the world, a perfect storm scenario is far from impossible.

York University mRNA processes expert, Mark Bayfield, is confident about the low risks of recombinant SARS-CoV-2 viruses, while acknowledging viruses are opportunistic. “It is not that they [viruses] are smart. Viruses do lots of things that are unexpected and the one out of trillions of trillions that did something that gave it an advantage, that one then persists. That’s the way viruses work,” says Mark Bayfield.

The issue basically lies in the ability a new recombinant virus not only to survive but also to potentially thrive.

‘How likely is it to happen?’ is a totally different question, acknowledges the Canadian researcher. “As a scientist, I am trained to never say it is impossible because I would need to see the data to show that it is impossible, and that is impossible to prove. What we talk about is likelihoods,” sums up Mark Bayfield. “If there is trepidation, I guess, it’s that they are new. We have not really used this type of systems for vaccines previously, at least not on such a wide distribution.”

“Do we know enough about this [mRNA] vaccine?” reflects University of Ottawa Earl Brown. “Given our experience and given safety reviews we are putting them through, [that is] not the full safety review? We are saying something earlier than when we would speak normally,” sums up the Canadian viral geneticist, still optimistic about the outcome yet also prudent.

The messenger RNA transcribes the DNA info to carry it outside of the nucleus (Source: DataBase Center for Life Science (DBCLS); CC BY 4.0, via WikiMedia)

The mRNA vaccine gets its name from the messenger ribonucleic acid. The mRNA is basically the carrier of the transcribed code of life making up the human biology recipe book: the double-helix DNA or desoxyribonucleic acid.

The ever so precious DNA is stored deep inside the cells, protected behind the walls of the nucleus, like inside a bank vault or in a top security facility. The role of the messenger RNA is to transport the information encrypted in the DNA out of the nucleus and unto the factory floor of the cell, the cytoplasm.

To do so, the messenger RNA first scans the super sensitive information in the DNA inside the vault and for added safety transcribes it into a slightly different language (transcriptome) before travelling outside the highly secure nucleus. So, the DNA information — stored as ACGT code — is replicated into the RNA language as ACGUs (where the U replaces the T during the transcription), as if Italian is translated into Spanish, or Portuguese into French.

In short, the messenger RNA (mRNA) is basically a mail carrier delivering its letters from the nucleus into the cytoplasm, to provide the assembling instructions (like a manual for a flat packed furniture) to put together the building blocks, the amino acids, into proteins (like the complete couch or set of shelves after assembling the different flat-packed furniture parts.)

The messenger RNA has a short shelf life. Once injected into the human body, in order to be able to reach inside the host’s cell, the mRNA in the COVID-19 vaccine is packaged inside a protective shell (for the Pfizer-BioNTech and Moderna shots) made out of two rows of lipides (fat) which are extremely small (nanoparticles, from the ancient Greek nano meaning ‘dwarf’.) Notably, this ‘fat cell packaging’ can easily get damaged and is thus required to be frozen so that the mRNA is not released and thus lost, or that the fat nanoparticles do not lose their functionality, explains Steve Pascolo, a researcher at the University Hospital of Zurich and who has worked on mRNA vaccine since 1998.

Protected in this fat bubble wrap, the mRNA can survive long enough inside the body near the injection site. The protecting bubble will eventually merge with some of the host’s cells, which have a similar fat-based envelope. The mRNA in the vaccine is now able to deliver its letter: the instructions or assembly manual to build a coronavirus spike, the antigen (from the Greek antí, ‘opposed to’ and genos, for ‘race’ or ‘family’).

Once inside the host’s cell, the mRNA displays its instructions as if it came out of the nucleus. The disciplined cell reads the codes and the elves in Santa’s workshop get busy based on the brand new assembly manual that has just landed into the cytoplasm. The human cell builds a coronavirus spike (a protein) as per the new orders just received.

“The messenger RNA is the instructions for how you express the DNA,” sums up Mark Bayfield, the York University RNA processes researcher. “The idea is that a version of the mRNA is going to make the spike protein, it will go in the muscle cell, and the cell’s machinery will take this mRNA and make the spike protein out of it, which will then be presented on the surface of the cell to the immune system.”

Once the SARS-CoV-2 spike protein is assembled and mounted onto the surface of the host’s cell, the immune security patrol identifies it as foreign, unwanted and dangerous. The adaptive immune response kicks into full gear. And 7 to 8 days later, it builds another protein, the antibody (the counter-weapon specific to the antigen, that is the spike present in the crown of the SARS-CoV-2). The antibody can now equip the Special Weapons and Tactics Unit (SWAT) team patrols: the lymphocytes. The new generation genetic vaccine training boot camp is then complete.

In case of a real infection, these anti-SARS-CoV-2 trained immune SWAT teams can now quickly localize, identify and neutralize anything wearing a similar spike regardless of the content of the virus — this is the reason why the mRNA vaccines could still be effective despite any mutations inside the coronavirus. Or how vaccines could become ineffective if the spikes were to mutate too much as could be the case with the new mutations identified in the United Kingdom, Brazil and South Africa late 2020/early 2021[30].

This new class of vaccines are generally referred to as a “nucleic acid vaccines” (including RNA and DNA-based vaccines, both containing the NA for nucleic acid.) The Pfizer-BioNTech BNT162b2 vaccine candidate was originally developed by the German biotech company BioNTech, specializing in researching immunotherapy cancer treatment by stimulating the immune response, including using mRNA technology. The Moderna vaccine was originally researched to prevent MERS [another novel coronavirus active in the Middle East] and adapted for COVID-19, by scientists from academia, government agencies and industry.

“These new vaccines contain just the instructions for one SARS-COVID protein,” sums up mRNA expert Mark Bayfield. “It does not have any of the rest of the virus. It does not have the virus code, it does not have the other virus genes. It is not even embedded in the virus. It is put in a lipid nanoparticule, which is basically a bubble made of fat.”

Pfizer BioNTech COVID-19 vaccine (Source: Arne Müseler / www.arne-mueseler.com, CC BY-SA 3.0 DE, via Wikimedia Commons)

3. Any drug or treatment has upsides and downsides. The challenge, any doctor or pharmacist will tell you, is to weigh the benefits against the risks. The green light to administer a specific drug or treatment comes on when the upsides far outweigh the downsides.

Viral geneticist Earl Brown feels that despite the short hindsight about the new generation of genetic vaccines, their impact can be monitored moving forward.

“We are still in the early days and we can’t really know yet. […] I am very hopeful, but we are looking through a new window,” says Earl Brown. “This window used to be closed before. This is another opportunity. But what do you pay for the opportunity? And that is the question we want to know: is there a cost and if that cost is acceptable. A sore arm for a day. Fine, I am good, especially if I get a good boost to the immune system reaction. I am immune. I am happy, as long as I don’t have downstream effects. We don’t know about them. We’ll look for them.”

This begs the question though: what could be some of these downstream potential effects. Especially when dealing with healthy people in the case of vaccines, as opposed to already sick patients, argues molecular geneticist Christian Vélot: “When you take a drug because you are sick, it is because you are not well and so you are ready to accept a certain amount of side effects. The risk/benefit ratio is favorable.”

In that sense, vaccines are similar to food, argues Christian Vélot. Food is ingested by healthy people so “the acceptability of risks is much lower than with a medicine for sick individuals”. Thus, the extremely stringent public health controls to insure nobody gets sick from a vaccine.

Vaccines could then be considered as mid-way between food and a treatment, suggests Christian Vélot. “A vaccine is like a drug because of its nature, yet the context is like for food, we are not sick when we take it, and we certainly don’t want to get sick after taking it. So, the requirements are much more stringent than for a traditional drug.”

A vaccine is actually considered as a ‘personal prevention’ tool in public health jargon, protecting someone from getting sick, before, that is upstream from disease. A drug, on the other hand, is usually associated with curing, that is after, downstream from disease.

In the case of a vaccine, authorities will consider both the effectiveness (upsides) and the safety (i.e., no potential risks or downsides). Usually, the effectiveness and safety of a potentially successful vaccine are monitored during phase III for one to four years before it is widely administered, in order to pick-up any negative unforeseen consequences. “Phase III trials are not yet finished,” reminds Christian Vélot. “All the vaccines that we have today, including the Chinese vaccines that are based on more traditional and classic strategies [whole pathogen vaccines], were approved when Phase III had barely started.”

At the population-level, the odds of a downside are very different when considering the large scale of the COVID-19 vaccines roll-out, warns Christian Vélot. “First of all, we are targeting a much larger number of people than in the case of a disease where the number of sick individuals involved is obviously lower. In the case of a [preventive] vaccine, we are targeting the whole population. In the case of COVID-19, it is a big share of the world population.”

According to the French molecular biologist Christian Vélot, when dealing with a genetic vaccine such as mRNA shots, the risk of a recombinant virus introduces an additional collective hazard at the population scale, that is for the whole human race: what if, by any chance, a new virulent recombinant virus equipped with the SARS-CoV-2 crown jewel was to appear in as little as one single individual. This person could become a patient zero.

And if this new recombinant virus was nasty enough, this could be the start of a new pandemic, similar to what happened after allegedly one single human was infected by the SARS-CoV-2 in a wet market in Wuhan, China.

For molecular biologist and mRNA processes expert Mark Bayfield, there is no doubt: the risk-benefit balance is in favour of mRNA vaccines. “SARS-COVID is a real risk, when weighing that risk against risks that are so unlikely that they are hypothetical risks. You don’t even know what the likelihood of the [recombination] risk is because we have never seen this happen. Can we say they will never happen. Of course not. But COVID very much happens. It is an acute risk that we are facing right now.”

On the individual-level, mRNA-based vaccines appear to be quite safe, considering mRNAs are short-lived and cannot travel back into the nucleus, adds Mark Bayfield: “The RNA is a copy of that [DNA] that never propagates after that. RNA never makes more RNA in a human cell under the normal programming that our cell runs. The messenger RNA is a dead-end,” says Mark Bayfield. “The permanent code is the DNA. The mRNAs are transient. They are there for a time, usually in the order of hours, if they are lucky maybe a day. Then they are degraded and they are lost. They never go back. In that sense the mRNA is a bit safer.”

Alain Fischer, a pediatrician and professor of immunology agrees that the transient nature of an RNA means less recombination risks: “The chances of a [different virus] viral infection of a cell carrying the vaccine mRNA is very low considering the half-life of this mRNA,”, explains Alain Fischer, the president of France’s national policy council on the immunization strategy and thus nicknamed ‘Monsieur Vaccine’ in his country.

Yet, Christian Vélot counters that if the vaccine mRNA was so short-lived, it would not be able to get translated into a Spike protein and trigger the immune response. “The half-life of a human mRNA (that is the time for 50% of this RNA to disappear) varies between 30 min. and 24h. For the RNA of a human virus, we are closer to the higher bracket. Indeed, the stability of an RNA will depend on its translation rate, because the translation machineries (ribosomes), when they read the RNA (to translate it [and build a protein], are protecting it. And a viral RNA is destined to be translated a lot,” explains Christian Vélot, the French molecular geneticist and a staunch advocate for vaccine prudency.

Figure 1 (click on diagram to enlarge)

Still, the risks of a virulent recombinant virus going wild are extremely low, acknowledges Christian Vélot. Indeed, what are the chances that another virus will be present near the injection site of a COVID-19 mRNA vaccine, be it in a muscle or a connective tissue cell — or possibly in the blood, if a tiny vessel, a capillary, is quite nearby the needle location.

“The frequencies are probably very low,” agrees Christian Vélot. “Because the person receiving the immunizing genetic material would need also to be infected at the same time with a similar type of virus, that is in the case of the mRNA vaccine, two RNA based viruses, in the same cells, then that a recombination happens, and that the recombinant virus is nastier.” Let alone that the recombinant virus is viable, that is functioning with the extra genetic material under the hood.

This chain-reaction may sound like “a stand-up comic joke,” concedes Christian Vélot, while adding: “Probably these are very low frequencies. Yet this is when it is important to consider the risk not only at the individual scale, but at the population scale,” that is, considering the millions or possibly billions of injections that could take place.

France’s top vaccine strategy doctor, Alain Fisher and also a staunch critic of Christian Vélot, seems to agree though about unforeseen risks due to the much higher number of injections during an immunization campaign such as the COVID-19 vaccination roll-out. “We can never say that a new […] product has no risks. During phase III trials during which more than 20,000 volunteers were vaccinated, small events were observed but there could occur rarer event than those that could be detected amongst 20,000 people, which statistically would require 100,000, 500,000 or 1 million people,” acknowledged the French immunology professor when interviewed on national public radio last Dec. 2020. “Thus the importance of pharmacovigilance. Yet, this tells us that if indeed a risk there is, it is infinitely smaller than the risk to develop a serious disease,” argues the president of France’s policy council on the immunization strategy.

On the one hand, a reassuring evidence would come from large immunization campaigns with ‘old-school’ vaccines injecting weakened or inactivated full viruses, or from the current epidemic, which do not show major risks of recombinant viruses, argue several scientists.

“If this is going to happen, then it will happen when you are infected with SARS-CoV-2,” says immunologist Steve Pascolo, a pioneer of mRNA vaccines since 1998. “So, if these coding RNAs for the spike or for others are so easy to recombine, then when someone is infected and he produces billions of viruses, these recombinations would happen regardless. So, I do not see how the vaccines, which consist of 30 micrograms injected twice intramuscular could have a higher risk than the virus itself,” continues Steve Pascolo, now a researcher at the University Hospital of Zurich in cancer immunotherapy, who also co-founded the private biotech company CureVac, which is currently developing an mRNA COVID-19 vaccine with Bayer. “So as a scientist, I would not say it is impossible, because once again, as long as something is not proven, one cannot say it is impossible. Yet, however, I am simply saying that if these things can exist, then the risk is to have them with the viral infection,” says Steve Pascolo.

On the other hand, mRNA vaccines have a higher risk of leading to a viable recombinant virus, counters Christian Vélot, when compared with the whole pathogen — either from an inactivated virus or an infection — where the recombinations possibilities are so diverse that it is more difficult to get a fully functional recombinant virus that could survive.

“With a whole genome [i.e., a complete virus], it can happen anywhere and in whichever ways and so the probability that it leads to a ‘viable’ recombinant, that is sequences that remain functional and are able to result in a functioning virus, is very low,” argues the French molecular biologist at the University of Paris-Sarclay.

“But as soon as the only sequence that could recombine with an infecting virus is that for the surface protein [SARV-CoV-2 Spike], then we are concentrating the recombination events on this sequence. This could give new viruses only different from the original one by their surface protein, which allows to dock and enter into the target cells, thus leading to a much more contagious virus,” concludes Christian Vélot, a long-time advocate warning against the biosafety risks of genetically modified organisms (GMOs) technology through the French NGO Criigen.

On the pharmaceutical manufacturers side, when asked about any potential of recombinant viruses from an mRNA vaccine injection, Pfizer is simply referring to early trial results: “We have robust safety data, available from over 44,000 people who enrolled in the clinical trial and we continue to monitor vaccine safety as the vaccine is introduced in the population,” replies Christina Antoniou, Director, Corporate Affairs, Pfizer Canada when asked about the potential of any long-term risks of recombinant virus following an mRNA vaccine injection. BioNTech who was also contacted did not reply. Moderna was contacted as well and has not responded.

Other vaccine candidates or currently approved immunization use a different technology: they inject the vaccinating genetic information as DNA (as opposed to as RNA), in the case of the British AstraZeneca, the American Johnson & Johnson/Janssen or the Russian Sputnik 5 vaccines (see Figure 1 and Sidebar 1 below). In these vaccines, the DNA genetic material needs to get all the way into the nucleus, which could mean another set of potential concerns. Then the genetic information to produce the SARS-CoV-2 spike protein gets transcribed as mRNA to get out of the nucleus and thus including similar potential risks as an mRNA-based vaccine.

Another technology is used in the American Novavax vaccine candidate. The shot injects directly the spike protein, that was produced outside of the human body and instead in a lab, by moth cells infected with a genetically modified novel coronavirus SARS-CoV-2. The Novavax candidate is thus called a recombinant protein vaccine (that is a protein produced with different DNA), which falls into the subunit class of vaccines (because it only injects one component of the virus as opposed to the whole pathogen).

As the end of the day, longer trials could definitely be preferable, hints the University of Ottawa virologist and geneticist, Earl Brown, who remains confident though based on the hindsight of his 40 years career. “Emergency use authorization [for the approved mRNA vaccines] sort of drops the bar of safety a little bit and that’s mainly the window of how long do you look,” explains Earl Brown, yet adding: “I have seen nothing to worry here, but just on my knowledge of viruses and vaccines, this is something I would want to be comfortable about in a couple of years.”

The H1N1 virus (Source: Centers for Disease Control — CDC Influenza Laboratory)

The H1N1 so called swine flu was a recombinant virus, including genetic material from pigs, from birds and from humans, which once combined altogether created a very severe new strain. Importantly, all these viruses were from the same flu family. Indeed, the closer cousins viruses are, the more chances they have to recombine.

Reversely, the chances for viruses to recombine are lower if two viruses are from different families (inter-family recombination). “The recombination of coronavirus RNA with that of other species would be an extraordinarily rare event”, acknowledges Health Canada, the Canadian public body responsible for approving the mRNA vaccines in the country, to prevent the spread of the novel coronavirus SARS-CoV-2 responsible for the COVID-19.

The coronaviruses family fills a very big tent and is not new to scientists. “Coronaviruses are a large group of RNA viruses, and scientists have identified hundreds of such viruses to date,” says Edison Liu, president of the Jackson Laboratory, an American nonprofit biomedical research institution based in Maine. “They have been known to be infectious for decades but were initially recognized for only mild illnesses such as the common cold,” continues Edison Liu, a medical doctor trained at Stanford University and a former president of the Human Genome Organization (HUGO).

While most coronaviruses are indeed mild, new strains (thus called novel coronavirus, ‘novel’ meaning ‘new’) have appeared in the past 20 years and are more serious and possibly deadly. “Coronaviruses are a large family of viruses that usually cause mild to moderate upper-respiratory tract illnesses, like the common cold,” confirms the American National Institute of Allergy and Infectious Diseases (NIAID), headed by Dr. Anthony Fauci, also the chief medical advisor to the presidents of the United States. “However, three new coronaviruses have emerged from animal reservoirs over the past two decades to cause serious and widespread illness and death,” reads the NIAID fact sheet on coronaviruses.

“A concern regarding coronaviruses is that they are zoonotic, meaning they can spread from animals to humans and take more virulent forms,” sums up Edison Liu, president of the Jackson Laboratory in the U.S.

The first novel coronavirus, that is the new deadly strains in the large coronaviruses’ family, first emerged in 2002 in Southern China and came probably from horshoe bats. It caused a severe acute respiratory syndrome and thus was named SARS (Severe Acute Respiratory Syndrome.)

The SARS epidemic started to spread Zhongshan City (near Macao just across from Hong Kong and 12 hours drive South of Wuhan). Internationally, the Canadian city of Toronto experienced the largest outbreak outside of Asia, for four months in the Spring of 2003. Toronto was hit by an international no travel ban from the World Health Organization, which reacted quickly and contributed to stall the budding epidemic. SARS-CoV-1 is now considered to have disappeared since 2004.

In 2012, a second serious novel coronavirus appeared in the Middle East, probably transmitted from camels. The Middle East respiratory syndrome (MERS) is still causing local outbreaks from time to time.

“The third novel coronavirus to emerge in this century is called SARS-CoV-2,” explains the fact sheet on coronaviruses by Anthony Fauci’s National Institute of Allergy and Infectious Diseases (NIAID). “It causes coronavirus disease 2019 (COVID-19), which emerged from China in December 2019.” (The CoVi-Disease is labelled 19 simply because it first appeared in 2019.)

To identify the possible source of the SARS-CoV-2, a team of World Health Organization (WHO) experts has started to investigate in Wuhan early February 2021, including at the Wuhan Institute of Virology (hosting a high security P4 lab originally built with the help of the French Pasteur Institute.)

“Both SARS and MERS had higher mortality rates than COVID-19 but spread through human-human transmission more slowly,” notes Dr. Edison Liu from the Jackson Laboratory.

All in all, there are three main groups of coronaviruses, with SARS-CoV belonging to group 2, while SARS-CoV-2 appears to hold the gold medal for the speed of transmission human-to-human, thanks to its crown-jewel, the spike (or s-protein) which can easily break into the lungs membrane.

Middle East Respiratory Syndrome (MERS) virus particles (yellow) attached to the surface of an infected VERO E6 cell (blue). (Source: NIAID, CC BY 2.0 , via Wikimedia)

Inter-family virus recombination does happen, still. For instance, flu viruses and minor coronaviruses have actually swapped genetic material in the past, says Canadian viral geneticist, Earl Brown. “Some viruses have picked up genes from each other such as the group II coronaviruses that all have the HE surface gene from influenza C virus. They benefit from this gene but have not gone on to randomly pick-up foreign RNA.”

The reason being is the RNA recombination process needs to serve a purpose and is not very frequent. “So, whereas viruses can pick up foreign genetic material, they do so rarely because such acquisition are not useful for survival,” underlines Earl Brown. “It is the environmental conditions that dictate whether a genetic change is selected; not just the ability to make changes. Viruses (especially RNA viruses) are very tightly organized (i.e., very small genomes where genes often overlap each other, to save space) and are not improved by a simple addition of a new gene,” continues the Canadian viral geneticist.

“We know by observation that humans and animals are frequently infected by two or more viruses (both RNA and DNA viruses), that occurs on a continuous basis and yet recombination is very rare,” concludes Earl Brown, explaining why he remains confident about the overall safety of mRNA vaccines.

How about, for instance, the HIV-AIDS virus, an RNA-based virus as well? Would there be any chance of recombination with the mRNA coding the SARS-CoV-2 spike?

“The recombination is very, very unlikely (that is, almost impossible)”, sums up the Canadian regulator for vaccines, Health Canada.

According to immunologist Steve Pascolo, researcher in cancer immunotherapy at the University Hospital of Zurich in Switzerland, the current COVID-19 has most likely already infected HIV positive people with apparently no inter-viruses genetic exchanges. “If recombinations can happen between HIV and SARS-CoV-2, then it would happen via the viruses themselves (probably hundreds of thousands of HIV+ people in the world were infected by SARS-CoV-2.) Especially considering the SARS-CoV-2 virus is present in the whole body (including in the blood), persists for days or weeks. And it would have the time and the ability to meet some HIV. The mRNA vaccine is local, intramuscular, does not wander throughout the whole body and does not persist more than a few hours,” explains Steve Pascolo, a pioneer in mRNA vaccine technology in the late 1990s.

Then again though, having just one part of the SARS-CoV-2 spike protein via a vaccine injection might increase the chance of a viable recombination, has argued French molecular biologist at the University of Paris-Sarclay, Christian Vélot.

The HIV-AIDS virus is actually genetically very different from the SARS-CoV-2, reminds York University molecular biologist Mark Bayfield: “HIV and SARS-CoV-2 are less related than flies are related to humans”.

Vaccine prudent scientist Christian Vélot agrees: “Yes the chances are much higher if two viruses are from the same family. HIV and SARS-CoV-2 are not from the same family, though they are both RNA viruses.”

This being said, the surface of the HIV virus displays a docking protein quite similar to the coronavirus spikes, continues Christian Vélot: “Some sequences are similar between the docking protein of the AIDS virus — which allows it to attach to the surface of lymphocytes that it will infect — and the docking protein of the spike in SARS-CoV-2,” explains the French molecular geneticist, who suggests this is probably why some conspiracy rumours early on the pandemic in Spring 2020, claimed incorrectly that the SARS-CoV-2 had been engineered by humans because it would contain some HIV genetic material.

In the end, what are the actual risks of getting a recombinant virus more virulent than the original coronavirus? Chances are indeed extremely small, “possibly as low as one person in 10 million or even one person in 100 million,” guesses Christian Vélot (while the odds could potentially be even lower.) “Except that it is not only the unlucky person that would be a victim. If the recombinant virus is very nasty, it might spread and infect other people,” suggests the University of Paris researcher in molecular genetics.

In this light, according to Christian Vélot, considering the sheer number of injections, in the hundreds of millions, or if not in the billions even, then the odds could be much higher for one single perfect storm event, whereby another RNA-based virus would recombine with the mRNA in the Pfizer-BioNTech or Moderna vaccines, to result in a new recombinant virus equipped with the SARS-CoV-2 spike, in a potentially patient zero.

“If SARS-Cov-2 has taught us anything,” suggests Christian Vélot, “it is that it is enough for one nasty virus to appear one day, somewhere — in this case it was in Wuhan — for the consequences to be colossal and world-wide. Unfortunately, we do not hear much about this kind of risk”, regrets Christian Vélot, underlining the types of risks at the population scale, as opposed to health risks at the individual scale.

“Aren’t we currently taking an important world-wide biosafety and environmental risk,” asks Christian Vélot, “because with these genetic vaccines we are going to take the risk to generate recombinant viruses, indeed at a very low frequency, yet when you vaccinate hundreds of millions of people or billions of people, the probability of such an event is no longer zero.”

A volunteer participating in a phase 3 trial of a COVID-19 vaccine in Indonesia. (Source: Rio Tuasikal/VOA, via Wikimedia Commons)

Early phase III trials seem to point to a relative safety for the Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines, at least in the short term and on an individual basis, though their effectiveness is still not entirely confirmed. For instance, how long will the host’s immune response last? Is the host no longer contagious? And now in early 2021, how about the impact of the most recent mutations of the spike in the United Kingdom (B1.1.7), Brazil (B.1.351) or South Africa (P.1/B.1.1.28). One could argue that the mRNA contained in the nanoparticles fat bubbles could easily be updated with the new variants spike information, then redeployed quickly as a version 2.0 of the mRNA vaccine — and similarly with DNA based or recombinant protein vaccines.

In the end, the two front runners mRNA vaccines could possibly even be safer than a traditional inactivated virus vaccine, at least individually and in the short-term, simply because only the genetic code for the spike is injected, as opposed to the whole virus material even inactivated, in a whole pathogen vaccine based on the traditional technology (see Figure 1 and Sidebar 2 below.)

Indeed, mRNA vaccines only carry the code for the assembly instructions to build the docking mechanism or the key to the city. It is not the code to reprint the whole book: the entire content of the novel coronavirus SARS-CoV-2, loaded with information to build a whole army of enemy soldiers ready to march in drove against our fortified city, the human body, or assembling the whole rogue spaceship full of hackers ever so adept at breaking into many of the sophisticated systems in our human machinery: respiratory, digestive, cardio-vascular or even neurological functions — as seen in patients with severe cases of COVID-19.

In addition, mRNA hardly ever returns into the nucleus, meaning there appears to be very little risk to rewrite or to overwrite the host DNA — except in the presence of an enzyme, a reverse transcriptase found in a retrovirus, such as the HIV causing AIDS or a human T-cell lymphotropic virus I (HTLV-I), responsible for leukemia. So, the Pfizer BioNTech and Moderna mRNA vaccines would probably have very little chances to modify the human DNA in the cell nucleus. (Currently, the French/American Sanofi-Pasteur/Translate Bio vaccine is also working on a similar mRNA vaccine.)

“… in the case of RNA converting into DNA, […] this would only target the one individual [and] the probability would be as low as for the [risk of] recombination,” confirms Christian Vélot, “But the recombination can have consequences that are not at the individual scale but at the population scale, at the planet scale,” insists Prof. Vélot.

In short, there could be a couple of key scenarios to monitor. The (most unlikely) risk of an mRNA vaccine genetic material to get into the host’s nucleus and DNA (in the presence of the retranscriptase enzyme).

A second set of circumstances of recombinant virus could be the recombination of the spike protein from SARS-CoV-2 into another virus, that could thus make this other virus extremely contagious by acquiring the highly effective key to enter into the human lungs cells: the spike.

4. Eleven months and counting into the COVID-19 global health emergency, including several periods of severe lock-down in many countries to curb the spread of the novel coronavirus SARS-CoV-2, no doubt, on the one hand, every citizen, including scientists or political leaders, is anxious to return to their regular life from before the public health crisis, with no masks, no physical distancing, the ability to hug one another and no restrictions to one’s daily whereabouts.

Many people are currently worried and eager to protect their loved ones, especially their elders, from potential harm or death. At the same time, grandparents can’t wait to see their children and grandchildren, especially considering time is counted for people at the dusk of their lives with less luxury of waiting out this pandemic.

On the other hand, the vaccine prudent voices are calling for a more cautious and less hasty roll out of the new generation genetic vaccines, approved earlier than more traditional class of inactivated whole pathogen vaccine candidates still in development.

The current dilemma the whole human race is facing globally after a dreadful year 2020, might then to take the present and real harms from the SARS-CoV-2 pandemic: the biological health risks, including deaths or possible long term disability; the mental health risks, including depression from isolation, loss of a relative or loss of a job; the financial risks (due to restrictions and lockdowns implemented to reduce the strain on intensive care units from the most severe cases), including economic depression and mounting public debts — and to weigh these ills against longer term potential biosafety risks, as remote as they are, yet possibly disastrous in case of a perfect storm leading eventually to one new patient zero.

“We are faced with a totally unpredictable virus, that is taking us by surprise on a daily basis, with very different symptoms from one individual to the next,” sums up French molecular geneticist Christian Vélot. “And to the unpredictability and the uncertainty of this virus, we are currently adding the uncertainty and the unpredictability of a technology. I find that cumulating the risks in this way is not very responsible and it would be wiser to use, like the Chinese have done, the strategy of an inactivated virus,” offers Christian Vélot, the vaccine prudent scientist, former Green Party candidate and long-time anti-GMOs biosafety risks activist.

“It is impossible for a scientist to say there is zero risk, because we cannot prove this is impossible,” reminds York University Professor Mark Bayfield, a molecular biologist specializing in RNA processes. Yet, he adds: “While it is not impossible that something strange could happen, the chances that their [HIV and SARS-CoV-2] different genetic systems could ‘talk’ with one another is very, very low.”

“What are the long term effects,” notes Earl Brown, the University of Ottawa Emeritus professor, “and will there be some other effects that we don’t know about? And that is the problem right now. We are looking at a short window,” he acknowledges. “And we’ll look very close to the short window to see if there is a sign that there might be a problem as we expand out the window,” adds the Ottawa-based retired viral geneticist who remains confident that all will work out fine.

“I am not very concerned about the effects of injecting an mRNA vaccine,” continues Earl Brown, “because — although this is a novel delivery system — it employs natural components (RNA and lipids) that will be degraded to naturally occurring constituents and further metabolized in cells. What is less known,” he adds, “is the ability of a coronavirus vaccine (the first in humans) to control the epidemic especially with the emergence of new variants such at the UK B1.1.7 SARS CoV-2. Questions also remain as to how effectively the disease will continue to be prevented and how long immunity will persist or whether the virus can spread among some vaccinated people”, concludes the Ottawa-based viral geneticist.

While individual prevention with vaccines is important, could massive government subsidies have targeted research for treatments aggressively as well, instead of putting all the public eggs into the vaccine basket and governments now scrambling to roll out immunization programs in haste?

In the face of the uncertainties about the long term efficacy of new generation genetic vaccines, what about focusing more aggressively on the other side of the ‘personal prevention with vaccines’ equation: curative treatments.

So far, in hindsight of almost a full year into this pandemic, vaccine prudent Christian Vélot urges to think outside of the vaccine box. The French scientist wonders why much of the public funds have gone into vaccine research, as opposed to investing into research for treatments to help sick patients to recover from COVID-19 and not die or require intensive care, for many weeks at times for some of the most severe cases.

“There is still no HIV-AIDS vaccine. But we have successful tri-therapy AIDS treatments,” reminds Christian Vélot “No phase III trials would involve large enough samples to be able to grasp the percentage of this risk [recombinant RNA viruses]. This is why maybe we should consider other immunization strategies and other therapeutic strategies, rather than putting all of our eggs in the same basket, that is the vaccines’ basket,” suggests Christian Vélot.

Bioethically speaking, another key question could also be: should citizens have the right to choose which type of vaccine they will receive — if they want to be immunized — as more different types of vaccines get approved and rolled out, such as the DNA-based AstraZeneca [see Sidebar 1 below] or more traditional technology such as inactivated viruses vaccine candidates [see Sidebar 2 below], in addition to the mRNA shots?

By the same token, citizens should also have the right to know how much each different vaccine costs (with currently absolutely no transparency in this regards, as governments and pharmaceutical companies argue this is contractual confidential information.)

Last and not least, vaccines are no doubt a key part of disease prevention on the one side of the health equation, across from curing ill-health with treatments - echoing the dual godly health team in ancient Greece, sisters Hygeia for prevention and Panakeia for curing. Yet any effective strategy to prevent a virus infection would also need to focus further upstream: making sure individuals in the population are healthy in the first place and able to better fight off any incoming germ.

Better nutrition, regular physical exercise, good living conditions and lower stress are some of the major socioeconomic factors and key determinants of health that can also contribute to acquiring herd immunity: to improve the health and well-being of the population as a whole and thus the ability to have a strong innate and acquired immune response, possibly even without a vaccine. For instance, it could possibly avoid that a larger share of underprivileged populations is infected with SARS-CoV-2, domestically in more affluent countries, but also world-wide, as poorer nations, let’s not forget, could become a long-term reservoir for the SARS-CoV-2 to continue to mutate and spread.

One thing is for sure: on the personal prevention front through immunization, being vaccine prudent, that is being staunchly pro-vaccine while also standing strongly for the precautionary principle, requires walking a fine line these days when dealing with the latest generation of genetic vaccines against COVID-19, when faced with the urgency, if not panic, to flatten the epidemic curve once and for all.

In the end, all we really know is: “We are in the era of synthetic biology. There are a lot of unknowns,” sums up Earl Brown, the retired Ottawa University multidisciplinary viral geneticist, adding with the hindsight of his 40 years career: “Vaccines are great, as long as they are safe.”

SIDE BAR 1

The Oxford AstraZeneca and Johnson & Johnson/Janssen vaccines

How different is this DNA-based technology?

Extracting a short string of the genetic code from the genome of a virus in order to create an mRNA vaccine may come across as basic biotechnology when compared with other truly genetically modified COVID-19 vaccines, such as the British Oxford AstraZeneca immunization recently approved in the United Kingdom, in India, and in the European Union.

Indeed, the AstraZeneca vaccine is going one step further in genetic engineering, compared to other mRNA-based COVID-19 vaccines. (The Johnson & Johnson/Janssen vaccine candidate is using a similar technology and is waiting for emergency use authorization in the U.S. and currently being evaluated in the European Union and Canada.)

The key difference lies both in the packaging as well as the format of the genetic material injected into the body, in order to trigger the adaptive immune response.

In short, the spike material from the SARS-CoV-2, an RNA virus, is first converted into DNA. Then, the spike protein is introduced into another virus as the container (vector) — when an mRNA vaccine is using tiny fat particle bubbles to protect the mRNA strings. “We are using the ability of the other virus to inoculate its material inside the cells of the person to immunize,” says molecular geneticist Christian Vélot.

More specifically, the vector (or carrier) is an adenovirus, meaning its genetic material is in DNA language as opposed to in RNA code (that is ‘adeno’ standing for ‘d-n-a’.) The adenovirus vector is a minor virus that would normally only give a sore throat and cold-like symptoms, including fever. This other type of nucleic acid vaccine is referred to as a “recombinant vector vaccine” — recombinant meaning the DNA from two or more sources has been assembled — using a non-replicating adenovirus (replication-incompetent vector.)

To create the AstraZeneca COVID-19 vaccine, the adenovirus vector is first ‘disarmed’ by removing some of the genetic material causing its virulence — like removing a powerful engine out of a car and putting under the hood a very small one. It then loaded up with the SARS-CoV-2 spike genetic material, to create a sort of hybrid vehicle with an adenovirus chassis (vector) carrying the s-protein (spike) as cargo.

But the SARS-CoV-2 genetic material is originally in RNA code. So it must be transcribed into DNA first, in order to speak the same language as the adenovirus vector.

“In a test tube, we transform the SARS-CoV-2 RNA into DNA. Then this DNA copy of the genome of SARS-CoV-2 [spike] is inserted into what is left of the DNA of the adenovirus that is used as vector. So, we have a recombinant adenovirus,” explains University of Paris-Sarclay Christian Vélot. In order to transcribe the RNA into DNA, “we are using an enzyme, a reverse transcriptase, found in retroviruses such as HIV,” adds Christian Vélot.

Once injected as a vaccine and inside the host’s cells, the spike instruction manual in DNA code gets into the nucleus (thanks to the capabilities of the original adenovirus vector machinery), gets read and transcribed back into RNA; then travels back out into the cytoplasm, the cell’s workshop where the spike protein (antigen) is put together, which will eventually trigger the immune response and the production of antibodies. (Notably, the shell or capsid around the adenovirus virus provides a very stable packaging for the spike instruction, which explains why DNA-based COVID-19 do not require extreme refrigeration.)

At the population-level, this type of DNA based vaccine could have a similar potential to recombine with other viruses, yet in this case, DNA-based viruses.

Yet, Christian Vélot warns about additional risks, potentially this time for the vaccinated person: the DNA from the vaccine could recombine with the host’s DNA, which could eventually lead to another type of perfect storm, the appearance of cancers, according to Christian Vélot, if the location where the DNA were to insert was oncogenic (a potentially cancer inducing gene). “There is a new risk of insertional mutagenesis, which means a risk that the genetic material inserts into [the host’s DNA.] This time around, it is possible. It is not possible with the RNA. The RNA cannot insert into the DNA. But DNA can insert into DNA,” concludes the University of Paris-Sarclay associate professor.

This type of DNA recombinant risk is observed in patients treated with gene therapy, continues Christian Vélot, while another French scientist argues newer technologies have not displayed this kind of risks.

“We know well these risks with gene therapy,” says French molecular geneticist Christian Vélot, “because gene therapy uses exactly the same viral vectors used in these DNA vaccines. In the case of gene therapy, it is not viral DNA that we bring into cells, it is human DNA. For instance, in the case of children that have a damaged gene which causes a severe disease. And we are trying to repair it by bringing in the normal version of the gene. And it has happened, in a gene therapy trial on 10 children [reported in 2003], in two of them — that is a lot — the repairing gene inserted itself into what we call oncogenes. […] These children developed leukemia. Of course, in the case of gene therapy, it is the intention that the DNA injected will insert, while in the case of the vaccine, no: this would be fortuitous and thus with much lower chances of happening.”

These cancer causing insertional mutagenesis concerns were recently dismissed by the head of France’s national policy council on the immunization strategy, Alain Fischer, a pediatrician and professor of immunology, arguing the newer technologies used are different and much safer.

“These events [leading to a leukemia] were connected to the use of retroviral vectors where the enhancer element had been kept,” counters Alain Fischer. “Since then, vectors were modified, they no longer contain this element (self-inactivating vectors — SIN) and in no cases the malignant process was observed, in patients treated with a therapy targeting hematopoietic stem cell [that is immature] (about 200 patients for over 10 years) or lymphocytes-T (CAR-T), several thousands for six years,” concludes Alain Fischer, also nicknamed “Monsieur Vaccine” in France.

“Furthermore, let’s keep in mind the successes of an adenovirus-based vaccine against Ebola,” adds Alain Fischer, in response to Christian Vélot’s controversial expertise notice on the biosafety risks of newer generation genetic COVID-19 vaccines.

Asked about this potential of oncogenic risk, AstraZeneca replied: “As background, we believe the [2003] study you are referring to focuses on retroviral vectors, which have the ability to integrate into the human genome,” confirms Mary-Anne Cedrone, Senior Manager, Corporate Communications at AstraZeneca in Toronto. “Alternatively, adenoviruses do not integrate into the genome and are not replicated during cell division. Adenovirus vectors have been used as vaccine candidates since the early 2000s. The vaccines have been shown to be safe even in cases where they were not effective,” concludes the AztraZenca spokesperson in Canada.

For Steve Pascolo, a cancer immunotherapy researcher and an mRNA vaccine technology pioneer — thus a competitor of the DNA-based vaccine technology — the main concern would be that the genetic material from the recombinant virus vaccine has to enter the host’s cell nucleus, which is basically the ultra-secure vault where the human genome, the full recipe book of life, is stored. So, the risk of overwriting the DNA would be greater, argues Steve Pascolo.

“Recombinant adenoviruses [vaccines] (AstraZeneca or Johnson & Johnson) appear to be in my opinion less safe than mRNA vaccines. […] The DNA of the vaccinating recombinant virus must go into the nucleus of our cells to be operating,” sums up Steve Pascolo, from the University Hospital of Zurich in Switzerland and previously the co-founder of CureVac, a biotech start-up company specializing in mRNA vaccine technology (said to be collaborating with GlaxoSmithKline to make COVID-19 vaccines addressing the new variants.)

“I started developing mRNA vaccines as early as 1998 as a matter of fact”, adds Steve Pascolo, “to avoid DNA vaccines which were associated with theoretical risks of persistence, of recombination with other viruses and of modification of our genetic pool,” concludes the scientist — who says he has no connections with CureVac since 2006 and is currently working with BioNTech on anticancer immunotherapy research (but not on COVID-19 vaccines.)

The AstraZeneca vaccine is based on the candidate vaccine AZD1222. It was originally developed by U.K. Oxford University and U.S. Rocky Mountain Laboratories of the National Institute of Allergy and Infectious Diseases (NIAID), based on a chimpanzee adenovirus vector, and licensed to the U.K. based company.

The Johnson & Johnson/Janssen vaccine uses a similar replication-incompetent adenovirus vector, using a human virus (AdV26).

The Russian Sputnik 5 also uses this recombinant adenovirus (DNA) technology. Phase III clinical trial started in August 2020, yet the vaccine has already been approved by Russian authorities and is currently being injected. It was reported to be approved in Mexico early February 2021.

Another similar type of DNA viral recombinant vaccine candidate researched at the French Pasteur Institute (named after the biologist Louis Pasteur) with a measles-based vector, has been abandoned in January 2021, citing an inferior immune response induced by the vaccine.

One of the Chinese vaccine candidate based on the traditional technology of inactivating a whole virus.(Source: Governo do Estado de São Paulo, CC BY 2.0, via Wikimedia)

SIDEBAR 2

Some old-school COVID-19 vaccines underway

Dead viruses used to prime the immune response with traditional vaccine technology

A few COVID-19 vaccine candidates are using the more traditional technology of inactivating a virus, such as the two Chinese shots currently tested. This type of “whole-pathogen vaccine” is said to have very little risks of triggering an infection, considering the virus is basically dead — as opposed to using a weakened virus, the second option in traditional vaccine technology (see Figure 1 above).

Yet the flip-side is these dead viruses have a reduced ability to be detected once injected. So, they need to be associated with other substances to draw the attention of the human immune system, also referred to as ‘boosting’ or ‘potentializing’ (i.e., increasing the immunogenicity potential.)

“Efforts to develop safe and effective vaccines increasingly involve the use of adjuvants — substances formulated as part of a vaccine to boost immune responses and enhance the vaccine’s effectiveness,” explains the U.S. National Institute of Allergy and Infectious Diseases (NIAID).

“For the inactivated vaccines,” explains French molecular geneticist Christian Vélot, “that is with dead viruses — that were killed by exposure to formalin or with a chemical process, either by heating them or exposing them to radiation, generally ultraviolets — the problem is they have a low immunogenic potential. So, they need to be injected several times, which can cause a problem in terms of manufacturing when dealing with a large population. And there is a need to potentialize the immunogenic effect with adjuvants such as aluminum salts or formaldehyde,” underlines Christian Vélot, associate professor and researcher at the University of Paris-Sarclay.

These vaccine adjuvants are not toxic, insists Alain Fischer, the president of France’s national policy council on the immunization strategy and nicknamed ‘Monsieur Vaccine’. “The alleged toxicity of aluminum has never been proven. Formaldehyde is present is some vaccines as vanishingly small traces non-toxic,” sums up the French pediatrician and professor of immunology.

“Aluminum-containing adjuvants, collectively termed alum, have been safely used in vaccines since the 1930s and are still widely used today,” says the U.S. NIAID. “Aluminum is among the most common metals found in nature and is present in food and water. Scientific research has shown that the trace amounts of aluminum in vaccines are safe and not readily absorbed by the body.”

The name aluminum comes from Latin alumen and describes potash alum, while “because of its chemical activity, aluminum never occurs in the metallic form in nature, but its compounds are present to a greater or lesser extent in almost all rocks, vegetation, and animals,” reads the Encyclopedia Britannica.

No proposed COVID-19 vaccine candidates to be released in the coming year is using the second traditional vaccine technology with a weakened yet still alive viruses, says Christian Vélot, “which is a good news”, considering the virus would not be completely dead, which could potentially create a problem (like in the case of the Cutter Polio vaccine in the 1950s.) “There is always a big risk with an attenuated virus that it is not attenuated enough,” acknowledges Christian Vélot, “especially with a virus which we do not know much about.”

Logo of the Court of Justice of the European Union (CVRIA) (Source: CVRIA, via Wikimedia)

SIDEBAR 3

GMO regulation lifted in Europe to allow COVID-19 new generation genetic vaccines

Precautionary principle not applied, warn environmental groups suing the European Union.

On the regulatory side, genetically-modified materials produced through biotechnology, such as some of these new generation genetic COVID19 vaccines currently developed and/or rolled out, will usually fall under extremely stringent regimes, such as the European Union directive 2009/41, with four different levels of containment, designed to protect both human health and the environment.

In mid-July 2020, the EU lifted this regulation with the directive 2020/1043, in order to fast-track COVID-19 vaccines deployment, with a derogation to by-pass any kind of environmental risks assessment, granting in essence “a level 0 of containment”, are suggesting some vaccine prudency advocates, including molecular geneticist Christian Vélot, researcher and associate professor at the University of Paris-Sarclay in France.

A group of non-governmental organizations has launched a legal procedure at the Court of Justice of the European Union in November 2020 to get this derogation cancelled, pleading the regulatory process should “respect the precautionary principle” in terms of public health and the environment.

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Charles A. Rouyer

University lecturer and journalist specializing in health & environment / Enseignant à l’université et journaliste spécialisé en santé et environnement.