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A Future-Proof Coronavirus Vaccine

We have tried to do it for the common cold and the flu. Can we create a universal coronavirus vaccine to protect us from future pandemics?

You may remember learning about Newton’s third law in school. It states that for every action there is an equal and opposite reaction. A classic example would be a rocket being propelled forward by expelling gases backward. In a tongue-in-cheek way, we could apply this law to the COVID-19 pandemic: the virus makes a move, we make a countermove. As important mutations arise in the virus that create a new variant that outcompetes the others, scientists start to work on a new vaccine that could be a better countermove to this new variant. Indeed, biotechs are crafting an Omicron-tailored vaccine right now. But by the time it’s ready, won’t it be too late? Won’t we need, let’s say, a Sigma-specific vaccine?

What if we made the ultimate move against which there is no countermove?

What if we created a universal coronavirus vaccine? “One vaccine to rule them all,” as Scientific American put it.

It would offer protection against any variant of SARS-CoV-2 (the virus responsible for COVID-19), as well as the viruses behind SARS and MERS, and the coronaviruses that give us the common cold. And it would act as insurance against any future bat coronavirus making its way into humans. This hypothetical coronavirus, pregnant with pandemic possibilities, would swiftly get rebuffed by our immune systems, trained to recognize its “coronavirusness.”

Is it a pipe dream? Maybe.

Transgenic mice and lollipops

This notion of a universal vaccine against a respiratory virus is not new. It has been tried before, and though direct comparisons are fraught, these examples unmask the challenges ahead.

Scientists have attempted to design a universal vaccine against the common cold, and it is not easy. There are more than 200 distinct viruses that give us the symptoms we have come to call “the common cold,” so a universal vaccine would have to trigger immunity against a whole menagerie of diverse viruses that can mutate quite easily. You may not think that eradicating something as mild as the common cold is a worthwhile endeavour, but a cold can worsen chronic airway diseases like asthma and COPD to the point where hospitalization is necessary, to say nothing of the economic cost of employees calling in sick with the sniffles. On average, adults get two to five infections a year; for children, the number goes up to 10. A universal cold-buster vaccine would come in handy.

Clinical trials were underway in the late 1960s, early 1970s for a vaccine against one specific type of cold virus, but it did not perform very well. A vaccine targeting ten different cold viruses was subsequently tested, to likewise milquetoast results, and research into these vaccines essentially dried up for over 20 years.

A major issue was the lack of a small animal model. Rhinoviruses represent roughly 160 of the 200 viruses that give humans the cold. Mice do not get infected by these rhinoviruses, which made it a problem for the vaccine-testing pipeline. Our eventual development of transgenic mice solved this problem. Scientists could now add a gene to a mouse’s genome: the one that codes for the human cell receptor that rhinoviruses use to enter our cells and make us sick. This led to renewed interest in cold vaccines, and biotech companies like Pfizer and Moderna are right now trying to develop a universal cold vaccine.

Then, there is the flu.

Vaccines against influenza date back almost a century. A monovalent vaccine is one designed to protect against a single strain of a germ, like a virus. The first monovalent flu vaccine was released in 1934, followed by a bivalent vaccine (two strains) approved in the United States in 1945. Then came the first trivalent flu vaccine in 1977, and in 2013 we saw the first quadrivalent flu vaccine. The four influenza strains chosen for the yearly quadrivalent vaccine are the result of international surveillance by the World Health Organization to predict which strains of the virus are likely to cause the most trouble in the upcoming flu season. This informed guess and the resulting vaccine are usually fine, but there is room for improvement. A flu vaccine’s effectiveness is what percentage of flu cases it prevents. The flu shot’s effectiveness, according to American data, has fluctuated between 10% (the 2004-2005 season) and 60% (the 2010-2011 season). Better than nothing, given the harm influenza can cause, but disappointing nonetheless. An effective universal flu shot would be welcomed.

But how do you train your immune system to recognize any version of the influenza virus, a tiny bug that is notorious for its shapeshifting ability? What do you put in that syringe? When we get the flu, most of our immune response focuses on a docking protein at the surface of influenza called haemagglutinin (HA for short). It is a ball carried on a slender stick and it makes contact with our cells, like a lollipop touching our lips and getting the mouth to open to welcome this sweet treat inside. The problem is that this ball of hard candy comes in too many flavours. A universal flu vaccine could not account for all of them. But the stick doesn’t change much, so many researchers have focused their efforts on making a “stick” vaccine (a much harder process than this simplistic analogy admits to). Others have found that, even though the confectionary ball is available in multiple flavours, there are parts of it that are the same between lollipops. These conserved regions could be turned into vaccines.

There are real challenges to bringing a “one size fits all” flu vaccine to market: small laboratory animal models do not live long enough to test the universality of the vaccine, infection after infection; larger and longer-lived animals, like pigs, are, well, large and resource intensive; and there is the ethical conundrum of keeping human volunteers in a clinical trial for years to test a universal flu vaccine season after season and withholding from them the already approved quadrivalent vaccines that can keep them out of the hospital.

But the technological innovations used in the development of a universal flu vaccine are also being used to solve a more urgent crisis: ending the COVID-19 pandemic.

Will our efforts pan out?

This “one coronavirus vaccine to rule them all” is often called a pan-coronavirus vaccine, from the Greek prefix “pan-” meaning “all.” In this context, however, the meaning of “pan-” is quite flexible. What do we mean when we say, “all of the coronaviruses?”

You may remember the Latin taxonomy of species in biology: for example, we are Homo sapiens, meaning that our genus is Homo and our species is Homo sapiens. While viruses are not widely thought of as being alive, they are classified in a similar type of family tree. If we look up SARS-CoV-2, for example, and its many variants, they belong to the subgenus of sarbecoviruses, alongside the virus that caused SARS in 2002. The virus that caused MERS, another coronavirus epidemic, is found in a different subgenus, but both of these subgenera are filed under the betacoronavirus genus. Alpha-, beta-, gamma-, and deltacoronaviruses are housed under the orthocoronavirinae family, which is itself a member of the coronaviridae family. So, when we speak of a pan-coronavirus vaccine, we have to specify how high up on the chart we’re willing to go.

The most restrained strategy is to go after a variant-proof SARS-CoV-2 vaccine, a way to train our immune system to recognize SARS-CoV-2 in all of its current and future incarnations, from the original strain all the way to a hypothetical Omega and beyond. A loftier goal is to create a pan-sarbecovirus vaccine, as all sarbecoviruses (including SARS-CoV-2 and SARS-CoV-1) use the ACE2 receptors at the surface of our cells to gain entry. Survivors of the SARS pandemic who received Pfizer’s COVID-19 vaccine were seen to produce very special antibodies that could neutralize both pandemic coronaviruses, as well as coronaviruses found in bats and pangolins, meaning that this desired cross-reactivity is possible in practice. For some researchers, however, this isn’t enough. They want a pan-betacoronavirus vaccine, which would take care of the sarbecoviruses, the MERS virus, and everything else under that genus.

Cutting-edge technologies are being used to craft these vaccines. One approach is to use nanoparticles. This is not new. Novavax’s approved COVID-19 vaccine, for example, uses nanoparticles: its spike proteins are made inside of moth cells and they are then stuck to tiny, soap-like molecules. The final result is a ball studded with a version of SARS-CoV-2’s spike protein which our immune system can recognize as foreign and attack. For a more universal coronavirus vaccine, a group at Walter Reed Army Institute of Research is using ferritin as its nanoparticle. Ferritin is a protein that living things make to store iron, and it seems to work well as a teeny bead on which, for instance, a specific part of the coronavirus spike protein, thought to elicit a broad immune response that could recognize other coronaviruses, is stuck. Finding which bit of the spike protein to attach to which type of ferritin, however, was hard: the research group had to try more than 200 combinations. But now they have a construct that, in combination with strong adjuvants—substances that help trigger an immune reaction as part of a vaccine—, holds a lot of potential.

Another strategy is one that has been used in the development of a pan-influenza vaccine: creating a chimera. In Greek mythology, the chimera was a hybrid monster made up of parts from different animals. Likewise, using biotechnology, scientists can create chimeric molecules. Experimental pan-influenza vaccines can be made that have the lollipop stick of the current seasonal flu, topped by the lollipop head belonging to exotic bird flus, in an attempt to get the immune system to notice the stick more and conjure up a broader, universal response. For coronaviruses, this chimeric design is being used to create hybrid molecules containing joined segments of the spike protein from many different coronaviruses.

Finally, there are mosaics. While a chimeric protein is made up of different parts stitched together, a mosaic refers to multiple proteins simply being present at the same time. A nanoparticle, instead of displaying three copies of the exact same protein, could exhibit three spike proteins from three different coronaviruses. A South Korean company called SK bioscience has developed a mosaic coronavirus vaccine that has been reported as one of the closest to being evaluated in humans. Meanwhile, Walter Reed’s vaccine mentioned above is already undergoing a small safety trial in human volunteers, the results of which should be known soon. Of course, even if this gamble pays off, boosters will not be off the table. While we hope for a broad immune protection, we do not know how long it would last.

The race is on to find variant-proof and broadly protective coronavirus vaccines. The National Institutes of Health have given 43 million dollars to four academic teams to solve this puzzle, while the Coalition for Epidemic Preparedness Innovations has invested between 135 and 200 million dollars (depending on the source) in seven smaller biotech firms.

But we humans are easily distracted. The technological hurdles to developing safe and effective universal coronavirus vaccines require time and constant money influx to overcome. Will we continue to fund these efforts? Or will we lose our focus and slide back into inaction before a new virus’ action catches us on the back foot and forces us to react?

Take-home message:
- Vaccines are being developed that could, in theory, give us protection from many coronaviruses all at once, including any future variant of the COVID-19 virus
- Different strategies are being used to design these vaccines, including using tiny molecules known as nanoparticles that can display bits and pieces that coronaviruses have in common, or different spike proteins from many coronaviruses, or even segments of spike proteins stitched together as “chimeric proteins”
- Universal vaccines against the common cold and the flu have been tried before and continue to be tested, but important challenges remain, such as finding conserved regions across all of these viruses and obtaining sustainable funding


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