For some insight, I reached out to two American scientists on the front lines of creating a COVID-19 vaccine. Darryl Falzarano, Ph.D., of the Vaccine and Infectious Disease Organization–International Vaccine Centre at the University of Saskatchewan, has spent several years working on vaccines for another human coronavirus, MERS-CoV, which causes Middle East Respiratory Syndrome.
Maria Elena Bottazzi, Ph.D., associate dean of the National School of Tropical Medicine at Baylor College of Medicine, has worked on a variety of vaccines targeted primarily at neglected tropical diseases, meaning infections that are under-studied because they affect the world’s poorest and most vulnerable populations. Since 2011 her group has been working on possible coronavirus vaccines, including vaccines for MERS-CoV and SARS-CoV (the virus behind the 2003 SARS outbreak). Here’s what they have to say about the road to a new coronavirus vaccine.
As we watch diagnoses of the new coronavirus disease increase globally and we hunker down to minimise transmission, the world holds out hope for a new coronavirus vaccine. There’s some excitement in the air now that research groups around the world are racing to find a viable vaccine, and clinical trials on humans are already beginning for the first potential new coronavirus vaccine. But what are the odds we’ll have a new coronavirus vaccine anytime soon so we can slow or even stop this pandemic? Will it really take 12 to 18 months, like we keep hearing?
How close are we to a new coronavirus vaccine?
Falzarano puts it simply: “We don’t have one,” he tells us. In fact, he explains, “there are no approved coronavirus vaccines that are used in humans.” This means that not only do we lack a vaccine for the new coronavirus, but also that none were previously approved for MERS-CoV or SARS-CoV either. (Though both of these coronaviruses have caused major outbreaks, neither was as explosive as the COVID-19 pandemic.)
That might be hard to believe, given how many experts have devoted countless hours to trying to develop these vaccines. But infectious diseases are wily beasts, and the process of creating vaccines can be lengthy and challenging even under the best of circumstances. Bottazzi sums it up well: “Vaccines are not easy to develop,” she tells SELF.
The current state of new coronavirus vaccine development definitely bears that out. There are reportedly at least 26 different potential new coronavirus vaccines somewhere in the development pipeline. Most are still in the very early stages, currently testing on animals and hoping to move to human testing in the next few months. So far the only new coronavirus vaccine testing on humans is happening in Seattle at the Kaiser Permanente Washington Health Research Institute, and the researchers behind the vaccine reportedly started testing on animals and humans on the same day instead of following the usual protocol of trying it with animals first – a move that has some ethicists up in arms – putting it ahead of the rest of the pack.
What’s the process of developing a new coronavirus vaccine?
The first choice involved when it comes to making any new vaccine is deciding on an antigen. This is the piece of the disease-causing pathogen that will be included in the vaccine to kickstart an immune response and fend off infection. The antigen should be something that your immune system will recognize when you encounter that pathogen in the wild (not just in a vaccine) and something that will easily stimulate the necessary response.
A key potential new coronavirus vaccine Bottazzi’s research group is working on is derived from the new coronavirus’s spike protein. (The group is actually building upon previous work they did on a vaccine for SARS-CoV, Bottazzi explains.) The spike protein is on the outside of the virus and gives the pathogen its name; the proteins look like the spikes of a crown. “These spike proteins are what the virus utilizes to bind to a human cell receptor,” Bottazzi says. The spike protein binding allows the virus to enter the cell and replicate. If you block spike proteins from binding to receptors, you can stop the virus from attaching in the first place and prevent the infection.
“Most of the [new coronavirus] vaccines that are being developed focus on trying to block this [protein],” Bottazzi says. Falzarano agrees. “We are pretty sure that we need to use the spike protein as the vaccine antigen,” he says.
Researchers also have to figure out how much of the antigen they can use to produce the right level of an immune response. Too little of the antigen might not stoke the immune system enough, whereas too much of it might create such an intense immune reaction that it inadvertently causes damage to the animal or person being tested. It’s a fine line. What Bottazzi’s group has done is focus on a piece of the spike protein called the receptor-binding domain, breaking it down into smaller and smaller pieces “until we found the minimal amount that we needed to…induce a very robust immune response but without that immune enhancement [that harmed the host],” she explains.
Once researchers have decided on an antigen to use and how much of it, they then have to determine how to produce the antigen so they can include it in vaccines, says Falzarano. “There are lots of different ways to do this,” he explains, including producing the antigen in bacteria, yeast, insect cells, mammalian cells, and even plant cells. Many vaccines that are not only proven to be safe and effective but also relatively cheap to mass-produce are made using proteins that organisms like bacteria and yeast synthetically produce, Bottazzi says. This is how other vaccines on the market, including the hepatitis B vaccine, protect against various infectious diseases. “Therefore we favor vaccines that use the same systems to be produced as other proven vaccines already in the market,” she says.
After that, researchers need to decide on the best way to deliver the antigen to the host, which will first be animals, then humans. There are lots of ways to do this, including as live attenuated vaccines (which contain weakened yet technically living antigens) and as inactivated vaccines (which contain dead antigens), says Falzarano.
There are pros and cons to every delivery method. For example, live attenuated vaccines often lead to longer-lasting immunity but can be tougher to transport and administer than other forms; inactivated vaccines are often safer but don’t usually produce as robust an immune response.
“We know various ways that we can deliver [the spike protein] antigen,” Falzarano says. “But we don’t really know the best way to do so.”
The first new coronavirus vaccine currently undergoing human clinical trials uses novel antigen delivery technology that has never resulted in a licensed vaccine. That technology involves mRNA (messenger RNA), molecules that carry DNA codes that the body uses to make various proteins. (Neither expert I spoke with for this piece is involved in developing this vaccine.)
Once researchers decide on the antigen delivery method, they can start testing on animals to see if the vaccine creates the immune response they’re looking for. Do the animals make antibodies that can fight off the virus? Do the antibodies stop the virus from infecting cells? (If so, these are called neutralizing antibodies.) After some observation, they can give the vaccinated animals the virus (“challenge” them with it, in science parlance) to see if the vaccine actually protects them against infection, or at least makes it less serious or deadly, Falzarano explains.
“Usually you would demonstrate that your vaccine works in two different animal models,” Falzarano says. “Safety testing is also performed in animals prior to proceeding into human clinical trials.” This safety testing can flag minor, expected effects of a vaccine, like fever and fatigue, but it also shows if animals are experiencing more serious problems, including autoimmune issues or organ damage.
Years ago, when Bottazzi tested her group’s SARS vaccine in animal models, they found that it protected the animals from illness and death compared to those who had not received the vaccine and did so without the potential harm that can come from using the whole spike protein, she says. But interest in SARS waned, and they weren’t able to secure additional funding for the final animal tests that would have been necessary to begin tests in humans. Bottazzi is hoping the pressing need for a SARS-CoV-2 vaccine will help her research group get the necessary funding to complete animal studies so they can eventually begin human clinical trials.
How will researchers test the new coronavirus vaccine?
Typically, once we have a vaccine that seems to work well in animal models, then we move to human trials. These consist of several different phases to test for safety and find out how well the vaccine really works.
Phase I vaccine trials, which are currently ongoing with the first potential new coronavirus vaccine to reach this stage, primarily address safety, Falzarano says. This phase typically happens in a small number of people, usually between 20 and 100, according to the Centers for Disease Control and Prevention (CDC). In addition to looking at safety, this stage is evaluating how well the vaccine appears to work, if any major side effects emerge, and how the dosage might influence those side effects, the CDC says.
The first possible new coronavirus vaccine to get to this point – the one currently in clinical trials – is reportedly in the process of enrolling 45 healthy adults between the ages of 18 and 55 years over the course of around six weeks, according to the National Institutes of Health. The plan is to split the volunteers into groups that will receive different doses of the vaccine. The researchers will give participants two doses of the vaccine around 28 days apart, both via injections in their upper arms. The volunteers will need to have follow-up check-ins for a year after receiving the second injection, the NIH says, in addition to providing information about their symptoms and doing blood tests at different points to measure their immune responses.
Generally, if a the vaccine appears to be safe after Phase I testing, it moves into Phase II. But given how quickly we need a new coronavirus vaccine, things might happen a bit differently. While the testing phases usually happen one after the other and only after each is complete, it’s likely that researchers will use short-term new coronavirus vaccine safety data to decide if it’s okay to move into the next phase (but still monitor volunteers from previous phases to see if anything pops up). In any case, Phase II testing usually happens in hundreds of people, Falzarano says. As the CDC notes, this expansion is meant to include people in the same demographics as the ones the vaccine will eventually protect when it’s on the market. This phase also addresses immunity in addition to safety, Falzarano explains: “Does the vaccine do what it is expected to do, and how well?”
Phase III then tests efficacy and safety in a much larger group of people, often thousands. “The primary goal is to determine if being vaccinated leads to protection – either immunity from infection or less severe disease,” Falzarano explains. To do this, researchers are often comparing how people who do and don’t get the vaccine fare after potentially being exposed to the pathogen. Having a larger number of participants means researchers may also pick up on side effects from the vaccine that are too rare to be captured in smaller studies.
After all of this testing has shown a vaccine to be both effective and safe, the pharmaceutical company sponsoring the vaccine needs to go through an approval process with the FDA before the vaccine can actually hit the market. This involves various steps, like submitting a Biologics License Application to the FDA, presenting information to the FDA’s Vaccines and Related Biological Products Advisory Committee, and preapproval inspections of the manufacturing facility that would produce the vaccine.
Even after a vaccine is approved, studies typically continue to look into its safety and effectiveness. These are Phase IV, or “post-licensure,” studies.
Falzarano cautions that this entire process takes time and money, as you can imagine, and the timeline is often approximately a decade. The good news is that various parts of this whole process can be expedited, as is clearly happening for the new coronavirus vaccine. In addition to moving into new testing phases based on short-term safety data instead of long-term safety data, there are also various accelerated licensing approval systems the FDA can use when we desperately need a drug or vaccine without time to spare.
Will this really all take at least a year?
This brings us back to the oft-repeated “12 to 18 months” estimate for a new coronavirus vaccine to be available. I wish I could say I think it’s realistic, but many infectious disease experts (including me) are a bit on edge with the 12-to-18-month estimates.
As this article in The Atlantic notes, many experts think it would take 12 to 18 months to develop and test a safe and effective vaccine. This doesn’t mean that the vaccine will actually be produced and available to the public in that time frame. That process could take additional months, unfortunately. This limitation is addressed in a recent Perspective review by virologists Fatima Amanat, M.A., and Florian Krammer, Ph.D., who remind us that it will take weeks just to vaccinate a large proportion of the population, people may need more than one dose of the vaccine, and demand for the vaccine will likely far outstrip availability at first if we need to wait for new vaccine production facilities.
Beyond that, even though the mRNA new coronavirus vaccine is the first one to have reached human clinical trials, the fact that this type of vaccine technology has never been used before may make it difficult to obtain approval and also make it hard for other countries – particularly those that are low-income – to adopt the vaccine even if it works well.
Twelve to 18 months may be the inspiration, but it’s unclear that it’s realistic. That doesn’t mean experts aren’t doing their absolute best to have a new coronavirus vaccine ready to go in that time frame. It doesn’t even mean we won’t have a vaccine at that time. It just means that there’s simply too much up in the air right now to make that promise. Until we do have a vaccine, proper hand hygiene, social distancing, quarantining if you’ve been exposed, and isolating if you’re sick remain the best way to keep the virus at bay for all of us.