The first COVID-19 vaccine approved for emergency use by the FDA isn't just a vaccine created in record time to combat the biggest pandemic in recent history. It's also a technological breakthrough that could change how we produce and deliver vaccines in the future.
The new vaccine, developed by biotech giant Pfizer and German startup BioNTech, uses messenger RNA, or mRNA, to stimulate the immune system into protecting against infection from the coronavirus. An extensive clinical trial with over 43,000 participants has shown Pfizer's vaccine to be safe and 95% effective against COVID-19. It heralds the beginning of the end for a pandemic that has killed over 1.6 million people across the world
However, it's the first mRNA vaccine ever to be used in humans, and it will be rolled out on a scale never seen before.
"This is a whole new world," says Nikolai Petrovsky, a professor at Flinders University and head of Vaxine, an Australian biotech startup developing its own coronavirus vaccine.
The uniqueness of the vaccine and the speed at which it has been developed has some questioning the safety and rigor of studies. Is the vaccine safe and effective?
Yes, medical experts say. But there are a few caveats. For instance, there isn't enough data for high-risk groups, such as people who are pregnant, are under 16 or have compromised immune systems. Questions also remain about how long immunity will last and whether the vaccine prevents infection or only stops people from developing symptoms.
As the Pfizer vaccine begins to roll out across the US, it's reasonable to feel concerned about elements of the vaccine's development and approval, especially as vaccine myths and misinformation generate fearful and false narratives. But there is good reason to trust in the vaccine's safety and efficacy, even as long-term data continues to be gathered.
Need for speed
It seemed almost impossible we'd have a vaccine within a year of discovering the coronavirus, but we do. In the US, vaccinations have already begun in high-priority groups such as health care workers and government officials. But that accelerated schedule doesn't mean scientists skimped on safety.
All vaccines must go through an extensive evaluation process that begins in the laboratory. The Pfizer vaccine is no exception.
Scientists conduct tests on cells and in animal models before they move onto humans. In non-pandemic times, this process can take a few months to a few years. If a particular vaccine shows promise in these preclinical studies, it moves to clinical trials in humans, which occur in three different phases. Each phase sees more participants and more data, assessing the safety and effectiveness of the new therapeutic.
Movement from one phase to the next usually occurs over a matter of years and finally, companies submit their vaccine for approval to regulatory bodies with all the data they've collected for evaluation.
During the pandemic, this timeline was condensed. It had to be. Evaluation is being performed simultaneously with each phase of the trial and regulatory bodies are getting information on safety in real-time. "They still need to see all completed data before they make the decisions," says Catherine Bennett, chair in epidemiology at Deakin University, Australia, "but they're hitting the ground running." Trials could also enroll more people in a shorter time span than usual, allowing the vaccine to be validated, produced and rolled out much faster than ever before.
The FDA's emergency use authorization is based on assessing all of the clinical trial data to date and weighing risks versus benefits. There are no shortcuts. "The vaccine's known and potential benefits clearly outweigh its known and potential risks," said Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, in a statement.
With a handful of nations, including the UK and Canada, now vaccinating the public en masse, safety evaluations continue. Each vaccine that receives authorization needs to be constantly monitored. "With any new vaccine, there is the possibility that rare side effects will be detected post-licensure, because clinical trials may not be large enough to detect rare side effects," says Raina MacIntyre, professor of Global Biosecurity at the University of New South Wales' Kirby Institute.
The US FDA follows serious side effects with a surveillance program known as the Vaccine Adverse Event Reporting System, she notes. No serious side effects have been seen in Pfizer's trial so far, though some participants have experienced pain at the injection site, fatigue and headaches, which MacIntyre says are all transient.
But concerns about speed or rushing the vaccine through evaluation are overblown, says Bennett. "We're not actually shortcutting anything except for the bureaucratic or administrative time."
Another element in speeding up vaccine development is the new technology used by Pfizer, which was built upon a strong foundation of research that stretches back three decades.
Delivering messenger RNA, or mRNA, in a vaccine is a clever sleight of hand.
Cells are tiny protein-making factories. They build proteins based on instructions -- the mRNA. Pfizer's vaccine slips a set of instructions into the cell telling it to build a coronavirus protein, which the immune system recognizes as dangerous. It's not infectious and it can't cause COVID-19, but it allows the immune system to mount a response.
Once these mRNA instructions are read, they're destroyed. Like the self-destructing messages delivered in Mission: Impossible.
"mRNA has quite a short survival time in cells, since its job is done once the protein is made," says Trevor Drew, director of CSIRO's Australian Centre for Disease Preparedness.
The novel vaccine strategy feels like it appeared almost out of thin air, but using mRNA as a therapeutic has a long history. As early as 1990, mRNA was used in mice and shown to kickstart protein production. mRNA's transient nature is one of the reasons it's considered to be safe and tolerable. This limited the capacity for it to be used as a therapeutic 30 years ago, but in the last decade a handful of biotech innovations have stabilized mRNA and allowed it to be delivered more successfully.
Numerous studies have evaluated the mRNA vaccine platform against different diseases. In 2012, a study in Nature Biotechnology showed mRNA could elicit a strong immune response against influenza in mice. In 2017, another mice study showed mRNA prevented infection from the Zika virus. Another study, published in the Journal of Experimental Medicine in 2018, showed mRNA vaccines elicited strong immune responses in mice and rhesus macaques against different viral proteins.
Cancer patients have received injections of mRNA in the past, too. It's not quite the same as a vaccine, but we have been able to evaluate its effects on the body. "We do know quite a lot about this molecule," notes Drew.
When the pandemic hit, the mRNA vaccine from Pfizer (and another, from Moderna) already had this research to build from. They could plug in the mRNA instructions and begin testing immediately. This is one of the key benefits of mRNA vaccines -- they are plug-and-play. If you have a gene sequence, you can plug it in and assess its safety and effectiveness on much more rapid timescales. It's no coincidence these are the first types of vaccines to receive emergency authorization.
Dealing with genes can often raise questions about playing God or unintentional mutations. There has been some commentary that the mRNA vaccines can alter your genetic code, but this is simply not true.
"mRNA does not enter the nucleus and cannot integrate with our DNA," says Drew.
Could there be effects decades down the track we haven't predicted? Potentially, but the transient nature of mRNA makes it one of the safer molecules we can use to combat disease.
Perhaps the most pervasive concern is around the lack of long-term data. Pfizer's study, published in the New England Journal of Medicine, shows no serious side effects in participants after two months. The trial will continue to look for effects for at least two years.
"We will have more long-term safety information as we go on," says Magdalena Plebanski, professor of immunology at RMIT University in Melbourne, Australia. "But can the world wait those two years for the vaccine?"
With coronavirus cases approaching 73 million since the start of the pandemic and deaths topping 1.6 million, waiting isn't an option. The FDA has studied the results of the Pfizer trials intensely, as have other national health bodies, such as Health Canada and the UK's Medicines and Healthcare products Regulatory Agency. Generally, adverse events occur shortly after receiving a vaccine, on the scale of days to weeks, rather than years. As more and more people are vaccinated across the globe, very few adverse events have been reported.
Still, long-term data will be critical for assessing how long immunity lasts and understanding whether the vaccine prevents the virus from infecting individuals entirely or only prevents serious illness. It's an important distinction, because the latter group may still be infectious and could hamper rollout efforts. These questions will be answered in the coming months.
Researchers haven't had enough time to study long-term effects, but we do have a solid grasp on human physiology and how the vaccine interacts with the immune system at different doses. In addition, the stringent monitoring protocols should reassure the public and help allay any hesitancy. As the vaccine has rolled out this week, three patients have experienced allergic reactions, including one Alaskan health care worker. Two British people, with a history of allergies, made a full recovery. The CDC's Advisory Committee on Immunization Practices suggests monitoring for these reactions after receiving the vaccine for 15 to 30 minutes.
Ultimately, the decision to approve Pfizer's vaccine comes back to balancing the known and unknown aspects of getting the COVID jab. Is the risk of developing an unforeseen adverse reaction lower than the risk of contracting the coronavirus, getting ill and dying? National health bodies and experts believe so.
We know vaccines can't put an immediate stop to the pandemic. Social distancing and mask-wearing are going to be required for many months. But as more people become vaccinated, we can dramatically slow its spread, preventing large outbreaks before they get out of hand. It takes all of us, though. The risks and benefits aren't just personal, they're communitywide.
Slowing down the pandemic means trusting that the science behind the Pfizer vaccine -- and any other that might be approved -- is sound. Yes, there will be limitations, but these aren't drugs being rushed to market. Their safety evaluations aren't slip-shod. The new technologies aren't unsafe. And they'll continue to be monitored more closely than any therapeutic in the history of humanity.
"I am not worried," says Plebanski, "because the world's attention is on these vaccines and their development."
Updated Dec. 16: Adds ACIP monitoring note