How COVID-19 Vaccine Developers Sprinted a Marathon
The prospect of a COVID-19 vaccine before the end of 2020 seemed preposterous just a few months ago. Yet, here we are, getting ready to roll up our sleeves.
What are we to make of this “rushed” vaccine? Could it really be as safe as those that take years to develop?
The short answer is yes.
COVID-19 vaccines are required to clear all the same hurdles as past vaccines in order to gain regulatory approval. Their compressed timelines do not reflect less rigorous testing; they reflect the fact that COVID-19 vaccine development was an “all hands on deck” global priority.
To better understand why COVID-19 developers smashed the world record, let’s see what it takes to develop a vaccine, and how these steps were safely accelerated.
How are vaccines normally developed?
Vaccine development always begins with a grueling search for the single best potential vaccine to test in humans. This pre-clinical (lab-based) stage often lasts for years, as developers simply can’t afford to place weak bets, given the steep costs of human trials.
Once a lead vaccine candidate is chosen, additional animal experiments are conducted to further evaluate safety. These experiments, which involve giving different vaccine doses to several species (e.g rodents and non-human primates, like monkeys) can take months, and are typically conducted prior to the first human trials.
The last phase of vaccine development is human testing, which is achieved through a series of carefully designed clinical trials. The three sequential phases of human trials are progressively larger and more expensive, reaching tens to hundreds of millions of dollars. At each phase, developers must gain approval from regulators, like the FDA, before proceeding.
Here is a quick summary of what happens at each phase:
- Phase 1 trials test dozens of healthy adult volunteers to get a first look at safety in humans.
- Phase 2 trials test hundreds of adults to get a first look at whether the vaccine might work, and to gather more safety data.
- Phase 3 trials are designed to provide enough data for regulators to make an approval decision. They typically test tens of thousands of adults, and use the gold-standard trial design (randomized, double-blinded, placebo-controlled) to evaluate both the risks and the benefits of the vaccine.
- Additional trials may be conducted to test how the vaccine performs in specific populations that were not well represented in the Phase 3 pivotal trial.
The New York Times Vaccine Tracker shows where the current and future COVID-19 vaccines stand in this marathon.
Why is the story so different for COVID-19 vaccines?
The secret to speedy COVID-19 vaccines lies in five forces coming together: money, regulators, volunteers, timing, and science. Together, they helped developers clear the necessary hurdles more quickly than ever.
Vaccine developers typically move very slowly and cautiously from one development phase to the next. They do so because every step forward is like an audacious Las Vegas gamble — one that involves placing a ton of chips on a bet with low odds.
I can personally attest to this arduous bet-making process based on my experience working at Genentech / Roche, a cancer drug developer, and the insights I’ve gained from my husband’s work in biotech venture capital. Drug, vaccine, and diagnostic developers all spend a lot of time and energy discussing the “Go No-Go” gates between each phase of development.
Thanks to deep pockets, vaccine developers have been able to move much more quickly. Rather than waiting to see whether or not a given phase works out before shelling out for the next phase, they are running phases back-to-back, and even overlapping them when possible.
For example, Pfizer-BioNTech and Moderna were given permission to conduct their animal experiments at the same time as their human trials, rather than before Phase 1 trials, as is normally the case. Similarly, vaccine developers have already spent a lot of resources manufacturing millions of doses, rather than waiting for clinical trial data results, as is normally the case. Together, parallel processing, and “at risk” investments are saving months to years of time.
When a vaccine developer wants to launch a human clinical trial, it needs a green light from regulatory bodies (like the FDA). Often, getting this green light involves a lot of of back-and-forth including requests for more data and tweaks to the study design. These exchanges between developers and regulators can add many months to timelines, simply because regulators don’t have the bandwidth to provide timely input to every product being tested.
Due to the urgency of the COVID-19 situation, regulatory agencies are making a point of not slowing things down; rather, they are working with developers to rapidly provide the input needed to move swiftly (yet safely!) from one testing phase to the next. Similarly, regulators are giving top priority to reviewing the extensive data packages that are being generated by each trial.
Trial duration is heavily influenced by how quickly volunteers can be recruited. With COVID-19 vaccines, recruitment has been “phenomenal”, according to one clinical trial operator. Thousands of motivated volunteers have eagerly stepped forward to roll up their sleeves in the name of public (and personal) health.
It is worth noting that Phase 1 volunteers for COVID-19 vaccine trials were particularly heroic. By enrolling in human trials before the usual suite of animal studies were completed, they took on more risk than most Phase 1 volunteers.
Vaccine trials must pre-specify how many “events” (confirmed COVID-19 cases) they will collect before trial data are analyzed and submitted for regulatory review. For example, current regulatory submissions for Pfizer’s Phase 3 trial will be based on the first 170 confirmed cases of COVID-19 (of which 162 were in the group that received a mock vaccine). Clinical trial plans may also specify an event target for a sneak preview (interim analysis), such as Moderna’s interim analysis after 95 COVID-19 cases were confirmed (of which 90 were in the placebo group).
The more common the condition, the faster the results come in, and the sooner the data are unblinded to reveal how well the vaccine is working. Thus, soaring rates of COVID-19 rates around the world over past few months have allowed clinical trials to complete much more quickly than they would have had the virus been suppressed. Indeed, for a rare illness, it can take years to gather enough cases to trigger data analysis.
It’s no surprise that the first two vaccines to emerge are both based on mRNA or messenger RNA. This novel approach to vaccines, which provides the genetic instructions for a small piece of virus, is both rapid and flexible. All you need is the sequence of the viral genome (now feasible in a single day!) and you can generate a candidate vaccine in weeks. According to Moderna’s timeline, the first clinical batch of mRNA-1273 (their vaccine candidate) was completed only 25 days after the target sequence was selected. By contrast, traditional vaccines, which are based either on live or killed viruses, or tiny fragments of virus, can be challenging to produce and optimize.
To be clear, while the Pfizer and Moderna mRNA vaccines are the first to receive approval, this approach is not unprecedented. As described by the US Centers for Disease Control, first generation mRNA vaccines were piloted in early stage clinical trials for influenza, Zika, rabies, and cytomegalovirus (CMV). The latest mRNA vaccines leverage advances in RNA biology and chemistry to provide better stability, safety, and effectiveness.
So… are the first COVID-19 vaccines safe?
So far, the safety profile of the first COVID-19 vaccines look very promising, with no greater risk of dangerous severe events in those who received the vaccine, but plenty of mild to moderate temporary symptoms (see Pfizer and Moderna reports).
It’s important to note that our knowledge of any freshly minted vaccine is good, but not perfect. By the end of Phase 3, a vaccine has been tested in fifteen to twenty thousand relatively healthy adults. These trials give us a good sense of the most common events in this population, but have limitations, as well.
For any freshly minted vaccine, the biggest knowledge gaps include an understanding of extremely rare events, risks that are specific to populations not well represented in the Phase 3 trials, and significantly delayed reactions. To address these gaps, it will take more time, more patients, and more trials.
The recent warning by UK regulators to hold off on using the recently approved Pfizer-BioNTech vaccine in people with severe allergic reactions is a perfect example of learning as we go about rare events.
The Bottom Line
There is no reason to be extra leery of COVID-19 vaccines simply because they were developed quickly. Their remarkable development speed is a testament to what we can accomplish when money, regulators, volunteers, timing, and science come together. These forces are acting like a jet pack propelling an ultra-marathoner to smash the world record.
In fact, the exceptionally short timelines for COVID-19 vaccine development highlight the inefficient nature of “normal” vaccine development, and give us hope that future vaccines will follow suit more quickly. As described in this insightful article in the Conversation, ten years to develop a vaccine is not a good thing!
We have no less information on the safety of COVID-19 vaccines than we did on the dozens of other approved vaccines at this same stage in development (see the FDA’s list of approved vaccines). The results have been very promising, but come with important caveats — they can’t capture rare events, risks unique to specific populations, or events that crop up far down down the road.
In medicine, every decision must balance the risks and benefits, often doing so with incomplete information. COVID-19 vaccines are no exception. The safety data to date are very encouraging, but incomplete, especially for rare events and specific sub-populations. At the same time, we can say with confidence that immunity to COVID-19 can save lives and help us return to normalcy.
My two cents? Now that Health Canada has approved the first of the COVID-19 vaccines (by Pfizer-BioNTech), I will be lining up to roll up my sleeve, and encouraging my parents to follow suit, as soon as they are available*.
*The risks of a COVID-19 vaccine, and any vaccine, varies depending on pre-existing conditions. Consult with your physician to determine whether or not you are in a high-risk bracket.
Disclosure: I have no conflicts of interest to declare. While I have worked for Roche in the past, I am not currently affiliated with any biotech companies. My husband invests in biotech companies (novel drugs) through Versant Ventures but does not have a direct link to COVID-19 vaccines. Neither of us stand to gain financially from the success of COVID-19 vaccines.
I’m a scientist and mother of three children, living in Vancouver, Canada. I completed my PhD in genetics at Stanford and spent the first decade of my career working in cancer research, drug development, and personalized medicine.
My new career chapter is dedicated to empowering others to make well-informed healthy choices, rooted in facts not fears. I’m also passionate about helping people to fall in love with the plants on their plates.
See more of my work, including articles, videos, podcasts, and healthy recipes at: https://FueledbyScience.com