Why a “Rushed” COVID-19 Vaccine Does Not Mean a Riskier One
Tags: Public Health, Pandemic, Covid 19, Covid 19 Crisis, Vaccines

Why a “Rushed” COVID-19 Vaccine Does Not Mean a Riskier One

The first vaccines against COVID-19 have arrived, and are being greeted with a mix of enthusiasm and skepticism. In some ways, it seems too good to be true. Can a “rushed” vaccine be as safe and effective as those that take years to develop?

The short answer is yes.

COVID-19 vaccines have cleared all of the same hurdles as past vaccines. Their compressed timelines do not reflect less rigorous testing; they reflect a running start, rapid trials, and much shorter (or no) gaps between development phases.

How did COVID-19 vaccine developers pull this off? With a lot of help.

To understand how COVID-19 broke vaccine development records, let’s see what it takes to develop a vaccine, and why COVID-19 is a special case.

How are vaccines normally developed?

Vaccine development begins with a search for the single best potential vaccine to test in humans — one that is both safe and effective. During this pre-clinical stage, scientists generate, tweak, and compare vaccine candidates using in vitro (cells in a dish) and in vivo (animal) experiments. This stage often lasts for years, as developers do everything possible to “de-risk” the steep investment needed to test in humans.

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.

The New York Times Vaccine Tracker shows how many COVID-19 vaccines have reached each phase of clinical trials.

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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.

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.

1. Money

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.

2. Regulators

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.

3. Volunteers

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.

4. Timing

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.

5. Science

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.

Indeed, our collective war on COVID-19 has benefited greatly from recent scientific advances, as well as from remarkable global co-operation, including shared resources and information.