By Brandi Greenberg, Vice President, Life Sciences and Ecosystem Research
Let's do this one more time.
Back in September, when the first coronavirus vaccine trials were still underway, I wrote an article called "A vaccine approval is coming. Get ready to ask these 8 questions." My goal was to pre-commit myself to a framework for evaluating FDA's decisions, to ensure that—when the time came—I could objectively consider whether a vaccine had truly been proven safe and effective.
Last week, I finally got the chance to reprise that piece, applying my eight questions to the recently authorized, and apparently very effective, vaccine from Pfizer and BioNTech.
Now it's time to turn our attention to Moderna's vaccine, which FDA is expected to authorize today for emergency use. Spoiler alert: My answers are similar to what I found for Pfizer's vaccine—but with a few notable wrinkles.
My 8 biggest questions, answered
Before we dive in, a disclaimer: I am not a clinician and don't have a medical background. But I've spent the last 20 years researching the health care industry with a particular focus on pharmaceutical companies—so I think I have a good grasp of the key issues at play.
1) Did the vaccine follow the traditional approval pathway, rather than being approved under an emergency use authorization (EUA) or other nontraditional path?
Technically not. FDA is expected to authorize the Moderna vaccine under an EUA based on two months of safety data. According to Dorian Fink of FDA's clinical division of vaccines and related products applications, drugmakers must collect six months' of safety data to apply for full approval.
But as I said with Pfizer's vaccine (which similarly was authorized under an EUA), I don't consider this a major concern. FDA is making a reasonable choice to await more data before issuing a final approval, and in the meantime, the EUA process has advanced at a speedy but deliberate pace.
2) Was clinical trial data on the vaccine released to the public?
Mostly yes. As with the Pfizer vaccine, FDA has published a lengthy staff report providing plenty of details about the clinical trial—54 pages of details, in fact.
According to FDA, Moderna conducted a double-blinded, placebo-controlled study of about 30,400 participants—half of whom received the vaccine, and half of whom received a placebo. Each participant received two doses, administered 28 days apart.
By comparing how many people in the vaccine and placebo groups later developed Covid-19, researchers determined that the vaccine was 94.5% effective. Side effects were generally mild-to-moderate and included pain at the injection site, fatigue, headache, and muscle pain.
This is all very good news.
3) Does the available study data clearly show that the vaccine offers meaningful, measurable protection from Covid-19 – such as fewer people getting sick, fewer people getting severely ill from Covid-19, or fewer people transmitting the virus after exposure?
In terms of preventing illness, yes. Of the 95 trial participants who developed Covid-19, only five had received the vaccine. That's overwhelming evidence the vaccine works.
When it comes to preventing severe illness, the data is encouraging but less decisive. According to FDA, 11 trial participants developed severe Covid-19—and all 11 had received the placebo. That's not enough data to draw firm conclusions, but it's a welcome sign.
My question also referenced a third, perhaps less intuitive measure of a vaccine's effectiveness: whether it prevents the spread of the coronavirus to others.
This might seem like a strange issue to raise—after all, if a vaccine stops you from getting sick, doesn't it also stop you from making others sick? Not necessarily! Some vaccines prevent you from developing a disease yourself without reducing the odds that, if you're exposed to the disease-causing virus, you'll pass it along to others.
Needless to say, while a vaccine that stops you from getting sick is great, one that also prevents you from infecting others is even better. So, can Moderna's vaccine pull off that trick?
Well, the data is fuzzy but promising.
To understand why, it's important first to know how the coronavirus commonly spreads. When the virus infects a new victim, it makes itself at home in their nose and throat, where it multiplies in enormous numbers. Then, when that person exhales, sneezes, or coughs, the coronavirus catches a ride into the outside world, where it can infect someone else.
So, to oversimplify: If you've got a lot of coronavirus in your nose, you're probably infectious—even if you aren't suffering any symptoms of Covid-19. But if there's no coronavirus in your nose, you probably won't infect others.
As it happens, Moderna took nasal swabs of its trial participants when they received their second vaccine dose—by which point they may already have gained some coronavirus protection from their first dose. It found that 52 asymptomatic patients had the coronavirus in their nasal passages: 38 patients in the placebo group, compared to just 14 patients in the vaccine group.
So… what should we make of all this?
It certainly suggests the Moderna vaccine can reduce (but not eliminate) the risk that, if you're exposed to the coronavirus, it will multiply enough inside your body to spread to others. As Eric Topol of Scripps Research said on Twitter, the data isn't "conclusive," but it's "very encouraging."
FDA, for its part, essentially punted on whether Moderna's vaccine prevents transmission, saying only that "[a]dditional evaluations … will be needed to assess the effect of the vaccine in preventing virus shedding and transmission."
4) Did the vaccine clear the 50% threshold for effectiveness that FDA previously announced as its approval requirement?
Yes. Moderna's vaccine, like Pfizer's, cleared this threshold by a huge margin.
5) Did the vaccine meet that effectiveness threshold for members of all major U.S. demographic groups (by age, gender, race, etc.)?
Yes. FDA's staff report broke down the trial data by age, gender, race, ethnicity, and more, and it found that vaccine efficacy rates "among the subgroups are similar to the [vaccine efficacy] seen in the overall study population."
To translate that into plain English: The vaccine seems to be similarly effective for everyone studied.
Still, the same caveats apply that I mentioned with the Pfizer vaccine. First, the study enrolled only limited numbers of people from certain minority groups, making it impossible to draw statistically significant conclusions. Second, the vaccine was not tested in children under the age of 18 or pregnant women.
I'll repeat here what I said about the Pfizer vaccine: "In a perfect world, would we have better data for every subgroup of the U.S. population? Of course. But based on what we know, this vaccine works well across a wide range of populations."
6) Is there a robust plan to follow up with participants to determine how long protection will last? Do early signs indicate that immunity will be durable over time?
Yes. So far, there's no sign that immunity is fading, but because some patients received their last injection only a few months ago, it's too soon to say for sure.
According to the FDA staff report, Moderna will continue to follow up on its current clinical trials, and it also will launch three new studies—including one monitoring pregnant women. And let's bear in mind that FDA is expected to issue only an emergency authorization for the vaccine, not a full approval, and it intends to continue monitoring safety and efficacy data over time.
7) Does trial data clearly show that the vaccine's benefits outweigh any safety concerns? Is there a plan to monitor safety once the vaccine is given to a much broader group of people?
Yes. The vaccine protects against a potentially fatal illness, and its only proven side effects are short-term and mild: fatigue, headache, and the like.
Moderna's trial also monitored for the possibility that the vaccine might cause more serious side effects. It didn't find anything terribly alarming—but it did uncover three cases of Bell's palsy, a type of facial paralysis, in the vaccine group, compared to only one case in the placebo group.
These numbers are very small, and FDA views them as "insufficient to determine a causal relationship with the vaccine." But it's worth noting that Pfizer's vaccine trial also found a disproportionate rate of Bell's palsy in vaccine recipients: four cases, compared to zero among placebo recipients.
I don't think this is something we should panic about. The numbers are so small they could be a statistical fluke, and Bell's palsy is non-fatal and generally very treatable. But it's worth keeping an eye on as the vaccine rolls out more widely.
If you're worried about the small risk of serious side effects that weren't uncovered during the clinical trial, I'd encourage you to read my last piece on Pfizer's vaccine, where I went into more depth on this possibility.
Here's the shortest version. In considering any medical treatment, we have to weigh benefits and risks. With this vaccine, the benefits are exceedingly clear: a 94.5% reduction in your odds of contracting a disease that already has killed 300,000 people in the United States. The risks, meanwhile, have already been proven to be low, and we'll gain an even better understanding of any side effects as Moderna and FDA monitor the vaccine's rollout.
Are the risks zero? No. But are they low enough to be clearly outweighed the vaccine's benefits? According to this study, absolutely yes.
8) Have any participants in the approval process criticized the decision or the process itself? Have outside public health experts, especially those who previously served as senior-level officials at CDC, NIH, or FDA, criticized the approval?
No. So far, health care leaders across the government appear united in supporting the Moderna authorization.
I will, however, raise one small flag—and I raise it with hesitation, as I don't want it to be misinterpreted. Part of the reason I posed this question in September was to surface any hint of political pressure in a vaccine's development.
So, it's worth noting Moderna received significant government assistance in developing its vaccine from the Biomedical Advanced Research and Development Authority, or BARDA. (This is separate from the pre-purchase agreements that vaccine manufacturers have struck with governments around the world.) As such, Moderna could theoretically be more subject to political pressures than manufacturers who didn't accept assistance.
Am I worried about this? Not really. BARDA funds important R&D all the time, generally without much controversy—and Moderna's vaccine has proven very effective in clinical trials. Unless news reports surface suggesting inappropriate political pressure, I don't think this is something patients should fret about.
A few more Moderna-specific wrinkles (and the answer to my 9th question)
There are a few more facts about Moderna and its vaccine that are worth considering—one a potential negative, and the other a potential positive.
First, the potential negative: This vaccine is Moderna's first-ever commercialized product of any kind. To be clear, that isn't a reason to doubt the vaccine's efficacy; Moderna ran a large-scale study that followed standard practices and was intensively scrutinized by the FDA. But I'll be paying close attention to how Moderna handles manufacturing, distributing, and monitoring, as well as how it approaches patient and provider education.
On the other hand, the potential positive: Moderna's vaccine has relatively straightforward storage requirements. While Pfizer's vaccine must be stored at -70 degrees Celsius—a temperature that is exceptionally challenging to maintain throughout transportation and delivery—Moderna's vaccine requires only more "normal" cold-chain conditions of -20 degrees Celsius. As such, Moderna's vaccine may be a better option for rural or harder-to-access communities.
That brings us to our bonus ninth question, which I didn't include in my September write-up but realized, while writing about Pfizer's vaccine, might be the most important one of all: "Would I take the Moderna vaccine myself?"
The answer is yes—without hesitation. I'd take the Pfizer vaccine, and I'd take the Moderna vaccine. I'll take whichever one can be injected to my arm first.