American Scientist

Michael Mina is an epidemiologist at the Harvard T. H. Chan School of Public Health and the director of molecular diagnostics at Brigham and Women’s Hospital at Harvard Medical School. He started the Broad Institute’s COVID-­19 testing program, which spearheaded automated PCR tests—the most commonly used tests for diagnosing the viral infection so far during the pandemic. PCR tests (PCR is short for polymerase chain reaction) for SARS-CoV-2 use a process that copies viral genetic material to make small amounts more detectable. Mina has been a leading voice advocating for the implementation of new testing strategies focused on screening, meaning identifying infectious individuals before they spread the virus, and of more widespread use of rapid antigen tests, which detect proteins that make up the virus, such as receptor proteins or components of the viral envelope. Mina spoke to digital features editor Katie L. Burke in January. 

This is an extended online version of the article that appears in the March–April 2021 print and digital editions.

How have past outbreaks affected the approach to the COVID-19 pandemic? 

This virus has forced a reimagination of how testing can be used. As we’ve been developing vaccines, our past experiences led to an immense effort to use PCR-based testing and contact tracing with surveillance testing as our primary approach toward controlling this virus.

Back in January and February [2020], every public health person pretty much was on board with saying that contact tracing is good when there’s not a lot of cases. Now, contact tracing is just sapping resources.

Staying tethered to the lessons of the past has hindered us from dealing with this pandemic. It is the first time in the modern era we’ve seen a virus like this one: something truly aerosolizing, spreading very quickly before symptoms.

What testing approach do you think is necessary instead?

What I’ve been pushing for is to entirely rethink what the purpose of testing is and what the downstream actions of testing must be. In this case, making the testing approach not so much a top-down public health surveillance, but rather a bottom-up personalized empowerment screening tool—­meaning that I know my status, much like HIV—changes the whole game. We can have many people using simple rapid tests in their home, twice a week. Without that frequent testing, people never know they’re positive until it’s too late and they’ve already transmitted. You don’t have to contact trace anyone, because you have more people who would be testing themselves regularly than you’d ever get with a contact tracing program. 

This screening approach requires a new way to think and a different type of test. The responsibility and the power lie with the individual. In a pandemic like this one, which is so out of control, we can’t expect a small department of health that’s underfunded in a state somewhere to tackle this. If we don’t get the public’s help dealing with this public health problem, we will not succeed. We would need our best marketing agents to help educate the public about the role of testing. There are so many tools at our disposal to deal with the pandemic. We just haven’t been deploying them.

Some studies of rapid tests have reported low sensitivity, the measure of how well a test detects positive cases, which conflicts with much higher sensitivities reported in other studies. How do you explain this disparity?

PCR’s sensitivity is why we keep getting these metrics of 40 percent sensitivity among the rapid tests. You get this bimodal distribution [a graph with two peaks] in rapid test sensitivity, either 95 percent sensitivity on some papers or 40 percent or even worse. The latter papers are all comparing rapid tests to PCR positivity. Only about 20 percent of somebody’s time when they’re PCR positive is spent being infectious. That’s why the U.S. Centers for Disease Control and Prevention (CDC) says not to test again after you get out of an isolation, because you’ll remain PCR positive. These antigen tests only tell you you’re positive when you’re infectious. If you’re just doing random samples of people who are asymptomatic, a person might not have ever known they were infected. You’re more likely to catch somebody during the 70 percent to 80 percent of the time that they’re PCR positive, but no longer transmissible.

Many people have heard that rapid tests may be less accurate. Why do you say they are essential to a better strategy? 

The major misconception about these rapid tests is that they’re not as sensitive. That needs to stop. They are extremely sensitive to catch infectious people. We’ve run over 3,000 Innova tests [a lateral-flow paper strip rapid antigen test with a readout that looks much like a pregnancy test’s, one line indicating a negative result and two lines a positive one] at one school and have had zero false positives so far. What we’re finding is the Innova test is detecting the false positive PCRs. We’re running PCRs along with the antigen tests to try to understand the antigen tests. Antigen tests such as BinaxNOW are getting around a 1 in 1,500 false positive rate.

Another point about sensitivity and rapid testing is if you’re not getting the test, or if a result is not available in the appropriate amount of time, then the most sensitive test in the world is useless. Right now, we have 100 people infect 140 new people on average. That means over a three- to four-week period, 100 people become 500. But what if we can just have those 100 infect not zero, but 90? That sounds like a bad testing program, but it’s a great one, because at a national scale after three or four weeks, those 100 people become 20 instead of 500. It just keeps going down from there. That’s the power of thinking about testing through an epidemiological lens instead of a medical lens.

Abbott reported a higher false positive rate (2 out of 100) for the BinaxNOW in their press release in August. Why would the false positive rate you found be lower?

The way we’re getting false positives down is to say that the sample line needs to extend all the way across the whole strip, and if it doesn’t, then it’s probably a false positive. If you see a speck, for example, that could just be some random protein getting caught up. I think Abbott may be looking for any speck that shows up along that sample line. What we’ve found in the field is that when you look for the whole line, you don’t lose any sensitivity, and you build up your specificity [false positive rate] to 1 in 1,500.

Some other types of rapid tests can have a higher false positive rate, right?

The first versions of antigen tests, such as the Becton Dickenson test and the Quidel test, weren’t optimized. They’re good, but they came out of the gate early to try to support the pandemic control efforts. They didn’t have the best sensitivity. They used a machine that might not have been optimized well enough to be accurate. It turns out the human eye is pretty good at figuring out a positive test from a negative one.

What happened to result in the hodgepodge of PCR testing in the United States?

When it comes to regulations, laws, and the way our labs are set up, we don’t have any sort of universal testing laboratory infrastructure. We don’t have any kind of quick way to share protocols.

The U.S. Food and Drug Administration’s (FDA) emergency use authorization process caused every single lab—hundreds of thousands of labs—to have to reinvent the wheel themselves. We at Harvard had a test, for example, that was working perfectly in January 2020 at our hospital, but we weren’t allowed to use it because it didn’t have emergency use authorization. When we were finally able to use it, we had to do all this documentation, send it to the FDA, and wait for them to get back to us. Eventually the FDA smoothed out some of that process. But it’s meant that every lab has had to create their own assets themselves.

How have other countries that have controlled the pandemic approached testing differently?

In places like China or South Korea, they were able to centralize resources to rapidly scale up PCR testing before things got totally out of hand. They were able to scale up building hospitals. They did not let the market forces determine what happens and allow a bunch of for-profit labs to get set up and make millions of dollars.

In the United States we weren’t able to centralize anything. There’s just been no use of efficiency in scale. The only places where it’s happened have been with the for-profit commercial companies that supply reagents, and then it’s super expensive. The labs are charging $150 per test with reagents that cost $5. The fragmentation and the free market aspect of our approach to tackling a public health problem has led to inequities in terms of our response and has caused this virus to keep transmitting pretty much unabated at this point.

When did you start seeing rapid antigen tests as an important part of an effective approach to the pandemic? 

The first time I held a paper strip test was back in March or April [2020]. One of the companies told me they were not quite at the sensitivity we needed, but they could scale a lot. I started doing epidemiological modeling with my laboratory to think of new ways to approach a pandemic.

At the Broad Institute, we run around 150,000 tests per day now. It’s probably the highest efficiency lab in the world. But even with that efficiency, I recognized it wasn’t going to be enough tests for what this country needs. I started recognizing, as we built more models, that it wasn’t even close. Frequency of testing and the speed to get results trump everything else. You could have sensitivity that’s a thousandfold lower [than that of PCR tests], but because the virus in everyone grows from 10 viral particles to a trillion, missing the first thousand is not a big problem.

Within a 24-hour period, the SARS-CoV-2 virus will grow from just detectable on PCR to a billion viral copies. PCR is likely to miss the peak of people’s transmission. If you do a rapid test every two or three days, you’re likely to catch someone early in their course of infection before they go on to transmit to others. That’s what we learned from all the modeling [published on medRxiv.org in June 2020]. I started talking about this widely back in May.

How did the website helping people advocate for rapid tests, rapidtests.org, start? 

I went on the show This Week in Virology (TWIV) [on July 16, 2020], and talked about how we have to think about testing in this new light. That video went viral. A lot of random people who normally don’t watch TWIV, including congresspeople and senators, wrote to me.

At the time, I had no support. It was just me talking to governors, talking to the president’s team, talking to prime ministers of other countries, and a lot of people asking me these questions. Then this grassroots effort popped up. 

The lead person is Chris Said, and he runs the website. He said, what can we do? At the time it was maybe 10 people. Now it’s grown to hundreds of people, who are really engaged, helping run that website and spread the message.

Our work is making a difference. One of the major reasons President Joe Biden is now making rapid testing approaches part of his campaign is because of us. In the United Kingdom rapid testing is being used a lot. It’s starting to be deployed [in new places].

What could such a deployment of rapid tests look like? 

There are different schools of thought about where they’re best used—what I call public health screening versus entrance screening. Both approaches use rapid tests, but one has an epidemiological goal in mind, and it’s the more powerful one, but one is maybe more politically palatable.

Entrance screening is what you might expect—detecting infectious people before they access facilities. The first place that President Biden will probably use these rapid tests is in schools by testing people on a frequent basis. I think we could use that for businesses, too, to keep the economy running, much more safely than we’re doing now. 

On the other hand, what I’d like to see, instead of entrance screening, is public health screening. It’s mass distribution of rapid tests to people’s homes, a tool from the government, no strings attached, that you can use twice a week to test yourself with a simple paper strip. You swab your nose, put the swab on the paper, drop some contact solution on it, and get a result in five minutes. People get immediate feedback that they are safe to go about their day. But if I’m positive, I can see the [second] line [on the test result]. It’s not some weird phone call I’m getting that I may not trust. That empowers me to know I shouldn’t go visit my mom tonight, or go to church, because I don’t want to get my church sick. And you don’t have to tell anyone about it. 

There’s stigma that comes with getting COVID now. A lot of people don’t get tested because they don’t want their friends who they hung out with last night to be told they can’t go to work for 14 days. People are actively not getting tested because they don’t want to get contact traced. For those who want to report their testing results, you could have one-click reporting. On the other hand, if someone wants their privacy, they can have that too. Maybe they need to go to work. But if they know they’re positive, then they can go to work knowing that, and maybe they don’t eat lunch in the break room, or maybe they really wear their mask that day more than they normally would. 

Everyone at the aggregate level can take small mitigating steps and combined that can quickly get the R value [the average number of people infected by one infected person] of this virus below one. Public health testing is designed so that in weeks, truly, we could get R below one [an R value below one means the viral spread is declining].

Your and several economists’ modeling, published in October 2020 on the preprint site medRxiv.org, shows the economic benefit of national screening testing. What did you find?

A $5 billion or $20 billion program is less than 0.1 percent of what this virus will cost Americans. If we could use $20 billion to get these tests out to most households in America for five months to use twice a week, that gets R down below one. The return on investment is in the hundreds of billions of dollars. Right now, every single day, this virus costs America $16 billion. If we can get the economy open one week earlier, that much more than pays for the whole program. But this public health screening approach could get the economy going months earlier. This program would ameliorate the pandemic, not just put a Band-Aid over its symptoms.

Stopping the viral transmission has gains we can’t even appreciate. For example, if we can stop transmission as much as possible before we roll out vaccines, then we cut down on the potential for mutations that escape vaccination.

With vaccine rollout already underway, why would screening testing still be worthwhile? 

Screening testing can get the virus under control much quicker and should be seen as a support to the vaccine program. If we can get R below one without even getting the vaccine out, then we’re not in a crisis mode as we roll out the vaccine. It buys us a lot of time. 

If we can scale up the Innova test’s production to 20 million to 30 million per day, which is possible given their current production, we could get R below one by mid-March. That’s months earlier. We probably wouldn’t hit herd immunity through vaccines alone until the end of the summer or so. The Innova test turns out to be one of the best tests we have. I’ve been evaluating them all. We’re exporting them to the rest of the world.

The other reason is, as we’re seeing in South Africa, Brazil, and many other places, mutant strains may well arise. We’ve created four vaccines for most of the Western world: Pfizer, Moderna, AstraZeneca, and Johnson & Johnson. All four target one spike protein [a receptor on the virus used to gain entry into host cells]. We have quadrillions of viral particles floating around today. It just takes one of them to find some new way to latch onto the cell, just by chance.

The more we can stop spread before the vaccine, the lower the likelihood [that the virus will adapt to escape the vaccine]. But this is a big world. If the virus does escape immunity, these tests also can be our support system at that point. We’ll have another control mechanism that works.

You mentioned you’re getting rare false positives in PCR tests. How do you explain that result? 

We’re finding a surprising number of false positive PCRs. I don’t feel great about that, but we’re finding that PCR labs in general—even with the best robotics that get rid of human handling altogether—still have a false positive rate of around 1 in 1,000. There are lots of reasons that could be happening when you’re doing so many. You can sometimes see primers [short genetic sequences used to identify the viral RNA] combine and start replicating themselves, throwing off a signal. But the signals are never high—Ct values [the number of cycles of PCR required to detect the viral RNA’s presence] of 36 or so. They get reported out as positives because we do see a lot of real positives at 36, usually when someone is right at the beginning of their infection.

What do you do if you suspect your test result is a false positive?

We’ve found that when there is a false positive on one antigen test and you run the same test again, the false result doesn’t repeat. That’s important. One of the most powerful aspects of these tests is that you’re not waiting days to get a result. You can repeat every single positive you get immediately.

The other way to check and reduce false positives is to use two different antigen tests. They have different molecules on them, so if there’s discordance, you know the positive one was probably a false positive. 

In the case of two discordant results, people get confused about which one to believe. But that doesn’t take into account the correct likelihoods. If one is positive, it’s likely that another test that’s 95 percent sensitive or more will also turn positive. It’s very unlikely that it would happen to be the 0.2 percent that results in another false positive. There are easy ways to use the benefits of a rapid test.

For various reasons, people say you need to confirm these antigen tests with a PCR test. That’s just wrong. When you have ready access to multiple antigen tests, you could take another one. The reason we’re using these antigen tests is because we don’t have enough PCR tests. We can’t confirm every negative if we use antigen tests frequently. We know that PCR tests can stay positive for weeks or months after the virus infected someone. It just takes a few days to kill the virus so that you’re no longer able to transmit it to others.

Accessible over-the-counter tests are needed for effective screening of asymptomatic cases. Why hasn’t the U.S. Food and Drug Administration (FDA) authorized more tests for this use?

The FDA only has a charge to evaluate medical diagnostic products. An over-the-counter product is already stretching what their interest is. That means it’s not a medical device. It’s a consumer device. This is a bad catch-22 that the government is in right now. 

We don’t have a regulatory landscape or an office that is charged with evaluating a test besides one that a physician would prescribe. The FDA is only in a position to evaluate a test the way that the companies want. Abbott can make only 1.2 million tests a day and doesn’t necessarily want to get an over-the-counter claim, because the test will have to be cheap. The FDA is not in a position to tell Abbott, “We’re giving you an over-the-counter claim for this test.” Our regulatory landscape has been designed to work with for-profit companies and commercialization. 

We need the U.S. Department of Health and Human Services (HHS) to authorize these differently. When BinaxNOW was first purchased by the government [in September 2020], Abbott only had a prescription claim on it. HHS said you can use these tests off-label in congregate settings without a prescription as part of your public health surveillance within nursing homes or schools. People criticized Brett Giroir, the coordinator of U.S. testing at HHS, for going around the FDA. Our country is just not set up to deal with public health crises.

The Ellume COVID-19 Home Test is the only test to get FDA’s emergency-use authorization for over-the-counter use. What made this test different?

Getting more rapid tests out to the public is good, but there are some that are better than others. A test like the Innova test, which is a simple paper strip encased in plastic, can be made at the scale of tens of millions a day, and it works extremely well. The Ellume test is great; it looks pretty. But the Ellume test is expensive [$30], and it requires a Bluetooth app, to which you input all this information. It has a circuit board. But inside all of that is a paper strip test. You have all the rest so that it can attach to your cell phone. They make it easy to link to Bluetooth, but what if you don’t have working Bluetooth? The Ellume test has a higher false-positive rate than the Innova and the BinaxNOW tests.

I don’t know why the Ellume test got emergency-use authorization [for over-the-counter use]. I’m in the middle of a lot of these conversations between government and companies, trying to bring them together with the FDA leadership. A question I often hear is, Where is it being produced? The Ellume test was funded in part by RADx and the U.S. National Institutes of Health. Innova is a California-based company, but the test is produced in a factory in China.

How have the new variants of SARS-CoV-2 (B.1.1.7, N501Y, E484K, and others) affected your approach?

People are realizing that we need to act quickly, or there could be a whole new cycle of this epidemic. It’s causing people to act how I think we should have been acting since February [2020].

I feel even more of a crisis—to make sure that these rapid tests are built in numbers that can serve not just the United States, but also central Africa. Some other countries don’t have any PCR testing. They have no way to monitor the virus and stop transmission. These rapid tests are accessible tools and can be made for 50 cents each.