Antigen Testing: Guest Post with Michael Mina

Last week, in advance of their return to school Monday, I took both of my kids to the RI Convention Center (also known as “The Dunk”) for a rapid COVID test. Rhode Island has among the most robust testing infrastructure in the country, and in the last few weeks they have moved to using BinaxNOW rapid tests, both for asymptomatic general population testing and for surveillance in schools. At the convention center, we showed our appointment email to the box office (although, based on the people in front of me, you apparently would be let in even without an appointment), waited in a short line in the stands and got a little grocery store meat counter piece of paper with our number on it. We were sent to a table where a nice national guards-person had the kids swab their noses (I had to do the five year old and, to be fair, he didn’t enjoy it but the 9 year old had no problems). We read graphic novels for 15 minutes in a set of socially distanced chairs and then when our number was called, went and got our (negative) results, along with a piece of paper certifying them. Reader, it was fantastic. I did not think the kids had COVID (the adults in the household are tested twice a week through work and we didn’t have any high risk exposures) but it did really feel better to get a negative result. And it was so easy, it gave me a glimpse into what could be. BUT: this is made possible by these relatively cheap rapid antigen tests. And they have their detractors, those who argue that the lower sensitivity of these tests means they shouldn’t be used. And the use case can be unclear — do we all go to the Dunk once a week? How should this really work? So: I asked antigen testing guru Michael Mina to weigh in. He did, and the interview is below. It’s long! But I really recommend it. I’m fully bought into the need for these tests, and our need (see call for action at the end) to push regulators to make them more accessible. Maybe we can help make it happen… First off: tell me how antigen tests are different from PCR tests? It would be great to hear both how the science differs, how the accuracy differs (if it does!) and how the cost differs? I think it’s important to first talk about why we are testing people and what we are trying to achieve with the various types of tests. Unfortunately, in this pandemic, public health authorities have failed time and again to define why we are testing, which has resulted in major confusion around clinical diagnostic testing (testing for medical purposes) and surveillance and screening testing (population-level testing to help stop transmission). People often say “PCR is the gold standard” and “antigen tests are not as sensitive as PCR.” These statements are both true and false depending on what the purpose is for the testing. A PCR test will detect miniscule amounts of viral RNA and it will show if someone has any evidence of an infection with SARS-CoV-2. This is important knowledge for diagnosis, especially in a hospital or other high-risk setting. However, PCR tests are expensive (between $50 - $150), require a laboratory to interpret results, and the results aren’t usually known for 24-72 hours (or sometimes longer). Plus, the need for processing has meant it is difficult to make them very accessible; at-home versions add to processing time and are difficult to obtain. By the time most people get a swab stuck into their nose, they are about to be or are past their contagious stage. This is problematic because the late stage of testing plus the amount of time it takes to get results makes the whole process as far as containing transmission almost useless. Perhaps more importantly: even though PCR is highly sensitive to viral RNA, it does not differentiate well if someone is infectious or not infectious. PCR test can stay positive for a long time after someone is contagious. In fact, although people are infectious for usually 5-7 days, they tend to remain positive on a PCR test for 20-40 or more days. This is, in part, why the CDC recommends not testing for 90 days after being positive. Interestingly, the PCR test does provide information about viral load and infectiousness, through the “cycle threshold” or “CT” count. This measures the number of PCR cycles that run before the test shows up positive, and (generally) more infectious people with a higher viral load have a lower CT count. If we reported CT counts with PCR results, we might learn more about infectiousness. But, generally, these are not reported. Bottom line: the PCR test is a very good test if you are a physician with a patient. But, if you are a public health official trying to stop the spread of the virus, whether you recognize it or not, the PCR test as it is currently used is nearly useless. If we are trying to slow the spread of the virus at the community level, we need a test that is frequent, simple and extremely accessible. Obviously, the more sensitive the test is, the better. However, if the goal is simply to get R < 1 (virus to be spread to less than one person per every infected person), which would slow community spread, then even a test that is only able to detect those with the highest viral loads is an exceedingly powerful tool if it can be used frequently. Rapid antigen tests can be the public health screening tool to slow the spread of the virus. They are simple inexpensive tests that look like strips of paper. To use them, you swab your nose (ideally yourself), and then put the swab onto a strip of paper – the antigen test - with a few drops of buffer that comes in a dropper with the set of tests. The fluid flows along the strip of paper and in 5-15 minutes, you see either one line or two lines. One line means you are negative. Two lines means you are positive. The technology is the same as a pregnancy test. Rapid antigen tests are inexpensive (can be produced for as little as $1/test), simple to use and interpret, and highly distributable – i.e. to people’s homes in packs of 5 or 10 or 20, etc. These tests are less sensitive to detect infection than PCR tests but are arguably MORE specific to detect contagious people. Because they require live (contagious) virus to produce a positive result, they do better to only identify people who are likely contagious. They will not remain positive for a long time after someone is contagious. When the purpose of the test is to find contagious individuals – people who probably should isolate away from others – the sensitivity of rapid tests is very good: between 90 to 99.9% as sensitive as PCR. However, since the PCR remains positive for long after someone is contagious (as noted above) direct comparisons are difficult. We have to be very careful to not assume that an antigen test isn’t working any time that it is negative but the PCR test is positive. Simply put, the tests look for different things. The antigen test looks only for infectious virus. The PCR test looks for any evidence whatsoever that the virus is or was recently infecting someone. We can imagine doing a better comparison, but it would require taking into account the CT counts on the PCR tests that I mentioned above. We would expect antigen tests to be better at picking up those with PCR tests with high viral loads (say, a CT count below 30) than those with lower loads. But, since these are generally not reported, this comparison is hard to implement. Antigen tests should not be considered to be not working just because they aren’t positive when a PCR records a Ct value of 35. They should be compared to PCR results with Ct values that represent likely contagious virus. In general, what many studies have shown us is that rapid antigen tests perform very well to detect virus when the amount of virus is still more than about 0.001% of the amount of virus detectable at peak contagious. During peak infectiousness, the rapid antigen tests are essentially 100% sensitive. At the very edge of someone potentially being infectious, they may be only 60% sensitive. And averaged over the full spectrum of being infective, they generally are >90% sensitive (despite being only 30% sensitive or so if you compare against “anytime PCR positive”). Since transmission mostly occurs when people are at peak virus load, the entire discussion about a lack of sensitivity of these tests, when the goal is to detect infectious people, has been entirely misguided. 2. This may seem obvious, but step me though again the value of pulling these infectious people out of the circulating population? We have learned with COVID-19 that you are transmitting high viral loads typically three to five days after your infection and usually before your own symptoms arise. Rapid antigen tests register the virus whether you have symptoms or not, making this a powerful tool to identify cases before the virus spreads. We know transmission begins before people begin to show symptoms, and by the time someone has symptoms, gets tested and receives their result, 90% of their transmission will have already occurred. Frequent serial testing of a large fraction of a community can induce vaccine-like herd effects. Testing only 50% of a community once or twice per week, with rapid return of results, can detect enough people early enough in their transmission window to stop them from spreading, on average, to more than 1 individual. Like a vaccine given to half of a community to induce herd immunity by blocking onward transmission, frequent rapid tests too block onward transmission, and can bring R to below 1 in weeks. The tests do not need to be perfect for the “herd effect” to work its magic. Right now, the reproductive number “R” of the SARS-CoV-2 virus is about 1.3. That means that if 100 people are infected, they will go on to infect about 130 more people. Those 130 people will go on to infect, on average about 170 people, and then 220, 285, 370, 480 and so on. So, within just a few weeks, 100 people can become nearly 500 people. But now, let's assume that frequent rapid testing is being used. It doesn’t need to be perfect and stop all cases. In the same scenario as above, let's say that instead of those 100 people infecting 130 people to start, they instead go on to infect 90 people. Clearly it’s not a perfect program if for every 100 people they still infect 90. But now let's say the program continues, and those 90 go on to infect 81, and then 72, 65, 59, and 53. Therefore, a rapid testing program that still allows 100 people to go on and infect 90 new people would mean that those 100 infections would turn into 50 new infections over the same amount of time that those 100 infections would have otherwise become 500 new infections. In other words, the goal of frequent rapid testing as a public health program isn’t to go from 100 to zero immediately; it’s simply to get 100 infected people to go on and infect fewer than 100 new people instead of more than 100 new people. If we can do that, we start winning the fight against coronavirus. 3. We talked about using these in households -- can you paint me a picture of how that would work? Like, literally, what would I do every day and why would it matter? The way to stop the spread of the virus is for every American household to have access to a fast test that they could use in the privacy of their home 1-2 times per week. The government could easily produce these tests and distribute them – the same way they send out the census packet. Ideally, each household would receive a small package of 10 tests, 10 tubes, and 10 swabs, plus an additional “confirmatory” test that looks similar, but has different chemistry on the paper strip. The regular tests might be in yellow packages and the confirmatory test could be in a red package. The purpose of the confirmatory test is to rule out false positives. It is rare, but sometimes depending on pollutants in the air or something you eat, the antigen test could show a false positive. By including a confirmatory test, you will know immediately if you are in fact positive. Twice a week, you would wake up and test yourself. You would swab the front of your nose, dunk the swab in the small tube and then dunk the paper strip into the tube (or drop a few drops from the tube onto the strip of paper). You would wait a few minutes for a line to form. One line means the test worked properly and you’re negative. Two lines means you’re likely positive for SARS-CoV-2. If positive, you would use the confirmatory paper strip test and check to see if it also turns positive. If positive, you are confirmed positive. Ideally, the public health guidance would then be to test yourself in a few days and then a few days after that. Go back to work once you’ve been negative for 48 hours. However, if the confirmatory red test is negative, then you remain home for the day, and test yourself in 24 hours. If the yellow test is no longer positive, then, in light of the red confirmatory test also being negative, you assume a false positive and go back to work. To put this in perspective, this is likely to happen once every 200 yellow tests with the current tests – or less than once per two years for an individual, so it is not so much, but does suggest we should try to have the confirmatory tests included in the package for each household. 4. Do you see these being useful in schools or child care settings? I think these tests would be most effective in the home, but, yes, these could definitely be used in schools. I do not however think it is the best use of the tests. I think that we should focus on limiting community spread and since we don’t think kids are the most transmissible then it doesn’t make a ton of sense to use them all in the schools. Nevertheless, getting them out is step #1 so if it can be used to keep schools safe, then that is great. The important thing is that we always have to keep in mind that when public health works, it is invisible. The only thing that remains visible is when a public health effort doesn’t work. Similar to vaccine adverse events. Vaccines work so well that when they are working, no one pays attention. But if someone has an allergic reaction or a seizure, then that is all people focus on. Same thing here. If these are going to be rolled out in schools, we have to be cognizant not only of the schools where breakthrough events occur, but more so we have to recognize how many schools are not having outbreaks as a result of the tests. I worry that this is going to be very, very difficult for the public to discern. Focus is always on the failures. A perfect example is the White House Rose Garden event. It was the one event that caused an outbreak amongst a sea of outbreaks that never happened. But most people did not take note of the outbreaks that were NOT occurring between March and October, and instead chose to only focus on the outbreak that did occur. This is natural human behavior and thinking. It is difficult to recognize the counterfactual. So, I worry that if this is rolled out in schools, the first time there is an outbreak, then the whole program across the country will be placed on hold and the tests will be deemed “unreliable” even if it is one event out of 1,000,000 possible other events that didn’t happen. 5. For a lot of people, the vaccine feels like it’s taken center stage. What’s the pitch for antigen tests still being important? For how long will they matter? Vaccines are great. But they will not get out to the average person for many months. We can see this by the spotty roll out that has already happened at the most well-resourced places. We can see this in the low number of doses currently available. We need other solutions for right now. These tests will help to control spread today – long before we get herd immunity. Importantly, it is possible that this virus could mutate at any moment. And it could mutate around the vaccine derived immunity. All of the leading vaccines are narrow scope single protein vaccines. Unfortunately, all four of the leading vaccines for use in the US are essentially identical – so not only are the vaccines themselves narrow in scope, but the entire vaccine program, the whole basket of vaccines is narrow in scope. That means we need just a single virus particle, somewhere out there in the world to learn how to evade the narrow single protein derived immunity of the vaccine to render the vaccines potentially useless or at least much less powerful. This should have been a major consideration long ago but it wasn’t and still is barely a talking point. No one wants to talk about this real risk. These tests will be “immune” to such changes in the virus and can induce herd effects through empowering people to know their status and thus help people to not transmit the virus to their loved ones. If enough people do this, R can fall below 1 and the virus can diminish at the community level, like we saw in Slovakia. In other words, these tests can stand in for vaccines during the rollout, or in the catastrophic case that the virus mutates and evades the vaccine derived immunity. 6. Okay, so, where can I get these? Or when? These tests aren’t readily available today. We are working hard to get the FDA, the CDC and the WHO to see these tests as public health tools and accelerate their introduction outside of the medical sphere and into the public domain. Already they are being used on university campuses, in Hollywood and in the executive suites of many, many corporations. So they are available to the connected and wealthy. They could however be available to the average person if we start to authorize them as public health tools and not medical tools. For example, Abbott’s $5 rapid paper strip test, the BinaxNOW test is an incredible tool. But, because it has only a medical claim, it is now being sold not for $5 but for $25 dollars because if you want to use it you have to pay for an eMedicine consult to go with your paper strip test. Which is simply, wrong. I believe firmly that the new administration is going to prioritize these tests and push them forward as public health tools. They will be up against a battle with the FDA, but public pressure will help. There is a small grassroots movement that started after I initially published on the rapid antigen testing idea last summer. The group’s website is rapidtests.org. You can directly lobby your elected officials to support rapid antigen tests by texting “RAPID TESTS'' to 50409. We are doing everything we can to convince the federal government to make these tests a priority, but the more they hear from their constituents, the better. If you want to learn more: follow Dr. Mina on Twitter at @michaelmina_lab.

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