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The path out of the pandemic for the United States—indeed, everywhere—centers around a massive scaling up of testing for SARS-CoV-2 (the virus that causes the disease Covid-19) and antibodies to the virus. Once we see a steep and sustained decline in cases in our hospitals, gradual withdrawal of social distancing measures will have to go hand in hand with identifying all lingering cases of the infection in our communities, isolating those individuals and quarantining their contacts, all in the context of protecting people’s human rights. Opening up the economy, returning to some normal activities outside our homes, is also dependent on having sufficient antibody tests to know who might have already been exposed to SARS-CoV-2 and has cleared the virus from their system.
But wishing doesn’t make it so. The United States will need to test tens of millions of people for the presence of the virus in this next phase of the response. Over the past week, the number of tests added has averaged 147,000 per day, when we need to be testing 2 million to 3 million a week. Some of this is due to shortage of tests, reagents, nasal swabs, and the people necessary for such as massive testing campaign, as well as the leadership crisis I’ve previously discussed. But we’re going to have to plow ahead at some point when it becomes clear that hospitalized cases have been consistently down and we have worn out the patience of the American public with social distancing in its strictest form.
How do we proceed when the number of tests we need greatly exceeds the number we have? Colleagues of mine at Yale have recently suggested that we prioritize what we might think of as hot spots for undiagnosed infections (large apartment buildings, nursing and long-term care facilities, public housing developments) or places still open for business during the pandemic (grocery stores, pharmacies, Amazon hubs) while retaining some random screening among the population. But this still leaves us with the question: Which of these places is first in line for available testing? My colleagues and I have thought about this in the context of HIV testing for a while now: How do you find “needles in a haystack,” new cases scattered around a city, a state? Without going into technical details, we ourselves don’t necessarily have to make the choice of locations to test in; there are adaptive mathematical algorithms that can assist us in homing in on the places that have the best chances of finding new cases. No matter what we do, we’re going to have to be creative in thinking about how to maximize our yield of new diagnoses until we have the millions of tests we need to do something akin to universal testing of high-risk populations in the United States.
Over the past few weeks, as people try to think about how to gradually relax social distancing, the idea of using antibody tests to “clear” people to go back to work has become a popular notion. However when I talked to my colleague, Professor Akiko Iwasaki in the Department of Immunobiology at Yale, she offered some caution on this approach based on the current knowledge of the immune response to SARS-CoV-2. Recent studies have suggested that not everyone develops an antibody response to this novel coronavirus. In fact, about 30 percent of patients develop very low levels of antibody, while some have no detectable levels at all.
We also don’t know where on the spectrum of immune protection exposure to SARS-CoV-2 lies. Is the immune response to SARS-CoV-2 more like those directed towards the coronaviruses that cause the common cold, and to which we have transient protection lasting only a few weeks? Or is it more like the response triggered by the cousin of our current coronavirus, SARS-CoV, which may last two to three years? These are open questions that have not yet been resolved. Until they are resolved using antibody tests as a guide, policy decisions, let alone a decision as to which individuals are ready to go back to work, could be premature, with potentially dire consequences.
Finally, not all tests—either for the virus or the antibodies to it—are created equal. Diagnostic tests can generate four kinds of results: true positive and negative results, and false positive and negative results. The test for the virus itself, using a technology called RT-PCR, is thought to be better at offering true positive results than true negative results, but the extent of false negative results isn’t well-documented right now. This means that tracking lingering infections is going to be imperfect at best and we’re going to need more sensitive assays to be developed or use multiple assays to confirm or rule out infections. It also means that if you have symptoms of the disease and test negative, you should probably still assume you have Covid-19 and take precautions to protect others and monitor your own disease course.
The worries about the accuracy and reliability of antibody tests are even more acute. As I mentioned earlier, we don’t yet know who will generate antibodies to SARS-CoV-2, or if these are the kinds of antibodies that will neutralize the virus, or what magnitude of a neutralizing antibody response might be able provide long-term protection against the disease. Yet antibody tests are currently being rushed to market without proper evaluation, with the FDA willing to allow the release of these tests even before the agency can examine the product themselves. Now add to that uncertainty questions about the extent of false positive or false negative results, and you get a situation fraught with trouble. What does a positive antibody test mean today? The answer is: We don’t know. However, according to ProPublica, the City of Chicago, getting way out ahead of the data, has recently ordered over 10,000 antibody tests from South Korea, which have yet to be vetted by the FDA.
Getting clarity on testing for SARS-CoV-2 and its antibodies and how to use this information in making public health decisions is going to take a urgent investment in additional research on the immune response to viruses—both the basic work in labs and the epidemiological kind to understand the prevalence of neutralizing antibodies in the community. It will also take more, not less, regulatory oversight, where the need for getting answers isn’t pushed aside for a need for speed to get things to market. Manufacturers will need to refine their tests, and band together when we need confirmatory assays to know more definitively if someone is actually SARS-CoV-2 positive or not. It will take all hands on deck.