Covid-19 test, the plan to give us back our lives

A group of epidemiologists, economists and dreamers are thinking of a new strategy to defeat the virus, even before a vaccine is deployed

Michael Mina is a professor of epidemiology at Harvard. There he studies diagnostic tests for infectious diseases. He witnessed, with disbelief, the worldwide struggle to have a decent number of tests for Covid-19.

In countries like Italy or the USA, the first wave of the virus was characterized by serious testing problems. An insufficient number of devices, reagent shortages and other factors have made the tests inadequate. In the US, this situation is even getting worse in this second wave. Over the past two weeks, and for the first time since the start of the pandemic, the country has carried out fewer Covid-19 tests than in the previous week. The system is deteriorating.

Testing is a huge problem

Tests allow you to perform the most basic task in disease control: identifying the sick and separating them from the healthy.

When tests are abundant, they can reduce the fear of contagion. “The only thing that makes a difference in the economy is public health, and the only thing that makes a difference in public health is testing,” he says Simon Johnson, the former chief economist of the IMF.

The most optimistic assumptions say vaccines will not be available in hundreds of millions of doses until May or June. There will be a transition period in which doctors and health workers will be vaccinated, but not teachers, couriers and police officers.

For this we will need better tests. But we need it even now.

How to revolutionize the Covid-19 test system?

In recent weeks Michael Mina has become the “prophet” of a total revolution in how the pandemic can be controlled. Instead of reorganizing daily life around the current way of testing, he argues, countries should incorporate testing into our way of life.

The standard bearer for this change is a thin strip of paper, no longer than a finger. It's a test for Covid-19. Mina says the US should mass-produce these inexpensive and easy-to-do tests (unlike other methods, they only require a saliva sample) in the tens of millions per day.

These tests, which can provide a result in 15 minutes or less, could become a constant part of daily life.

The heart of the matter

Before someone walks into a school or an office, a movie theater or a supermarket, they might take one of these tests. Negative test? You are welcome. Positive test? You come home and decide what to do.

In summary, Michael Mina's idea is to test almost everyone, almost every day.

The tests described by Michael Mina already exist: they are in the office of e25 Bio, a small start-up in Cambridge, Massachusetts; half a dozen other companies are working on similar products.

But this is not enough: we will need to change the very way we think about testing. We are talking about 20 million Covid-19 tests per day that should be produced in Italy. 100 million per day in the USA. A truly daring undertaking.

With equally bold goals: Mina says this method could bring down the coronavirus within three weeks. (Other epidemiologists aren't so sure it would work, at least without serious drawbacks.)

Although expensive, his plan is one of the few of a scale commensurate with the pandemic: it looks like a war plan, and for this reason it can work in a war scenario, in a war economy.

What do you think?

If the new proposals make anything clear, it is that in theory we can return life to normal, or something close to it, even before a vaccine. In short, they make it clear that there is a way out of the situation pandemic. But several things must be considered: first of all, the type of test itself.

PCR, cross and delight of Covid-19 tests

Today, if you have a dry cough and fever and take a COVID-19 swab, you'll likely be taking a test that wasn't designed for an out-of-control pandemic. Which?

It's called a “reverse transcription polymerase chain reaction” test, or PCR, and it's one of the miracles of medicine. Its invention, in 1983, paved the way for the Human Genome Project, early detection of certain cancers, and more.

When serving as a Covid-19 test, the PCR technique looks for a specific sequence of nucleotides that is unique to the coronavirus. An RNA sequence that exists nowhere else. Every time a PCR machine (for example, that of the multinational Roche) encounters that strand, it makes a copy of both that sequence and a fluorescent dye. If, after multiplying both the thread and the dye hundreds of millions of times, the Roche machine detects a certain amount of dye, its software interprets the sample as positive. To have a “confirmed case of COVID-19” requires a PCR machine to detect the dye in a sample and pass it on to a technician.

Tested time and time again, the PCR technique works remarkably well: the best PCR tests can reliably detect as little as 100 copies of viral RNA in one milliliter of saliva or nasal mucus within hours.

Why the PCR must be passed

The accuracy of the PCR-based Covid-19 test makes it by far the most recognized and preferred. But today it is effectively "paralyzing" the global response to the pandemic. Why?

A growing body of clinical evidence shows that PCR-based Covid-19 tests have a major Achilles' heel. Which? The most important questions a test can answer are: Is this person infected and contagious now? and if it's not contagious, could it soon be? The PCR cannot answer these questions.

Imagine you got Covid-19 (God forbid). Here: now you are sick, it is day zero, but it is impossible for everyone to know. Only in the following days, the virus will silently spread through the body, replicating itself. By day XNUMX there may be enough virus in the nose and saliva that a sample of both would test positive by PCR.

Soon your respiratory system will be so crowded with the virus that you will become contagious, spraying the virus into the air every time you talk, smoke, or scream.

But you probably won't feel like you're sick until day five, when you start to develop symptoms, such as fever, dry cough, or loss of smell. In the next few days, then, you will be even more contagious.

And here's the first problem with PCR. To break a chain of transmission, healthcare workers must move faster than the virus. If they could test people early, for example around the third day, and get a result in a day or two, they might be able to isolate them before they infect too many people.

It doesn't happen.

Apart from so many virtuous models, the average of the controls cannot keep up with these rhythms. And if it fails, it does not contain the virus.

After symptoms begin around day five, you may remain symptomatic for several days or several months. But some recent studies suggest that by about day 14, nine days after symptoms begin, you are no longer contagious, even if still symptomatic.

At that point there are no more live viruses in the upper respiratory system. But as millions of dead virus particles line the mouth and nasal cavity, PCR sensitivity could give positive Covid-19 tests. For weeks one could still be positive, even without being.

And here's the second problem with PCR: At this point in the disease, a positive PCR test does not mean that you are contagious, nor does it mean that the SARS-CoV-2 virus is still alive. It no longer makes sense to trace the contacts you had in the last five days, because you are not infected. Nor does it make sense to stay at home. With the PCR-based Covid-19 test, public health is unable to easily distinguish between a positive day two and a positive day 35.

The final problem with PCR testing, however, is even simpler: there will never be enough of them.

For months, as I said, it has been difficult for laboratories to obtain the expensive chemical reagents that enable RNA duplication. Earlier this summer, there was a global rush on pipette tips: the disposable plastic sticks used to move liquid between vials. Sometimes the bottleneck is the PCR machines themselves: ultimately, the number of tests has far exceeded the capacity of the machines to run them.

And when testing declines, as mentioned, the entire medical system suffers. Without CERTAIN and TIMELY results there is no way out.

And imagine the asymptomatic

The “Superpower” of Covid-19 is precisely this. There are silent spreaders who can remain infectious for weeks but never develop any symptoms. They represent 20 to 40% of all infections.

Some studies suggest they may be more contagious than symptomatic people, carrying viral loads longer.

The challenge is clear: we need a huge number of tests. The population must be screened. Assuming you want to test all Italians once a week: 8 million tests a day would be needed. How do we get there?

Pooling

In the immediate future, the only way to increase testing is to squeeze more tests out of the existing PCR system. The best solution to do this quickly is through a technique called “pooling“, which could eliminate a few hundred thousand more tests from the system every day.

The system is simple: Instead of testing each sample individually, labs combine a few samples, then test that “grouped” sample as one.

The technique was invented by Robert Dorfman, a Harvard statistician, to test American soldiers for syphilis during World War II. Today it is commonly used by public health laboratories to test for HIV.

This approach saves hundreds of tests over the course of a day.

But pooling is just a fallback

Pooling works best for relatively rare diseases, such as HIV and syphilis. If a disease is too common, then the pooling work of mixing and reshuffling samples may not be worth it.

The key to changing our approach is “front-end pooling”. Imagine that every day, when children arrive in their classroom, they briefly remove their masks and spit into a container. The pooled sample could be analyzed with a result by the next morning. Negative sample? Everyone in class. Positive sample? Everyone at home and individual tests.

Front-end pooling could reduce time and cost, in part by saving on materials. Of course, there is currently no device that allows so many children to spit safely into one vial. It would need to be developed quickly.

The front-end pooling approach has never been tried before, because it only makes sense in a pandemic.

Then the test we talked about at the beginning of this post.

What if there is a test that can be produced in large numbers, and it doesn't require a specialized reader? What if it works more like a pregnancy test, a procedure you can do at home and not just in a doctor's office?

These tests, as mentioned, exist (since April) and are made by e25 Bio, a startup of 12 people. An e25 test is a strip of paper, a few centimeters long and less than one centimeter wide. It only needs a little saliva, a saline solution and a small cup and provides a result in 15 minutes. Just like a pregnancy test, it doesn't require a machine, reagent, or doctor to work.

Its quality is that it reacts to the presence of the characteristic spike protein of the coronavirus, the structure on the "skin" of the virus that allows it to dock and enter human cells.

The spike protein is the most important structure of the coronavirus. It plays an important role in determining the infection of the virus, and this is what both antibodies and many prototypes of future vaccines are aimed at.

If these tests were produced in sufficient and massive numbers, would you accept to submit yourself every day, every day for whatever?

Mind you: the plan, says Michael Mina, would not be limited to mitigating the damage of the pandemic. It could end it.

To escape the pandemic, basically, the goal is to outrun the enemy. Flooding the world with billions of tests that are not perfect, but good enough (and fast) to stop Covid-19.

Tests of this kind have drawbacks, of course.

Testing tens of millions of people every day would be an unprecedented biotechnical intervention, it could have unpredictable and unpleasant side effects. Mina's plan has probably not yet taken into account all the operational consequences.

Basically, here's what my May 2021 could be like

vaccines are being distributed. I haven't done it yet, but there's no social distancing anymore. When my daughter enters class, she briefly removes her mask and spits into a plastic bag; so do all the other children and the teacher. The bag is then delivered to a nearby laboratory. When I get to work, I spit into a plastic cup, then go to drink a coffee in a secluded room. In 15 minutes, I receive a notification: daily screening passed, I can start my day. I still wear my mask at my desk and try to avoid common areas, but infection levels are very low. On Saturday evening, the family and I go with friends and relatives to a restaurant and, before going in, we do another test. It is now normal to see containers of saline solution, test containers with the strip of paper that changes colour, at the entrance to every public place. Before putting the little girl to bed, another message from her school warns me: no one in class tested positive this morning. Tomorrow we will also be able to have lessons in person.

There are no technical obstacles to this view. Just a lack of political will.

I already know that on paper this daily Covid-19 test scenario looks like a nightmare, albeit much less than the current one. But the road is long, and the virus may be here to stay.

There may be few alternatives to a current system. We may needlessly, painfully waste time trying to restore a past that simply cannot return.

At least for a while.