By MDS C19 Staff , December 3 2020

A world of continuous Covid-19 tests over the span of a day? It sounds terrible, but it could be the only way out of the pandemic for a long time to come.

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.

Michael Mina, Harvard epidemiologist (Staff Photo by Nancy Lane / MediaNews Group / Boston Herald)

In countries such as Italy or the USA, the first wave of the virus was characterized by serious test problems. An insufficient number of devices, shortages of reagents and other factors have made testing inadequate. In the US, this situation is even getting worse in this second wave. In the past two weeks, and for the first time since the start of the pandemic, the country has performed fewer Covid-19 tests than 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 plentiful, they can bring down 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 the tests," 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 lifestyle.

The bishop of 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 tests. We are talking about 20 million Covid-19 tests per day that should be produced in Italy. 100 million a 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 clarify anything, it is that in theory we can bring life back to normal, or something similar, even before a vaccine. In short, they make it clear that there is a way out 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 the "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.

How does PCR work?

It basically works a bit like Photoshop's “clone stamp”. With a specific blend of chemicals called "reagents" and a special machine called a "thermal cycler", PCR duplicates a certain strand of genetic material hundreds of millions of times.

When serving as a Covid-19 test, the PCR technique looks for a specific nucleotide sequence that is unique to the coronavirus. A sequence of ANNs that does not exist anywhere else. Every time a PCR machine (for example, that of the multinational Roche) encounters that filament, it makes a copy of both that sequence and a fluorescent dye. If, after multiplying both the yarn 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 report it 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. Because?

A growing number of clinical trials show that PCR-based Covid-19 tests have an important 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 sick until day five, when you start developing symptoms, such as fever, dry cough, or loss of smell. In the next few days, 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 be symptomatic for several days or several months. But some recent studies suggest that by about the fourteenth day, nine days after the onset of symptoms, 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 allow for 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 far exceeded the machines' ability to run them.

And when the tests go down, as mentioned, the entire medical system suffers. Without CERTAIN and TIMELY results, it does not come out.

And imagine the asymptomatic

The “Super Power” of Covid-19 is just that. There are silent diffusers that can stay infectious for weeks but never develop any symptoms. They account for 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 foreseeable future, the only way to scale up tests 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.

Sample pooling test

The system is simple: instead of testing each sample individually, laboratories combine a few samples, then test that "pooled" 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.

It works like this: a technician does not examine the samples individually, but creates a group of 50 and tests them together. If the pooled sample is negative, none of the 50 have the virus, and to find out the material necessary for a single test will have been used.

If the pooled sample is positive, a new phase begins. The technician groups the same samples again, this time in smaller groups of 10, and checks them again. When one of these smaller pools is positive, it tests every single sample it contains. At the end of the trial, he tested 50 people, but only used a dozen tests.

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 scrambling samples may not be worth the effort.

The key to changing approach is "front-end pooling". Imagine that every day, when children arrive in their classroom, they briefly take off 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? All at home and single 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 the event of a pandemic.

Then the test we were talking 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 cup and gives 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 latch onto and enter human cells.

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

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, in practice, the goal is to exceed the speed of the enemy. Flooding the world with billions of tests that aren't perfect, but good (and fast) enough 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 is no longer social distancing. When my daughter enters the classroom, she briefly takes off 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 for a coffee in a secluded room. In 15 minutes, I get a notification: daily screening passed, I can start the day. I still wear the mask at my desk and try to avoid common areas, but the infection levels are very low. On Saturday night, the family and I go with friends and family to a restaurant and, before entering, we do another test. It is normal now to see containers of saline solution, binders for tests with the strip of paper that changes color, at the entrance of every public place. Before putting the baby to bed, another message from her school warns me: no one in class tested positive this morning. Also tomorrow it will be possible 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 quite a while.

Gianluca Riccio