The U.S. does not have a universal health care system, which means that it fails to provide a consistent level of minimum care across its population. That means that basic and preventative care often falls through the cracks, even as the U.S. continues to excel at medical innovation and offer the most highly regarded health care in the world to those who can afford it.

But now, with the COVID-19 pandemic, that situation has translated into a lack of widespread, affordable access to diagnostic and antibody testing in the U.S. even as innovation by major companies and startups keeps churning out a vast array of newer, faster and better tests. Physicians and executives at the World Medical Innovation Forum on May 11 worked to untangle the current state of COVID-19 testing in the U.S. – and what is needed to improve upon it. The virtual event was presented by Mass General Brigham Innovation, a unit of the Boston-based health care system.

Innovation, not coordination

“It’s really asking a lot to roll-out tests at the speed that we needed to do that, especially in a complex distributed system like in the United States. We don't really have a centralized ability to roll out tests across the country, like some of the other countries were able to do. And maybe that's a weakness of our system,” said John Iafrate, the director of Center for Integrated Diagnostics at Massachusetts General Hospital. “Often, we can lead in innovation, but in this particular instance maybe the U.S. was at a disadvantage. So, it may have been a little bit unfair to expect the diagnostic system to respond so quickly.”

“What we did need was a two-phased response – and that's exactly what we saw. In the future, we will also do something similar,” he continued. “The first phase is most likely to be a lab developed test or homebrew type version of diagnostic assays, which the CDC has deployed across multiple sites as an example, followed by companies like BD and Roche having the ability to come in with low cost, high-quality commercial grade assays that can be deployed at scale across the country. That's what we did; it just took a few weeks longer than what we wanted – or a month longer than what we wanted.”

He went on to note that the congressional effort with the Verifying Accurate, Leading-edge IVCT Development (VALID) Act introduced in early March to make laboratory-developed tests (LDTs), which have long been largely outside the purview of the FDA, suddenly subject to the agency’s oversight disrupted the efforts of labs across the U.S. Labs were already busily developing their own LDTs at this point.

Working to address the longstanding, uneasy chasm between LDTs, which can be developed and used within a certified lab without agency oversight, and in-vitro diagnostics (IVDs) that are approved by FDA isn’t simple or easy, particularly amidst a pandemic. The introduction of that legislation at that time destabilized LDT development, suggested Iafrate. The FDA has since stepped up its emphasis on prompt submission for an emergency use authorization (EUA) for COVID-19 diagnostic and antibody tests, under pressure after frequent reports of widely varying testing accuracy.

Small window for PCR

Panelists uniformly praised the FDA on accelerating quality testing, and seemed hopeful that the agency is equipped to continue to rapidly disseminate innovation in COVID-19 testing. But a lot of unknowns remain, most importantly around establishing a precise sequence and timing for various testing. And, of course, the ultimate usefulness of antibody tests hinges on the extent to which COVID-19 patients gain some immunity after infection.

“Early on in the acute infection, obviously PCR remains the gold standard; it is very sensitive, declines over a few days,” said Matt Sause, president and CEO of Roche North America, “By about day seven, on about half of people who are symptomatic we don’t do PCR. That's important for people doing diagnosis to know. On the other hand, antibodies, you can say are bad. They're not necessarily bad, you have to know what day you're looking at.”

“By about day seven, half of people have antibodies. So, the antibody test becomes better and better over time. By day 14, essentially everyone has antibodies,” Sause continued. “In the asymptomatic population, we're still learning. Until about seven days PCR tells if you are infectious. But data from Germany and now the CDC says that after about 10 days, you don’t detect infectious virus even if you do detect it with PCR. From an immunity standpoint, it's just going to take months and months for us to figure out what protection you have even If you're a strong positive.”

That suggests that the window of usefulness for PCR tests is quite narrow, falling off by the seventh day after symptom onset, which is precisely when antibody tests start to become useful.

If antibody-associated immunity can be established and tested for, then it becomes easier to identify the best former COVID-19 patients for plasma donation to develop a therapy based on the most effective antibodies. Interestingly, researchers are also starting to look at the challenge of identifying which patients could also benefit the most from convalescent plasma.

“There are a number of research approaches currently to neutralization, in vitro assays that you can use. In our hands, most of the patients with high-titer antibodies to the receptor-binding domain of the spike protein should show neutralization in vitro,” said Iafrate. “But that needs to be borne out in clinical trials of convalescent blood products.”

“One thing that many people aren't currently looking at are the recipients and are their antibody or other biomarkers that could be used in the recipients to define who would benefit the most,” he continued. “So, we're actively learning about the correlates of immunity, especially in those that are severely affected in our ICU and hospitals, and that may lead us down the road of not just finding the right donors but the right recipients.”

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