ROCHESTER, Minn. — The depth and breadth of new research generated by COVID-19 has been unlike any period in history. With the entire global scientific community focused on the same novel pathogen, keeping up with what has been learned about the pandemic has been like drinking from a firehose.

Many basic questions about the coronavirus were answered quickly. A pressing set of questions, however, remain unanswered. Here are five gaps needing answers in 2021.

1) Does "viral load" matter?

Up until now, the diagnostic result of a COVID-19 test has been an either-or outcome -- you provide the lab with a sample, and the lab comes back with a yes or a no.

This assumes the course of illness is the same whether the virus is found in large quantities or small, and that any difference in how a person fares under COVID-19 comes down to personal characteristics. But what if the degree to which people did worse was driven in part by how much COVID a person had at diagnosis?

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This metric is known as "viral load."

It is identified in most diagnostic tests, and it is increasingly believed to offer a signal as to whether the patient will need hospitalization, or is more likely to infect others.

Viral load changes throughout a person's course of illness, however. It rises as the virus incubates, and falls as the immune response kicks in. Some research even shows an inverse relationship between the amount of virus in the body and outcome.

Recently, regulators have begun to advise testing centers to report the metric with a person's PCR status.

2) Does "viral load" cause worse outcomes for persons with underlying conditions?

The data is clear that minority communities fare worse under COVID-19, both in terms of incidence and severity of illness.

Higher incidence rates among minorities are attributed to jobs lacking the freedom to work from home, as well as larger households and smaller living quarters that make quarantine impossible.

Poor outcomes among minorities are believed to be driven by a complex set of variables, including delayed care, poor care, chronic, stress-driven inflammatory states causing a state of heightened immunoreactivity, and a higher prevalence of underlying medical conditions.

But research shows this vulnerability among minorities is not associated with higher viral loads upon diagnosis. What research has shown is that patients with underlying conditions are admitted with higher viral loads. So it is possible that something about these underlying conditions isn't the problem, rather, that they cause COVID-19 to load in greater quantities.

3) What does the new strain of COVID-19 tell us about lockdowns?

A new strain of COVID-19, first identified in southern England, is now in circulation in the U.S. It is almost twice as infectious, albeit not associated with worse outcomes. (It is associated with higher viral loads.)

More infectiousness increases cases, however, and that increases bad outcomes on a population basis.

Lost in the news about this new form of COVID-19 is whether the virus mutated to a higher level of infectiousness due to evolutionary pressures created by the circumstances of lockdown, or the lack thereof.

Evolutionary biology looks at viruses from the point of view of the pathogen's search for survival and replication. Because COVID-19 is airborne and not waterborne, if we shelter, mask and distance in a strict lockdown, the virus risks its survival by evolving to more deadly strains. When you can't travel, you don't want to kill your host.

Currently, the new virus has shown up heavily in two places with divergent approaches to lockdown -- England (high lockdown), and South Africa (low lockdown). It's unchanged virulence suggests that the lockdown in England held the severity of the virus in check as it learned to better attach to spike proteins.

That is good news, because if COVID-19 were to mutate in regions where it could travel more easily, evolutionary pressures should cause it to mutate towards faster spread (to push out other strains), and possibly more death per case.

The arrival of vaccines will almost certainly cause the virus to mutate again. Scientists believe any mutations that invalidate the current antibodies will happen over a course of years, however, not months.

4) Can you transmit the virus after becoming vaccinated?

Just because the new vaccines have 94-95% effectiveness in preventing mild illness does not mean they prevent infectiousness, serious illness, or even death.

The manufacturers did not study those outcomes, because that would have required a much larger trial than was possible.


Instead,. they effectively placed a bet that any vaccine which prevents mild illness will also prevent death and your ability to give it to others.

But those remain unknowns.

As a result, the first year of the new vaccines will require close study of infection and death rates. If they begin falling, the manufacturers' bet will have proven correct, and the masks can come off.

5) Where did COVID-19 come from?

A very close form of the virus exists in horseshoe bats found in China, and has for decades. But that virus appears to have mutated before jumping to humans, likely via an intermediate host.

The leading suspects for that host are pangolins, endangered, scaly anteaters that are the most trafficked species in the world, traded for the supposed medicinal qualities of its scales (which are really just keratin, the material in fingernails).

To definitively trace COVID-19 to pangolins, the scientific community would need to find a pangolin with the same virus discovered in Wuhan, something that has not yet happened. Complicating this question -- humans can give COVID back to animals. Meaning, it's possible any animal found with COVID-19 got it from us.

Preventing the next COVID-19 will have as much to do with shutting down the wildlife trade as anything carried out in a pharmaceutical laboratory.