What if more of us have fought off COVID-19 than we think?

So-called serology research looks for antibodies in the blood that fight the illness, and how many of us have them. Other research looks at how long these antibodies last. The latest results from these studies are said to show us two kinds of bad news — that immunity after exposure to the illness is not such a sure thing, and that the number of us who have been exposed and fought off COVID-19 are fewer than hoped.

This pushes our goal of herd immunity farther into the distance, potentially even calling it into question altogether. But in measuring antibodies for COVID-19, might we have overlooked other blood markers that help fight off the sickness? Is it possible we are under-estimating both how long immunity lasts, and how close to herd immunity we really are?

Consider some recent observations.

COVID-19 cases may be surging across the state and the nation, but in former hotspots for the virus like Wuhan, China; New York; Spain; Sweden and the Lombardy region of Italy, case numbers and deaths have been declining steadily. Lombardy, once the source of a horrific COVID-19 outbreak, recently had two straight days with no deaths linked to the virus.

These declines have come about despite seroprevalence surveys that say just 5, 15 or 20% of the population has had the illness in those locales, and other data suggesting that antibodies fade quickly. For health officials, such big declines, with only small exposure to illness in the population, prove the power of lockdowns, social distancing, masking, handwashing and PPE.

Others have begun to argue something far more hopeful. That while masking, social distancing and handwashing and lockdowns are all powerful tools in reducing the spread of illness, they aren’t enough to get the credit for so many hotspots having gone cold. Instead, they say, more of us may be immune than we realize.

“When we get exposed to an infection, two big types of immune responses occur,” says Dr. Vincent Rajkumar, an oncologist at Mayo Clinic who conducts research on the type of blood cells that help us fight infection. “One is called antibody-mediated immunity. This is where you make specific proteins called antibodies to fight infections.”

“The second type of response is called cell-mediated (or T-cell) immunity. Here you don’t make antibodies, but you actually have specific cells that target the offending infection.” Serologic studies measure antibodies, but do not measure cell-mediated immunity.

In addition, Rajkkumar says, serologic tests can miss antibodies that are present in lower concentration than the assay can detect, or we may have other antibodies directed at the virus than what a given serologic test is designed to identify.

“The virus has many proteins,” he says, “and it is possible that a person is developing antibodies against other parts of the virus that we are not checking.”

Some even wonder if recent immunizations in children are what’s made them less susceptible to bad outcomes from COVID-19.

“Back in March when we were all thinking out loud,” Rajkumar says, “one of the thoughts I had was, why were children relatively protected from being seriously ill with COVID-19? Was it because of the multiple childhood vaccines they receive leading to a more responsive immune system?”

Answering these questions in the lab is no small task.

“We would have to do T-cell assays in a well-defined population to find out how many people have only antibodies, how many have only T-cells responses, and how many have both,” he explains. “Then we need adequate follow-up to determine what proportion get COVID-19 in the future. Those studies are hard to do.”

Researchers do know some persons appear to have T-cells that are cross-reactive to SARS-Cov-2 from blood samples collected before the pandemic. A recent study from Sweden has shown there are close family contacts who have reactive T-cells after having been exposed to COVID-19 without developing antibodies.

“I think the big decline in new cases we see in many hotspots are partly explained by masks, partly explained by social distancing, and may partly be explained by a larger portion of the population already being exposed.”

“All of these observations put together makes us wonder if a greater proportion of the population is not susceptible to COVID-19 than what current sero-prevalence studies suggest,” Rajkumar says.

Rajkumar has been sharing these questions on Twitter, and they are the subject of lively interactions between some of the nation’s top scientists.

So, if serology studies only show us part of the picture, how many of us are potentially immune to COVID-19?

“I think it’s much higher,” Rajkumar says. “I think it’s at least double what sero-prevalence studies are reporting.”