Since the start of the coronavirus pandemic, scientists have been puzzled about why many people who contract the virus develop symptoms of Covid-19 while others don't experience any symptoms at all. Now, recent research has produced a handful of theories, Ariana Eunjung Cha reports for the Washington Post.

Cheat sheets: Population Health 101

Large numbers of asymptomatic patients

Data has shown that a large percentage of people who've been infected with the novel coronavirus do not experience symptoms of Covid-19, the disease the virus can cause. For instance, 88% of 147 infected residents at a Boston homeless shelter were asymptomatic, while 95% of the 481 people infected at a Tyson Foods factory showed no symptoms, Cha reports.

This trend is significant, Cha reports, because understanding what shielded asymptomatic individuals from severe illness could help researchers develop vaccines and therapies to treat Covid-19, or to potentially create ways to develop herd immunity against the virus.

Now, initial research is finally revealing some clues, Cha writes. Here are four theories research suggests may be the reason so many people infected with the new coronavirus are asymptomatic:

Report: Investing in the well-being of the health care workforce

1. T-cell memory

One theory suggests that some people have partial immunity to the coronavirus due to so-called "memory" T cells—white blood cells that run the immune system and are in charge of recognizing invaders, Cha reports.

For instance, researchers in a study published in the journal Cell compared blood samples from people recovering from Covid-19 with samples from uninfected people who donated blood between 2015 and 2018. According to the researchers, the T cells in 40% to 60% of the old samples appeared to recognize the new coronavirus—a finding echoed by research teams in the Netherlands, Germany, and Singapore.

A related paper published this week in the journal Science suggested that this partial immunity could come from exposure to other coronaviruses, such as those that cause the common cold. And the immune system's strongest response, according to the study, was against the spike proteins used by the novel coronavirus to break into cells—indicating "that fewer of these viral copies get past these defenses," Cha writes.

"The [new coronavirus] didn't even exist back [when the old blood samples were taken], so to have this immune response was remarkable," Alessandro Sette, one of the authors of the Science and Cell studies from the La Jolla Institute for Immunology, said. And citing the immune response to spike proteins in particular, Sette added, "The current model assumes you are either protected or you are not—that it's a yes or no thing. But if some people have some level of preexisting immunity, that may suggest it's not a switch but more continuous."

NIH Director Francis Collins said this theory could "potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill."

However, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, cautioned that the theory is premature, though he agreed that some partial, already present immunity in some patients is a possibility. "There are so many other unknown factors that maybe determine why someone gets an asymptomatic infection," such as age and overall health, he said. "It's a very difficult problem to pinpoint one thing."

Infographic: Past, present, and future care for an aging population

2. Immunity from childhood vaccinations

Another theory suggests that childhood vaccines may have provided partial immunity against the new coronavirus for some patients, Cha reports.

Andrew Badley, a researcher at the Mayo Clinic, and his team collaborated with data experts from nference to examine 137,037 Mayo patient records to look for a link between vaccinations and infection from the novel coronavirus.

They found that seven types of childhood vaccines—administered one, two, or five years previously—were associated with having a lower infection rate from the coronavirus. This was especially true among people who recently received a pneumonia vaccine, which was associated with a 28% reduction in coronavirus-infection risk, and polio vaccines, which were associated with a 43% reduction in coronavirus-infection risk. And those associations held even after adjusting for a variety of factors, including geographic incidence of the virus, demographics, and underlying conditions, the researchers said.

However, since the study is observational and cannot show causality, researchers at Mayo are now looking at ways to quantify how the vaccines affect the new coronavirus, Cha reports. After all, as Badley pointed out, if existing vaccines end up being as effective against the coronavirus as vaccines currently under development, the finding could upend how countries are approaching vaccines against the novel virus altogether.

Resource library: Expedite patient diagnosis

3. Biology

Researchers at NIH are looking into a theory that suggests ACE2 receptors may affect the severity of illness a person develops from the new coronavirus.

According to Cha, the coronavirus can "latch" onto ACE2 receptors, which in healthy people keep blood pressure stable, then travel through the body and replicate. Researchers are intrigued by the receptors because they've theorized that minimizing those receptors may obstruct the virus' ability to replicate or "trick the virus into attaching itself to a drug" instead, so it's not able to replicate and travel through the body, Cha reports.

In addition, counterintuitive findings suggest that "allergic reactions may protect you by down-regulating the receptor," Alkis Togias, an NIH researcher, said—although he cautioned it was "only a theory."

Specifically, recent research has found that ACE2 receptors were diminished in children with lots of allergies and asthma—findings that, when paired with hospital data, indicate that asthma doesn't appear to be a risk factor for the new coronavirus.

As a result, Togias and his team are working on a study of 2,000 American families to see how ACE2 receptors are expressed differently as people age, hoping to better understand how the receptors affect the new coronavirus by comparing the receptors' differences and immune responses within the families, Cha reports.

Cheat sheets: Evidence-based medicine 101

4. Masks

Researchers are also exploring whether widespread mask use affects the severity of Covid-19, Cha reports.

Monica Gandhi, a researcher at the University of California, noticed how different asymptomatic case numbers were on two different cruise ships. On the Diamond Princess, where masks weren't used, 47% of those infected with the virus were asymptomatic. But on an Argentine cruise ship, where all passengers were given surgical masks and crew received N95s, 81% of cases were asymptomatic. Similarly, according to Gandhi, countries that implemented population-level mask mandates—including the Czech Republic, Singapore, and Vietnam—"got cases, but fewer deaths."

And Gandhi also noted, in an article published in the Journal of General Internal Medicine, that in some early coronavirus outbreaks where people weren't wearing masks, 15% of those infected were asymptomatic. However, later in the pandemic, when more people were wearing masks, asymptomatic rates jumped between 40% and 45%. Gandhi said that data indicates that masks may not only protect others—as health officials in the United States have stated—but they may also protect the wearer (Cha, Washington Post, 8/8).