We all have friends or relatives who, somehow, have managed to avoid catching COVID-19, which has infected more than 91.5 million Americans. You may even be one of the lucky ones yourself.
But health experts are saying: Not so fast. because they didn’t have symptoms or had mild cases they mistook for a cold or allergies.
The upshot: These silent COVID-19 cases reflect a hidden side of the pandemic that may be helping to drive new surges and viral variants.
Still, infectious disease experts say there is little doubt that some people have indeed managed to avoid COVID-19 infection altogether, and they are trying to understand why.
Several recent studies have suggested certain genetic and immune system traits may better protect this group of people against the coronavirus, making them less likely than others to be infected or seriously sickened. Researchers around the world are now studying these seemingly super-immune people for clues to what makes them so special, with an eye toward better vaccines, treatments, and prevention strategies.
Infectious disease specialists say both types of cases – those unknowingly infected by COVID-19 and people who’ve avoided the virus altogether – matter greatly to public health, more than 2 years into the pandemic.
“It’s definitely true that some people have had COVID and don’t realize it,” says Stephen Kissler, PhD, an infectious disease researcher with the Harvard T.H. Chan School of Public Health, Boston. “It is potentially good news if there’s more immunity in the population than we realize.”
But he says that being able to identify genetic and other factors that may offer some people protection against COVID-19 is an “exciting prospect” that could help find out who’s most at risk and improve efforts to get the pandemic under control.
Some studies have found a person’s genetic profile, past exposure to other COVID-like viruses, allergies, and even drugs they take for other conditions may all provide some defense – even for people who have not been vaccinated, don’t use masks, or don’t practice social distancing.
A person’s medical history and genetics may help decide their risk from new diseases, meaning “we may be able to help identify people who are at especially high risk from infection,” Dr. Kissler says. “That knowledge could help those people better shield themselves from infection and get quicker access to treatment and vaccines, if necessary. … We don’t yet know, but studies are ongoing for these things.”
Amesh Adalja, MD, an infectious disease specialist with the Johns Hopkins Center for Health Security, Baltimore, agrees that emerging research on people who’ve avoided infection offers the chance of new public health strategies to combat COVID-19.
“I’m sure there is some subset of people who are [COVID] negative,” he says. “So what explains that phenomenon, especially if that person was out there getting significant exposures?”
Have you had COVID without knowing it?
In a media briefing late last month, White House COVID-19 Response Coordinator Ashish Jha, MD, said more than 70% of the U.S. population has had the virus, according to the latest CDC data. That’s up from 33.5% in December.
But the actual number of people in the U.S. who have been infected with SARS-CoV-2, the scientific name for the virus that causes COVID-19, is likely to be much higher due to cases without symptoms that are unreported, experts say.
Since the early days of the pandemic, researchers have tried to put a number on these hidden cases, but that figure has been evolving and a clear consensus has not emerged.
In September 2020, a study published in the Annals of Internal Medicine said “approximately 40% to 45% of those infected with SARS-CoV-2 will remain asymptomatic.”
A follow-up analysis of 95 studies, published last December, reached similar findings, estimating that more than 40% of COVID-19 infections didn’t come with symptoms.
To get a better handle on the issue, CDC officials have been working with the American Red Cross and other blood banks to track COVID-19 antibodies – proteins your body makes after exposure to the virus to fight off an infection – in donors who said they have never had COVID-19.
While that joint effort is still ongoing, early findings say the number of donors with antibodies from COVID-19 infection increased in blood donors from 3.5% in July 2020 to at least 20.2% in May 2021. Since then, those percentages have soared, in part due to the introduction of vaccines, which also make the body produce COVID-19 antibodies.
The most current findings show that 83.3% of donors have combined COVID infection– and vaccine-induced antibodies in their blood. Those findings are based on 1.4 million blood donations.
Health experts say all of these studies are strong evidence that many COVID-19 cases continue to go undetected. In fact, the University of Washington Institute for Health Metrics and Evaluation estimates that only 7% of positive COVID-19 cases in the U.S. are being detected. That means case rates are actually 14.5 times higher than the official count of 131,000 new COVID infections each day, according to the Centers for Disease Control and Prevention, which reports the virus is still killing about 440 Americans daily.
So, why is all this important, in terms of public health?
Experts say people are more likely to be cautious if they know COVID-19 cases are high where they live, work, and play. On the other hand, if they believe case rates in their communities are lower than they actually are, they may be less likely to get vaccinated and boosted, wear masks indoors, avoid crowded indoor spaces, and take other precautions to fend off infection.
How do some avoid infection altogether?
In addition to tracking cases that go unreported and don’t have symptoms, infectious disease experts have also been trying to figure out why some people have managed to avoid getting the highly contagious virus.
Several leading lines of research have produced promising early results – suggesting that a person’s genetic makeup, past exposure to less-lethal coronaviruses, allergies, and even certain drugs they take for other conditions may all provide at least some protection against COVID.
“Our study showed that there are many human genes – hundreds of genes – that can impact SARS-CoV-2 infection,” says Neville Sanjana, PhD, a geneticist at New York University and the New York Genome Center who co-led the study. “With a better understanding of host genetic factors, we can find new kinds of therapies that target these host factors to block infection.”
In addition, he says several studies show some drugs that regulate genes, such as the breast cancer drug tamoxifen, also appear to knock down COVID-19 risk. He suggests such drugs, already approved by the Food and Drug Administration, might be “repurposed” to target the virus.
Studies in other countries show that patients taking tamoxifen before the pandemic were protected against severe COVID-19, Dr. Sanjana says. “That was a really cool thing, highlighting the power of harnessing host genetics. The virus critically depends on our genes to complete key parts of its life cycle.”
The NYU research findings echo other studies that have been published in recent months.
In July, a team of researchers led by the National Cancer Institute identified a genetic factor that appears to determine how severe an infection will be. In a study involving 3,000 people, they found that two gene changes, or mutations, that decrease the expression of a gene called OAS1 boosted the risk of hospitalization from COVID-19. OAS1 is part of the immune system’s response to viral infections.
As a result, developing a genetic therapy designed to increase the OAS1 gene’s expression might reduce the risk of severe disease.
“It’s very natural to get infected once you are exposed. There’s no magic bullet for that. But after you get infected, how you’re going to respond to this infection, that’s what is going to be affected by your genetic variants,” said Ludmila Prokunina-Olsson, PhD, the study’s lead researcher and chief of the National Cancer Institute’s Laboratory of Translational Genomics, Bethesda, Md., in an interview with NBC News.
Benjamin tenOever, PhD, a New York University virologist who co-authored the 2020 research, says the new genetic research is promising, but he believes it’s unlikely scientists will be able to identify a single gene responsible for actually preventing a COVID-19 infection.
“On the flip side, we have identified many genes that makes the disease worse,” he says.