Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.
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. A mounting pile of scientific evidence suggests millions of Americans have been infected with the virus without ever even knowing it 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. “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 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,” 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, 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 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 Medicinesaid “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 CDC, 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 FDA, 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, 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, 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.
T Cells “Remember” Past Viral Infections
As tenOever and Sanjana suggest, another intriguing line of research has found that prior viral infections may prime the body’s immune system to fight COVID-19.
Four other common coronaviruses – aside from SARS-CoV-2 – infect people worldwide, typically causing mild to moderate upper respiratory illnesses like the common cold, says Alessandro Sette, PhD, an infectious disease expert and vaccine researcher with the La Jolla Institute for Immunology.
In a recent study published in Science, he and his team found past infection with these other coronaviruses may give some protection against SARS-CoV-2.
T cells – white blood cells that act like immunological ninjas to ferret out and fight infections – appear to maintain a kind of “biological memory” of coronaviruses they have seen before and can mount an attack on similar pathogens, such SARS-CoV-2, Sette says.
The new work builds on a prior research he helped lead that found 40%-60% of people never exposed to SARS-CoV-2 had T cells that reacted to the virus – with their immune systems recognizing fragments of a virus they had never seen before.
Sette says his research shows that people whose T cells have this “pre-existing memory” of past coronavirus exposures also tend to respond better to vaccination for reasons not yet well understood.
“The question is, at which point will there be enough immunity from vaccination, repeated infections from other coronaviruses, but also some of the variants of the SARS-CoV-2 … where infections become less frequent? We’re not there yet,” he says.
In addition to these exciting genetic and T-cell findings, other research has suggested low-grade inflammation from allergies – a key part of the body’s immune response to foreign substances – may also give some people an extra leg up, in terms of avoiding COVID infection.
Last May, a study of 1,400 households published in The Journal of Allergy and Clinical Immunology found that having a food allergy cut the risk of COVID-19 infection in half.
The researchers said it’s unclear why allergies may reduce the risk of infection, but they noted that people with food allergies express fewer ACE2 receptors on the surface of their airway cells, making it harder for the virus to enter cells.
The Big Picture: Prevention Still Your Best Bet
So, what’s the takeaway from all of this emerging research?
New York University’s tenOever says that while genes, T cells and allergies may offer some protection against COVID, tried-and-true precautions – vaccination, wearing masks, avoiding crowded indoor spaces, and social distancing – are likely to provide a greater defense.
He believes these precautions are likely why he and his family have never contracted COVID-19.
“I was tested weekly, as were my kids at school,” he says. “We definitely never got COVID, despite the fact that we live in New York City and I worked in a hospital every single day of the pandemic.”
Ziyad Al-Aly, MD, an infectious disease specialist and director of clinical epidemiology at Washington University in St. Louis, agrees that the new research on COVID-19 is intriguing but won’t likely result in practical changes in the approach to fighting the virus in the near term.
“Getting a deeper understanding of potential genetic factors or other characteristics – that could really help us understand why the virus just comes and goes without any ill effects in some people, and in other people it produces really serious disease,” he says. “That will really help us eventually to design better vaccines to prevent it or reduce severity or even [treat] people who get severe disease.”
In the meantime, Al-Aly says, “it’s still best to do everything you can to avoid infection in the first place – even if you’re vaccinated or previously infected, you should really try to avoid reinfection.”
That means sit outside if you can when visiting a restaurant. Wear a mask on a plane, even though it’s not required. And get vaccinated and boosted.
“In the future, there may be more tools to address this pandemic, but that’s really the best advice for now,” Al-Aly says.
CDC: “COVID Data Tracker.”
The White House: “Press Briefing by Press Secretary Karine Jean-Pierre and COVID-19 Response Coordinator Dr. Ashish Jha.”
Center for infectious Disease Research and Policy: “CDC: 58% of Americans have had COVID-19.”
Stephen Kissler, PhD, infectious disease researcher, Harvard T.H. Chan School of Public Health, Boston.
Amesh Adalja, infectious disease specialist, Johns Hopkins Center for Health Security, Baltimore.
Neville Sanjana, PhD, geneticist, New York University and the New York Genome Center.
Benjamin tenOever, PhD, virologist, New York University.
Alessandro Sette, PhD, infectious disease expert, vaccine researcher, La Jolla Institute for Immunology, La Jolla, CA.
Ziyad Al-Aly, MD, infectious disease specialist, director of clinical epidemiology, Washington University in St. Louis.
Annals of Internal Medicine: “Prevalence of Asymptomatic SARS-CoV-2 Infection.”
JAMA Network: “Global Percentage of Asymptomatic SARS-CoV-2 Infections Among the Tested Population and Individuals With Confirmed COVID-19 Diagnosis,” “Estimated US Infection- and Vaccine-Induced SARS-CoV-2 Seroprevalence Based on Blood Donations, July 2020-May 2021,” “Global Percentage of Asymptomatic SARS-CoV-2 Infections Among the Tested Population and Individuals With Confirmed COVID-19 Diagnosis.”
Smithsonian Magazine: “What Scientists Are Learning About Covid-19 Using the Nation’s Blood Supply.”
CNN: “Rise in at-home testing means we could be undercounting Covid-19 cases even more than before.”
The New York Times: “Coronavirus in the U.S.: Latest Map and Case Count.”
NBC: “Scientists are narrowing in on why some people keep avoiding COVID-19.”
Cell: “Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells,” “Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed individuals.”
Genome Biology: “Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.”
Cancer Research: “Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome.”
Nature Genetics: “Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries.”
ResearchSquare: “Outcomes of SARS-CoV-2 Reinfection.”
Science: “Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans,” “Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.”
Cell Host & Microbe: “Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response.”
The Journal of Allergy and Clinical Immunology: “Risk factors for SARS-CoV-2 infection and transmission in households with children with asthma and allergy: A prospective surveillance study.”
Proceedings of the National Academy of Sciences. “Asymptomatic SARS-CoV-2 infection: A systematic review and meta-analysis.”
Annals of Internal Medicine: “Prevalence of Asymptomatic SARS-CoV-2 Infection.”
NPR: “Why hasn’t my daughter caught COVID? 2 factors likely protect her – and maybe you too.”
T Cells ‘Remember’ Past Viral Infections