Seasonal Coronaviruses: OC43, 229E, NL63 & HKU1

When most people hear "coronavirus," they think of COVID-19. But four members of the family have circulated among humans for a long time, mostly causing runny noses, sore throats, and coughs. OC43, 229E, NL63, and HKU1 are among the many viruses behind the common cold, and they share a surprising connection to SARS-CoV-2: understanding why they stay mild, and why we keep catching them, tells us a lot about immunity itself.

Educational content, not medical advice. Talk to a clinician about any symptoms or treatment decisions. Information here reflects published research, but every person's situation differs.

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What a coronavirus is, and why the name fits

Coronaviruses belong to the family Coronaviridae. They are enveloped viruses, meaning each particle is wrapped in a fatty membrane taken from the host cell, and their genetic material is a single strand of RNA. Their genomes are large for RNA viruses, about 30 kilobases in the case of OC43 according to the 2005 genome analysis by Vijgen and colleagues, and 29.9 kilobases for HKU1 according to the team that first sequenced it.

The name comes from the Latin corona, a crown. Under an electron microscope, the spike proteins sticking out of the envelope give each particle a halo. Those spikes matter more than anything else about the virus, because they are what the virus uses to find and enter cells.

Three structural proteins do most of the work:

• Spike (S): the entry tool. One part (S1) attaches to a receptor on the host cell, and another part (S2) helps fuse the virus and cell membranes. Spike is also the main target of neutralizing antibodies.
• Envelope (E) and membrane (M): help shape the particle and assemble new ones.
• Nucleocapsid (N): wraps and packages the RNA genome.

A useful analogy: the spike is a key, and the receptor on a cell is the lock. A virus can only infect cells whose locks its key fits, which is why different coronaviruses pick different targets in the body. For the full step-by-step process of entry, copying, and exit, see How Viruses Work: From Infection to Replication.

Coronaviruses that infect humans fall into two genera. 229E and NL63 are alphacoronaviruses. OC43, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2 are betacoronaviruses.

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The four seasonal coronaviruses at a glance

Virus	Genus	Receptor	First reported	Notes
229E	Alpha	Aminopeptidase N (APN, also called CD13)	1966	First human coronavirus isolated
OC43	Beta	9-O-acetylated sialic acid	1967	Close relative of bovine coronavirus
NL63	Alpha	ACE2	2004	Uses the same receptor as SARS-CoV
HKU1	Beta	Acetylated sialic acid	2005	First found in a patient with pneumonia

The discovery dates tell a story of their own. The two oldest were found with 1960s techniques, in tissue culture and organ culture. NL63 and HKU1 were reported in 2004 and 2005, and the NL63 team's own screening of respiratory samples suggested the virus was already widespread when it was found. Newer viruses are often old residents that finally met a better detection method.

229E: the first human coronavirus

Hamre and Procknow described 229E in 1966, isolating a new virus from the respiratory tract of a person with a cold. It binds aminopeptidase N, an enzyme found on the surface of cells in the lining of the airway and elsewhere, rather than ACE2. It mainly infects the upper airways and typically produces cold symptoms.

OC43: a possible visitor from cattle

OC43 was recovered by McIntosh and colleagues in 1967 using organ cultures of human tracheal tissue. Its genome is very similar to that of bovine coronavirus (BCoV), a cattle virus, and both use sialic acid-based receptors. In their 2005 paper in the Journal of Virology, Vijgen and colleagues used molecular clock analysis of spike gene sequences to date the most recent common ancestor of the two viruses to around 1890. They described the pair as the first animal-human coronavirus pair suitable for studying how a nonhuman coronavirus adapts to humans.

A molecular clock is a method that estimates when two lineages diverged by counting the mutations that separate them and assuming a roughly steady rate of change, much as you might estimate how long ago two copies of a handwritten manuscript were made by counting the differences between them. It gives an estimate with real uncertainty, not a precise date.

NL63: a familiar receptor, a mild outcome

NL63 was reported in 2004 by van der Hoek and colleagues, who isolated it from a seven-month-old child with bronchiolitis and conjunctivitis. They found seven more infected people when they screened other respiratory samples, which suggested the virus was already widespread.

A year later, Hofmann and colleagues showed that NL63 uses ACE2, the same receptor as SARS-CoV, to enter cells. They also found that most blood samples from people aged 8 and older neutralized NL63, which suggests infection is common and usually happens in childhood. That finding matches what the virus does in practice: most people meet it early and recover.

HKU1: found in a pneumonia patient

HKU1 was described in 2005 by Woo and colleagues in Hong Kong. It was found in a 71-year-old man with pneumonia who had recently traveled from Shenzhen, China, and the team later found it in a second patient, a 35-year-old woman with pneumonia. Its genome has the lowest G+C content (32 percent) among the coronaviruses known at the time, and it proved difficult to grow in cell culture. Like OC43, it belongs to the betacoronaviruses and uses acetylated sialic acid receptors.

The fact that HKU1 was discovered in sick patients does not mean it is typically severe. Researchers find new viruses where doctors send samples, and serious cases are the ones that get tested. Surveillance data, discussed next, show that most detections are in ordinary respiratory illness.

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How common are they?

Several of the best numbers come from large laboratory surveillance. A US study by Killerby and colleagues, published in 2018 in the Journal of Clinical Virology, looked at 854,575 human coronavirus tests reported by 117 laboratories between July 2014 and June 2017.

Virus	Share of tests positive (US, 2014 to 2017)
OC43	2.2%
NL63	1.0%
229E	0.8%
HKU1	0.6%

Two cautions. First, these are percentages of tests ordered, which are not the same as percentages of all colds, because only some people with symptoms get tested at all. Second, the figures describe one country over three years, and the mix of viruses changes from season to season.

For perspective on the share of colds, a classic study by Mäkelä and colleagues (1998, Journal of Clinical Microbiology) tested 200 adults with colds in Finland. It found rhinoviruses in 105 of the 200 (about 50 percent) and coronavirus (OC43 or 229E) in 17 (8.5 percent). Different years, countries, ages, and test methods give different numbers, so treat any single figure with caution. The CDC says more than 200 respiratory viruses can cause colds, and rhinoviruses are the most common cause in the United States; see Rhinovirus and the Common Cold Explained for that group.

The winter pattern

Killerby and colleagues also found that the percentage of positive tests peaked from December to March each year. That is the familiar cold-season rhythm for temperate climates.

Researchers have proposed several reasons for winter seasonality in respiratory viruses in general: people spend more time indoors in close contact, and cold, dry air may affect how well the airways clear and how well viruses survive. Which factors matter most for each virus is still studied, so it is more accurate to say these are plausible contributors than established causes. The CDC notes that colds can occur at any time of year, and that other cold-causing viruses circulate in spring, summer, or fall.

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Why do the same colds keep coming back?

If you feel as though you catch a cold every few months, you are not imagining a weak immune system. Seasonal coronaviruses are a case study in immunity that works but does not last.

In 2020, Edridge and colleagues published a study in Nature Medicine that followed healthy people for more than 35 years. They found that reinfection with the same seasonal coronavirus often occurred about 12 months after the first infection. That is a short window, and it tells us that the antibody response against these viruses wanes over a year or so, not over a lifetime.

Two mechanisms plausibly contribute, and the evidence for each varies:

1. Waning protection against infection. Antibodies that block the virus at the nose and throat decline over months. When the next season arrives, the virus finds less resistance.
2. Changing viruses. Seasonal coronaviruses can drift, accumulating small spike changes that make old antibodies a poorer match. The evidence is stronger for some of these viruses than others, and it is easy to overstate.

A subtler idea comes from the modeling paper by Lavine, Bjornstad, and Antia (2021, Science): immunity that blocks infection fades quickly, while immunity that reduces disease severity lasts much longer. Together, that pattern could explain why adults catch seasonal coronaviruses repeatedly but usually have mild illness. Think of it as a smoke alarm that stops being sensitive to a brief puff of smoke but still wakes you for a real fire. Reinfection happens, but the immune memory still limits how bad it gets.

For how the antibody part of this works, see Antibody Structure: How the Immune System's Y-Shaped Weapon Works, and for the broader process, How the Human Immune System Fights Viruses.

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NL63 and SARS-CoV-2: same lock, different outcome

NL63 and SARS-CoV-2 both use ACE2 to enter cells, yet one usually causes a cold and the other can cause severe pneumonia. This is one of the instructive puzzles in the field, and a few points are worth stating carefully.

Receptor choice alone does not decide severity. A lock only lets the virus in. What happens afterward depends on where the virus replicates, how fast it spreads between cells, how well it blocks early immune signals, and how the host responds. NL63 is generally associated with upper airway infection and common colds, while SARS-CoV-2 can infect the lower respiratory tract.

Several factors are discussed in the research literature. They include how tightly each spike binds ACE2, how each virus's spike is activated by host enzymes, how well each suppresses the body's interferon alarm signals, and which cells each infects. These factors are studied and debated, and published fold-differences vary with the method used, so none are quoted here.

Population immunity changes the picture. Hofmann and colleagues found that most people have been exposed to NL63 by age 8. First exposure in childhood, when disease from many respiratory viruses is milder, may be part of why the experience is mild. This is the same point Lavine and colleagues raise about SARS-CoV-2 as it moves toward endemicity.

The takeaway is that "uses ACE2" describes the lock, not the damage.

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How scientists tell the four apart

A runny nose does not reveal which virus caused it. Telling OC43 from 229E, NL63, or HKU1 takes a laboratory test, usually a PCR assay (a method that copies and detects a short stretch of a virus's genetic material). Hospital laboratories often run respiratory panels that check for many viruses at once, which is where surveillance numbers like Killerby's come from.

That has two consequences for how to read the numbers. A test is ordered when someone is sick enough to seek care, so mild infections in people who stay home are undercounted. And because panels look for several viruses at the same time, a sample can be positive for more than one, which complicates the question of which virus caused which symptoms. A 2026 retrospective study in Virology Journal that retested 127 swabs from Panama illustrates both points: it found 229E in three samples and OC43 in three, some alongside other respiratory viruses, in a set that included samples that had tested negative on the routine panel.

Researchers also use serology (testing blood for antibodies) to learn who has been exposed. That is how Hofmann and colleagues inferred that infection with NL63 is common in childhood, and it is how Edridge and colleagues tracked reinfections across decades. Antibody tests tell you about past exposure, PCR tells you about current infection, and each answers a different question.

Open questions

Several things remain unresolved, which is a reminder that even old, common viruses are not fully understood:

• How much each seasonal coronavirus changes its spike over time, and how fast that drift erodes existing immunity.
• Why the mix of the four viruses shifts from one winter to the next.
• How much earlier exposure to seasonal coronaviruses shapes the course of COVID-19, a question that remains under study.
• Whether the pattern seen in adults, repeat infection with mostly mild illness, will hold for SARS-CoV-2 as exposure begins earlier in life.

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Who can get seriously ill?

For most healthy adults, a seasonal coronavirus is a nuisance. Severe disease is uncommon, but not nonexistent, and the pattern resembles other respiratory viruses.

• Infants and young children can develop lower respiratory tract illness, as the original NL63 case of bronchiolitis showed.
• Older adults and people with chronic lung or heart conditions are more likely to have complications from any respiratory virus.
• People with weakened immune systems, such as some transplant recipients and those on strong immunosuppressive drugs, can have longer or more serious infections.

The word "mild" in this article describes a population average, not a guarantee for any one person. Anyone with trouble breathing, a persistent high fever, or symptoms that worsen should seek medical care. Fever itself is part of how the body fights infection; see Why Fevers Help Fight Infections for the mechanism.

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Could OC43 have caused the "Russian flu" of 1889 to 1890?

This is the most intriguing, and most speculative, story in this field. The "Russian flu" pandemic of 1889 to 1894 killed roughly one million people worldwide according to international estimates cited in a 2025 historical study in the Archives of Iranian Medicine on its spread into Iran. The OC43 molecular clock gave a date near 1890 for the cattle-to-human divergence. Those two facts line up, and some researchers have suggested that a coronavirus entering a population with no prior immunity could have caused that pandemic. A 2024 paper in Brain, Behavior, & Immunity - Health notes the coincidence and argues OC43 can serve as a research proxy for studying SARS-CoV-2's neurological effects.

Treat the idea as a hypothesis, not a finding. There are no preserved viral samples from 1889 to test. The date estimate comes with uncertainty, and the overlap in timing could be coincidence. What is not in doubt is the general principle: viruses do jump from animals to humans, and a spillover that causes severe disease in the first generation can settle into a milder pattern later. For how those jumps happen, see How Viruses Jump From Animals to Humans.

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Will SARS-CoV-2 become a fifth seasonal coronavirus?

The Lavine paper offers one of the clearest frameworks. Using immunological and epidemiological data on endemic coronaviruses, the authors built a model that reproduces both the current severity of SARS-CoV-2 and the mildness of common cold coronaviruses. It suggests that once SARS-CoV-2 becomes endemic and most people first meet it in childhood, it may be no more dangerous than a common cold. They add a caveat: this would not hold for a new coronavirus that causes severe disease in children, and they stress that this outcome depends on immunity building up, with vaccination and behavior during the transition mattering.

So the optimistic path is real but conditional. Nothing in this reasoning says the timeline is short, or that new variants cannot bring new waves along the way. For the severe relatives, see SARS and MERS: Coronaviruses Explained.

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Why is there no vaccine for the common cold coronaviruses?

No vaccine against the four seasonal coronaviruses is in routine use. The reasons are more about practicality than science, and the list below reflects commonly offered explanations rather than a single proven cause.

1. Mild disease, low urgency. A vaccine for a disease most people shrug off has a high bar to clear for cost and benefit.
2. Short-lived natural immunity. If infection itself protects for roughly a year, a vaccine would likely need frequent boosting to do better.
3. Four viruses, not one. Covering OC43, 229E, NL63, and HKU1 would mean a multi-strain vaccine, and the mix in circulation shifts from year to year.
4. The COVID-19 era changed the technology. Vaccines that teach the body to recognize a spike protein worked at scale against SARS-CoV-2; see mRNA Vaccines: The COVID-19 Breakthrough. That shows the method is feasible, not that a seasonal-coronavirus vaccine is planned.

Researchers are pursuing broader coronavirus vaccines. One example is a 2021 Science study by Cohen and colleagues, who built nanoparticles displaying receptor-binding domains from several animal betacoronaviruses alongside SARS-CoV-2's. In mice, the mixed "mosaic" particles produced antibodies that recognized a wider range of coronaviruses. That was an animal study of related viruses, not a vaccine tested in people against seasonal colds. For how vaccines build lasting immune memory, see How Vaccines Actually Work.

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How the seven human coronaviruses compare

Virus	Genus	Receptor	Discovered	Usual severity	Pattern
229E	Alpha	APN (CD13)	1966	Mild cold	Seasonal, winter peak
OC43	Beta	9-O-acetylated sialic acid	1967	Mild cold	Seasonal, winter peak
NL63	Alpha	ACE2	2004	Mild cold; lower respiratory illness in some young children	Seasonal, winter peak
HKU1	Beta	Acetylated sialic acid	2005	Mild cold in most detections	Seasonal, winter peak
SARS-CoV	Beta	ACE2	2003	Severe pneumonia; 9.6% case fatality among 8,096 probable cases	Outbreak ended in 2003
MERS-CoV	Beta	DPP4	2012	Severe pneumonia; about 37% of reported cases died	Sporadic cases linked to camels
SARS-CoV-2	Beta	ACE2	2019	Variable	Global pandemic, now recurring

The SARS figures come from the World Health Organization's summary of probable cases from November 1, 2002 to July 31, 2003: 8,096 cases and 774 deaths across 29 areas. For MERS, the WHO fact sheet reports more than 2,600 laboratory-confirmed cases, about 37 percent of which have died, and says the figure may overstate the true rate because mild cases can be missed. It describes dromedary camels as the primary reservoir.

Note what the table reveals. Genus does not predict severity: SARS-CoV and MERS-CoV are betacoronaviruses, like OC43 and HKU1, but behave very differently. Receptor choice does not predict it either, because NL63 and SARS-CoV share a receptor.

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How they spread, and what is known about prevention

According to the CDC, most respiratory viruses spread through droplets from coughs or sneezes that can be inhaled or picked up from surfaces and transferred to the eyes, nose, or mouth, and some also spread through close personal contact. Seasonal coronaviruses are generally thought to follow the same routes, though the relative importance of each route is hard to pin down for any specific virus.

General measures such as washing hands, staying home when sick, and ventilating indoor spaces are consistent with how these viruses spread. This article does not give individualized medical advice, and people at higher risk of complications should ask a clinician what steps make sense for them. For the sneeze reflex that sends droplets out, see Why Do We Sneeze?.

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Common misunderstandings

"Coronavirus" does not mean "dangerous." It is a family name. Four of its seven known human members are routine seasonal viruses.

Mild does not mean harmless for everyone. Hospital studies find seasonal coronaviruses in some patients, particularly young children and people with other conditions, even though most infections are brief.

Reinfection is not proof of a broken immune system. For these viruses, reinfection about a year after the first is a documented feature of how immunity to them works.

A shared receptor does not mean a shared disease. NL63 and SARS-CoV-2 both bind ACE2. The receptor tells you where the virus docks, not what happens next.

Cold weather does not cause colds. Viruses do. Seasonal patterns reflect how winter conditions and behavior change the odds of transmission.

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The takeaway

The four seasonal coronaviruses show what a long-established relationship between humans and a virus can look like: endless reinfection, short-lived protection, and usually mild illness. They also show how little a single feature, such as a receptor or a genus, predicts about severity.

The most useful lesson may be the immunity pattern. Protection against catching the virus fades within about a year, but memory that limits severity seems to last longer, which is why adults catch the same virus repeatedly without becoming seriously ill. Whether SARS-CoV-2 settles into the same pattern depends on how immunity accumulates in the population, and the comparison with these older relatives is the best guide scientists currently have.

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Frequently asked questions

Q: Are OC43 and HKU1 more closely related to SARS-CoV-2 than 229E and NL63? A: Yes, in the classification sense. OC43 and HKU1 are betacoronaviruses, the same genus as SARS-CoV, MERS-CoV, and SARS-CoV-2. 229E and NL63 are alphacoronaviruses. All four seasonal viruses are still distant relatives of SARS-CoV-2, and genus does not predict how severe a virus is.

Q: If NL63 uses ACE2 like SARS-CoV-2, why is it usually mild? A: ACE2 is only the entry point. Differences in where each virus replicates, how well it evades early immune defenses, and how long people have been exposed all matter. Most people meet NL63 in childhood, according to Hofmann and colleagues, and first infections at young ages tend to be milder for many respiratory viruses.

Q: Could the 1889 "Russian flu" have been OC43? A: It is a hypothesis, not an established fact. A molecular clock study dated the OC43 and bovine coronavirus common ancestor to around 1890, which overlaps with the pandemic, but there are no preserved samples from that period to test it.

Q: Why do we keep catching the same coronavirus cold? A: Protective immunity against these viruses is short-lived. A 35-year study by Edridge and colleagues found reinfection with the same seasonal coronavirus often happened about 12 months after the first infection. Memory that limits severity may last longer than protection against infection itself.

Q: Is there a treatment for seasonal coronavirus colds? A: There is no specific antiviral in routine use for these four viruses. Care is supportive, such as rest and fluids, and a clinician can advise on symptom relief and when to seek care. People with trouble breathing or worsening symptoms should seek medical attention.

Q: What share of colds do seasonal coronaviruses cause? A: It varies by year, place, age group, and testing method. In one Finnish study of 200 adults with colds, coronavirus (OC43 or 229E) was found in 8.5 percent and rhinovirus in about 50 percent. In US laboratory testing from 2014 to 2017, each of the four was found in 0.6 to 2.2 percent of tests.

Q: Is a vaccine possible for all four seasonal coronaviruses? A: Researchers are working on broader coronavirus vaccines, and a 2021 mouse study showed that mosaic nanoparticles can elicit antibodies against a range of related coronaviruses. That is early-stage work, and no vaccine against these four seasonal viruses is in routine use.

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Read next:

• Rhinovirus and the Common Cold Explained
• SARS and MERS: Coronaviruses Explained
• Adenovirus Explained: The Hardy Virus Behind Many Diseases