Coronaviruses are a byword for inconvenience; illness, disruption and death. Almost always in a contemporary setting we mean the pandemic virus that crept out of Wuhan in late 2019 and turned normality upside down for 2020.
But this coronavirus is not a loner. It belongs to a large family of viruses ignored by infectious disease scientists for many years, yet now a prime suspect in causing previous pandemics.
Veterinary virologists always recognised coronaviruses as menaces, inflicting new lethal diseases on farms. In the 1990s, a respiratory coronavirus devastated cattle herds. Before that, a diarrheal coronavirus disease emerged in pigs, spread around the world and killed millions of swine.
Meanwhile, human coronavirus research remained a backwater. "It was just a bunch of coronavirus hobbyists doing research on human coronaviruses, because we weren't getting funding," says Dr Frank Esper, infectious disease clinician at the Cleveland Clinic in the US, who has studied "common cold" coronaviruses in patients.
The Sars outbreak in 2003 upended assumptions about coronaviruses. The Sars virus spilled from bats to people in China, causing outbreaks also in Hong Kong, Taiwan and Canada, with high death rates. It pushed virologists to hunt for more human coronaviruses.
Two had been identified in the 1960s, and two more common cold coronaviruses were discovered in patients after Sars. The forgettable names reflect how uninteresting most viewed them – OC43, 229E, NL63 and HK1.
These four coronaviruses receive little attention, yet "the endemic coronaviruses are still teaching us lessons", says Prof Ralph Baric, a coronavirus researcher at the University of North Carolina at Chapel Hill. For starters, each of these viruses probably sparked its own pandemic. And they show that reinfection with coronaviruses is the norm.
Three jumped into people between 200 and 800 years ago from bats, says Baric. “They were probably quite severe, but were written off as flu.” Their hazy signatures are probably lost among many disease outbreaks in the Middle Ages.
After Sars, scientists scrutinised the two known human coronaviruses (OC43 and 229E). Belgian coronavirus researcher Prof Marc Van Ranst sequenced the genome of OC43 in 2003. He reported that it originated in cattle or pigs and likely first infected people in the 1890s.
Van Ranst blamed this virus for “the Russian flu”, a mysterious pandemic that began around 1890. Only a small band of coronavirus scientists took notice. Most, including Baric, now agree that OC43 from cattle likely caused the “Russian flu” in the late 19th century.
Subsequent genetic studies of the 229E human coronavirus and its relatives in animals pointed to it origins in African bats, before it moved to camels, and then first infected people around the 18th century. It is now just one of dozens of respiratory viruses that inflict us with common cold symptoms.
Baric, however, suspects that common cold coronaviruses cause more harm that is assumed. “During the Sars coronavirus-1 epidemic there was an outbreak in a retirement community in Canada that was initially diagnosed as SARS, but it turned out to be OC43,” recalls Baric. “It had a 10 per cent mortality rate in that retirement community.” Note that this is the virus blamed for the last coronavirus pandemic in the 1890s.
Immunologist Dr Joseph Mizgerd, director of the pulmonary centre at Boston University School of Medicine, agrees such coronaviruses are too quickly dismissed. "Though we call them common cold coronaviruses, they can cause severe lung infections as well," he adds. They also can be really important causes of pneumonia; ranking seventh in the US.
For most of us, we first catch common coronaviruses before the age of five. The infection is usually fairly mild, because it’s occurring in young children, Baric explains.
Immunity to these viruses wanes after a year or so, especially in the nose, and you get reinfected every two to four years. Symptoms may be mild or non-existent. “It is not until people are much older or have underlying conditions that affect immune functions that they can become serious life-threatening illnesses,” he explains.
Esper suspects endemic coronaviruses can cause bad lung infections in patients undergoing chemotherapy or anyone on immune-suppressing drugs, such as after an organ transplant. Since there are no effective antivirals for coronaviruses, however, clinicians see no urgency in testing for them – it won’t much influence treatment.
The endemic coronaviruses can also offer a glimpse into the future of Sars-CoV-2. “A vaccine will take it out of the pandemic phase, but the virus will remain, like the other coronaviruses, and show up at certain times of year,” says Esper. He predicts it will still cause serious infections, like flu, but will become less severe with time.
Experts disagree on whether we should invest in a vaccine for common cold coronaviruses. “It’s a few per cent of the pneumonia cases every year in the US,” says Mizgerd, who would welcome a vaccine. But other germs with no vaccine cause more illnesses and deaths.
“I don’t think there’s going to be much push to get a vaccine for the other coronaviruses,” says Esper, because they are not major killers.
Dr Cillian De Gascun, director of the national virus reference laboratory in UCD, says there are higher priority viruses, such as respiratory syncytial virus (RSV), which we need a vaccine for. But there are arguments for new coronavirus vaccines too, he accepts.
There had been efforts to develop a vaccine for the sixth coronavirus discovered in humans – the middle eastern respiratory syndrome (Mers) virus. This was first reported in Saudi Arabia in 2012 and mostly is contracted from camels. Some human-to-human transmission is possible, highlighted by hospital outbreaks in South Korea in 2015, triggered by a man who had returned from the Middle East. The Oxford vaccine group worked on a Mers vaccine, and this research quickened development of their Covid-19 vaccine.
This tees up a reason to consider a vaccine for “common cold” coronaviruses. More experience here could edge us closer to a vaccine against multiple coronaviruses. “We need a universal coronavirus vaccine,” says Baric. “There’s still a large number of coronaviruses out there that have the potential to grow in human cells, so we really do need a vaccine against Mers, and various related strains.”
In 2018, scientists reported that a bat coronavirus killed almost 25,000 piglets in China, close to the origin of the first Sars virus. They dubbed the disease Sads (swine acute diarrhoea syndrome).
Baric’s lab showed Sads coronavirus can grow in many human cells, including in lung and gut cells. It is a problem because “it could cause a global pandemic that would affect swine”, impacting food production, “but also has the potential to spill over into humans”, he warns. Its spike protein seems to be completely unique.
This is the third coronavirus to cause a global outbreak since the turn of the millennium, Esper notes, before predicting that another pandemic is almost a certainty
There is no cross protection between contemporary coronavirus and this Sads virus, Baric adds, meaning infection with one would not protect you against the other. “The potential exists that you could have two or three coronaviruses within different genogroups co-circulating in human populations. That’s a little scary.”
Baric argues that science and medical funders should push for a universal coronavirus vaccine, which would protect against endemic coronaviruses and hopefully new strains. There is also a population ready to trial a common coronavirus or universal coronavirus vaccine in – those in assisted living care facilities, where the common cold coronaviruses may be causing more deaths than we realise.
While business representatives and politicians may describe the 2020 pandemic as a one-in-a-100-year event, many scientists and clinicians are not so sanguine. “This is not an isolated event,” Esper insists. “This is the third coronavirus to cause a global outbreak since the turn of the millennium,” he notes, before predicting that another pandemic is almost a certainty.
This gloomy outlook is held by other virologists. “In the 21st century, there have been eight epidemic or pandemic viruses,” Baric points out. “I don’t know if people are paying attention. They need to realise that there’s a new epidemic or pandemic virus arriving every two to three years.”
He suggests ecological changes we’ve wrought across the planet brought on this dire situation. Baric and others had warned of the dangers of a coronavirus pandemic after Sars, and hoped for more research funding, but interest dried up as the Sars experience faded from memory.
Fortunately, with the recent advances in vaccines for Covid-19, we are in a much better position to develop vaccines for current and emerging viruses. The crucial move will be not to drop the ball after this pandemic is finally brought under control by vaccines, and to get ready for another one. “We need to be better prepared,” Baric concludes.