When the first signs of an unknown virus began showing up in Wuhan, China, in December 2019, scientists raced to understand what was happening. In the five years since, they haven’t stopped running, with over published about SARS-CoV-2 and covid-19. Yet despite this outpouring, some big scientific questions about the virus remain.
Is the virus lurking within wildlife?
Early in the pandemic, it became clear that the coronavirus could jump from humans into other animals and back again. This was initially seen with domesticated species, including pets, zoo animals and farmed mink, and was quickly identified as potentially troublesome. In November 2020, 17 million mink in Denmark were culled after it was discovered that the virus was circulating among them and had infected a farm worker.
Wild animals, too, were soon found to be susceptible. In November 2021, researchers at Pennsylvania State University revealed that SARS-CoV-2 was circulating in white-tailed deer, a common species in the Americas. The virus was also detected in a Eurasian river otter and feral mink. This raised the spectre of “wildlife reservoirs” that could brew up new and dangerous variants capable of jumping back into humans – or re-expose us to older lineages to which our immunity has largely waned.
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A 2023 analysis confirmed that this “reverse zoonosis” can and does occur. A team led by researchers at the US Department of Agriculture’s Animal and Plant Health Inspection Service: Wildlife Services in Fort Collins, Colorado, analysed nearly 9000 samples from white-tailed deer across 26 states and Washington DC and found evidence of at least 109 SARS-CoV-2 spillover events from humans into deer, creating 39 wildlife reservoirs – and three potential reverse spillovers back into humans.
Until recently, however, the full extent of wildlife reservoirs beyond white-tailed deer has largely been overlooked, according to at the Fralin Biomedical Research Institute at VTC in Roanoke, Virginia. But the problem has only become more pressing, she says. As the virus shifts towards endemicity in humans (see “Could we go back to square one?”, below), one of the main threats to our progress in controlling covid-19 is the emergence of more virulent and/or transmissible strains, possibly from wildlife reservoirs.
“We’ve made great strides, but we can’t ignore the risk that wildlife can still be a problem,” says Finkielstein. “First, they can pass the virus back to humans. And second, they can be a source of new mutations that make the virus more contagious or harder to control.”
Between May 2022 and September 2023, she and her colleagues from 24 species of wild mammal in Virginia and Washington DC. As expected, they detected the virus in white-tailed deer, but also in six other species: the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail and Eastern red bat.
They have since expanded their search to other geographical areas and additional wild species and discovered more of the same. Their initial findings are “absolutely” the tip of an iceberg, she says.
One sample from an opossum contained a previously unknown mutation, which Finkielstein says demonstrates that the virus can evolve outside humans. “The key takeaway here isn’t necessarily this specific mutation, but the fact that the virus is mutating within a wildlife host,” she says. “This raises the possibility that a future mutation could confer adaptations that allow the virus to spread more efficiently.”
The discovery, she says, emphasises the fact that “wildlife reservoirs do pose a potential threat to the progress we’ve made in controlling SARS-CoV-2. If we look at the history of previous pandemics, we can see how animal reservoirs played a key role in re-emerging infections, for instance, the plague. To stay ahead of this, we really need to keep monitoring wildlife closely.”
How many people have persistent infections?
In January 2022, a team of researchers led by at the University of Missouri in Columbia detected a previously unknown mutant of SARS-CoV-2 in waste water in Wisconsin. That was no great surprise: infected people often shed the virus in faeces and urine, and waste water is surveilled to monitor its presence, spread and evolution.
The Wisconsin mutant, however, was a watershed discovery. Before then, we had occasionally seen “cryptic” lineages with no clear origin and a genetic sequence that didn’t match any found in clinical samples from infected people. The first was and they have since turned up all over the world.
This time, Johnson and his team painstakingly traced the source of the Wisconsin cryptic by following it up the waste-water stream, eventually draining the toilets in a commercial building. The only explanation, says Johnson, is that someone in the building had a persistent infection and was shedding – literally – shitloads of virus.
This scenario, he says, is almost certainly the source of cryptic lineages. “For the longest time, I thought they were coming from animals, specifically rats,” he says. “But it was a total red herring. Our suspicion, based on various factors, is that it’s probably cases of the virus adapting to infect the gastrointestinal tract. People have gotten infected and are unable to clear the virus.”
Although there is no direct evidence of a cryptic lineage going on to infect humans, Johnson believes they can and have. “Omicron and [its subvariant] BA.2.86 – both of which went on to sweep the world – we’re all but certain that those were also from persistent infections,” he says. The thinking is that an extended stay in the gastrointestinal tract allows the virus to evolve new and useful mutations, enabling it to evade the immune response, sometimes giving rise to a new source of infections.
Indeed, many of the adaptive mutations seen in new variants were first spotted in cryptics. “When omicron first came out, I looked at the sequence for about 10 minutes before I could convince myself it wasn’t one of our cryptic lineages because every one of its mutations we had seen before, just not in the same combination,” says Johnson.
What causes some people to develop persistent infections, and the health effect of this, isn’t known, but it is clear that these are a potential source of new, dangerous variants. They are a major public health problem that should be prioritised for further investigation, says at the University of Wisconsin-Madison. “We don’t know how many are out there,” says Johnson. “We would like to know.”
Where did the virus come from?
Natural origin or lab leak? After five years and numerous investigations, we still don’t definitively know the answer and probably never will. But one has a lot more going for it than the other.
First, consider the basic facts. The earliest recorded infections occurred in Wuhan, China, in December 2019, clustered around the Huanan Seafood Wholesale Market (which also traded in wild mammals). Of those 155 cases, 35 had had direct contact with the market.
When researchers sequenced the virus’s genome, they found it belonged to the coronavirus family, with its closest-known relative being a virus found in horseshoe bats in China. The only other wild species known to naturally harbour a SARS-CoV-2-like virus is the Sunda pangolin, which is native to South-East Asia and is one of the world’s most trafficked mammals. These facts quickly led to the idea that the virus jumped from bats to pangolins (or another terrestrial mammal), which were subsequently trafficked to the market and infected humans.
But Wuhan also happened to be home to two research bodies known to work on bat coronaviruses, the Wuhan Institute of Virology (WIV) and the Wuhan Center for Disease Control (WCDC). This led to the alternative hypothesis that the virus came from a laboratory.
The lab leak hypothesis is actually an umbrella term for multiple, often mutually exclusive, claims, says at the University of Sydney in Australia. These include an infection during fieldwork, a lab accident and the deliberate release of a bioweapon and are superficially appealing, he says, but the evidence is circumstantial at best.
Among other things, WIV is located more than 30 kilometres from Huanan market and had no connection to any of the earliest cases. WCDC is a few hundred metres from the market, but, until November 2019, it was in a different part of the city, and its virus-related work was focused on collecting and sequencing samples from wild animals, not on culturing or genetically manipulating viruses.
There are many reasons to discount a lab leak, says Holmes, and many more pointing to a natural origin. “SARS-CoV-2-like viruses have natural transmission cycles in a region spanning Yunnan province [in China] and southwards into South-East Asia and were most likely imported into Wuhan via the wildlife trade,” he says. “All the scientific evidence points to this. There is no scientific evidence for any other hypothesis.”
“The lab leak theory remains completely unsupported and, worse, incoherent and inconsistent, frequently requiring complex conspiracies to be a viable hypothesis,” says at the University of Glasgow, UK. “Indeed, it seems clear that there’s a political agenda behind much of the proponents of the lab leak theory.”
We probably won’t ever know for sure. “I honestly can’t see any other new evidence coming to light,” says Holmes. “Research on this matter in China is at a standstill as the official narrative is that the virus is not from China. Besides, it is now far too late to find any intermediate animal species that still has the virus or antibodies to it.”
Does it even matter at this point? Yes, says Robertson. “The lab leak theory has become part of a wider, anti-science disinformation landscape. This is all very unfortunate, as preparedness to virus threats requires strong international cooperation and evidence-based response.”
Could we go back to square one?
The covid-19 pandemic is over… right? “Covid-19 has become endemic,” says at the University of British Columbia in Vancouver, Canada. “Scientifically, that means it’s persistent within a population and does not disappear.” Yet the virus isn’t harmless, and could still spark a fresh pandemic.
Exactly when the virus made the shift from pandemic – characterised by huge global surges of infections as it burns through susceptible populations – to endemic is a grey area, says Otto, but it probably happened after the omicron variant became dominant in late 2021.
“It’s certainly endemic,” says at the London School of Hygiene & Tropical Medicine. “Formally, that means low levels of spread and relatively constant over time, perhaps with fluctuation.”
That may sound like cause for celebration, but isn’t. “Endemic” is often misinterpreted as meaning “harmless”, says Otto. “Scientifically, that is not a part of the definition at all. A lot of people think that when you say the word endemic, you’re dismissing it as a disease. When I use the word endemic, it’s exactly the opposite. It’s like, it’s here to stay and we better deal with it.” There is no prospect of eradicating it, she says.
Endemic diseases such as malaria and polio are far from harmless. So is covid-19. “It is a dangerous virus,” says Otto. “For sure, there’s susceptibility – older individuals are much more likely to die or land in hospital. But I also know many cases of 30-year-olds who landed in hospital and have died.”
The number of cases fluctuates over the course of the year, with peaks in the winter and troughs in the summer when people spend more time outdoors, says Otto. “That is happening because immunity is waning and the virus is evolving fast enough that it continues to be able to find new, susceptible hosts at any time of year.”
That, however, could change. The virus arguably became endemic before, in 2021, but then omicron appeared. “It was really a different disease type,” says Otto. “It gets into our cells differently. It wasn’t a lower lung infection, it was an upper lung infection. There wasn’t much immunity to it, so we saw this massive spike in cases, and so you could say that that was a shift from an endemic virus to a pandemic virus because everybody was susceptible to it.”
That could happen again, sparked by a radically different variant from an animal reservoir or a persistently infected, immunocompromised person, which was the probable source of omicron and the beta and delta variants that preceded it, according to Markov. Another potential black swan is recombination, where two different variants of the virus co-infect a single host and create a mash-up of their genomes. “Then there is a risk of production of a new virus which has bits of the two genomes combined, and perhaps maybe in one bit we have a gene that is giving it high transmission rates and the other part is perhaps giving it ability to evade immunity,” says Markov.
These are unlikely, but can’t be ruled out, says Markov. “If that happens, then we may have a very fast wave because it will be almost like a new virus.”
And we may be less lucky next time. Omicron was less lethal than previous dominant variants, says Otto, but that was just a coincidence. There is nothing in evolution pushing viruses to become less dangerous over time, says Markov. So, while the pandemic is over, it isn’t gone for good.
Read more in our special report about the five years since covid-19
