Long before COVID-19 became a household word—in 1946, to be precise—veterinary researchers at Purdue University reported that something invading the guts of young pigs was causing diarrhea, vomiting, and weight loss, ultimately killing most of them. The scientists did not know the cause of the sickness, which devastated U.S. pig farms, but they could trigger the disease by feeding ground-up bits of a sick pig’s guts to healthy piglets. This pig farmers’ nightmare, in time, proved to be a coronavirus, which was named transmissible gastroenteritis virus (TGEV).
To this day, TGEV has never harmed a human, and its relationship to SARS-CoV-2, the driver of COVID-19, is distant. But after spreading around the world through the 1970s, TGEV took a strange turn: The disease it caused basically vanished when a TGEV variant that was even more transmissible, but less harmful, essentially immunized pigs against the original virus. “The very best coronavirus vaccine was done by nature,” says Stanley Perlman, a veteran coronavirus researcher at the University of Iowa.
TGEV’s fate was unraveled years ago, but it has recently had some researchers wondering whether the latest SARS-CoV-2 variant of concern, Omicron, might produce a similar plot twist in the ongoing human pandemic. Omicron is causing far too much severe disease and death to celebrate it as a savior—last week, it had a higher daily death toll in the United States than the Delta variant at its peak. But some suspect it, too, will turn out to be a “natural vaccine” against more pathogenic strains.
In contrast to COVID-19 vaccines, veterinary vaccines developed for TGEV had little impact and could not stanch the massive losses suffered by the livestock industry. But in the late 1970s, European farmers experienced a most unexpected relief: The disease caused by the virus began to fade and, in time, disappeared. “We didn’t quite understand what was going on,” says Maurice Pensaert, an emeritus professor at Ghent University who was then one of a handful of scientists in the world who studied TGEV.
One oddity was that litters continued to test positive for TGEV on standard antibody tests. “There was no diarrhea at all, but the percentage of pigs with TGEV antibodies was very high,” recalls Pensaert, whose fascination with the virus dated back to the 1960s when he did graduate work on TGEV at Purdue University.
It occurred to Pensaert and his co-workers that maybe some other, related virus was triggering the antibody production, protecting the little pigs. In 1984, they reported confirmation of this unprecedented hypothesis—a new variant of TGEV. Just as Omicron has a different “tropism” than the original SARS-CoV-2 and other variants—it targets the bronchi in the upper respiratory tract rather than the lungs—the TGEV variant attacked different tissues from its relative. Although TGEV preferred the cells of the gastrointestinal tract, the mutant favored the trachea, bronchi, and lungs. So Pensaert and colleagues christened it porcine respiratory coronavirus (PRCV). “We never imagined that PRCV would emerge,” says Linda Saif, a veteran coronavirologist at Ohio State University Agricultural Technical Institute who developed TGEV vaccines in the 1970s as part of her master’s and Ph.D. theses.
Work on the pig coronaviruses progressed slowly in the 1980s, as research funding was scarce. “Coronaviruses weren’t important in humans, so nobody paid any attention to this enteric virus or this respiratory strain in pigs,” Saif says.
PRCV surfaced in the United States in 1989, again protecting newborn pigs from TGEV. But its genetic sequence differed from the European cousin. “It wasn’t like it arose in Europe and then traveled to the U.S. and started infecting pigs,” Saif says. “It rose independently.”
Like Omicron compared with earlier variants, PRCV spread much more easily than its forerunner. It began to show up at farms with what Saif calls “high-security herds,” kept several kilometers away from other herds. “That’s how transmissible this coronavirus was by the respiratory route,” she says.
In yet another COVID-19 parallel, the pig story has its own speculation about the origins of a pandemic virus tracing back to a laboratory. Pensaert wonders whether the PRCV in Europe evolved from a potential TGEV vaccine he and his co-workers at Ghent made by repeatedly passaging the original virus in cell culture to weaken, or attenuate, its pathogenicity. The still-live virus in the vaccine was clearly different from PRCV, but it might have mutated further, perhaps in vaccinated animals or during commercial production of the vaccine, to create the variant. “It’s hard to say this, but I’ve asked myself that question several times,” he says.
Saif pondered the same thing about attenuated TGEV vaccines used in the United States, but sequencing experiments found the PRCV there had more in common with natural TGEV than the vaccine strains. (There’s no clear explanation for how Omicron arose, which has also fed some speculation the variant came from lab mice infected with SARS-CoV-2 or other research.)
Sequencing of TGEV and PRCV did reveal a startling difference, however. In the gene for the surface protein, spike, PRCV had a deletion of more than 600 nucleotides. “That was a surprise to everyone,” Saif says. More peculiar still, the deletion did not affect spike’s receptor binding domain, the small portion of the protein whose shape plays a key role in attaching to a host cell and infecting it.
Research into PRCV and TGEV—which only began to receive serious funding after a deadly human coronavirus disease, severe acute respiratory syndrome, emerged in 2002—ultimately showed the missing PRCV sequence codes for the region of spike that binds to sialic acids, sugars that decorate cells. The hypothesis, Saif says, is that this domain allows TGEV’s spike to bind to gut mucins, gel-forming proteins that are rich in sialic acids and make up the sticky goop between certain cells. (They are best known for being an ingredient of snot.) Once attached to spike, the sialic acids “keep the virus from being washed out [of the intestines] before it can latch on to the cellular receptor,” Saif says. The absence of this sialic acid binding site is “the likely reason PRCV no longer could infect the gut.”
When PRCV emerged, “suddenly we had a mild respiratory infection, we developed widespread herd immunity, and that virus was able to out compete some of the other strains,” Saif says. As PRCV spread, larger pig farms coincidentally stepped up their measures to protect animals from all pathogens, so it’s difficult to tag TGEV’s demise entirely to this natural vaccine. But she thinks the new variant had a role.
“Everyone’s hope is that is going to be the case with Omicron,” she adds. Omicron, too, may interact with mucins differently from earlier variants, which could explain why it prefers to park in the upper respiratory tract rather than deep in in the lung, causing milder disease.
The Omicron-PRCV parallels break down in one critically important way: The SARS-CoV-2 variant is still causing many cases of severe disease in people who have not been vaccinated or lack immunity from a natural infection. Saif and Pensaert both emphasize that we also don’t yet know whether an Omicron infection protects people from other variants that more readily cause severe disease.
Still, a later plot point in the pig saga suggests another way Omicron may help humans in the future. Some have worried Omicron and Delta could swap genetic material to produce a “recombinant” with the worst traits of both: Omicron’s high transmissibility and Delta’s severity. But there’s a contrasting, optimistic scenario suggested by TGEV and PRCV: They eventually recombined in a new, dominant variant in the United States that spreads more readily than TGEV, doesn’t cause disease in piglets, and may further stymie TGEV-driven disease, Saif says. If Omicron safely immunizes people and similarly recombines with and tames more pathogenic SARS-CoV-2 variant, that would be “a best-case scenario,” she says.
The pig story has a big asterisk next to this fairy tale ending. In 2010, another coronavirus from the same lineage began to devastate little pigs. Called porcine epidemic diarrhea virus (PEDV), it had circulated among pigs for decades without causing much serious disease, but then a highly virulent strain popped up in China. The variant found its way to the United States by 2013, possibly introduced through imported pig feed, Saif suggests.
PEDV vaccines have come to market to combat this deadly strain, but there’s scant real-world data to show they work. And recently, PEDV/TGEV recombinants have begun to circulate. If this saga of the three little pig viruses has a moral that applies to humans, Omicron or later, even milder variants could help curb the COVID-19 pandemic—for now. But they might not protect us from the next big, bad coronavirus to find a way to our door.