The virus mutation lottery

Pandemics are unavoidable. In order to better assess the acute danger posed by influenza A viruses, Professor Martin Schwemmle has investigated 2,500 pig farms as part of a major Europe-wide collaboration. A virologist from the Department of Medical Microbiology and Hygiene at the Freiburg Medical Center, Schwemmle, working with colleagues, found potentially dangerous viruses requiring only small changes to cause new pandemics. The researchers are therefore calling for better protective and preventive measures. The dangerous pathogens did not occur frequently; however, their presence showed that the virus mutation lottery is well under way among Europe’s farmed pigs.

Putting pig farms under the microscope: The researchers collected and tested more than 18,000 samples from almost 2,500 farms across Europe. Photo: oyoo/stock.adobe.com

Experts have long been aware that new influenza viruses breed readily among pigs. A Chinese study recently reported on “a serious threat to human health” from new influenza viruses in pigs. “Nonsense,” says Martin Schwemmle; “That is fearmongering.” The virologist from Freiburg and the Friedrich Loeffler Institute (FLI) were in charge of a comparable large study on European pig farms, in which more than 18,000 individual samples from almost 2,500 farms were analyzed. In such places, new virus variants, called reassortants, are constantly emerging. “We did find potentially dangerous reassortants,” Schwemmle admits, but hastens to add that such finds are rare.

Schwemmle says he does not want to frighten people, but nor does he want them to have a false sense of security. “The next pandemic is waiting in the wings, and it will come from pigs” - of that, Schwemmle is convinced. But the key question is - will it be waiting long, or is the pandemic going to enter the stage any time soon? With their study on pig farming and breeding, the scientists sought to discover how often Influenza A viruses (IAV) occur there; which IAV variants circulate in European pigs, and whether the viruses have zoonotic potential. “That means they are capable of passing from pigs to humans,” Schwemmle explains. Without zoonotic potential, there can’t be a pandemic - at least, not among humans.

Viruses that meet and mix

In more than half of the pig farms, the researchers found year-round influenza virus infections in the animals. Of the IA viruses investigated, four lines predominate in Europe, the frequency of which varies regionally. In farmed pigs, the quartet can meet and mix - reassort. The IAV genome consists of eight segments. They are remotely comparable with the chromosomes over which the human genome is distributed. “If two different IAVs infect a cell, they can exchange one or more of the segments with each other,” Schwemmle explains. This sometimes involves entire blocks of characteristics changing viral owners.

But what are the properties that make IAVs dangerous to humans in the first place? “MxA resistance plays a huge role,” Schwemmle says. The protein MxA is part of the innate human immune system. MxA recognizes IAVs and inhibits their reproduction. This means that even without the corresponding antibodies, humans have a certain degree of protection against these pathogens. As early as 2017, a Freiburg cooperation, in which Schwemmle was involved, developed an MxA test system. That shows whether - and to what extent - IAV have adapted to humans and their MxA - how infectious the viruses can become for humans. “Some IAV that we have found in Europe are virtually MxA-resistant.” These reassortants could make the leap from porcine to person.

Avian, swine, human

Where does this resistance to a human protein like MxA come from? “When IAV-infected people cough on pigs,” suggests Schwemmle as an example. “The infected animals do not always really get sick, but often do not grow so well.” And they are now a playground for viruses that are adapted to humans. There is also viral input from another source - pigs can become infected with IAVs from birds. “For these viruses, the conditions among birds are very good,” says Schwemmle. Birds do have an Mx protein, but it does not attack viruses. Birds lack an antiviral barrier comparable to MxA. That means IAV genes that cause MxA resistance can mutate wildly without functional pressure. Countless novel avian IAV combinations encounter Mx1 after crossing the species barrier in pigs - a weak counterpart to human MxA. Only a few IAVs fail due to Mx1. So it is a low hurdle. IAVs from birds can jump it - the first step towards adaptation to mammals. “This also lowers the higher bar set by human MxA,” Schwemmle explains.

The big uncertainty factor is the reassortment, says Schwemmle. In pigs, IAV gene segments from pigs, birds and humans can meet and mix. It's almost like playing a slot machine with three reels. If all three stop on the “right” symbol, it means the optimal combination of pandemic IAV properties - and pays out a disaster jackpot. The authors of the Chinese study say they have found such pathogens with “all the essential characteristics of a pandemic candidate” in China. The FLI, Schwemmle and the other research partners say this is going too far. The IAV reassortants found in Europe had zoonotic but by no means pandemic potential. To achieve this, viruses have to overcome a further  hurdle, namely that they can be transmitted from human to human.

Preventive vaccines may help

The human infection process is modeled using ferrets. The FLI teams headed by Professors Martin Beer and Timm Harder used a ferret model to test how infectious some European IAV reassortants are. Only one combination was able to spread among the animals. “None of the other combinations worked,” Schwemmle says. His working group also found that people who are vaccinated against influenza have antibodies against all the IAV reassortants tested. “The extent to which they are protected varies. But it is enough to make these IAVs spread poorly. They are then not fit enough for a pandemic.”

The step from pig to human is much easier than from human to human, Schwemmle explains. But he does not want to paint an overly rosy picture, pointing out that the European researchers only examined a small selection of IAV reassortants from pigs. “Furthermore, all our test systems have their limitations,” he warns, “We need better screening models for viruses with pandemic potential.” Schwemmle says it is important to prevent birds from settling near pig farming operations. In the case of potentially dangerous viruses, Martin Schwemmle believes it makes sense to maintain a low but constant production of vaccines. Vaccinated pigs would thrive better and at the same time pose less of a threat to humans. This would benefit all parties. Then society would not be caught off-guard when an IAV influenza pandemic breaks out. Because it will be along one day.

Jürgen Schickinger