What the world doesn’t need now is a pandemic on top of a pandemic. So a new finding that pigs in China are more and more frequently becoming infected with a strain of influenza that has the potential to jump to humans has infectious disease researchers worldwide taking serious notice. Robert Webster, an influenza investigator who recently retired from St. Jude Children’s Research Hospital, says it’s a “guessing game” as to whether this strain will mutate to readily transmit between humans, which it has not done yet. “We just do not know a pandemic is going to occur until the damn thing occurs,” Webster says, noting that China has the largest pig population in the world. “Will this one do it? God knows.”
When multiple strains of influenza viruses infect the same pig, they can easily swap genes, a process known as “reassortment.” The new study, published today in the Proceedings of the National Academy of Sciences, focuses on an influenza virus dubbed G4. The virus is a unique blend of three lineages: one similar to strains found in European and Asian birds, the H1N1 strain that caused the 2009 pandemic, and a North American H1N1 that has genes from avian, human, and pig influenza viruses.
The G4 variant is especially concerning because its core is an avian influenza virus—to which humans have no immunity—with bits of mammalian strains mixed in. “From the data presented, it appears that this is a swine influenza virus that is poised to emerge in humans,” says Edward Holmes, an evolutionary biologist at the University of Sydney who studies pathogens. “Clearly this situation needs to be monitored very closely.”
As part of a project to identify potential pandemic influenza strains, a team led by Liu Jinhua from the China Agricultural University (CAU) analyzed nearly 30,000 nasal swabs taken from pigs at slaughterhouses in 10 Chinese provinces, and another 1000 swabs from pigs with respiratory symptoms seen at their school’s veterinary teaching hospital. The swabs, collected between 2011 and 2018, yielded 179 swine influenza viruses, the vast majority of which were G4 or one of five other G strains from the Eurasian avianlike lineage. “G4 virus has shown a sharp increase since 2016, and is the predominant genotype in circulation in pigs detected across at least 10 provinces,” they write.
Sun Honglei, the paper’s first author, says G4’s inclusion of genes from the 2009 H1N1 pandemic “may promote the virus adaptation” that leads to human-to-human transmission. Therefore, “It’s necessary to strengthen the surveillance” of pigs in China for influenza viruses, says Sun, also at CAU.
Influenza viruses frequently jump from pigs to humans, but most do not then transmit between humans. Two cases of G4 infections of humans have been documented and both were dead-end infections that did not transmit to other people. “The likelihood that this particular variant is going to cause a pandemic is low,” says Martha Nelson, an evolutionary biologist at the U.S. National Institutes of Health’s Fogarty International Center who studies pig influenza viruses in the United States and their spread to humans. But Nelson notes that no one knew about the pandemic H1N1 strain, which jumped from pigs to people, until the first human cases surfaced in 2009. “Influenza can surprise us,” Nelson says. “And there’s a risk that we neglect influenza and other threats at this time” of COVID-19.
The new study offers but a tiny glimpse into swine influenza strains in China, which has 500 million pigs. While Nelson thinks the predominance of G4 in their analysis is an interesting finding, she says it’s hard to know whether its spread is a growing problem, given the relatively small sample size. “You’re really not getting a good snapshot of what is dominant in pigs in China,” she adds, stressing the need for more sampling in the nation's pigs.
In the paper, Sun and colleagues—including George Gao, head of the Chinese Center for Disease Control and Prevention—describe lab dish studies that show how G4s have become adept at infecting and copying themselves in human airway epithelial cells. The viruses also readily infected and transmitted between ferrets, a popular animal model used to study human influenza. The researchers found antibodies to the G4 strain in 4.4% of 230 people studied in a household survey—and the rate more than doubled in swine workers.
In addition to stepping up surveillance, Sun says it makes sense to develop a vaccine against G4 for both pigs and humans. Webster says at the very least, the seed stock to make a human vaccine—variants of a strain that grow rapidly in the eggs used to make a flu vaccine—should be produced now. “Making the seed stock is not a big deal, and we should have it ready,” Webster says.
China rarely uses influenza vaccines in swine. Nelson says U.S. farms commonly do, but the vaccine has little effect because it’s often outdated and doesn’t match circulating strains.
Ideally, Nelson says, we would produce a human G4 vaccine and have it in the stockpile, but that’s an involved process that requires substantial funding. “We need to be vigilant about other infectious disease threats even as COVID is going on because viruses have no interest in whether we’re already having another pandemic,” Nelson says.