Does 2022 H5N1 bind, replicate better in the respiratory tract?

Since the first case of H5N1 clade 2.3.4.4b in a farm worker in Texas was reported in April this year, the number of confirmed H5N1 cases in humans as of December 20 has shot up to 64 in the U.S., with 34 cases in California alone. Yet, despite H5N1’s high fatality of 52% since 2003, there have been no deaths so far. While 63 cases in the U.S. have been mild, on December 18, the CDC reported that a patient in Louisiana had been hospitalised with a severe case of H5N1 infection. While the B3.13 genotype of H5N1 clade 2.3.4.4b, which is spreading in dairy cows, has caused infection in 63 people, the Louisiana patient has been infected by the D1.1 genotype of H5N1 clade 2.3.4.4b, which has been detected in wild birds and poultry.

The Louisiana case is similar to Canada’s British Columbia teenager whose condition rapidly progressed to acute respiratory distress syndrome, requiring intensive care. The British Columbia teenager too was infected by the D1.1 genotype found in wild birds and poultry.

The H5N1 clade 2.3.4.4b has retained the specificity for avian receptors, thus explaining why most human cases have been mild. The specificity for avian receptors also explains why human-to-human transmission has so far not been reported. For the H5N1 clade 2.3.4.4b to cross the species barrier and infect humans and spread from one person to another, the virus requires to efficiently infect the cells in the respiratory epithelium of the upper respiratory tract. In a study posted in a preprint server, which is yet to be peer-reviewed, researchers have found that H5N1 clade 2.3.4.4b attached to and replicated more efficiently in the respiratory epithelium than the 2005 H5N1 clade 2.1.3.2.

“As per the study, the increased replication efficiency was noted in nasal epithelial cells. Independent evaluation of the polymerase activity in cells suggested there was no significant virus polymerase activity This would mean that the replication efficiency in the cells could be contributed by cellular factors, which remains unknown,” Dr. Vinod Scaria, senior consultant at Karkinos Healthcare, Bengaluru told The Hindu. “The wild bird to human spillover was estimated with 50% fatality, but we don’t really know the denominator, since screening especially in asymptomatic is not typically done.”

“The data suggest that there might be an increased risk of human infections with the currently circulating 2.3.4.4b H5N1 viruses, which might facilitate opportunities for human adaptation,” the authors caution. As per a paper published in the journal Science, studies carried out in a lab showed that a single mutation at one hemagglutinin site — 226L — was sufficient to change the specificity of receptors from avian to human. “In nature, the occurrence of this single mutation could be an indicator of human pandemic risk,” the Editor’s summary notes.

The researchers of the preprint study found that the H5N1 virus that has been spreading since 2022 “attached more abundantly to and replicated more efficiently in cells of the human respiratory tract compared to the 2005 H5N1 and seasonal H3N2 viruses”. Influenza A virus is endowed with the ability to attach to and replicate in the upper respiratory tract can lead to infection and transmission of the virus, while the ability to attach to cells in the lower respiratory tract is associated with its ability to cause severe respiratory disease. The study found that the currently circulating H5N1 virus attached to a moderate number of epithelial cells in the upper respiratory tract, while the 2005 virus showed no capability.

While avian influenza A viruses prefer to bind sialic acids present in the avian digestive tract as well as in the human lower respiratory tract, human influenza viruses preferentially bind to sialic acids that are abundantly present in the human upper respiratory tract. “So for efficient infection of and transmission among humans, influenza A viruses need to overcome the differences between avian and human receptor repertoires in order to attach to and replicate in cells in the human upper respiratory tract,” they write. Also, the virus has to acquire the ability to efficiently spread through aerosols in order to spread among people. But studies using ferrets have found that H5N1 clade 2.3.4.4b is inefficient for airborne transmission but has higher efficiency to spread through contact transmission.

Based on lab studies, the researchers found that the currently circulating clade 2.3.4.4.b H5N1 virus attached better in the human respiratory tract than a well-characterised 2.1.3.2 clade H5N1 virus. “This difference likely contributed to more efficient replication and a more robust innate immune response in human respiratory epithelial cells,” they write. “Our data show abundant attachment of 2022 H5N1 virus to upper and lower respiratory tract tissues, which contrasts with 2005 H5N1 virus. This suggests that the receptor binding repertoire of 2022 H5N1 virus has expanded to attach to receptors in the human upper and lower respiratory tracts.” The efficient attachment of H5N1 virus clade 2.3.4.4.b in the human respiratory tract was also associated with more efficient replication.