Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets

TLDR

Highly pathogenic H5N1 influenza A viruses infect humans but are not efficiently transmissible, and their HA protein determines host receptor binding, raising the possibility that evolving receptor‑binding variants could acquire pandemic potential. The study aims to identify HA mutations that enable an H5 HA–bearing virus to transmit among mammals. A reassortant virus containing an H5 HA with four mutations and the remaining seven segments from 2009 H1N1 was engineered and shown to transmit via respiratory droplets in ferrets. The transmissible reassortant preferentially bound human receptors, replicated efficiently, caused lung lesions and weight loss without mortality, demonstrating that H5 HA can acquire mammalian transmissibility, though it is unclear if the same mutations would render a fully avian H5N1 transmissible, underscoring the need for surveillance and pandemic preparedness.

Abstract

Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to host-specific cellular receptors. Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals. We identified a reassortant H5 HA/H1N1 virus-comprising H5 HA (from an H5N1 virus) with four mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virus-that was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality. These results indicate that H5 HA can convert to an HA that supports efficient viral transmission in mammals; however, we do not know whether the four mutations in the H5 HA identified here would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral gene segments may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avian-human reassortant viruses as tested here, may emerge. Our findings emphasize the need to prepare for potential pandemics caused by influenza viruses possessing H5 HA, and will help individuals conducting surveillance in regions with circulating H5N1 viruses to recognize key residues that predict the pandemic potential of isolates, which will inform the development, production and distribution of effective countermeasures.