Flu: TrailMap-One Health

The world is as close as ever to the emergence of an influenza pandemic caused by an H5N1 influenza virus. This is a deadly bird flu virus and the current strain, known as clade 2.3.4.4b, has now spread across 5 continents, a geographically unprecedented distribution. The virus kills wild birds as well as poultry. The virus also appears to have additional environmental resilience in that it has survived over the summer in regions where bird flu does not normally persist outside of winter. More worryingly, wild mammals that have scavenged dead bird carcasses have been infected, often with fatal consequence. In the UK this includes foxes and otters, in the Americas, sea lions and other marine mammals. So far, only 11 people have been reported infected, but the virus has now found its way into farmed or domesticated animals including farmed mink in Spain, farmed foxes in Finland and cats in Poland. There is much higher and more frequent contact between humans and these animals compared to the wild scavengers or marine mammals, so the likelihood of more human infections, or 'spillovers', from exposure to an animal carrying the virus has increased. At the population level, we are also at risk that this bird flu mutates and gives rise to an epidemic or even a new pandemic. All previous influenza pandemics have originated from viruses that originally circulated in wild birds. Most avian influenza viruses, including this one, cannot immediately cause a new pandemic because they are not adapted for efficient replication in the human airway or for transmission through the air, even if they can infect humans. The pandemic influenza viruses of the last century have sometimes reached humans after infecting and mutating in an intermediate domestic mammal such as pigs.

At times like this governments are faced with truly difficult decisions about how much time and money to invest in pandemic preparation for a particular strain. Should we stockpile antivirals and matched vaccines and invest in PPE, or wait and see what develops? In the early 2000s a different strain of H5N1 caused public health concern but never acquired the adaptive mutations to transform into a pandemic virus. Is this one any different? The virus in 2005 killed around 50% of the people it infected during spillover events. Because so few people have been infected as of yet by the current clade 2.3.3.4b H5N1 strain we don't really know how dangerous this virus is for humans and how severe a pandemic would be.
To answer these questions, we need to compare the new virus to previous strains, to assess the susceptibility of intermediate animal hosts, and to understand the barriers for this virus to acquire further adaptation to humans at the molecular level.
We propose to work as a consortium and take a multipronged approach to risk assess in depth the current clade 2.3.4.4b H5N1 avian influenza viruses for human spillover infection and pandemic potential. The contemporary viruses will be compared with those of the early 2000s, and with other influenza viruses that did cause human pandemics in 1968 and 2009.
We will use state of the art approaches to study virus/host molecular interactions, and define how these vary with different isolates of the clade 2.3.4.4b virus and between different host species. We will consider the interactions the virus makes with the human airway from children and adults, to understand who is most likely to be infected by and transmit the virus and who is most at risk of disease. We will incorporate modelling approaches to inform surveillance, asking where and how the virus is most likely to infect mammals that could serve as intermediate hosts. We will develop systems by which mitigations such as antiviral drugs or vaccines could be assessed, if the virus were indeed to jump species.

The highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b is panzootic in birds. Its widespread geographical distribution, sheer numbers of infections and frequent incursions in mammals indicate it to be a virus with pandemic potential. We propose to work as a consortium to achieve a coordinated in-depth risk assessment of clade 2.3.4.4b viruses.

In the first work package (WP), we will assess the threat of these viruses for relevant farmed or domestic animals and whether they might act as intermediate hosts for the adaptation of the virus to humans.

In a second WP, we will test the zoonotic potential of the current clade 2.3.4.4b viruses.

In a third WP, we will assess their pandemic potential.


We will infect primary cultures and ex vivo explants of animal and human airway, and ferrets (the gold standard animal model). We will use a panel of viruses regularly updated to keep track with virus evolution, and reverse genetics to define the genotype to phenotype relationship for the traits we uncover. We will characterize airway glycomes of relevant species and use glycan arrays to define the receptor preference of these H5 HAs. We will use single cell RNAseq to compare tropism and cell responses to infection between airways from children and adults.
We will solve the structure of the clade 2.3.4.4b H5 HA in conjunction with sialic acid receptors using cryoEM, and use deep scanning mutagenesis to probe which mutations might adapt the HA for human transmission.
Critically, our experimental designs explicitly avoid Gain of Function research.

Our data will be fed directly to UKHSA to inform policy, and our approach will serve as a blueprint for rapid responses to future emerging influenza viruses.