The Covid pandemic is the latest concern regarding potential zoonotic spillover of a dangerous virus. What will actually be the next virus? In the game of spillover roulette, some have put their bets on yet another coronavirus. Lately, however, the smart money seems to be betting on avian flu, or more specifically, H5N1 avian flu.
Why is this? There are several reasons. One is the nature of the flu virus itself. It lacks an RNA editing enzyme, so the likelihood of point mutations is quite high. More importantly, the viral genome consists of eight separate segments, which independently reassort. One segment encodes the hemagglutinin (HA) protein, a viral surface protein that mediates cell attachment and is a target of neutralizing antibodies. A second segment encodes the neuraminidase (NA) protein, also a surface protein and a neutralizing antibody target, which cleaves sialic acid residues to facilitate viral release into the extracellular space. There are 18 different and distinct subtypes of HA and 11 of NA in bird flu viruses. The other 6 segments encode other viral proteins, including non-structural proteins. When a cell is infected with two different flu virus subtypes, the eight segments can assort in different combinations that represent fundamentally new viruses, including those with new pairings of HA and NA that may be poorly recognized by preexistent herd immunity.
Other reasons are more specific to H5N1 avian flu. Migratory waterfowl carry H5N1 without signs of disease, ensuring a global reach for the virus, and they can transmit infections to domestic poultry. Domestic poultry are generally kept in high density in huge numbers, conditions that are ideal for extensive viral spread. H5N1 has been identified in more than 60 countries and has killed hundreds of millions of wild and domestic birds, either directly or by mass culling. Alarmingly, it has been transmissible to an incredibly wide range of mammals, including sea lions, foxes, skunks, bobcats, cougars, tigers, bears, possums, and mink. Mink infections are notable; 4% of the animals at a mink farm in Spain died of hemorrhagic pneumonia, with evidence of mink-to-mink spread. There is also evidence of transmission occurring between wild mammals (seals) in the Caspian Sea. Thus the virus has both a worldwide reach and has developed the ability to transmit to mammals.
H5N1 in chickens exists as two types based on its virulence. The low pathogenic form is the most prevalent and causes only mild symptoms in commercial birds. The high pathogenic form, which derives mutationally from the low pathogenic form, causes a much more severe disease in these birds, and sudden death can be the first symptom. This process occurs mainly in chickens(1). Wild birds including migratory waterfowl can be asymptomatically infected with the high pathogenic form, although such infections have resulted in the deaths of large numbers of a wide variety of such birds, as for example the recent deaths of thousands of snow geese in Colorado. They can also transmit the high pathogenic form back to chickens.
H5N1 in humans can be deadly. These infections in the past have been reported to have up to a 60% fatality rate. Recently, 7 cases of H5N1 have been reported in humans. Four were asymptomatic, while three involved severe disease (one died). Fortunately, there is no evidence of human-to-human spread, similar to the situation in earlier outbreaks. This is primarily because humans lack viral receptors in upper airway tissue, and the virus therefore only infects lower airway tissue, making further spread difficult. The hope is that the virus will not evolve in such a way as to be able to infect upper airway cells, but as is evident from the above, flu virus is highly mutable by a variety of means. Hope is not a strategy. In view of what seems to be a clear and present danger, what steps should be taken? Poultry is raised in high density conditions that are ideal for the transmission of infections. It is hard to see how this can be greatly mitigated, given that chickens provide a high portion of the world’s diet and chicken farms are optimized for efficiency. Vaccination of poultry farm workers should be strongly encouraged. It may be possible to ban mink farming worldwide: several countries have banned fur farming, including the United Kingdom, Austria, the Netherlands, Croatia, Slovenia, Macedonia, Serbia, the Czech Republic, Malta, Ireland, Italy, Belgium, Luxembourg. Other countries (Bosnia and Herzegovina, Estonia, Slovakia, Norway, Latvia) also banned fur farming, with a phase-out period. In the event of a major spillover event, vaccination of the at-risk public will be critical, but existent stocks of vaccines are not be in sufficient amounts. The current method of vaccine production, which involves growing virus in eggs, is too slow and inefficient, especially if widespread death of chickens restricts the supply of eggs. Recently, an HA-based subunit vaccine that was produced in cell culture (Audenz) was effective in Phase 3 trials and has been approved. This is a much quicker and more convenient approach to vaccine production, and the manufacturer, Seqirus, claims to be able to provide 150 million doses within six months of a pandemic declaration. While impressive, this would clearly be only a drop in the bucket relative to what would be needed. In such a situation, it could well be that, as with Covid, mRNA vaccines will provide the quickest and best answer. H5N1 may never cause a major pandemic, but it has the potential, and preparations should be made accordingly. The current public perception of the dangers is inconsistent with the public risk.
1. Kaplan, B.S. and R.J. Webby, The avian and mammalian host range of highly pathogenic avian
H5N1 influenza. Virus Res, 2013. 178(1): p. 3-11.