No one doubts that it will occur, the problem is that we don’t know what will cause it, or when. Years ago, the WHO already defined disease X as a threat to global health. The causative microorganism would probably be an easily airborne, very virulent and ?new? for our human immune system.
The vast majority of scientists thought the most likely candidate would be a new flu virus, but the SARS-CoV-2 coronavirus beat us to it. While the threat of a new coronavirus remains latent, the flu virus is still the most likely candidate to cause the next pandemic.
The champion of variability
The flu virus, or influenza, belongs to the family Orthomyxovirus. In fact, there are four genetically distinct types of influenza (A, B, C and D). In humans, influenza A is the most common; influenza B appears every 2 to 4 years and is generally less problematic; influenza C is rarer and generally causes mild infections; and type D viruses affect livestock.
The flu virus is surrounded by a membrane, or “envelope”, and has a genome distributed in eight RNA fragments with information for the manufacture of ten proteins. In the influenza A virus, two of these proteins are called hemagglutinin (abbreviated as H) and neuraminidase (N). To date, 18 different types of H and 11 different types of N are known. The type with H type 1 and N type 1 is called H1N1; the type with H type 1 and N type 2, H1N2, and so on up to H18N11, depending on the possible combinations.
This virus varies in two ways. When replicating its genome, it can suffer errors or mutations in the H and N genes, which give rise to subtypes or strains that change over time. These are the causes of seasonal flu epidemics and the need to renew vaccines every one or two years. In general, they are prepared with a cocktail of viruses that were transmitted among the population in the previous year.
Furthermore, because its genome is made up of multiple segments, the virus can mix or recombine when different strains infect the same animal at the same time. For example, this can happen in a pig infected with a human influenza virus of the H2N2 type and an avian influenza virus of the H3N8 type. In pigs, the new H3N2 strain is produced – which carries the H3 from the bird virus and the N2 from the human virus – and can infect and multiply in our species.
Therefore, the pig would function as a true natural test tube. This explains the emergence of new types of flu viruses, which can cause pandemics because the human population has never been exposed to the new pathogen, so has no defenses against it, and it can be easily transmitted.
Flu is a bird virus
The natural hosts of influenza viruses are not humans but waterfowl such as ducks or geese, the large natural reservoirs or storehouses of most subtypes of influenza A. These birds can disseminate the pathogen and easily transmit it to birds domestic, but can also infect pigs, horses, bats, domestic animals, marine mammals and, of course, humans.
Flu viruses capable of binding to receptors on human cells are generally H1N1, H2N2 or H3N2 types. It is, therefore, a zoonosis: an animal disease that passes to humans.
Influenza pandemics
According to WHO data, seasonal flu can affect up to one billion people per year. It causes between 290,000 and 650,000 deaths annually due to complications from viral infection, mainly in children under five years of age.
To date, there have been four pandemics of this disease: the 1918 influenza strain, which was of avian H1N1 origin and caused the largest influenza pandemic in history, with 20 to 40 million deaths worldwide; that of 1957, which originated from the emergence of a new pathogen of the H2N2 type through recombination between avian and human viruses; that of 1968, which caused a new H3N2 strain also originating from a mixture of bird and human viruses; and the threat of a pandemic in 2009 from an H1N1 strain whose origin was the recombination between strains of influenza viruses from swine, birds and humans. In this case, unlike H1N1 in 1918, it caused “only” around 200 thousand deaths.
H5N1: a bird flu pandemic
In the late 1990s, the H5N1 virus appeared in China, causing high mortality in wild birds and occasional human cases. Later, it arrived in Europe through migratory birds and began to circulate massively and diversify. Since 2020, a highly virulent variant of H5N1 (called 2.3.4.4b) has been detected and has infected many birds: ducks, geese, seagulls, chickens, pelicans, swans, vultures, eagles, owls, crows. Species previously free of the disease suffered unprecedented mortalities.
Furthermore, not only the number but the extent of outbreaks in Asia, Europe, Africa and the Americas have increased significantly. Hundreds of millions of birds were slaughtered in the US and Europe. The H5N1 virus can be classified as a true pandemic in birds, which is called panzootic.
That passed to mammals
In recent months, H5N1 has also been detected in many mammals: badgers, bears, cats, lynxes, otters, raccoons, dolphins and porpoises, ferrets, mink, foxes, leopards, pigs. In October 2022, an outbreak was identified in Galicia (Spain) on a mink farm and almost 50,000 animals had to be slaughtered. A few weeks earlier, the virus had been detected in gannets and seagulls, so it was able to “jump” from these birds to mink. The pathogen had a mutation in a polymerase gene that could facilitate replication in mammals.
In 2023, there were massive outbreaks in seals and sea lions in Scotland, Peru, Brazil, Uruguay and Argentina, with unprecedented mortalities. Outbreaks have also been reported in domestic cats in Poland and South Korea. The disease has even been detected as a cause of mortality in wild birds and mammals in the Antarctic region.
All of this shows that this is not a sporadic jump from birds to mammals, but a continuous transmission. And it confirms the transmission of the H5N1 virus between mammals, which is unusual. This can not only pose a threat to public health, but also a problem for the preservation of biodiversity.
And now also in cattle
Last March, U.S. officials announced that the H5N1 virus had been detected for the first time in dairy cattle in eight states. It is the same 2.3.4.4b type that has spread throughout the world. Although, as mentioned above, it is highly pathogenic in poultry, affected cows only suffer from a lack of appetite and reduced milk production.
The infection of an employee at one of the farms was confirmed, but the only symptom was conjunctivitis. The tests did not find changes that would make the virus more transmissible to humans. The presence of virus fragments in pasteurized milk samples has also been reported.
Very sporadic cases of H5N1 have been recorded in humans. Since the first detection in 1999 in China, around 900 infections have been reported, always in individuals in very close contact with birds or other animals. Fortunately, the virus is not transmittable from person to person. However, in certain situations, its lethality in humans can reach 50%. We must remember that virulence and transmissibility are different things.
Still far from a real threat
The H5N1 virus is increasingly spreading in birds and mammals. But, to become pandemic, it would have to become more capable of being transmitted by air between humans, improve its ability to enter our cells and multiply, in addition to being able to bypass the immune system.
It is difficult for all this correct combination of mutations to occur, but not impossible. It is a virus that has been warning us for a long time, and it is getting closer and closer. The fact that it is affecting more and more mammal species and starting to be transmitted increases the chances that it will mutate or recombine.
As the human population expands and the environment deteriorates, the relationship between people and animals is altered and new opportunities for contact and disease transmission are created. This highlights the importance of a collaborative strategy and communication between all sectors involved in human, animal and environmental health care: One Health?One Health?, or ?Global Health?.
It is necessary to continue to closely monitor influenza viruses and continue to develop new therapies and universal vaccines against it, as influenza remains a real threat.
* Ignacio López-Goñi, is a member of Spanish Society of Microbiology and professor of Microbiology at University of Navarra. This article is republished from The Conversation under a Creative Commons license. Read the original article here.
