The next big pandemic? Avian flu takes a worrying step closer to humans

Most people associate influenza virus infections with a respiratory cold that sometimes comes with fever and malaise, often requiring bed rest for a couple of days. 

Many people even believe that influenza is not a problem for them, since despite not having been vaccinated, they have never experienced what other people may refer to as a bad flu that put them in bed for a couple of days. 

What these people do not know is how lucky they are, as influenza causes an average of 5 million hospitalisations per year, resulting in approximately 290,000 to 650,000 respiratory deaths worldwide. 

Most of these cases occur in high-risk individuals – either the elderly or those with health complications. However, there are also severe cases among healthy individuals who never had a bad flu.

Pandemic threats from influenza

Cases of severe influenza are even more frequent during pandemic flu years. We just came out of a bad pandemic caused by a coronavirus, SARS-CoV-2, and we do not want to think about the possibility that we could face another bad pandemic soon. 

It will most likely be a while until a novel pandemic takes place, as pandemics are rare events. 

Although pandemics are rare, influenza viruses have caused four pandemics in humans since the 1900s. The 1918 pandemic resulted in more than 40 million deaths – a number not reached even by Covid-19. 

The last influenza pandemic, in 2009, was fortunately less severe than previous ones. 

While we cannot predict when, where, or how severe the next influenza pandemic might be, it is certain that another will eventually occur.

The animal reservoir of influenza viruses

This is because influenza pandemics are caused by influenza virus strains that are at this moment not circulating in humans, but in animals. The highest diversity of influenza viruses exists in wild birds, though strains also circulate in pigs, horses, and dogs.

Pandemics occur when an influenza virus from animals acquires changes that allow it to infect and transmit between humans. These changes can occur through mutation or by exchanging genetic material between avian and mammalian viruses. 

Since we do not know how many changes an animal influenza virus strain would need to become transmissible among humans, predicting the risk of a flu pandemic from any particular strain is difficult.

Why H5N1 poses a special concern

Why, then, are we particularly concerned with the so-called H5N1 avian influenza viruses as the possible cause of the next flu pandemic?

First, H5N1 viruses are not ordinary avian influenza viruses. These viruses are highly pathogenic for birds, and cause high mortality in chickens. The potential consequences of a human influenza pandemic caused by a highly pathogenic avian influenza virus remain unclear.

In fact, a high proportion of the few humans infected with H5N1 viruses have died. Fortunately, these human infections have been rare, with no cases of human-to-human transmission.

Global spread and evolution of H5N1

Second, since H5N1 viruses were first identified in poultry in Hong Kong in 1997, migratory birds have extended H5N1 infections to other parts of Asia, Europe, and Africa, causing outbreaks in poultry and occassional severe infections in humans in contact with infected birds.

H5N1 has continued to evolve, diversifying into multiple variants that cause severe infections in poultry and wild birds.

Recent infections in mammals raise alarms

It took until 2022 for H5N1 to reach the Americas via migratory birds. Since then, H5N1 has caused multiple outbreaks in poultry across North America and South America, has become abundant in wild birds, and has generated an explosion of multiple genetic variants. 

These variants also appear to be more likely to infect mammals than previous H5N1 viruses. Some have started to transmit among seals and sea lions, associated with high mortality in these animals. 

More recently, H5N1 viruses have started to infect and propagate among dairy cows in the US.These cases in mammals are worrying. 

Not only have H5N1 viruses in these animals shown genetic changes associated with adaption to mammals, but the virus in cows, in particular, has a greater likelihood of coming into contact with humans. 

In fact, several cases of human infections linked to cows have been documented in the US, though many more cases may be undetected. In cows, the virus seems to be present in the mammary glands, acquiring high titers in milk. 

Contaminated milk appears to be the main cause of spillover infections, affecting farm workers, cats, and mice within the affected farms. Luckily, there have not been severe cases of infection in cows or in the humans infected from the cows. 

Due to the lack of severity in cows, the mild infections in humans, and the lack of human-to-human transmission, the virus is considered low risk. 

However, given that the measures that have been adopted have not eradicated the virus in cows, and as we remain uncertain about how close this virus is to becoming transmissible between humans, proactive steps should be taken to eliminate the virus from cows, reducing the frequency of human exposure to mammalian-adapted H5N1 viruses. 

Towards improved influenza prevention strategies

Since current flu vaccines do not protect against these animal-origin influenza viruses, we need to invest in exploring improved influenza vaccination strategies that generate protection not only against circulating strains in humans but also against any influenza virus strain. 

This might be possible by generating new vaccines that target conserved regions of the virus. These type of vaccines are often referred to as universal flu vaccines, and there are multiple prototypes being investigated. But due to a lack of support and of commercial interest for a universal influenza vaccine, research on this area is very slow.

But even a universal human flu vaccine would not solve all the problems related to influenza viruses. More efforts need to be made to eliminate the circulation of the virus in domestic animals, and to develop novel therapies to prevent severe disease by influenza. 

These measures are not only applicable to prevent pandemic flu, but also to prevent other possible pandemic viruses, such as novel coronaviruses or monkeypox.

Effective pandemic prevention requires collaboration across multiple sectors of society, including academia, the pharmaceutical industry, government, journalists, public health and community leaders, and international cooperation, since viruses do not know of borders. 

Let’s not forget all the problems in pandemic preparation that were evidenced by the Covid-19 pandemic and let’s work together to develop effective measures to prevent and mitigate future pandemics.

(Professor Adolfo García-Sastre will be talking in more detail about these issues in his presentation this Wednesday at the Norwegian Academy of Sciences and Letters)

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