Editors note: This article first ran in Wageningen World, the quarterly magazine for associates and alumni of Wageningen University & Research, and is written by Nienke Beintema.

Never before have there been so many outbreaks of bird flu in Europe. With hundreds of farms affected and millions of birds culled, the question arises: why don't we vaccinate poultry?

The numbers are alarming. Between September and December 2021 there were over 300 outbreaks of bird flu on poultry farms in 27 European countries. More than eight million birds were culled. As for wild birds, more than 500 outbreaks were discovered among them in the same period, sometimes involving thousands of animals, such as barnacle geese in the United Kingdom and cranes in Israel. The Netherlands, too, was hard hit by the virus – and the end is not yet in sight. In January 2022 alone, hundreds of thousands of birds were culled and bird flu was detected in red knots and seals. What is going on? And more importantly, what can be done about it?

Vaccinating poultry would be a logical solution. Several vaccines against bird flu have been developed around the world, but none of them are perfect. In the Netherlands, only a vaccine based on a ‘low pathogenic strain’ from 1986 has been registered. ‘That doesn’t work against this highly pathogenic variant of bird flu in the field,' says Mart de Jong, professor of Quantitative Veterinary Epidemiology at Wageningen. ‘And the question is whether the new modern vaccines against highly pathogenic bird flu are effective enough, whether they provide sufficient protection against transmission.’

Chicken-and-egg situation

New variants are constantly emerging through genetic mixing with low pathogenic bird flu viruses. But why aren't pharmaceutical companies working flat out on improving vaccines? According to De Jong, it is a chicken-and-egg situation. ‘Within Europe, countries only trade in non-vaccinated poultry and meat,' he says, 'because vaccinated birds are diagnostically difficult to distinguish from infected ones.’ For this reason, there is no international market for vaccinated birds, so poultry farmers do not want to vaccinate, and pharmaceutical companies therefore do not invest in making really good bird flu vaccines.

In any case, vaccines would have to be continually adapted to the prevailing avian flu strain, just as already happens with human flu vaccines. But there is something else going on as well, according to De Jong. ‘Many of the existing vaccines work well in the lab, but their effectiveness in the field is very disappointing,' says De Jong. ‘This is especially true of the traditional vaccines, which consist of an inactivated virus. With them, we see much lower quantities of antibodies in the field. The question now is whether this is also the case with newer types of vaccine.’

Losing control

If the antibody level is too low, a vaccine does not provide adequate protection against virus transmission, so vaccinated animals can still pass on the virus to each other. ‘You don't want that,’ says De Jong, 'because then you lose control of transmission. Newer vaccines, such as those against SARS-CoV-2, are more complex. They not only activate the B cells, the white blood cells that produce antibodies, but also ensure T-cell immunity.’ T cells are white blood cells too. They stimulate many facets of our immune system, including the B cells. And both types of cells can live in the body for a long time, thus providing immune memory. De Jong: 'But it is not clear whether this helps to protect birds from transmission at low levels of antibodies, and if so, how it does it.’

At the end of 2021, Agriculture Minister Carola Schouten announced that she was releasing funds for research into better vaccines. ‘We are involved in that,' says De Jong. ‘One of the things we will be researching is how you can stimulate immunity better with newer types of vaccine so that you do actually prevent transmission.’

But even if vaccines become more effective, there is another problem: international trade. Countries only want healthy animals to cross their borders, and this is strictly controlled in the supply chain. But how do you distinguish infected animals from vaccinated ones? This concept, also known as DIVA (differentiating infected from vaccinated animals), is one of Nancy Beerens’ specializations. Beerens is head of the bird flu reference laboratory at Wageningen Bioveterinary Research. This lab is to bird flu what RIVM (the National Institute for Public Health) is to Covid-19. It analyses all the Dutch specimens from poultry and wild birds suspected of carrying bird flu and advises the government on risk control.

‘Many older types of vaccine consist of an inactivated virus,' explains Beerens. ‘The immune system makes antibodies against all the proteins in that virus. As a result, you cannot tell the difference between vaccinated and infected birds from their blood. New types of vaccines are often based solely on the haemagglutinin (HA) protein, a protein that is characteristic of the virus variant in question and is found on the outside of the virus particle. In animals vaccinated with these vaccines, antibodies will only be present against this HA protein. Beerens: 'If you find antibodies against other viral proteins in a blood test, then you know that an infection is present.’

Testing vaccines

Wageningen will soon be testing various types of vaccine for effectiveness. Also on the research agenda is the ability to differentiate between infected and vaccinated animals. The highest hopes are pinned on newer types of vaccine such as a DNA vaccine, which works in a similar way to the mRNA vaccines we are currently being given against Covid-19: the body makes a specific piece of virus protein itself. In the case of Covid-19, this is the spike protein on the coronavirus; in the case of bird flu, it is a piece of the HA protein. Another option is a vector vaccine, in which a harmless virus is introduced that will make a piece of the HA protein from the bird flu virus. In both cases, screening will show the difference between vaccinated and infected animals as vaccinated animals will only have antibodies against the HA protein. In the same way, in the case of the coronavirus the public health service can differentiate between vaccinated people and infected people: vaccinated people will only have antibodies against the spike protein.

Clear differentiation between infected and vaccinated animals can help overcome the resistance in Europe to vaccinating against bird flu, Beerens thinks. ‘Bird flu is not going to go away,' she says. ‘We will have to make the disease controllable. To do that, we have to explore several avenues at the same time: better diagnosis, risk reduction, monitoring and control. And in my opinion, vaccination really is part and parcel of it.’

Another obstacle is the practicalities of a vaccination campaign. The vaccine is administered by injection, just like our own flu and Covid vaccines. ‘That is manual labour and very intensive, especially for a farmer with tens of thousands of birds,' says Henk Hogeveen, professor of Animal Health Management. ‘What is more, it takes several weeks before an animal is optimally protected. So it’s of little use for broilers: they are sent for slaughter after six or seven weeks. Theoretically, you could also administer the vaccine in a different way, Hogeveen notes, by putting it in the water, for instance. But there are no such vaccines yet - once again because the European pharmaceutical companies do not see much future in them.

Market for diseased chickens

Hogeveen himself is researching practices related to bird flu in Indonesia, where the disease is endemic: the virus brews under the radar in many places and re-emerges here or there on a regular basis. ‘Culling is a rare occurrence there,' he says. ‘A farmer who discovers that his chickens have bird flu often rushes them to market – even though they are not yet fully grown. A small profit is better than none.’

There is a market for diseased chickens in many parts of Indonesia, continues Hogeveen. ‘People prefer to buy live chickens,' he explains, 'not packaged chicken fillets like we do. Interestingly, lean chickens are also in demand. If a chicken is fat, people are afraid it has been given hormones.’

For individual farmers, the existence of this market for diseased chickens reduces the damage caused by the bird flu virus, and thus also the incentive to do something about it, according to Hogeveen. And they are not very inclined to take measures against the virus in the first place, because they cost money. So there is little in the way of strict hygiene throughout the supply chain, from poultry farm to market. ‘It is not standard practice to disinfect crates, for example'. On the other hand, in many places in Asia, as well as in Egypt, poultry is vaccinated, because overall, that benefits farmers: their chickens are healthier, and the mortality rate is lower. A bird flu vaccine is used that was developed in Southeast Asia and is cheap. And the vaccination itself, using injections and therefore manual labour, is affordable In Asia as labour costs are low. ‘It is not a fantastic vaccine, but it does reduce the severity of the disease,' says Hogeveen.

Spreading to humans

‘The fact that bird flu is rife in Southeast Asia is cause for concern for us too. After all, new variants can be brought in by migratory birds. And there is always the risk of a variant spreading to humans. So it is in our own interests to limit the spread of the virus in Asia as much as possible,' emphasizes Hogeveen. He is involved in a number of projects investigating possible measures. ‘Education about hygiene is an important strategy,' he says, 'as is vaccination. In Indonesia, farmers decide on that for themselves. There is no central control, which is something that could help.’

That is his message to the Netherlands too: he sees a role for the Dutch government when it comes to vaccination policy. First of all, the government can push for changes to European trade agreements, so that vaccination does get accepted and progress can be made on developing better vaccines, improving their administration, and differentiating between infected and vaccinated animals. ‘Sometimes the market fails, and then it's OK for the government to intervene,' says Hogeveen. ‘As far as I’m concerned, they can make vaccination compulsory in Europe, or subsidize it, or both. Make sure that vaccination becomes part of the cost structure. Then manufacturers will take the initiative to develop better vaccines.’

Animal welfare

But the driving forces here should not be economic interests or human health risks alone, Hogeveen comments. Animal welfare is a factor that should not be ignored. There is increasing public resistance to mass culls and the confinement of all poultry every winter. ‘Ultimately, our country must work towards a socially acceptable poultry sector,' emphasizes Hogeveen. ‘We must then aim for a One Health approach, in which we consider the health of humans, animals and the environment more in conjunction with each other.’

This is only possible if you get the wider public on board. Once people see the advantages, public opinion will start to shift, he predicts. ‘Just as we are now seeing in relation to the overuse of antibiotics in livestock farming. People don’t want that anymore. And livestock farmers are quite willing to go along with that, as long as they can maintain a profitable business model.’

Mutations resulted in pathogenic viruses

Bird flu viruses have always been around. They have traditionally circulated in wild birds and are often hardly pathogenic. Poultry can become infected with them too. If chickens do not become very ill, we speak of low pathogenic bird flu. But in poultry farming, mutations sometimes occur that result in variants that are pathogenic, and even highly pathogenic. This happened in the Netherlands in 2003. Around 30 million chickens were culled, and a vet died of the virus.

Initially, highly pathogenic variants tended to cause problems only locally. They were so deadly that wild birds that caught them never got very far. But around the turn of the century, a highly pathogenic variant that was able to hitch a ride with migratory birds emerged on poultry farms in Asia. Genetic mixing occurred with low pathogenic bird flu viruses, as a result of which dozens of new pathogenic variants have since emerged. As Asian migratory birds share their breeding grounds in Siberia with migratory birds from Europe and Africa, these variants have been able to spread around the world. And birds that deviated from their usual migratory route even brought the virus to North America.

Danger to humans

In Asia, bird flu virus strains have emerged that can also infect humans through intensive contact with poultry. There is no precise data on exactly how many people become infected, and how pathogenic the virus is: many infections remain under the radar. But half of the people who end up in hospital with this type of bird flu die. For unknown reasons, there seems to have been an acceleration in the number of human infections in the last two years.

The virus strains in question are not present in Europe. But the more infections there are, the greater the chance that a variant will emerge that is easily transmissible from person to person. Only five mutations are needed for this, discovered the Rotterdam virologist Ron Fouchier in 2011. In the past, bird flu and human flu have sometimes been genetically linked, causing pandemics. The Asian flu of 1957 and the Hong Kong flu of 1968, which killed between one and four million people each, could certainly be traced back to bird flu viruses, and the Spanish flu of 1918 probably also had bird flu links.

Learn more at www.wur.eu/birdflu

This article first ran in Wageningen World, the quarterly magazine for associates and alumni of Wageningen University & Research, and is written by Nienke Beintema.