Everyone’s sniffling in class and students’ coughing echoes through the Aletta Jacobs Hall. Some students spend days in bed, with a head that feels like it’s filled with concrete. A pack of tissues on the left and a bottle of vitamins on the right. Did you manage to escape the flu this year?

The same thing happens every winter: the Netherlands suffers a flu outbreak. Although at-risk people receive a flu shot every year, the virus spares but a few. 

Or, more accurately put, the viruses, plural. ‘The flu has many different strains. They can be distinguished by the proteins on the outside’, Anke Huckriede explains. This makes it difficult to develop a proper defence. Nevertheless, the vaccinology professor and her research team are attempting to contribute to a remedy for the flu. 

According to Huckriede, this Holy Grail will come in the form of a vaccine with special characteristics. It should protect people from a myriad of flu strains, including future ones. In an ideal world, the vaccine would work for more than just a year and prevent people from infecting others. ‘The vaccines we have right now could be so much better’, she says. 

The current flu shot only contains virus particles from the four flu strains that are going around any given year. That’s enough to weaken the effects somewhat, but not enough to prevent contamination.

Vaccination also gives the immune system just a temporary boost. The number of antibodies increases drastically to protect you from the flu, but this effect wanes in less than a year. ‘Ideally, the number of antibodies should stay high at all times’, says Huckriede.

Vaccinate the airways

‘One of the reasons the flu shot isn’t doing all it can is that the vaccine is intramuscular’, Huckriede explains. That means it’s injected into the muscle tissue. Research has shown that while the immune system does respond to this, it doesn’t provide enough protection against that first infection. ‘Ideally, we want to vaccinate the location where the infection actually is’, she says. For the flu, that means the airways.

That’s where Huckriede’s research comes in. Vaccinating the upper airways isn’t a new invention: vaccines in the form of nasal spray already exist.

Ideally, we want to vaccinate the location of the infection

But one that can actually penetrate the lungs is less common. Together with the pharmacy department, Huckriede’s team is developing dry powders. Through an expensive method called spray drying, dead virus particles were made into a powder that can be inhaled.

To study whether the vaccine worked, Huckriede and her team used it on mice and cotton rats, observing how they responded to the drug. It turned out that the rodents who’d been vaccinated with the powder were less susceptible to the virus than their unvaccinated peers.

Promising results, Huckriede says. ‘The plan was to do a clinical trial on people.’ Unfortunately, this plan was scrapped in part because the vaccine was too expensive to produce in large enough quantities, and because of the Covid pandemic.

Other proteins

Her research also focuses on creating a vaccine that protects against different flu strains. For this, she studies proteins other than just the surface antigens in the virus cells. Surface antigens are the proteins on the outside of the virus that enable the immune system to recognise the virus. ‘Viruses contain so many other substances besides surface antigens, so why shouldn’t we try and utilise those?’

When a virus enters the body, the B cells, a type of white blood cell, identify the intruder. They then produce unique antibodies to exclusively neutralise that particular virus. It’s like a key that perfectly fits the antigen’s lock. 

It’s a clever system, but it falls short when it comes to the flu. B cells are only ever prepared to tackle one specific viral strain. And the flu comes in many, many different strains. Not to mention all the variations we can expect in the future. When a virus mutates, its antigens change slightly. This occurs regularly in the flu virus, which is why the flu shot has to be taken every year. 

Long-term protection

Huckriede has decided not to focus on these surface antigens; instead, she focuses on the other proteins in the viruses. These mutate at a lower rate than the antigens on the outside of the virus, but they do alert the immune system. She hopes her research will result in long-term protection against a wider range of virus varieties. 

Viruses contain so many other substances besides surface antigens

The first results have been promising. Research done by one of her PhD students showed that the production of antibodies capable of neutralising specific antigens strongly depends on a patient’s age. ‘One example of this is the Mexican flu from 2009’, she says. ‘The elderly were much better equipped to handle it than children and adults.’

But when they looked at the antibodies that recognise other viral proteins instead of the surface antigens, Huckriede almost didn’t believe her eyes. Not only was the immune on alert during the patient’s entire life, the production of antibodies was also remarkably high.

Huckriede: ‘Responses to these other viral proteins probably have probably always played a big role in the protection against diseases, but very little research has been done on them. I secretly always hoped they were the answer.’

Covid pandemic

Other scientists have been working on new vaccines as well. Some of them are currently working on an mRNA vaccine for the flu, to replace the traditional vaccine that uses dead virus particles. If mRNA sounds familiar, it should: the first vaccine that used this technique was the Covid vaccine.

I secretly always hoped the other viral proteins were the answer 

The Covid pandemic proved very valuable for the field of vaccinology, Huckriede says. Not only did it kickstart the development of mRNA vaccines, but it also taught us that, in addition to antibodies, the T cell activity is an important factor in protecting against viruses. 

T cells, too, are white blood cells, sisters to the B cells. They play a large role in the immune system by cleaning up infected cells. This curbs the infection and helps prevent the worst of the symptoms. ‘That means we shouldn’t just focus on antibodies, but also on T cell immunity.’ 

Challenges

Huckriede and her team are slowly getting closer to finding their holy grail. But that doesn’t mean there aren’t any questions left to ask. One important question is why the flu is so hard to defeat. 

‘Children get three shots of the measles vaccine and they’re protected for the rest of their life’, says Huckriede. ‘We don’t know why this doesn’t work for the flu. Perhaps it has something to do with proteins or the virus’ genetic code, but we don’t know enough about it.’

Another challenge is ensuring that flu vaccines are future-proof. ‘Every year, scientists work very hard to try and predict which virus will be going around the upcoming season’, says Huckriede. For this, they use data from the southern hemisphere, where it’s winter when it’s summer up here. This enables them to predict which virus strains might arrive during our winter so they can put them in the vaccine. ‘Unfortunately, sometimes those predictions are wrong.’

Dutch