FLUNIVERSAL: Rethinking influenza vaccination for a more predictable future

The FLUNIVERSAL project is using novel vaccine design, controlled testing models and scalable manufacturing technologies to deliver broader and more durable protection. We talk to key project partners about rethinking influenza vaccination and strengthening Europe’s preparedness for future outbreaks and pandemics.

Influenza is one of the most persistent global health challenges and, despite decades of vaccination programmes, it continues to evolve unpredictably, remains difficult to contain and places a significant burden on both public health services and the global economy every year.

“Influenza is an enormous problem worldwide,” explains Geert Groeneveld of Leiden University Medical Centre. “It causes significant sickness and mortality every year, with around 700,000 people dying annually. Even in countries with strong vaccination uptake, protection remains far from optimal at around 50%, meaning that even with vaccination, you still have a reasonable risk of infection.”

At the heart of the FLUNIVERSAL project is this fundamental question: if vaccination programmes are widespread yet protection remains limited, is the problem simply vaccine uptake, or is the way influenza vaccines themselves have been designed really the main cause? So, rather than simply refining an approach that continues to deliver these inconsistent results, the project is exploring whether a different vaccination strategy could offer a more effective way forward.

A moving target
The core difficulty lies in the nature of the virus itself and how it constantly mutates, shifting its structure in ways that allow it to evade immune protection. This forces vaccine developers into a reactive cycle. “Each year, vaccine strains are selected based on what is currently circulating,” explains Amy Aspelund of Vivaldi Biosciences. “But if the virus mutates after that selection is made and people are then vaccinated, the vaccine used is far less effective than it should have been.”

Having a system based on prediction rather than knowing exactly what virus is in play at any particular time means vaccine strains need to be chosen months in advance, manufactured at scale, and then deployed, only to sometimes miss the mark. In bad seasons, this means that protection drops sharply.

Compounding this is the fact that the underlying production process has changed little over time. As Ed Schmidt of Leiden University Medical Centre (LUMC) notes: “The vaccine being used today is essentially based on the same process developed over 80 years ago. It’s a primitive vaccine, but it’s cheap and safe and does provide some protection to many people.”

Paradoxically, we have a system that works just well enough to be worth persisting with, but not well enough to address the underlying challenge of delivering broad and reliable protection across constantly evolving virus strains.

Beyond prediction
To break out of this reactive cycle, FLUNIVERSAL is taking a different approach. Rather than designing vaccines around the specific influenza strains expected to circulate in a given season, the project is investigating whether broader and more durable protection can be achieved by targeting elements of the virus that remain relatively unchanged over time.

The ambition is often described as a “universal” flu vaccine, although the consortium itself is careful not to overstate the claim. “Let’s be honest,” says Schmidt. “It’s broad protection, not universal. We should not overplay our cards.” Even so, achieving reliable protection across multiple strains, including those not yet circulating, would represent a major advance over the current seasonal model.

At the centre of this effort is a novel vaccine platform developed by project partner Vivaldi Biosciences. Unlike conventional influenza vaccines, which typically rely on selected viral proteins or fragments, FLUNIVERSAL uses a live attenuated virus, a weakened form of the virus engineered so that it cannot cause disease, but can still train the immune system to recognise and respond to infection. “We create a virus that is unable to replicate in humans,” explains Aspelund, “but still expresses all the antigenic parts needed to induce a broadly protective immune response.”

This approach allows the vaccine to mimic important aspects of a natural influenza infection without allowing the virus to multiply in the body and cause illness. But the innovation extends beyond simply weakening the virus. Researchers have also removed a gene that would normally help influenza suppress the body’s first line of immune defence, effectively turning the immune response itself into an advantage. “The virus goes into the upper respiratory tract and immediately activates the immune response,” Aspelund explains. “This creates a strong mucosal immunity exactly where infection would normally occur.”

This differs from traditional injected vaccines, which primarily generate a systemic immune response. By stimulating protection at the point where influenza first enters the body, researchers believe they may be able to trigger broader and potentially more effective protection.

Targeting what doesn’t change
A second innovation lies in how the vaccine directs the immune system’s attention. Conventional vaccines tend to focus on the most visible part of the virus, the “head” of its surface proteins, which also happens to be the most variable.

FLUNIVERSAL takes a different approach. “The head changes constantly,” explains Ingrid de Visser-Kamerling, of the Centre for Human Drug Research (CHDR). “But the stem is much more conserved. If you can target that part, the vaccine could work not just this year, but also in future years and across different strains.

“To achieve this, we use a prime–boost strategy, exposing the immune system to different viral variants in sequence. The effect is to steer immunity towards these conserved regions, potentially unlocking broader protection.” Early data from this aspect of the project’s work is encouraging. “We’ve seen broad cross-reactive antibody responses in humans,” adds Aspelund, though she is quick to emphasise that larger efficacy studies are still to come.

If successful, the implications would be profound. As Manfred Reiter of Vivaldi Biosciences, puts it, “anything above 70–80 per cent protection would be a huge improvement over current vaccines.”

Controlled testing
At the same time, FLUNIVERSAL is aiming to contribute more than a single vaccine candidate. The consortium is also developing a broader scientific toolkit intended to support how future influenza vaccines are tested, evaluated and improved.

One important element of this work is the development of controlled human infection models, where volunteers are exposed to influenza under carefully regulated clinical conditions. While the approach may sound unusual, the project believes it can provide critical early insight into whether a vaccine is genuinely protective before moving into much larger and more expensive trials. “If you vaccinate people and then challenge them with the virus, you can very quickly see whether the vaccine has real potential,” explains Groeneveld. “If only one person becomes ill instead of seven or eight, then you know the vaccine is doing something important.”

Alongside this, the project is also developing new animal models and working to identify stronger “correlates of protection”. These are the measurable biological markers that indicate whether a vaccine is likely to work effectively. “We think these tools could help accelerate influenza research by making it easier to evaluate future vaccine candidates with greater confidence and consistency,” says Groeneveld. “These outputs will contribute not only to this vaccine, but to influenza vaccine research worldwide.”

Scaling up
For any vaccine to have real impact, however, it must also be manufacturable at scale, and this is another important element of FLUNIVERSAL’s work. Most influenza vaccines are still produced using fertilised chicken eggs, a method that has changed little in decades and requires enormous specialised egg supplies to support global production. While effective, the approach is time-consuming and potentially vulnerable to supply disruption, particularly during a large-scale outbreak affecting animal populations.

FLUNIVERSAL is instead using a cell-based manufacturing approach, which researchers believe could provide a faster, more flexible and more scalable alternative. Once the genetic sequence of a newly emerging influenza strain has been identified, the system allows researchers to rapidly engineer vaccine candidates without relying on the lengthy egg-based production cycle used in conventional influenza vaccines.

“Within weeks, we can engineer new virus strains from sequence data,” says Reiter. “And using established cell lines, we can scale production to millions of doses.”

The implications for pandemic preparedness are significant. In a crisis scenario, speed and flexibility are critical. “If a new virus appears, we could produce a vaccine in weeks and begin large-scale manufacturing within months,” he adds.

The model also lends itself to decentralised production. Instead of relying on a small number of large manufacturing sites or vulnerable international supply chains, vaccine production could potentially be distributed across multiple facilities in different countries. In the event of a future pandemic or supply disruption, this could help Europe maintain vaccine production capacity and respond more quickly to emerging outbreaks.

Rethinking delivery
Beyond efficacy and production, FLUNIVERSAL could also change how vaccines are delivered and improve how people experience the process of being vaccinated, moving away from injected doses to intranasal administration. “You could simply go to a pharmacy and receive a nasal spray,” says Reiter. “It’s a completely different vaccination strategy.”

By reducing the need for injection-based administration in clinical settings, the approach could make vaccination easier to distribute across wider populations, including areas where access to healthcare infrastructure may be more limited.

“We also believe that this intranasal approach may offer another important advantage,” says Schmidt. “Because the vaccine is designed to generate immunity directly in the upper respiratory tract, where influenza infections typically begin and spread from, it may help reduce transmission as well as disease severity.”

There are already early indications of this in animal studies. Vaccinated animals exposed to infected peers remained protected, even under close-contact conditions. “Even when co-housed with infected animals, the vaccinated ones did not get sick,” adds Aspelund.

“If replicated in humans, this could represent an important shift: not simply reducing how ill people become after infection, but helping interrupt the spread of the virus itself.”

Towards preparedness
Taken together, these different elements of FLUNIVERSAL all point towards something larger than a next-generation influenza vaccine. The project is also exploring how Europe could respond more quickly and more effectively to future influenza outbreaks and potential pandemics.

Faster vaccine design, scalable cell-based manufacturing, distributed production models and simplified nasal delivery all contribute to a system intended to move more rapidly than traditional influenza vaccine approaches have allowed in the past. Combined with the project’s controlled testing models and broader scientific toolkit, the consortium believes this could help strengthen Europe’s long-term preparedness capacity. “It’s a good example of how experienced experts across Europe can work together with a common goal,” says Reiter.

For Schmidt, this collaborative approach has become increasingly important in the years following COVID-19. “The EU realises that you cannot depend on big pharma and preparedness is a responsibility we need to take ourselves,” he says. “It is not simply about the EU funding individual products, but about building the scientific, manufacturing and regulatory capabilities needed to respond rapidly when new threats emerge.”

The project is now entering a critical phase. With vaccine candidates successfully manufactured, the focus is shifting towards first-in-human trials and controlled infection studies that will determine whether the early promise seen in preclinical work can be replicated in clinical settings. The underlying platform already shows potential for adaptation to other infectious diseases and future vaccine applications. “We’ve already explored expressing antigens from other pathogens,” says Aspelund. “There’s potential for a much broader product profile.”

For now, however, the immediate ambition remains to develop broader and more reliable protection against a virus that has consistently outpaced conventional vaccination strategies. FLUNIVERSAL does not claim to have eliminated the challenge of influenza. But by rethinking how vaccines are designed, tested, manufactured and delivered, the project is attempting to address some of the structural limitations that have shaped influenza control for decades.

And if that approach succeeds, the impact may extend far beyond a single vaccine and help to reshape how future influenza outbreaks, and potentially future pandemics, are approached altogether.