Professor Deborah Fuller, writing for The Conversation in February 2023, states that “for everything there is a season, and for the flu, it’s wintertime”. As we, in the northern hemisphere, enter peak winter, and therefore peak flu, season, we read with interest her reflections on the possibility that mRNA presents in achieving a universal flu vaccine.  

Following data in November 2022 that suggested “breakthrough” progress, we are eager to hear of any updates to this end. However, as with all vaccine development, there are myriad challenges associated and many reasons to apply caution to our optimism.  

Flu vaccines 

Professor Fuller notes that currently the “best defence” against serious illness from the flu is to take a seasonally updated vaccine, which allows the immune system a bit of a head start in the “constant race” against flu variants. However, the time between identification of the contemporary flu strain and the development of an appropriate vaccine for it is approximately 6 months, she suggests.  

Thus, a vaccine that gives us a “leading edge” against flu by protecting against “any eventual strain” would be a huge step forward. Fuller identifies “two buckets” of potential in the route towards this vaccine. 

Two buckets 

The first method of developing a universal influenza vaccine focuses on “conserved, or unchanging” components of the virus. This would train the immune system to recognise and respond to antigens that are shared across variants. These can’t mutate without weakening or killing the virus.  

The second method includes mosaic vaccines, a “cocktail of protein pieces taken from different variants”. The blend comprises versions of haemagglutinin, which is essential to the virus’ ability to infect cells. As we recall from November 2022, the mosaic mRNA vaccine design included “multiple versions” of this protein and induced broad immunity against each of the 20 subtypes of influenza in mice and ferrets.  

Further mRNA approaches 

Other researchers are exploring the potential that mRNA might hold for conserved antigen approaches, and Professor Fuller suggests that animal studies demonstrate the efficacy of mRNA vaccines against “highly conserved, vulnerable parts of the virus” whilst inducing “broad immunity” against a range of subtypes.  

Another approach that Professor Fuller identifies uses computational modelling to “leverage both conserved and mosaic approaches”. This exposes both conserved and variable regions of the virus to the body by displaying “multiple haemagglutinins” on a nanoparticle. These approaches sound creative and exciting, but there are “several challenges” to overcome before a universal flu vaccine can be deployed.  

Holes in buckets 

The first challenge that Professor Fuller acknowledges is the lack of clarity surrounding the conserved antigens that provide broadest protection. Furthermore, some “don’t naturally induce strong immune responses”. Thus, mRNA vaccines “may need improvements like additional components” to activate immunity.  

The mosaic approach is also restricted by dose limitations, as “higher doses could cause increased adverse reactions to the vaccine”. If a dose must be divided between 20 or more antigens, the dose for each of those antigens “may drop below the threshold needed for protection”.  

Using new mRNA technologies, particularly with a focus on lower doses, scientists are trying to overcome these challenges.  

“If mRNA vaccines work for universal protection from influenza, the same strategies could also apply to other frequently mutating viruses, such as the virus that causes COVID-19 and maybe even HIV.”  

Until then, Professor Fuller hopes that mRNA vaccines will “usher in a new era” of more effective flu vaccines.  

“With mRNA vaccines, I believe that we are at the beginning of starting a new race against flu that we may finally win.”

To hear more about approaches to flu vaccination at the World Vaccine Congress in Washington 2023, get your tickets here.