In a Phase 3 trial of more than 18,000 volunteers across three countries, an mRNA influenza vaccine from Pfizer has outperformed standard seasonal flu shots by 34.5%. It's yet another sign that this biotechnology is here to stay.
In the trial, 18,746 participants aged 18 to 64 years were randomly assigned either the quadrivalent modRNA influenza vaccine (modRNA) or a conventional flu shot (Fluzone), with researchers then assessing both medicines on their ability to prevent sickness, the amount of antibodies generated and their side effects. Both vaccines contained two strains each of the influenza A and B virus.
"The relative efficacy of the modRNA vaccine as compared with the control vaccine against influenza-like illness was 34.5% on the basis of 57 cases in the modRNA group and 87 cases in the control group, a finding that met the criteria for both noninferiority and superiority," the researchers found.
However, the "influenza-like illness" experienced by participants was almost entirely A/H3N2 and A/H1N1 – or influenza A strains – meaning that data on the mRNA vaccine's efficacy with influenza B was inconclusive. And while both groups experienced mostly mild or moderate side effects, they were more prevalent in those who had received the mRNA jab: 70.1% versus 43.1% for local injection-site reactions, and 65.8% versus 48.7% for overall issues. Incidence of fever was the most common side effect, with a 5.6% rate of reaction in the mRNA group, compared with 1.7% in the control.
"In this study, a modRNA vaccine is used in which components of the mRNA (nucleosides) are replaced by naturally occurring modified nucleosides (including pseudouridine for example)," explained Professor Paul Griffin, Head of the Mater Clinical Unit for the University of Queensland School of Medicine. "This improves performance, including being translated more efficiently. The use of modRNA as a platform for influenza has many potential advantages over traditional egg-based influenza vaccines, including being quicker and easier to make and likely to make it quicker and easier to match circulating strains."
While mRNA vaccines rose to prominence during the pandemic, their overnight success was more than 10 years in the making. The first human trial – to treat prostate cancer patients – was back in 2008. Despite more than 10 billion doses of the COVID-19 vaccine now administered worldwide, skepticism of the technology remains.
However, there are several key reasons why scientists are focused on adapting mRNA for influenza. Firstly, making mRNA vaccines is significantly faster than developing traditional flu shots, which rely on growing the virus in eggs or cells – a process that can take six months or longer. Quick turnaround would mean vaccines could be developed in response to more currently circulating flu strains, potentially better protecting people from serious illness.
"Moreover, as demonstrated with COVID-19 vaccines, mRNA technology can activate multiple arms of the immune system, including long-lived killer T cells that recognize multiple different influenza strains," noted Dr Emma Grant, Group Leader at the Institute for Molecular Science at La Trobe University. "Indeed, results from this study indicate that the new vaccine demonstrated some increased cellular responses compared to the traditional influenza virus vaccine tested. This capability moves us closer to the long-sought goal of a 'universal' influenza vaccine, one that provides broader and longer-lasting protection."
It's worth noting that the trial was funded by Pfizer, with independent researchers at each location in the US, South Africa and the Philippines. While results are promising, there are some limitations, such as an increase in side effects and unproven ability to protect against influenza B illness – and whether it would be safe and effective in older populations, a vulnerable section of society most in need of protection.
"It would have been nice to see people 65 or over included in the study as they represent a group prone to complicated influenza," said Sanjaya Senanayake, infectious diseases specialist and Associate Professor of Medicine at The Australian National University. "Also, the mRNA caused more side effects than the standard flu vaccine. While these tended to not be serious, in the current climate where vaccine suspicion is relatively high, the result may make it just that bit harder to get the mRNA vaccine accepted.
"The issue of cost wasn't mentioned," he added. "This would be important to determine if the reduction in cases of influenza would be cost effective with the new mRNA vaccine versus the current flu vaccines. After all, a government will have to fund the program."
And while the side effects seen were not severe, they were significantly more common in those who received the mRNA shot – something that could discourage uptake in the real world.
"Recipients of the mRNA vaccine reported more frequent side effects like fatigue, headache, muscle pain, and fever," said Vinod Balasubramaniam, a molecular virologist and Associate Professor at Monash University Malaysia. "These were mostly mild to moderate and short-lived (one-to-two days), but were about three times more common for some symptoms."
The results are promising, but nonetheless narrow in scope. While only 0.63% of people injected with the mRNA vaccine got sick, compared with 0.95% of those who received the conventional shot, there are questions that remain.
"We only know it's better than an existing vaccine, not its exact standalone efficacy; the trial was limited to one season and excluded vulnerable groups like children and the immunocompromised; and most crucially, it showed no significant benefit for adults over 65, the group most at risk from severe flu, highlighting that this is a promising step forward but not a complete solution for all," Balasubramaniam added.
It's also worth noting that there has been no evidence of heart inflammation experienced by any trial participants.
"Myocarditis or pericarditis has been a concern with the early mRNA vaccines, but as there is no reported incidence, it may be more a side effect of COVID vaccines rather than mRNA vaccines," added Dr Rodney Pearce AM, Chair of the Immunization Coalition.
Professor Archa Fox, from The University of Western Australia, added: "Despite the strong anti-mRNA vaccine sentiment seen in some parts of the world and some corners of the internet, this study shows the mRNA vaccines are safe and effective."
Rival pharmaceutical company Moderna is also hoping to create an mRNA flu vaccine, however, it experienced a setback when early trial results proved disappointing.
The research was published in the New England Journal of Medicine.
Source: Baylor College of Medicine via Scimex
