Each year, a billion people around the world come down with the flu and up to 650,000 of them die. The majority of deaths occur in people older than 65 years of age, although other groups like pregnant women, children under five, and those with chronic medical conditions are also at high risk of severe disease or complications. And even for those that are not at high risk, getting sick with the flu is still a significant disruption to normal life and adds strain on health care systems, making preventive measures essential — the most effective of which is getting the flu vaccine every year.
But the flu vaccine is not always the best match for the circulating strain of influenza. While most of the time it’s about 40 to 60 percent effective at preventing illness, a mismatched year can mean effectiveness as low as 13 percent, like it was during the 2014-2015 season.
This October, researchers at the British Columbia Centre for Disease Control published early data showing a mismatch between this year’s flu shot and a newly emerging variant, H3N2 subclade K, that is predicted to be the dominant flu strain for the 2025-2026 season. The team recommended enhanced surveillance and vaccine effectiveness monitoring in the northern hemisphere this season to guide the public health response.
Fortunately, with new vaccines and other novel preventive tools now in clinical trials, mismatched vaccines could one day become a problem of the past.
Making better vaccines
One solution to the mismatch problem would be the use of mRNA vaccines, as these can be safely and rapidly produced in a matter of days or months — compared to the slow process of growing influenza viruses in fertilized eggs or mammalian cells to produce conventional vaccines by fall.
Last week, Pfizer published results in The New England Journal of Medicine showing that a Phase 3 trial of their mRNA influenza vaccine resulted in 34.5 percent greater efficacy compared to the control Sanofi Fluzone shot. However, side effects were more common, with 70.1 percent of participants having local reactions like redness and swelling compared to 43.1 percent of the control group, and 5.6 percent of the mRNA participants having a fever compared to just 1.7 percent with the non-mRNA version.
Novel delivery methods could help lessen the side effect profile and make mRNA vaccines more palatable to the public. In a study published in Nature Nanotechnology earlier this month, scientists from the Massachusetts Institute of Technology (MIT) engineered a new class of ionizable lipids as part of a lipid nanoparticle used to deliver an mRNA flu vaccine in mice. Their top-performing particle, AMG1541, allowed them to immensely reduce the dosage.
“It’s almost a hundredfold lower dose, but you generate the same amount of antibodies, so that can significantly lower the dose. If it translates to humans, it should significantly lower the cost as well,” said Arnab Rudra, a chemist at MIT and coauthor on the work, in the press release.
Another option to enhance the effectiveness of annual flu vaccines is to make them with broader protection against multiple variants. Researchers from the University of Maryland School of Medicine recently reported Phase 1 trial results of an intranasal H5N1 flu vaccine that elicited mucosal immune responses — rather than only a systemic response from conventional intramuscular shots — that resulted in broad cross-clade immunity.
“The intranasal vaccine’s ability to elicit mucosal and cellular immune responses, coupled with strong antibody-dependent cell cytotoxicity, underscores its promise as part of next-generation influenza prevention strategies,” said Franklin R. Toapanta, a vaccine immunologist at the University of Maryland and coauthor on the study.
The holy grail flu vaccine, of course, would be one that elicits not just broad immunity to multiple variants, but to all flu strains. In 2018, the US National Institute of Allergy and Infectious Diseases proposed a plan to guide future investments in research towards a universal flu vaccine. The stated goals included a vaccine that would offer at least 75 percent efficacy against symptomatic influenza, protection for both group I and group II influenza A viruses with influenza B as a secondary target, and protection that lasted over a year for all age groups.
Yet, despite continued research, no flu vaccine candidate has reached a single one of these goals.
A new kind of flu shot
In the future, the most effective way to prevent the flu may still come in the form of an injection — but not from a vaccine. Merck recently announced they will pay $9.2 billion to acquire San Diego-based biotech Cidara Therapeutics, which will give the company access to an antiviral engineered to prevent all strains of the flu in individuals at higher risk. The main advantage for this group is that the antiviral doesn’t require a response from the body’s immune system.
The compound, CD388, is a first-in-class antiviral drug–Fc conjugate (DFC) that works by inhibiting the neuraminidase enzyme on the influenza virus’s surface, which blocks the enzyme from releasing virions and thereby stopping proliferation of the virus.
CD388 was given the Breakthrough Therapy designation by the FDA, and is currently being investigated in the Phase 3 ANCHOR study in adults and adolescents at high risk. A prior Phase 2b trial in healthy unvaccinated adults showed that a 450mg dose of a subcutaneous injection led to 76 percent protection over 24 weeks compared to a placebo.
Cidara also claims on their website that flu DFCs have “near-immediate protective effects” — an advantage that could change the future of flu prevention to mean getting a single shot at the doctor’s office and walking out with significant protection against every variant of the flu.
“This milestone represents a transformational moment for Cidara and for our mission to redefine influenza prevention,” said Jeffrey Stein, President and CEO of Cidara in the press release.
