mRNA-based candidate enters clinical trial – Ars Technica

Enlarge / The influenza virus, showing the H and N proteins on its surface.

An mRNA-based flu vaccine designed to provide long-lasting protection against a wide range of influenza viruses is currently in Phase I clinical trials, the National Institutes of Health announced this week.

The trial brings the remarkable success of the mRNA vaccine platform to long-standing efforts to develop a universal influenza vaccine. Currently, healthcare systems around the world are battling the seasonal plague with injections that must be reformulated every year to match circulating strains. This reformulation occurs months before the typical transmission, which gives manufacturers time to produce large-scale doses, but also gives strain circulation the chance to shift in unexpected ways. If the vaccine of the year does not match the strains circulating in a given season, the effectiveness against the infection can be catastrophic. Yet even when the shot is well matched, people will need another shot next year.

“A universal influenza vaccine would be a major public health achievement and could eliminate both the need for annual development of seasonal influenza vaccines, as well as the need for patients to get their influenza vaccine every year,” said Hugh Auchincloss, acting director of the NIH. National Institute of Allergy and Infectious Diseases, said in a press release. “In addition, certain strains of the influenza virus have significant pandemic potential. A universal influenza vaccine could serve as an important line of defense against the spread of a future influenza pandemic.”

A successful design has been elusive. Influenza vaccines often generate immune responses against pieces of rapidly changing proteins outside of influenza virus particles, hemagglutinin (Ha or H) and neuraminidase (Na or N). These proteins are responsible for helping the virus enter and exit human cells, respectively, during an infection. Both proteins look a bit like lollipops stuck on the outside of the virus particle, their tips evolving and being prime targets for strong antibodies against the virus.

For the universal vaccine design, the NIH researchers targeted not the top of these proteins, but part of the stalk of the Ha protein, a highly conserved part of the protein that does not evolve as rapidly. Human antibodies that target this conserved region will likely target Ha proteins from a range of different influenza strains within the same class. And, since this section does not evolve as quickly, the vaccine could induce long-term immunity. With this design, the mRNA-based vaccine will include a snippet of genetic code in the form of mRNA that gives human cells blueprints for this conserved stem region. From there, the immune system can learn to target it.

There is already data to suggest that this lens might work. Before NIH researchers used an mRNA-based design, they developed a similar vaccine targeting the HA stem that was shown to be safe and effective in a Phase I trial. The vaccine uses stabilized protein fragments of the Ha rod stuck to a nanoparticle. Last month, NIH researchers published results showing that this nanoparticle vaccine induced cross-reacting neutralizing antibodies against influenza viruses in the same virus group (H1). And these neutralizing antibodies remained for more than a year after vaccination. The vaccine candidate has moved on to a second trial. The researchers hope that having multiple platforms in the works will increase their chances of getting an effective vaccine.

For now, the mRNA vaccine is starting with a small trial of just 50 people recruited through partners at Duke University. Three groups of 10 volunteers will receive different doses of vaccine to find the optimal dose. Once found, another 10 will be vaccinated and their responses will be compared to a control group of 10 people who will receive a standard annual flu shot.

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