Influenza kills up to 650,000 people annually, and seasonal vaccines must be reformulated each year, leaving populations vulnerable when pandemic strains emerge. A universal shot could become possible by targeting the M2e peptide—a highly conserved, mutation-resistant fragment of the virus’s M2 protein—but M2e’s poor immunogenicity has long been an obstacle.

A CIFRE PhD project by Louis Bourlon, jointly overseen by Sanofi, CEA-Leti, and the Institut pour l'Avancée des Biosciences (IAB), tackled this by leveraging CEA‑Leti’s Lipidots®, lipid nanoparticles refined over 15 years. The core challenge was conjugating M2e onto the nanoparticles without distorting its native structure. The solution used “click chemistry”: modified peptides and nanoparticles chemically “click” together to form stable Lipidots® displaying M2e on their surface. In vitro and in vivo, this vectorization markedly boosted the immune response, elevating both antibody quality and T‑cell activity.

Beyond the M2e work, cationic Lipidots® formulations have also successfully complexed with a vaccine adjuvant and with messenger RNA. Unlike conventional lipid nanoparticles that encapsulate mRNA through difficult‑to‑control processes, Lipidots®–mRNA complexation is achieved by simple mixing at the point of use. Preclinical mRNA vaccine results are highly promising. The technology, protected by 15 patents, uses a solvent‑free, high‑pressure homogenization process that is straightforward to scale for industrial production.

​​​​​In partnership with Sanofi and Institut pour l'Avancée des Biosciences (IAB), researchers from CEA-Leti have succeeded in enhancing the immune response to an antigen that could be used in a universal flu vaccine. Their approach is based on Lipidots®, lipid nanoparticles developed by CEA-Leti.​​

According to the WHO,influenza causes between 290,000 and 650,000 deaths each year. This is why vaccination against the disease is strongly recommended, particularly for people over the age of 65.

This approach requires annual revaccination and proves inadequate in the event of a pandemic, where the virus undergoes major mutations.

A better solution would therefore be to target another, more stable part of the virus. This is the case for the “M2e" peptide, a fragment of the M2 protein that changes very little across strains and over time, making it an ideal candidate for a universal vaccine.

Unfortunately, unlike hemagglutinin, M2e has insufficient immunogenicity, meaning it triggers only a weak immune response.

As part of a CIFRE PhD project involving Sanofi, CEA-Leti, and Institut pour l'Avancée des Biosciences (IAB), Louis Bourlon aimed specifically to improve the immunogenicity of M2e in order to develop a universal influenza vaccine.

This objective relied on a technology developed at CEA-Leti for more than 15 years:Lipido​ts®.

The manufacturing process is simple and based on shear forces, enabling easier industrial scale-up through a well-established high-pressure homogenization process.

The key challenge of the PhD work was the following: how can M2e be grafted onto Lipidots® in a controlled manner while preserving the peptide's natural structure?

The answer came through a method known as “click chemistry."

The method consists of bringing the two elements together: a chemical reaction occurs between the nanoparticles and the modified peptides, which “click" together and bind.

The result is Lipidots® displaying the M2e peptide on their surface.

Both in vitro and in vivo tests confirmed that the method increased the immunogenicity of M2e. Researchers observed a strong improvement in the immune response thanks to the vectorization of M2e by Lipidots®, by measuring both the presence and quality of antibodies and T lymphocytes.

During this work, other formulations of Lipidots®, known as cationic Lipidots®, were used to vectorize an adjuvant.

In previous projects, these formulations demonstrated significant added value in both human and veterinary healthcare applications, particularly for nucleic acid delivery.

Highly promising preclinical results have been obtained in several models using messenger RNA (mRNA) vaccines complexed with Lipidots®.

Unlike the encapsulation of mRNA by conventional lipid nanoparticles (LNPs), which is complex to control, the complexation between mRNA and Lipidots® is achieved through a simple extemporaneous mixing process.

This technology, protected by 15 patents, also benefits from an optimized manufacturing process enabling large-scale industrial production without solvents.​