On the road to a universal influenza vaccine
Emerging flu viruses escape immunity by modifying haemagglutinin (HA) glycosylation, a process that contributes to virulence and antigenicity, thus reducing host ability to induce an immune response. Seasonal vaccines target the HA protein located at the outer surface of the predominant A and B circulating strains. Research shows that there have only been five to six changes in HA glycosylation patterns in a century of evolution. Harnessing this fact, the SAMUFLU (Self-amplifying RNA technology applied to the development of a universal influenza vaccine) project investigated the development of a universal vaccine based on HA glycosylation. At the heart of the research for the new vaccine is the newly developed SAM® technology that consists of synthetic self-amplifying messenger RNA (mRNA) delivered by lipid nanoparticles (LNPs). Using selected HA antigens, the team prepared SAM(HA) vectors to deliver the vaccine. After an extensive literature search for the most relevant flu strains, researchers selected 20 strains based on their glycosylation patterns and antigenic properties, using 2D maps created by antigenic cartography. Via computational biology and researched methodologies, they designed SAM vectors to transport single or multiple HA. SAMUFLU characterised the immunogenicity of SAM(HA) variants in mice by measuring functional antibody titres. An in-depth analysis identified HA-specific memory and effector CD4+ and CD8+ T-cells induced by SAM(HA) vaccine and these were characterised by state-of-the-art flow cytometry techniques. In tests for broadly-reactive immune responses, the scientists characterised SAM(HA) replicons carried by LNPs that expressed the full length HAs they encoded in vitro. Immunogenicity tests showed induced multifunctional cross-reactive CD4 and CD8 T cells, with effector cytokines profile and cytotoxic activity. Functional antibody responses are currently being assessed. The SAMUFLU project research results support the use of the SAM® platform for the development of broad-spectrum universal influenza vaccines. SAM®-based multivalent vaccines and related therapies can also be used against other pathogens.
