There is perhaps no tougher event in the immunity games than the vaccination all-around. Live-attenuated vaccines score high on efficacy, but they lack both speed (new formulations take months to produce) and endurance (they have short shelf lives). In addition, they have to work hard to avoid losing points on safety. Purified antigen vaccines have a bit more speed, but they tend to score lower on efficacy.
Recently, a gene-based approach has made some inroads in the field, with a strategy based on getting host cells to express antigens in vivo. Vaccines performing this routine have scored highly on speed and flexibility, but none have yet mastered delivery. DNA-based delivery loses safety points for its potential to mutagenically recombine into the host genome. RNA-based delivery scores higher on safety, but so far these performances have faltered on efficacy.
Now, having just burst onto the scene this summer, a gene-based newcomer is going for the all-around vaccination gold. These modified dendrimer-RNA nanoparticles (nicknamed MDNPs) are coached by Jasdave Chahal and Omar Khan, train in Daniel Anderson’s lab at MIT, and hope to have finally solved the delivery problem.
Drawing inspiration from the performances of other all-around vaccine hopefuls, MDNPs masterfully weave their best elements into a truly medal-worthy routine. Adopting the gene-based approach to vaccination, they use self-replicating replicon mRNA to squeeze maximum efficiency out of each dose. For delivery, MDNPs use charge-dense dendrimers (branching polymers) that powerfully protect RNA from degradation, but elegantly release their cargo at intracellular pH.
In their first qualifying round, MDNPs mounted an impressive performance:
- Maximizing safety points, dendrimers completely avoided an anti-vector immune response.
- Encoded antigens were beautifully expressed in target cells both in vitro and in live mice.
- Receptor-expressing T-cells were effectively activated.
- New antigen-recognizing CD8+ T-cells were consistently stimulated.
- Showing their potential for range, MDNPs could encode multiple antigens in the same formulation.
- MDNPs blew traditional vaccines out of the water for speed, with new formulations ready in just one week.
Of course, while technique, speed, and safety points are critical, no vaccine can win the all-around without efficacy, and here the MDNPs did not disappoint. Single-dose MDNPs protected 100% of mice exposed to lethal doses of influenza H1N1, Ebola, and Toxoplasma gondii, handily beating both non-encapsulated and non-replicating RNA.
MDNPs look like a true gold medal threat in the vaccination all-around, and with patent pending, they may even go pro. How will these promising MDNPs hold up in the big games? Stay tuned, and in the meantime, you can check out their masterful prelim performance at PNAS, 2016.