| There are competing philosophies in the messenger-RNA world, andCureVac still has to prove its approach can really work with Covid-19. The vaccines from Moderna and Pfizer are smash hits, validating mRNA in the eyes of mainstream medicine and raising expectations that CureVac could offer a third highly potent product to the mix. On Wednesday night, CureVac dashed those hopes—at least for now—when it reported its vaccine was only 47% effective against Covid infections in an interim analysis.
Maybe Pfizer, Moderna made mRNA look too easy. What went wrong? CureVac points to the proliferation of variants in its late-stage trial—something Pfizer and Moderna didn't encounter last year. Still, the rival shots appear to remain highly effective against variants, including the alpha strain first seen in the U.K. and delta strain that's ravaged India. The obvious answer, then, is that CureVac uses a lower dosage of mRNA, according to Zhiqiang Shu, an analyst with Berenberg. CureVac's shot has 12 micrograms of mRNA, while each dose of Pfizer's has 30 and Moderna's has 100. Should CureVac simply stick more mRNA into each vial? It's not that easy, unfortunately, and that brings us back to the competing philosophies.  First, a little background. The body's immune system is no fan of foreign mRNA circulating and quickly eliminates any that it finds. That forces drug developers to mask their mRNA products so they aren't destroyed before they can be effective. The Moderna and Pfizer shots do this by making chemical modifications to the mRNA. CureVac, on the other hand, has spent decades working on an "optimization" of mRNA approach that leaves it in a more natural state. Turns out, people can tolerate a lot more of Pfizer's and Moderna's modified mRNA than CureVac's optimized version. If CureVac put in more mRNA, people would have too many side effects. However, CureVac isn't giving up. For one thing, its product is a lot more stable at refrigerator temperatures than the rivals, which could be a major advantage in the developing world. The company is still seeking approval for the shot, while also developing a second-generation version—in partnership with GlaxoSmithKline—that should enter clinical trials in the next few months. The second-generation version also contains 12 micrograms of mRNA, but the optimization is different. In early studies with non-human primates, it has induced far more Covid-fighting antibodies than the first-generation shot did. It's unclear, though, if the second-generation product will be as effective as the Pfizer and Moderna shots. Or if CureVac can bring it to market fast enough to help end the pandemic.—Tim Loh | 
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