Defeating Infectious Agents — 6

Simply, the mRNA vaccines lacked durability in the face of new variants. Getting an annual flu shot is one inconvenient and undesirable thing; nobody wants to get COVID shots every six months, especially when the side effects may include fever, severe fatigue, headache, and a flu-like illness for at least twenty-four hours. Even in the first two months after a booster, the ability to block infections was less than 50 percent and fell off quickly.

These deficiencies all have potential solutions. The lack of durability of mRNA shots may be tied to a reduced T cell response from the body’s immune system (especially CD8+ cytotoxic cells), which has been noted when compared with the Johnson & Johnson adenoviral vector vaccine. That vaccine, which incorporates double-stranded DNA coding for the spike protein, had to be withdrawn due to rare but serious clotting events—but this problem might be fixed. Either way, self-amplifying RNA vaccines are a new and attractive innovation because a very low dose of mRNA tells the body to make more mRNA. This leads to fewer early side effects and potentially a more durable result than can be seen with the first-generation mRNA COVID vaccines. After a large trial in sixteen thousand participants, Japan approved the first self-amplifying mRNA COVID vaccine in late 2023. It elicited more durable levels of neutralizing antibodies in a head-to-head trial against the Moderna vaccine. Much lower doses of mRNA or more protection and stability afforded by better nanoparticles might also reduce the side effect of myocarditis, a rare but important adverse effect of these vaccines predominantly seen in younger men. Chemical modification of mRNA can give it much enhanced staying power, lasting two to three times longer and boosting activity levels in cells by up to twentyfold. This has been achieved by adding multiple tails to the mRNA, giving it a branching structure instead of its current linear form. Another modification has been to make “nanocages,” assembling four receptor-binding domains (part of the spike protein) in a quartet to markedly strengthen the immune response. There are just a couple of examples of how mRNA can be made more potent, specific, and durable. It builds on the prior ways we’ve manipulated mRNA with the pseudouridine and 2-proline substitutions that helped usher in its clinical success. These are ways to take mRNA to the next level, and that’s apart from what we can do with nanoparticles. Beyond mRNA and nanoparticles, what the vaccine is mixed in—the adjuvant—can further strengthen the immune response.