Chapter 138
Defeating Infectious Agents — 2
But for many years it seemed this wouldn’t be possible because introducing mRNA into animals led to massive inflammation. The mRNA sequence consists of four letters or nucleotides: adenine, guanine, cytosine, and uracil; a three-nucleotide sequence codes for an amino acid, the backbone of proteins. A breakthrough occurred in 2005, when Katalin Karikó and Drew Weissman discovered that changing the nucleotide of mRNA from uridine to pseudouridine largely preempted the inflammatory response. This discovery, recognized by the 2023 Nobel Prize, ultimately paved the way for the rapid development of mRNA COVID vaccines in 2020.
What protein the mRNA should make once it gets into cells is the next critical challenge. In January 2020, the first sequence of the SARS-CoV-2 virus genome became available. That identified the codons (or specific instructions) for making the spike protein, the business part of the virus that attaches to a host’s cells. The science community had been building toward this moment over many years—without realizing it. In 2013, the National Institutes of Health Vaccine Research Center program for respiratory syncytial virus determined the atomic-level structure of the fusion protein that is analogous to SARS-CoV-2’s spike protein. The research showed how stabilizing the fusion protein before it fused to the host cell membrane or entered the cell was key to generating high levels of antibodies that neutralized the virus. By 2015, there had been even more extensive work, using cryo-electron microscopy, to determine the structure of the spike protein of a common cold coronavirus, structurally closely aligned with SARS-CoV-2. That led to a discovery that substituting 2-proline (2-P) amino acids in the prefusion spike protein would induce a far more robust immune response once it got into cells. Accordingly, just one day from having the first SARS-CoV-2 sequence, the design of the vaccine moved forward incorporating this key structure-based 2-P feature. Compressed in that one day was the public health breakthrough result of decades of research.
Substituting things for the way nature built them helped our response to COVID, like using pseudouridine instead of uridine to make mRNA injection in the body noninflammatory, and the two prolines to power up our vaccine-induced immune response. Indeed, much subsequent work has been done with a 6-proline substitution that takes the immune response to an even higher level, although it is not yet incorporated in COVID vaccines.
It wasn’t just the mRNA or the spike protein target. When mRNA is injected into the body, it must be packaged so that it’s not quickly degraded and maintains its ability to get into cells. For about six decades, in parallel to work with mRNA, there has been relentless pursuit of nanoparticles for efficient delivery. That has culminated in the use of lipid nanoparticles, little bubbles of fat, that wrap the mRNA. The nanoparticles also function as an adjuvant to facilitate the immune response. Each of the four components of these nanoparticles (polyethylene glycol lipid, helper lipid, ionizable lipid, and cholesterol) can and will be improved to reduce the early side effects, ease entry into cells, and promote the durability of the targeted immune response.