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Immunology is wildly complicated so my description is going to fall short of reality, but my understanding of the role of the adaptive immune system as it would relate to mRNA therapies is different. Lymphocytes, or T cells & B cells, are immune cells which have receptors on their surface that recognize a specific, tiny chunk of protein. For any given lymphocyte, the type of receptor on its surface is fixed for its life and that receptor is able to recognize exactly one distinct protein chunk. Through some very cool mechanisms, very early on in life we all develop a massive number of lymphocytes, each of which recognize different protein chunks. I've not read any research which quantifies the scope here, but it's not unreasonable for the sake of a thought exercise to the assume that at one point we all have a lymphocyte receptor repertoire that's capable of recognizing every conceivable natural protein. Through what I consider one of my top 10 most jaw-dropping biological mechanisms [0], we cull the population of lymphocytes that recognize self, leaving us with a cell population capable of recognizing and responding to every non-self protein conceivable. No training is needed here, each of us at this exact moment has several T cell and B cell populations ready to recognize proteins produced by the next novel pandemic causing virus, whatever future protein mRNA vaccines might make, and whatever proteins these future mRNA therapies might produce. What you refer to as training is probably more like immunological memory, which allows for a ramping up of the immune response on a quicker timeline. We give vaccines where it's generally not safe (or survivable) to wait out an effective immune response, because the disease causes so much havoc in the meantime. This doesn't really apply for the introduction of novel, useful proteins. Your point about Onasemnogene abeparvovec is a very interesting one. I'm truly only guessing here, but people with SMA almost universally produce functional protein via SMN2, but very little of it. It's not enough to serve its function, but is perhaps enough for effective self-tolerance. I'm also not entirely sure about the timeline of self-tolerance development, it's possible Onasemnogene abeparvovec is given young enough to allow effective tolerance development! [0] - https://en.wikipedia.org/wiki/Autoimmune_regulator |