A Potential Reason Behind COVID Vaccines’ Waning Benefit

The inability of COVID vaccines to reach the long-lived plasma cell compartment in the bone marrow may explain their waning protection compared with vaccines for influenza or tetanus, according to a recent study published in Nature Medicine.

In this exclusive MedPage Today video, study author Frances Eun-Hyung Lee, MD, of Emory University School of Medicine in Atlanta, discusses the findings and the implications for future research.

Following is a transcript of her remarks:

The COVID mRNA vaccines were introduced in 2021, and it’s really made a game changer for us to get out of the pandemic. But the one question is how long did those responses last? So that was one of the major questions that we had. And we find out that the titers really fell quickly even after primary immunization, after boosting immunization and everything else.

So we study human plasma cells in the long-lived plasma cell compartment of the marrow, and if it makes it to that long-lived compartment, we find that those titers last for a very long time, decades. So we were very happy to say, “Oh, well we can find tetanus responses that last 10-year half-life of that vaccine, as well as if you get an influenza infection, it can last for a very long time in that long-lived compartment.” So we could easily find those responses in what we call the “longest-lived” compartment of the bone marrow.

But what was really surprising in a stark finding was that the SARS-CoV-2 responses after vaccination in these individuals, they just did not make it into that longest-lived compartment that we’re accustomed to seeing. With that being said, we just were trying to understand why are they different, and how are they different — and are they different? So that was the question we asked and we find that they are really, really different and they’re not making into that compartment. And what we really need to think about is trying to make sure we get vaccines that last for the long haul and make it into that compartment.

So I think one of the questions we could potentially address — and we’re trying to see if we can look at some of these questions — is the mRNA vaccines, there’s protein vaccines that are available now for the RSV [respiratory syncytial virus], so is it something unique to spike or SARS-CoV-2 or is it something unique to the mRNA platform?

We want to take a look at the RSV vaccine that Moderna has just put out on the mRNA platform compared to just the protein vaccines that I think Pfizer and GSK — one of them is adjuvanted, one of them’s not. And so I think that those will be some of the questions that we want to ask: Is it unique to the platform or is it unique to the protein that we’re trying to stimulate in the body?

When you really think about it, the body’s really, really smart because most of the time it works fairly well. Whereas we have autoimmunity and we have a whole other area where we study autoimmunity in terms of that. So there’s something unique about the repetitive nature of the proteins on the surface of a B cell.

So the spike protein — and we wrote about this in the discussion and you can read more about it in the paper — is that the spike protein is very far apart. Normally a lot of viruses have repetitive protein epitopes on their surface. They’re really close together, so they like to cross link that B-cell receptor that’s coming across. So the B cell has all these receptors and they bring them close together. They aggregate the receptors fairly well and stimulate them. So if you have a lot of repetitive epitopes, it seems to do better. It’s not a foolproof 100%, it needs that signal plus something else, plus something else. Multiple things that you need to make sure that the signal goes well.

So is there something unique about the spike protein that’s really far apart? The virus and all the proteins just sit far apart as opposed to the flu antigens that sit closer together. Is it that, or is it something with the mRNA platform itself? Is it being stimulated at the right sites? Is there the right cytokines? Is there the right T-cell help and everything else that you need to make a long-lived response? So those are some of the questions that I think are really interesting and important. Is it unique to the platform or is it unique to the protein itself?

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