My New MDPI Publication

Cross-Priming and Cross-Tolerance After Intramuscular mRNA Vaccination for Viral Infections: Feasibility and Implications

This is why you have not heard from me in a while: https://www.mdpi.com/2075-1729/15/10/1575

JUST PUBLISHED!

It was a ton of work. But a big shoutout to MDPI. Even though, after initial submission, some of the reviewers requested quite a large number of modifications and additions, overall, the process was very fair. The editors and everyone involved were fair and supportive.

Sorry, I cannot go into detail about it, as I am currently revising TWO other manuscripts that I have under review (deadlines!).

I seem to have stumbled onto something that could have far-reaching implications.

Briefly, the article reviews, for the first time, what can be gleaned about antigen cross-presentation in general, and how this impacts mRNA vaccine immunity. A rigorous literature review provides evidence, albeit often indirect, of its involvement as a natural process of T cell activation. Critical aspects necessary during protein/subunit vaccine design cannot be applied to pro-drugs, such as mRNA vaccines. The differences in antigen cross-presentation between mRNA- and more traditional vaccine platforms, and how these support antigen-specific T cell responses, indicate the potential for specific as well as off-target and heterologous immune activation or tolerance development after mRNA vaccination. In all, the article provides the first characterization of the inherent benefits of this natural process, as well as unrecognized challenging aspects of antigen cross-presentation in the context of intramuscular mRNA vaccines.

Here is the abstract. First, in words:

The induction of robust CD8 T cell immunity after intramuscular (i.m.) mRNA vaccination has remained a challenge. Due to the limited presence of professional antigen-presenting cells (APCs) in muscle tissue, this route of administration tends to result in the transfection of muscle cells at the injection site with insufficient T cell activation capacity. The attraction of migratory APCs and related processes that lead to the acquisition of antigenic material from transfected non-APCs arises as a potential alternative to facilitate activation of CD8 T cells in the draining lymph nodes. This indirect pathway, known as antigen cross-presentation, has remained underappreciated for mRNA vaccines. This review provides a comprehensive analysis of this process. Due to the paucity of information available in this context, it also extrapolates from insights for antigen cross-presentation more generally and for traditional vaccines. Arguments are provided as to why this natural process in the context of pro-drugs, such as mRNA vaccines, may engender both specific and nonspecific responses and, in certain situations, evoke cross-tolerance rather than immunity. This widely unaccounted T cell activation process may, therefore, explain several key mysteries surrounding i.m. RNA vaccination, including its impact on heterologous infections. But it also raises numerous open questions that are clearly described.

And as a Graphical Abstract:

Source: https://www.mdpi.com/2075-1729/15/10/1575. Created in BioRender. Mueller, S. (2025) https://BioRender.com/v52b520 (accessed on 22 September 2025).

Thanks for reading and sharing!