Japanese scientists demonstrate mRNA vaccine-induced refocusing of effector memory T cells but don’t seem to bother to demonstrate their functionality…..

I read the following publication: “CD8+T cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by shifts in clonal dominance” (cell.com/action/showPdf?pii=S2211-1247%2824%2900215-8).

This study is focusing on the characterization of mRNA vaccine-skewed T cell clonotypes and the dynamics of the shift in immunodominance in spike (S) epitopes following repeated mRNA vaccination.  

These scientists have conducted sophisticated molecular characterization studies on T cell clones induced or recalled by mRNA vaccines. Their findings simply confirm what I have been telling all along: that mRNA vaccines initiate immune refocusing of the Covid-19 (C-19) vaccinee’s immune system. Successive SARS-CoV-2 (SC-2) mRNA vaccinations have already been shown to shift humoral immunity to subneutralizing and eventually IgG4 Ab responses, which promote viral immune escape and contribute to immunopathology, respectively (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222767/; https://bit.ly/3NYokkE : see chapters 1.2.7. and 1.2.9.; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178835/). The current study is now showing that such repeated mRNA injections also cause a shift in clonal dominance of T effector memory cells between S epitopes. As low-affinity anti-S antibodies (Abs) induced at an early stage of mRNA transfection of host cells enable immune refocusing (https://bit.ly/3NYokkE : see chapters 1.2.2., 7.1.,11.2.), it is not surprising that these Japanese researchers established that mRNA vaccine-induced anti-RBD[1] Ab titers were positively correlated with the shift in clonal dominance (i.e., immune refocusing) of  CD8+ and CD4+ T cell responses. While skewing of T cell clonotypes and concomitant inter- or intra-epitope shifts in clonal dominance of anti-S T cells after the second and third injection of mRNA-based C-19 mRNA-based vaccines may lead to increased T cell diversity, the authors didn’t seem to bother about investigating the functionality of the re-oriented T cell responses. This omission is a significant flaw as enhanced TCR[2] diversity does not necessarily imply enhanced functional effectiveness of these T cells.

It is well known that vaccines promoting immune responsiveness to a more diverse spectrum of pathogen variants may drive large-scale immune escape if the functional capacity of the induced immune effector cells is suboptimal, meaning they are unable to fully eliminate the pathogen. This particularly applies when such vaccines are used in mass vaccination programs. It is, indeed, astonishing to a seasoned vaccinologist how these researchers can even suggest that the results from their  research, pointing to ‘re-writability’ of T cell  immunological memory, may enable mRNA vaccine-induced T cells ‘to effectively generate responses to variant strains of the virus’…… unless they mean that ‘effectively’ does not relate to the functionality of the immune responses generated! In summarizing this publication, Tokyo University of Science misleads the scientific community by erroneously concluding that the provided insights pertaining to mRNA vaccine-induced T-cell responses ‘will be crucial for developing next-generation vaccines for more effective and broad protection against viruses’ (https://www.tus.ac.jp/en/mediarelations/archive/20240306_8340.html).

Why are their conclusions misleading?  

The effectiveness of vaccine-induced T cell (Tc) responses significantly relies on their functionality  rather than solely on the magnitude of these immune responses towards viral Tc epitopes. Failure to analyze the cytolytic capacity of vaccine-induced Tc responses, including shifted or refocused Tc responses, inevitably leads to erroneous interpretations and misunderstandings regarding the significance of these Tc responses, as well as the implications of successive mRNA vaccinations.

Every seasoned vaccinologist would indeed ask the following relevant questions:

-          Why did these researchers not investigate the functional capacity of the shifted T cell repertoire to kill virus-infected cells?

In the current context of sustained viral transmission, no single T effector memory cell is relevant to individual or public health unless it can kill virus-infected cells. The expansion and clonal diversification of non-cytolytic T cells, for example, has repeatedly been shown to facilitate viral immune escape and immune pathology rather than eliminate the infection. This omission represents a significant limitation of the study that the authors failed to acknowledge. Characterizing the diversity of the TCR repertoire without exploring the role of targeted epitopes in the viral life cycle and their susceptibility to functional immune responses does not contribute to a comprehensive understanding of elicited T cell responses.

-          Why did the researchers not conduct epitope mapping of the skewed T cell clonotypes to examine and monitor a potential association between shifted Tc target epitopes and the mutations observed in dominantly circulating variants within highly C-19-vaccinated populations?

-          Why didn’t they extend their analysis to real-life conditions, where C-19-vaccinated individuals are exposed to vaccine breakthrough infections (VBTIs), thus further influencing the evolutionary dynamics of immune refocusing?

If they had pursued this inquiry, they would undoubtedly have found that shifts in clonal dominance of T cells targeting viral proteins other than the S protein are now driving the emergence of immune escape mutations that bolster viral replication and production of viral offspring. (https://www.biorxiv.org/content/10.1101/2024.03.05.583578v1).

How many more years will it take before vaccine researchers realize that vaccine-induced immune diversity and the magnitude of immune effector recall responses do not necessarily equate to functional effectiveness of these immune effector cells?

Is it  that difficult to comprehend that whenever the functional capacity of immune effectors fails to neutralize free-circulating virus, or otherwise inhibit its infectivity, or to kill virus-infected host cells, the immune response will inevitably lead to immune escape? Until this fundamental understanding permeates the scientific community, we remain at risk of wasting significant amounts of our precious time deciphering results from sophisticated analyses that only remain accessible to researchers entrenched in their respective expertise, yet detached from the real-life issues and challenges posed by the current ‘immune escape’ pandemic.

Conclusions that appear straightforward and rigorous but stem from complex and elaborate exercises in ‘molecular stamp collection’ should always raise suspicion as enhanced complexity only implies enhanced credibility in the kingdom of the blind (where one-eyed is king….).

In summary, my conclusions are as follows:

The results from this study merely confirm the detrimental impact of mRNA vaccines in failing to elicit a highly functional immune response targeted at the specific epitope(s) responsible for viral infectiousness. As mRNA vaccines, akin to VBTIs, steer immune responses away from these epitopes, mass vaccination inducing adaptive immune cells against vulnerable viral proteins will inevitably result in functional degradation of the immune response.

I have consistently emphasized that the intrinsic property of mRNA vaccines to trigger immune refocusing, as corroborated by the authors of this publication, renders this technology unsustainable as a vaccine technology. Furthermore, the authors appear to be minimizing the correlation between the skewing of T cell clonotypes and the severity of adverse events. It is reasonable to infer that this correlation extends beyond CD4+ T cell-induced immune inflammation (https://doi.org/10.7774/cevr.2022.11.1.121) to encompass immune pathology such as autoimmunity and cancer facilitated by noncytolytic CD8+ T cell effector memory cells.

By presenting these study results as propaganda for next-generation vaccines mRNA vaccines, Tokyo University of Science is conveying a wholly misleading message that can only backfire in terms of enhancing viral immune escape and immune pathology.

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[1] RBD: Receptor-binding domain

[2] TCR: T cell receptor