How often have I said to you that (immune) correlations do not equate with causality!

I recently came across a publication by M. Veldhoen and A. Bertoletti. The title intrigued me as I was unsure what they meant by 'happy T cells'. This paper primarily refers to a publication by M. Koutsakos et al.

However, I must admit that the concept of 'happy T cells' didn't bring me much joy...

Many immunologists posit that memory T cells are crucial for long-lasting, vaccine-induced immune protection against COVID-19. Although Koutsakos et al. established a strong correlation between high activation levels of multiple spike (S) epitope-specific CD8+ T cells and viral clearance or the rate of virological control during SARS-CoV-2 infection, there is currently no proven evidence of a causal relationship between these measurable correlates. The authors did not demonstrate that highly activated S epitope-specific CD8+ T cells exhibit cytolytic activity against SARS-CoV-2-infected cells. Consequently, rapid recall of these T cells has not been shown to lead to elimination of SC-2-infected cells and did not affect the peak of viral load. This does not support the authors' hypothesis that priming of S-specific memory CD8+ T cells effectively contributes to viral clearance. Despite their rapid recall, vaccine-induced S-specific memory CD8+ T cells are, therefore, unlikely to explain the observed fast decline in viral load in the upper respiratory tract.

Hence, there is no proof that vaccine-induced S-specific CD8+ T cells contribute to protecting vaccinees from severe COVID-19 disease. As I previously explained in my book ('The Inescapable Immune Escape Pandemic'), this protection is most likely due to the virulence-inhibiting effect of polyreactive non-neutralizing antibodies (PNNAbs)1, and not to 'rapid T cell memory'. Rapid viral clearance is likely due to activation (but not priming!) of MHC class I-unrestricted cytolytic T cells that recognize universal (and thus, immunodominant), highly conserved peptides found within viral proteins (e.g., B7-N105 peptide [SPRWYFYLL] within the nucleocapsid [N] protein [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9970913/] or SAIEDLLF/SFIEDLLY within the S protein.

This assumption is entirely consistent with the observation that most universal antigen (Ag)-specific (e.g., B7-N105-specific) CD8+ T cells detected ex vivo were Ag-inexperienced, with no evidence of priming by cross-reactive pathogen-derived epitopes (Koutsakos et al., 2023). Unlike the relatively higher frequency of vaccine-primed S-specific CD8+ T cells after vaccine breakthrough infection (VBTI), B7-N105-specific CD8+ T cells vastly dominated the S-specific CD8+ T cell population following a primary SARS-CoV-2 infection. This is consistent with the notion that de novo activation (but not priming!) of universal epitope-specific, MHC-unrestricted cytolytic CD8+ T cells (CTLs) curbs viral infection after initial viral replication. This is why SARS-CoV-2 infections qualify as 'acute self-limiting' viral infections, even though these effector T cells lack immunological memory. This could also explain why—in contrast to the frequency and activation measured for recalled S-specific memory T cells—neither the frequency nor activation of the primary (i.e., B7-N105-specific ) CD8+ T cell response was significantly associated with the peak of viral load or viral clearance. The authors acknowledge that analyses of primary responses to other N-associated epitopes could be informative. I certainly concur as this observation may not apply to other, non-universal N-associated epitopes!

As T-helper independent PNNAbs lack memory and gradually decline over time, the protection against severe COVID-19 disease - which healthy vaccinees are currently still benefiting from - is considered to be temporary and susceptible to promoting viral immune escape from the above-mentioned virulence-inhibiting PNNAbs ('The Inescapable Immune Escape Pandemic').

Early-stage cell-mediated viral clearance can only be explained by activation of MHC-unrestricted cytotoxic T cells (CTLs). The latter are probably to be classified as unconventional, innate-like cytotoxic T cells (NK-CTLs). Universal peptides, by definition, are not Ag-specific. Therefore, T cell reactivity towards these peptides cannot be qualified as protein-specific (e.g., N- or S-specific). As Ag re-exposure during a vaccine breakthrough infection recalls previously primed S-specific CD8+ T cells, it is tempting but incorrect to suggest that high levels of S-specific memory CD8+ T cell activation (i.e., due to a recall effect) contributed to the observed rapid decline in SARS-CoV-2 RNA levels. The authors seem to overlook that enhanced CTL-mediated viral clearance in COVID-19 vaccinated individuals is associated with a strongly diminished neutralizing capacity of vaccine-induced Abs, a phenomenon shown to stimulate infection-enhancing non-neutralizing Abs (https://pubmed.ncbi.nlm.nih.gov/34384810/).

As these PNNAbs are thought to be endowed with virulence-inhibiting capacity, it is reasonable to assume that the resulting gradual decline of suboptimal immune pressure on viral virulence could significantly risk promoting the natural selection of new viral variants that can escape the virulence-inhibiting effect of these Abs ('The Inescapable Immune Escape Pandemic').

While the authors seem uncertain about whether or how accelerated viral clearance in the upper respiratory tract relates to protection from severe COVID-19 disease in vaccinated individuals contracting a vaccine breakthrough infection, they consider that immune responses contributing to viral clearance in the upper respiratory tract could also prevent viral spread to the lower respiratory tract, thus mitigating disease progression. They also acknowledge the potential contribution of antibodies to preventing viral spread to the lower respiratory tract: "In this context, both antibodies and cytolytic T cells could contribute to the containment of viral replication." This aligns precisely with what I explain in my book titled 'The Inescapable Immune Escape Pandemic'.

To date, there is no evidence that enhanced clearance of SARS-CoV-2 at the upper respiratory tract prevents severe COVID-19 disease, especially not when this occurs after the peak of the viral load has been reached. Based on findings published by F.A. Lempp et al., I posit in my book that PNNAbs prevent trans infection and trans fusion of dendritic cell surface-adsorbed virions to susceptible alveolar epithelial cells in the lower respiratory tract, thereby preventing severe COVID-19 disease.

While M. Koutsakos et al. concede that "additional studies will be required to gain mechanistic insights into the role of cytotoxic T cells indirectly controlling viral replication during breakthrough infections" and note the importance of stating "we were unable to assess the role of T cell activation in the context of diverse clinical outcomes", M. Veldhoen and A. Bertoletti overinterpret the data published by these authors. They claim a critical role for memory T cells in curtailing viral infection in those who experienced vaccine breakthrough infections, asserting that "this finding also confirms the ability of memory T cells to be recalled multiple times, contributing to rapid viral clearance and disease prevention". Such a statement presupposes that recalled S-specific memory T cells serve as cytolytic effector cells, whereas Koutsakos et al. clearly state that "given our data, a key consideration for future research will be to define how functional attributes of CD8+ T cells, including cytokine production or cytolytic potential, compare with phenotypic activation and viral decay during vaccine breakthrough infection." Indeed, the studies conducted by Koutsakos et al. do not provide information on the functionality of epitope-specific T cells, contrary to what Veldhoen and Bertoletti allege ("they [i.e., Koutsakos et al.] demonstrate a direct correlation between the T cell response, their functionality, and viral clearance").

Initially, Veldhoen dismissed scientists who expressed concerns about the potential for new variants to escape vaccine-induced antibodies due to immune selection pressure exerted by highly vaccinated populations against COVID-19. Now, however, he posits that COVID-19 vaccines robustly protect against severe disease in the event of immune escape-mediated vaccine breakthrough infections, that is, when the vaccine fails to protect against symptomatic infection/disease! Yet, there is not a single example of a vaccine that protects against severe disease without also protecting against mild/moderate disease. His overreaching conclusions lack scientific logic. It is not because infection- or vaccine-primed T cells regularly target conserved viral epitopes (i.e., less affected by mutations characterizing novel variants) that they play a significant immunological role in eliminating virus-infected cells! Their conserved nature merely indicates that they are not involved in enabling viral entry and are not expressed on the surface of virus-infected cells at an early stage of viral replication.

Yet there are even far more renowned experts who confuse 'correlation' with 'causal relationship'. Paul Offit is one of them. Offit concludes that (memory) T cells are responsible for the continued protection of COVID-19 vaccine recipients against severe COVID-19 disease in the absence of significantly diminished neutralizing capacity of vaccine-induced antibodies towards further evolving Omicron variants (https://open.substack.com/pub/pauloffit/p/the-next-wave-of-severe-covid-a-prediction?r=fx0fr&utm_campaign=post&utm_medium=email). Unfortunately, the same conclusion is drawn by T cell guru, Dan Barouch, who similarly believes that immune recognition (by T cells) equates to immune protection. He states, “in contrast to neutralizing antibodies, vaccine-induced CD8+ T-cell responses are highly cross-reactive against Omicron and most likely contribute substantially to protection against severe disease” (https://www.nejm.org/doi/full/10.1056/NEJMra2206573).

None of these experts seem to concern themselves with the lack of evidence that memory T cells prevent or protect against infection. The absence of viral immune escape from T cells has become their mantra. The latter, however, does not imply the absence of natural immune selection of variants that have developed resistance to the virulence-inhibiting effect of PNNAbs! If these antibodies, and not memory T cells, are responsible for the currently observed protection of vaccine recipients against severe COVID-19 disease, then we indeed have a problem that will likely surprise these experts. However, as they continue to endorse the mainstream narrative and the COVID-19 vaccination frenzy, all of society (in highly vaccinated countries) is now at risk of being caught off guard. As these experts' credibility relies more on their reputation and influence than on deep insights into the evolving viral and immunological dynamics at play in this pandemic, I predict that it will take Nature's intervention for society to understand that it has been backing the wrong horse.

In summary, it cannot be denied that the activation of cytotoxic T cells (most likely MHC class I-unrestricted CTLs) after infection in both vaccinated individuals contracting vaccine breakthrough infections and unvaccinated individuals is critical for viral clearance. However, this does not imply that rapidly recalled cytokine-secreting memory T cells in vaccine- or infection-primed individuals are responsible for eliminating virus-infected host cells, as these memory T cells have not been demonstrated to kill SARS-CoV-2 infected host cells. There is no evidence from ex vivo phenotype characterization or in vivo monitoring of cytolytic effector function (in an appropriate animal model) that vaccine-induced memory T cells kill SARS-CoV-2 infected host cells. MHC class I-unrestricted (NK-)CTLs following infection with SARS-CoV-2 remain antigen-inexperienced, with no evidence of Ag priming.

1 These Abs have previously been shown to have an FcR-independent infection-enhancing effect (p. 620: https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8351274&blobtype=pdf)

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