December 23, 2021

When anti-S(pike) antibodies against Omicron can no longer sustain the narrative, why not resort to T cells?

I recently came across an article in which the author had hoped would serve as a plausible immunological explanation as to why Omicron manifests itself as a mild illness and as a rational for continuing the mass vaccination program ( T Cells Might Be Our Bodies’ Best Shot Against Omicron). I’ve repeatedly debunked arguments of those claiming an important role of cross-reactive T cells in controlling spread of SARS-CoV-2 variants, yet T cells are once again put in the spotlight as a last resort to rescue the vaccine narrative! 

Now that we have a variant that has largely become resistant to neutralization by vaccinal Abs, some immunologically naïve people are leading us to believe that vaccine-induced T cells explain Omicron’s mild infectious behavior and why “the capacity of the immune system to limit the spread of the virus would still be preserved.” Their story attempts to build the case for people to remain confident that they’re at much lower risk of getting seriously ill if they’re vaccinated. Lucky enough, we’re not mainstreamers who buy stories that are rooted in biased analysis, such as those reporting protection of vaccinees against severe disease based on assessments involving hospitalized patients only! We don’t swallow stories that are not based on sound scientific grounds or that suffer from confounding bias.  

The author of this article is confusing T cell-mediated immune recognition with T cell-mediated cytolysis. There is no evidence that natural coronavirus (CoV) infection or any C-19 vaccine induces fully functional cytolytic T memory cells in vivo (1, 2). As a result, CoV-specific T cells do not provide sterilizing immunity and therefore cannot prevent viral transmission. 

A multitude of studies have shown that T cells are involved in SARS-CoV-2 infection (3, 4, 5, 6-11), but the contribution of these responses to protection has largely remained elusive. A number of these publications report cognate priming of cytokine-secreting SARS-CoV-2-specific CD4+ and CD8+ T cells as of an early stage of infection or disease onset. CD4+ T cell activity against any of the SARS-CoV-2 antigens correlates with the total amount of RBD-specific antibodies (Abs) and CD8+ T cell activity, suggesting that antigen (Ag)-specific CD4+ T cells serve as helper cells for either RBD-specific antibody production or CD8+ T cell responses (10). The induction of T cells, in particular CD8+ T cells, has been associated with asymptomatic infection or enhanced recovery and prevention of progression to severe disease in symptomatically infected individuals (5, 12, 13). In asymptomatically infected individuals, CD8+ T memory cells against peptides conserved across coronaviruses were found to be far more abundant than T cells against peptides unique to SARS-CoV-2. However, asymptomatic infection implies prevention of productive infection or abrogation thereof at an early stage of infection. Such abrogation can only be effectuated by cytotoxic immune cells (i.e., NK cells or cytotoxic T cells [CTLs]), not by inflammatory cytokines secreted by T cells (e.g., IFN-γ, IL-2, TNF-α) as those cannot sterilize infectious virus or virus-infected cells. As far as T cells are concerned, there is not a single shred of evidence indicating ex vivo killing of CoV peptide-loaded or CoV-infected target cells by T cells isolated from previously asymptomatically or symptomatically infected individuals (as this would require CoV-specific T memory cells to be endowed with cytotoxic capacity). It is, therefore, unlikely that the occurrence of asymptomatic infection is due to expansion of these T cells as a result from previous exposure to seasonal human CoVs or other beta-coronaviruses of clinical importance to humans (e.g., SARS-CoV-1, MERS-CoV). The observed expansion more likely results from rapid clearance of SARS-CoV-2 by innate Abs and/ or NK cells, thereby resulting in short-lived exposure of the immune system to the virus (14) and hence, favoring induction of CD8+ T cells that are capable of recognizing immuno-dominant CD8+ T cell epitopes comprised within early CoV proteins (i.e., ORF-1) and phylogenetically conserved (5). As common cold CoVs are endemic, it would also be difficult to understand how previous exposure to these viruses would lead to better protection against SARS-CoV-2 in children than in older age groups. A higher incidence of infection with common cold CoVs has been reported for children, but those data are based on serology tests, which are likely to vastly underestimate asymptomatic infections. The lower susceptibility of children to SARS-CoV-2 is thought to be due to their more abundant levels of innate Abs (15). These Abs are mostly of IgM isotype and featured by broad reactivity and a variable affinity.    

The association between the preferential recruitment of cross-reactive, cytokine-secreting MHC class I-restricted CD8+ T memory cells and enhanced recovery from C-19 disease and mitigation of disease in symptomatically infected individuals (5, 12) suggests that these cells serve a role as non-cognate helper cells assisting CTL-mediated killing of virus-infected cells. Upon recognition of their cognate Ag, these T cells would be recalled and provide inflammatory mediators that mediate activation of CoV-specific cytotoxic T cells devoid of memory markers and thereby enhance viral clearance in symptomatically infected patients (see below). Activation of such cytotoxic T cells could, therefore, expedite recovery from symptomatic infection and thereby decrease the likelihood of progression to severe disease. As SARS-CoV-2-specific T memory cells recognize T cell peptides across a broad spectrum of distinct CoVs, previous infection with a given CoV species could enhance recovery from disease and avoid a more severe course of C-19 illness. 

Furthermore, if in vivo priming of previously CoV-primed cross-reactive memory T cells were responsible for Omicron’s mild course of C-19 disease, one wonders why cross-reactive T memory cells were not already our bodies’ best shot at attenuating disease caused by the Delta variant. 

Based on all of the above, it is reasonable to conclude that CoV-specific T cells cannot be responsible for the predominantly mild course of infection caused by Omicron. The author’s interpretation of published SARS-CoV-2-related T cell data being supportive of C-19 vaccination is also completely at odds with the observation that CoV-specific cytokine-secreting CD8+ T memory cells, the preferential recruitment of which is correlated with enhanced recovery and mitigation of disease symptoms, are not primarily directed at the spike (S) protein (3, 5, 11-13, 16) and that severe C-19 disease is rare in the unvaccinated as well. Consequently, it is a complete misconception that vaccination with S-based C-19 vaccines would provide any advantage over natural exposure, even in terms of promoting recall of a T cell-mediated adjuvant effect. 

The statement, therefore, that Omicron causes a milder course of disease in vaccinees and that vaccination will significantly lower the risk of getting seriously ill defies all immuno-‘logic’ and reason. In her blind excitement about mass vaccination, the author rages on pretending that more vaccination is needed to prevent immune escape of dominant SARS-CoV-2 T cell epitopes (“too many people around the world remain unvaccinated!”). Interestingly enough, she seeks supportive evidence from a reference which actually advises for caution in regards to the impact of population-level immunization (“As vaccine and naturally acquired population immunity increase further, the frequency of variants we have described should be monitored globally, as well as further changes arising within all immuno-dominant T cell epitopes”; 17) 

In conclusion, it is fair to say that the more plausible explanation for Omicron’s mild behavior lies in its escape from neutralizing vaccinal Abs which prevents the latter from suppressing relevant innate Abs (18, 19). In contrast, non-neutralizing, short-lived Th-independent anti-S Abs that unvaccinated acquired upon previous asymptomatic/ mild infection may now be a better match to Omicron’s S protein than the vaccinal Abs targeted at the S protein of the original Wuhan strain. This might explain why a small part of the unvaccinated population may currently see their relevant innate Abs being suppressed to an extent that makes them more susceptible to severe disease than the vaccinated. However, as already reported, this is likely to change when Omicron becomes dominant; high infectious pressure exerted by the predominantly circulating Omicron variant would primarily suppress poorly trained innate immune Abs in vaccinees (20).

Lastly, no matter how hard some vaccine producers will try to induce CoV-specific T cell responses by incorporating conventionally selected T cell epitopes in their new candidate vaccines, they won’t be able to induce a universally protective T cell response capable of abrogating and blocking viral transmission in vaccinated target populations. Even though equipped with an impressive arsenal of conserved CoV-specific T cell epitopes, C-19 vaccines targeting S protein will still be prone to expediting the expansion in prevalence of more infectious immune escape variants when used in a pandemic. Furthermore, recovery from symptomatic infection and protection against severe disease in these individuals will be no better than that of naturally exposed unvaccinated subjects. I, therefore, firmly disagree with those pretending that conventional T cell-oriented vaccines could allow for controlling the C-19 pandemic (21). On the contrary, loading C-19 vaccines with immunodominant T cell epitopes could potentially promote immune escape from T cell recognition as has recently been described to occur as a result of population-level immune pressure (17). This may ultimately result in loss of the above-described T cell-mediated mitigation of disease severity in both vaccinated and non-vaccinated individuals who contract symptomatic infection. Personally, I do not believe that non-sterilizing vaccine candidates comprising a multitude of different SARS-CoV-2-specific T cell epitopes will be capable of preventing an expansion of variants that also escape T cell recognition when used in a mass vaccination program. It seems that many of us have forgotten about the myriad of miserable clinical failures previously reported for HIV-1 vaccine candidates using a panoply of constructs that resulted from all kinds of sophisticated T cell epitope engineering. Suboptimal immune pressure in a limited number of chronically virus-infected patients may, indeed, have the same effect on the virus’ evolutionary capacity as suboptimal immune pressure exerted by the majority of a population when exposed to an acute viral infection.  

This being said, recovery from CoV-disease, an acute viral infection known to be ‘self-limiting’ in nature, is clearly not restricted by the genetic MHC background of the host. It is, therefore, conceivable that viral clearance leading to recovery from CoV disease is mediated by cytotoxic T cells (CTLs) that are triggered by up-regulation of a universal immuno-dominant CTL epitope that is presented on cell surface-expressed MHC class I molecules without imprinting immunological memory. Such a universal immuno-dominant CTL epitope has, indeed, been identified within the S2 subunit of Coronaviruses (22). A vaccine designed in a way that enables induction of cytotoxic T memory cells against this universal epitope (i.e., SF[A]IEDLLF) would hold great promise in protecting vaccinees from productive infection, thereby conferring sterilizing immunity and hence, enable herd immunity.   



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Geert Vanden Bossche received his DVM from the University of Ghent, Belgium, and his PhD degree in Virology from the University of Hohenheim, Germany. He held adjunct faculty appointments at universities in Belgium and Germany. After his career in Academia, Geert joined several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) to serve various roles in vaccine R&D as well as in late vaccine development.

Geert then moved on to join the Bill & Melinda Gates Foundation’s Global Health Discovery team in Seattle (USA) as Senior Program Officer; he then worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. At GAVI he tracked efforts to develop an Ebola vaccine. He also represented GAVI in fora with other partners, including WHO, to review progress on the fight against Ebola and to build plans for global pandemic preparedness.

Back in 2015, Geert scrutinized and questioned the safety of the Ebola vaccine that was used in ring vaccination trials conducted by WHO in Guinea. His critical scientific analysis and report on the data published by WHO in the Lancet in 2015 was sent to all international health and regulatory authorities involved in the Ebola vaccination program. After working for GAVI, Geert joined the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He is at present primarily serving as a Biotech / Vaccine consultant while also conducting his own research on Natural Killer cell-based vaccines.


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