Cross-reactive memory T cells are associated with (but not responsible for) protection against SARS-CoV-2 infection in COVID-19 contacts.

I recently came across yet another article suggesting that cross-reactive memory T cells serve a critical role in protecting COVID-19 contacts against infection and thereby abrogate subsequent induction of de novo SARS-CoV-2-specific antibody responses: https://www.nature.com/articles/s41467-021-27674-x.pdf.

I do not concur with the suggestion of the authors that pre-existing cross-reactive memory T cells could be responsible for protection against infection (i.e., by causing abrogation of infection). The association / correlation between pre-existing IL-2-secreting cross-reactive T cells and protection from infection in COVID-19 contacts does not imply causality. Whereas there can be no doubt that pre-existing cross-reactive CoV-specific T cells are boosted in COVID-19 contacts, there is no proof that these cells are responsible for controlling infection and abrogating subsequent induction of de novo SARS-CoV-2-specific antibody responses in COVID-19 contacts.

Exposure-mediated boosting of pre-existing cross-reactive memory T cells requires antigen (Ag) presentation as neither ORF-1 nor N¹ are presented on the surface of infected cells at an early stage of SARS-CoV-2 infection. In order for these early proteins to be presented by Ag-presenting cells, virus-infected target host cells must be lysed at an early stage of infection (see my comments to a similar paper: here). There is no evidence, however, that pre-existing cross-reactive memory T cells have such cytolytic capacity. This is in sharp contrast to Natural Killer (NK) cells, which have been postulated to synergize with innate IgM-secreting B1 cells to enable elimination of virus-infected cells at an early stage of viral infection (R. Carsetti et al., https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7772470/pdf/fimmu-11-610300.pdf).

In other words, boosting of pre-existing cross-reactive memory T cells is to be considered the consequence but not the cause of abrogation of infection at an early stage of infection. The role of innate immune effector lymphocytes (IgM-secreting B1 cells and NK cells) in controlling SARS-CoV2 infection still seems contradictive as it is not within the conventional paradigm of immunology, let alone vaccinology. This is highly problematic as the possible misinterpretation of immune mechanisms underlying the expansion of pre-existing cross-reactive memory T cells leads some scientists to support the inclusion of non-spike antigens (i.e., including cross-reactive T cell epitopes) in second-generation vaccines. This will only bring grist to the mill of those addicted to the mass vaccination program and claiming that such novel vaccines will protect against novel SARS-CoV-2 variants with potential to escape naturally acquired or vaccine-induced humoral immunity.

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1. The higher frequency of T cells specific for the cross-reactive pool in SARS-CoV-2 exposed PCR-negative contacts implied ORF1 and N-, not S-, reactive T cells;