I don’t know how many more contributions I need to write to kill this idea.
Quite recently I was once again confronted with a paper (L. Swadling et al. 2021; 1) leading some scientists to believe that pre-existing cross-reactive T cells against Coronavirus (CoV) replication-transcription complex (RTC) can abort infection and thereby prevent seroconversion against SARS-CoV-2 (SC-2).
Firstly, the authors don’t even claim what many seem to infer from their publication—it merely suggests a role of these pre-existing RTC-specific T cells in aborting SC-2 infection (e.g., ‘we hypothesize that pre-existing memory T cell responses would expand to support rapid viral control, aborting infection’; ‘Pre-existing RTC-specific T cells would be expected to favor early control, explaining their enrichment after abortive compared to classical infection’ or: ‘suggesting abortive infection’, or: ‘supporting a potential role [of NSP12- specific T cells] in protection from PCR-detectable infection and seroconversion’). Secondly, I will illustrate below why this [peer-reviewed] paper does nothing to prove that pre-existing RTC-specific T cells with cross-reactive potential abort infection.
To summarize, T cells can only mediate prevention of disease or recovery therefrom provided they can abrogate infection. In order for antigen (Ag)-specific T cells to prevent disease, they need to be primed (memory) and have cytolytic capacity. There is no single piece of evidence showing that natural CoV infection (or even any of the C-19 vaccines) induces Ag-specific cytolytic T memory cells. One is therefore unable to reasonably speculate that CoV-specific T memory cells prevent disease. If this were the case, their existence would long have been proven by ex vivo or even in vivo cytolytic assays. Why hasn’t anyone shown thus far that adoptive transfer of T memory cells from previously CoV-exposed syngeneic nonhuman primate donors to CoV-naïve recipients provides protection from symptomatic, laboratory-confirmed infection upon challenge with SC-2? Furthermore, why would the level of protection from disease provided by cross-reactive T memory cells to previously SC-2 exposed individuals be higher in the case of re-exposure with the Omicron variant than in case of re-exposure with the Delta variant (2)?
Of course, cross-reactive T memory cells can be re-stimulated by reinfection and lead to a substantial increase in magnitude of corresponding T cell responses while broadening the specificity and functionality thereof. Cross-reactive T memory cells (which, of course, do exist) secrete a variety of cytokines and chemokines. This is fully acknowledged by the authors: ‘The abundant SARS-CoV-2-specific CD4+ T cells may also contribute to protection in SN-HCWs by antibody-independent mechanisms, such as antiviral cytokine and chemokine production’. However, neither cytokines nor chemokines can eliminate SC-2-infected cells. Sure, they can contribute to protection from severe disease (3), but they can also occasionally lead to immune pathology! There is, indeed, no virus-mediated immune pathology that does not also involve strong stimulation of T memory cells, especially CD4+ T memory cells. Whether their stimulation during SC-2 infection will result in a positive or negative outcome likely depends on the genetic background of the host and particularly on the MHC haplotypes. In other words, some individuals will be predisposed to promoting control of the disease by virtue of a favorable combination of protective MHC alleles whereas others may be genetically predisposed to progressing to severe disease. The impact, therefore, of MHC restriction on the outcome of natural disease is unpredictable. However, this is not to say that there are no cytotoxic [CD8+] T cells that can eliminate CoV-infected cells. If this were not the case, individuals contracting C-19 disease would not be able to recover from it. As already mentioned in a previous contribution (3), such Ag-specific cytotoxic T cells do not need to be endowed with memory in order for them to enable abrogation of infection and allow the host to recover from disease instead of progressing to severe disease.
Lack of consensus that immune protection against CoV (and likely against Flu as well) is primarily provided by self-centered innate immune effector lymphocytes (e.g., innate antibody [Ab]-secreting B cells and NK cells) and not by conventional foreign-centered T and B cells is only grist to the mill of those who advocate for C-19 vaccination across all age groups. So, not surprisingly, the authors of this article are proposing that ‘The boosting of such T cells may offer durable pan-Coronaviridae reactivity against endemic and emerging viruses, arguing for their inclusion and assessment as an adjunct to spike-specific antibodies in next-generation vaccines.’ On the other hand, however, they seem to realize that they may be missing the key mechanism that is responsible for abortion of SC-2 infection and that expansion of pre-existing RTC-specific T cells in seronegative (SN) health care workers (HCWs) is only the result of asymptomatic infection but not the cause: ‘A caveat of this work is that we analysed only peripheral immunity; it is plausible that mucosal-sequestered antibodies had a role in our seronegative cohort. It also remains possible that innate immunity mediates control in abortive infections, with RTC-biased T cell responses being generated as a biomarker of low-grade infection.’ And furthermore: ‘A transient/abortive infection that is not detectable by PCR or seroconversion could conceivably result from a lower viral inoculum and/or from a more efficient innate and/or adaptive immune response.’
From what follows below, it will hopefully become obvious that there are several important observations made on naturally infected individuals that cannot be explained by boosting/ expansion of cross-protective CoV-specific T cells, but rather find their justification in changes to the functional capacity of innate polyspecific Abs. The latter have, for example, relatively low efficiency in the presence of high infectious pressure and exhibit a relatively low level of resistance to high immune pressure from S-directed high affinity Abs (4).
What follows is a series of observations on diminished infectious case rates that cannot be explained by boosting/ expansion of cross-protective CoV-specific T cells:
Related to the bar diagrams appended below:
Furthermore, the publication authored by L. Swadling et al. (1) does anything but provide sound evidence that pre-existing cross-reactive anti-RTC-specific T cells are the cause of abortive infection in SN HCWs. The major reasons for lack of demonstration of causality can be summarized as follow:
Based on all of the above, it is reasonable to postulate that the enhanced expansion of RTC-specific T cells with cross-reactive potential is not the cause of abortive infection at an early stage after exposure, but rather the result of NK cell-mediated killing of virus-infected host target cells. Once released from the infected host cells, these early RTC-associated proteins can be presented to the host immune system by APCs. Additionally, this would explain why the expansion of RTC-specific T cells is not immediate but takes time before reaching its peak.
It's also difficult to understand why the authors of this and similar SC-2 T cell-dedicated papers are not more skeptical about their own conclusions or postulates on using conserved, cross-reactive T cell epitopes in future C-19 vaccines. Are they unaware that there are no licensed or ‘successful’ candidate vaccines that (universally!) induce T cell-based abrogation of infectious transmission? Or that no vaccines exist that use non-structural proteins as targets for fighting infectious pathogens? All fields in infectious diseases, whether dealing with viruses, bacteria, or parasites, have explored T cell-based immune interventions to abrogate infection and prevent or cure disease, but all have miserably failed. In contrast to what the authors state, T cells don’t seem to be particularly effective vaccine targets and it is difficult to understand, for example, how ORF1lab-reactive T cells could remove SC-2-infected cells unless they have cytolytic capacity (which has never been demonstrated in any of the papers that invoke cross-reactive T cells as being protective against disease). The very same applies to cross-reactive T cells isolated and identified in this paper, as the vast majority of those were CD4+ T cells and not CD8+ T cells. The former typically serve as helper cells and only rarely as cytotoxic killer cells. Similarly for antibodies, some scientists still believe that inducing those foreign-centered immune effector lymphocytes at the level of the portal of pathogen entry (e.g., respiratory mucosae) will do the job. However, once again, up until now, there is no single non-living ‘mucosal’ vaccine that protects against viral disease. As the textbook says: The vaccine is only as good as the antigen—it’s neither the adjuvant, nor the new technology, nor the alternative route of vaccine administration that will make your vaccine work!
Lack of virus-sterilizing capacity is not only a feature of pre-existing or de novo primed structural CoV-reactive T memory cells recalled upon moderate, laboratory-confirmed SC-2 infection but also of pre-existing or de novo primed non-structural CoV-reactive RTC-specific T memory cells recalled at an early stage of infection. In other words, SC-2 reactive T memory cells are neither responsible for early nor for late abrogation of SC-2 infection and, therefore, can neither prevent nor terminate C-19 disease. Recovery from disease is most likely mediated by activation of cytotoxic CD8+ T cells directed at a universal (i.e., MHC class I-unrestricted) epitope (5).
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.