Twitter book review The Inescapable Immune Escape Pandemic

I reviewed the following Twitter thread on my book

Gomez Addams @tradsperger

LIVE BOOK REVIEW - THE INESCAPABLE IMMUNE PANDEMIC In this thread I will be sharing my thoughts on a book I just bought. The book may frighten, it may disappoint, it may enlighten, we'll find out as we go through it.🧵

His comments fairly reflect the poor understanding of cell-based innate immunity as a critical/first line of immune defense against viral infection. It is true that in my book, I emphasize the contribution of Natural Killer (NK) cells, whereas the role of pathogen/virus-associated NK cell responses is still not well understood in the life science community.

First, it is important to realize that NK cells comprise a diversified spectrum of immune cells that are regulated by a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanisms of NK cell activation are:

• i) “Missing self MHC (Major Histocompatibility Complex)” detection, i.e., the recognition of virally infected or otherwise pathologically altered cells (e.g., transformed/cancer cells) that exhibit reduced expression of MHC-I molecules on target cells or express altered MHC-I molecules (e.g., MHC class I chain-related molecule) on target cells. This mechanism involves NK cells that have inhibitory receptors which interact with conserved MHC molecules (so-called ‘killer immunoglobulin-like receptors’, KIRs).

• ii) Antibody-dependent cellular cytotoxicity (ADCC). NK cells involved in ADCC express Fcγ receptors. These receptors recognize and bind to antigen-specific antibodies (Abs), which bind to the surface of a pathogen-infected target cell.

However, the NK cells I am alluding to in my book do not involve those described above, but rather NK cells equipped with Natural Cytotoxicity Receptors (NCRs) (e.g., NKp44, NKp30 and NKp45, which is the more relevant one in regard of recognition of self-mimicking viral peptides!). In contrast to KIRs, these germline-encoded receptors are involved in non-MHC-restricted recognition. They have primarily been studied within the context of cancer, but they are also capable of recognizing virus-associated self-mimicking peptides (in my book, I refer to those as ‘pathogen-derived self-mimicking peptides’; PSMPs). The latter are expressed on the surface of virus-infected cells at an early stage of infection¹. NK cell immunology is still incompletely understood and not at all paid attention to by vaccinologists. However, there are many interesting reviews describing different mechanisms of NK cell activation, including activation of NK cells that are endowed with NCRs:

“Recent success in identifying the various ligands for the NCRs is now beginning to illuminate the biological roles that this important class of receptors plays in NK cell surveillance of malignant or pathogen-infected cells and in different tissue microenvironments. One striking aspect that has become apparent is that each NCR may interact with several different pathogen- and host-encoded molecules that can either be expressed on cell-surfaces, secreted or shed extracellularly, or incorporated into the extracellular matrix (ECM)” (https://www.frontiersin.org/articles/10.3389/fimmu.2019.00909/full).

Some publications on mRNA-based C-19 vaccination suggest vaccine-induced training of cell-based innate immunity. However, these observations do not relate to innate immune imprinting mediating enhanced cytotoxic activity of NK cells towards virus-infected cells but merely to enhanced secretion of cytokines and expression of cell surface-expressed chemokine receptors. These characteristics have to do with immune regulation but not with pathogen-nonspecific cytotoxic killing of infected cells. Such publications are misleading in that they talk about trained innate immunity that is not enabling sterilizing immunity and fail to demonstrate vaccine-mediated enhancement of cytotoxic NK cell activity. I’ve never pretended that C-19 vaccination (and in particular, mRNA-based C-19 vaccines) ‘perturb’ cell-based innate immunity in a major way, but rather that vaccination sidelines training of NK cells such as to prevent their enhanced cytotoxic activity towards SARS-CoV-2 (SC-2)-infected epithelial cells. The following conclusion drawn by these authors is therefore absolutely misleading (and BTW, Netea et al., 2016 does not at all describe vaccine-mediated innate immune training of cytotoxic NK cells!):

“Although the results here presented do not exclude subtle vaccine-induced imprints, such as long-term signs of trained innate immunity (Netea et al. 2016), they do indicate that NK cells maintain their key phenotypic and functional properties throughout the course of vaccination. Therefore, it is of importance that immune effector cells such as NK cells will not be significantly perturbed by vaccination, particularly, in respect to their abilities to respond to future infection challenges and vaccination. The present results also argue against the idea that specific immune cells, or the immune system as such, are perturbated in a major way by vaccination.”

The twitter thread’s author wonders how SIR prevents training of cell-based innate immunity. SIR results from vaccine breakthrough infection. The latter is triggered by infection-enhancing Abs or is due to enhanced intrinsic viral infectiousness. Enhanced viral infectiousness expedites the onset of viral replication and production of viral progeny. Since viral replication (including replication of Coronavirus (CoV); https://www.nature.com/articles/s41467-021-26910-8) reduces cell surface-expression of MHC class I molecules, it is reasonable to assume that MHC class I surface expression is already downregulated at an early stage of enhanced viral infection.

As MHC class I-dependent immune responses provide key host defense mechanisms against viral infection, many viral species (including CoV) have evolved diverse strategies for targeting the MHC class I pathway to evade host immunity (https://www.biorxiv.org/content/10.1101/2022.05.29.493850v1.full). Downregulation of MHC class I molecules in epithelial cells hampers CTL (cytotoxic T lymphocytes)-mediated recognition of virus-derived peptides that are presented on the MHC class I peptide-binding groove (PBG) and thereby impedes elimination of virus-infected cells at an advanced stage of infection. However, in case of enhanced viral infectiousness, downregulation of MHC class I molecules in epithelial cells could even prevent NK cell-mediated recognition of virus-associated self-mimicking peptides (‘altered self’) that are typically presented outside of the MHC class I PBG at an early stage of infection. This would explain why enhanced viral infectiousness prevents training of NK cells endowed with NCRs. In my book, I call this phenomenon ‘sidelining of the cell-based innate immune system’ (CBIIS).  As PSMPs presented outside of the MHC class I PBG are thought to play a key role in the elimination of virus-infected cells at an early stage of infection, lack of trained NK cell-based innate immunity prevents the infected individual from sterilizing virus-infected cells before progeny virus is produced.

Of course, macrophages and other white blood cells are equally part of the cell-based innate immune system. In my book, however, cell-based innate immunity primary relates to NCR-bearing NK cells as only those are capable of pathogen-nonspecific recognition of ‘altered self’ peptides (i.e., PSMPs), and hence enable CoV-nonspecific cytolytic killing at an early stage of infection.

I hope this clarifies some of the questions readers may have on the role of trained cell-based innate immunity to fighting SC-2. It is important to realize that the impact of epigenetic reprogramming and imprinting on pathogen/variant-nonspecific innate immune cells (e.g., NK cells and natural Ab (IgM)-producing B cells) enabling adaptation to exposures to endogenous or exogenous factors during critical periods is still poorly studied and obviously not of interest to the vaccine industry.

¹ As explained in my book, PSMPs are not expressed during mRNA vaccine-mediated transfection of host cells.

More information on the book can be found on our website