Shapes in the Fog

Making sense of COVID and vaccine risks

It’s been two and a half years now since a new virus stormed the globe, leading to massive disruptions that were – depending on who you ask – completely unnecessary or woefully insufficient.

Since that time, billions of humans on planet Earth, myself included, have parleyed with the virus awkwardly known as SARS-CoV2. Many have now had it two or three times. Of these, around one in five hundred – most commonly those already approaching natural death – have died as a result of infection, and a small but significant proportion continue to experience distressing or debilitating post-viral syndromes that are collectively known as “long covid.” The vast majority have made a complete recovery, and getting “the coof” or “the rona” has become a common enough occurrence that life-altering levels are fear are now mostly confined to the immunocompromised, the elderly, and the hypochondriacs – the same folks who have long been taking extra precautions during every flu season.

It’s been eighteen months since vaccines targeting the virus were rolled out to great fanfare, in the hope that this would quickly build “herd immunity” and drive the virus to extinction. Since then, exactly the opposite has occurred, with infection rates rising to even higher levels and many people experiencing multiple “breakthrough” infections after vaccination. At the same time, rates of death and serious illness have declined substantially since early 2021. The vaccines have almost certainly played a role in this improvement, although it is difficult to fully separate this effect from that of ever-rising natural immunity (from previous infection) and the emergence of a new (“Omicron” or BA.x) family of viral variants that has a lower affinity for lung cells than previous versions.

It’s been a year since I felt personally under great pressure to consent to receiving these vaccines, with restaurants and venues imposing vaccination mandates and the federal government attempting to mandate vaccination for all employees in various categories. Since that time, as it has become clear that vaccination does not prevent infection or transmission but at best tilts the odds slightly and reduces severity, the pressure has decreased and most mandates have been relaxed. Plenty of true believers remain, however, eager to get their fourth or fifth dose as soon as it is allowed. As an unvaccinated person I remain banned from entry to Canada, to my local contra dances, and to one of my favorite hot springs. Given the current trajectory I am hopeful that these remaining barriers will be removed in the months ahead and that we will not ultimately end up with a two-tier society with an unvaccinated “underclass” as many – myself included – have feared.

I have written plenty about my concerns regarding particular vaccine risks and the strange and divisive media-driven mob mentality that has has surrounded all things covid since the beginning. I have also participated in ongoing discussions on these topics on John Michael Greer’s Ecosophia forum, where it seems that I have been assigned the role of scientist-in-residence. Whether this role is befitting is certainly open to debate. I am not a virologist, immunologist, vaccinologist, epidemiologist, or even someone with a biomedical background. I place a higher value on functional and evolutionary understanding of biological processes than on mechanistic details, which has both strengths and weaknesses. Although I have delved deeply into some scientific papers, I rely heavily on other critical thinkers – among them Bret Weinstein, Brian Mowrey, and the mysterious quantity known as El Gato Malo – for critical assessment of the current literature.

My own academic background – a PhD in biological engineering with a focus on genetically modifying cyanobacteria to produce hydrogen from sunlight – has provided me with a solid understanding of both biochemistry/molecular biology and the pervasive ideology (Scientism, Religion of Progress, transhumanism, whatever you want to call it) that dominates the worldviews of all modern scientific institutions and leads to willful blindness and failure of critical thinking in certain areas, most prominently those that relate to the completeness of our understanding (of everything from the human body to the known universe) and the ability of modern technology to solve problems ranging from resource shortages to climate change to infectious disease.

Eighteen months after these novel genetic vaccines became available and a year after a majority of the population received them, it is clear from my perspective that they are simultaneously one of the most dangerous medical experiments of the past century and also that they are nowhere near as harmful as many of their most vocal detractors have claimed. Considering that these alternate worldviews have effectively polarized to “the vaccines are the safest medicines ever produced” and “all vaccinated people will die”, the probability that reality will land somewhere in the middle approaches 100%. Exactly where in that middle reality will end up remains unknown and quite probably even undetermined at this point: dependent on ongoing booster shot deployment and ongoing viral evolution. That said, however much good these shots may have done, it is clear at this point that they have also directly contributed to many thousands of cases of death and disability, and the tools of science are just beginning to peel back the curtain to understand what may be going on.

The understanding that I present below is a blend of science and hypothesis: an attempt to distill the risks posed by infection and vaccination into broad categories and disruptions of biological processes, without getting too bogged down in details. I provide citations where possible, but I acknowledge that some of the logical connections remain conjecture. As such, I don’t claim to present the truth, only to present my own understanding of the present situation. I hope that it can prove helpful to others, and perhaps can provide inspiration to survey the available literature or conduct the necessary studies to further reveal the shapes in the fog.

1. Immune Disequilibrium, Three Ways*

*A shameless reference to Brian Mowrey’s brilliant discussion of immune equilibrium over evolutionary time.

Our popular understanding of the human immune system is far too simplistic, and this appears to extend into the field of vaccinology as well. Pathogens are detected and fought. B cells develop antibodies which bind to and neutralize the pathogens to prevent future infections. High titers of neutralizing antibodies are good, and vaccines that elicit this effect are good. Vaccines are unlikely to have deleterious effects on immune function – the worst that usually happens is that they just don’t work.

I think it’s helpful to think of the human immune system as a Department of Defense. It has had nearly four billion years of evolution to develop, beginning as a bacterial defense against bacteriophage viruses and evolving layer upon layer of nuance and complexity as we evolved into multicellular organisms in an ongoing coevolutionary dance with viruses and other microbes – some of them harmful, some beneficial, some neutral, and some not fitting easily into one of these groups. Its cells and subsystems perform the roles of special operations, intelligence, central command, heavy artillery, surveillance, and just about every other role essential to an effective Department of Defense.

The immune system has the following tasks:

  • Identify and destroy infectious agents that are actively evolving to evade detection and destruction.
  • Identify and destroy human cells that are mutating to become dysfunctional and cancerous.
  • Avoid launching attacks on healthy tissues.
  • Tolerate the presence of foreign molecules on non-infectious particles (e.g. pollen, bee venom, food allergens).
  • Facilitate the development of a healthy intestinal microbiome, by tolerating beneficial/commensal organisms and attacking those that are parasitic or pathogenic.

A healthy immune system can occasionally be defeated by a pathogen that is able to evade the innate defenses and establish a serious infection before the second line of adaptive defenses are activated. Vaccination aims to activate that second line of defense ahead of exposure or (in the case of rabies) following exposure but before the pathogen has a chance to multiply significantly. In practice, success is dependent upon the nature of the pathogen, the route of exposure, and the rate of pathogen mutation. Vaccines against rabies and smallpox are nearly 100% effective while those against influenza have a much lower efficacy. Vaccines against rapidly-mutating respiratory viruses like SARS-CoV2 have always been an iffy proposition at best.

In addition to suffering defeat in battle, the delicate balance maintained by the human immune system can be disrupted in three ways, all of which are relevant to the covid and vaccine story. These are:

  • Autoimmunity. Immune cells can misidentify normal human proteins and biomolecules as pathogenic, resulting in a sustained attack on healthy tissues that can be progressively debilitating.
  • Allergy/overreaction. Immune cells can misidentify inert particles like pollen as pathogenic, or they can launch a life-threatening inflammatory attack on a pathogen that is out of proportion to the threat level.
  • Tolerance. Immune cells can fail to attack pathogens and nascent cancers, and this effect can be specific to particular antigens or broader in which case it is more often described as immunosuppression or immunocompromise.

From what I have been able to gather, spike protein exposure and genetic vaccination both carry risks of autoimmunity. Genetic vaccination shifts the major failure mode from overreaction to tolerance.

It is important, at this point, to understand that immune disequilibrium is largely probabilistic rather than deterministic. Just as different military generals will make different decisions in the same situation leading to different outcomes in battle, so will different immune systems respond in varying ways to the same stimulus, resulting in health or dysfunction. Therefore perturbations or disruptions to the immune system will tend to have probabilistic effects – to increase or decrease the odds of a particular outcome. Give everyone the same amount of lead or arsenic, and they will all get sick and display similar symptoms. Give everyone the same immune disruption, and perhaps 5% will suffer debilitating immune dysfunction and the other 95% will be fine. Such is the nature of the immune system, which can make it difficult to attribute causation to disruption (“all these other people got it too, and nothing happened to them…”) unless we are carefully tracking outcomes vs. interventions over a longer term – something that is most definitely not happening with these vaccines.

Spike protein and autoimmunity

One of the tricks viruses use to evade the immune system is to mimic portions of human proteins, such that any antibody or T cell epitope targeting that section of protein will also be autoreactive. For the most part, these nascent autoreactive responses are weeded out by central and peripheral tolerance processes, thus decreasing the breadth of the effective immune response against the virus. Occasionally these tolerance systems fail, resulting in an autoimmune reaction. The spike protein of SARS-CoV2 exhibits a surprising degree of sequence overlap with a number of human proteins, suggesting a potential for autoimmunity development, and indeed long covid appears to have a significant autoimmune component.

The risk of autoimmunity development posed by spike protein exposure will be present with both infection and spike-based vaccination, and indeed many people have reported long-term autoimmune-type symptoms following vaccination, quite similar to those experienced by long covid sufferers.

Genetic vaccination: a novel and confusing immune stimulus

In understanding the immune response, it is useful to assess what signals it is looking at to determine the presence of an infection. In a genuine viral infection, there will be viral particles present displaying antigen proteins. There will be infected cells displaying these same proteins as a signal that they are infected. And there will be a whole host of other signals coming from infected cells generally informing the immune system that it’s time to do battle. The result of this will be activation of both an immediate innate immune response to destroy free viruses and infected cells, as well as an adaptive immune response to develop antibodies and cellular memory as a second line of defense and to ward off future infections.

Live attenuated vaccines – the oldest vaccine technology – replicate all of these processes, with the difference that the strain of virus or bacteria used is unable to cause severe illness.

Inactivated-virus vaccines and protein subunit vaccines – the most common type in widespread use for childhood vaccination – present only the antigens on inert particles and do not infect any cells. In order to sufficiently activate the immune system they include “adjuvants” – essentially immune-cell-irritating chemicals. It makes sense to me that overuse of adjuvanted vaccines could also easily cause immune disequilibrium leading to higher rates of allergies and autoimmune conditions such as are currently being observed among children. More work is needed to test that hypothesis – work that seems to be mysteriously retracted when it does get published – but I think it is likely that over-vaccination of children is causing more harm than good, and I will readily admit that this perspective helped to inform my initial skepticism toward the novel covid vaccines.

Genetic vaccines – including all covid vaccines available in the US until the very recent approval of the Novavax protein subunit vaccine – utilize a novel and fundamentally different technology that has previously seen very limited application in humans in the form of the Ebola vaccine. With genetic vaccines, the antigens are not directly injected, and are therefore not encountered on free-floating particles by immune cells. Instead, the vaccines supply genetic instructions to produce an antigen – either in the form of mRNA in lipid nanoparticles that fuse with cells (Pfizer/Moderna) or in the form of unrelated viruses that inject DNA into cells (viral vector: J&J/AstraZeneca/Sputnik). In molecular biology, this process would be called transfection.

What the immune system sees following genetic vaccination is the sudden appearance of large amounts of a novel protein on the surface of otherwise healthy and uninfected cells, in the absence of any viruses or virus-like particles containing that protein. The lipid nanoparticles themselves are pro-inflammatory and act a bit like an adjuvant, but it is otherwise unclear that this really looks like an infection to the immune system. It might instead look more like a tissue transplant, or exposure to fetal antigens during pregnancy. It is most definitely unlike any natural infection process.

We know that genetic vaccination results in the production of large amounts of anti-spike neutralizing antibodies and also generates anti-spike T-cell responses. Prior to the arrival of Omicron-family variants, this provided strong protection against covid infection for the six months or so that antibody titers remained high. That said, the post-vaccination immune attack on otherwise-healthy spike-expressing cells (itself possibly implicated in rapid-onset inflammatory reactions such as myocarditis) is likely to be perceived by at least some of the immune system’s intel apparatus as an autoimmune error. Repeated vaccination is thus likely to induce tolerance, as I proposed in my immune tolerance hypothesis nearly a year ago. The recent discovery that tolerance-inducing IgG4 antibodies increase following two genetic vaccinations and especially following the third shot adds credence to this hypothesis – see also Brian Mowrey’s discussion of these findings.

It is also reasonable to hypothesize that while some immune systems will react to the sudden appearance of foreign proteins on otherwise healthy cells by inducing tolerance, other immune systems might well interpret the same phenomenon as a sign that those cells are abnormal or infected and in need of destruction, which could lead to development of an immune response to other proteins on the same cells which would then trigger autoimmunity. Coupled with the fact that the spike protein seems predisposed to trigger autoimmune reactions, this could further increase the odds of debilitating autoimmune reactions following genetic vaccination, as appears to be the case with many of the harrowing stories published on Real Not Rare

Disequilibrium begets disequilibrium?

Autoimmunity can induce tolerance as the immune system responds to self-attack by downregulating both specific and general responses, leading to a state of immunosuppression. This may actually be occurring on a large scale if the immune regulatory apparatus generally recognizes the attack on spike-producing cells as an autoimmune error and responds accordingly by suppressing the innate immune response, at least temporarily.

It is also true that breaking tolerance can induce autoimmunity. So it is reasonable to expect that infection with SARS-CoV2 following vaccination-induced tolerance might lead to a breaking of spike-specific tolerance with a concomitant breaking of tolerance toward molecularly-similar human proteins which would then lead to autoimmune disease. This particular mode of harm remains entirely hypothetical in this instance, though I would not be surprised to see it validated in the months and years ahead.

Implications of immune disequilibrium

Early on in the pandemic, most severe and deadly infections appeared to be mediated by a cytokine storm – an immune overreaction that caused more damage than the virus itself. Suppressing this overreaction – making the immune system more tolerant of the virus – could actually improve outcomes. Based on this I consider it reasonably likely that at least part of the observed efficacy of genetic vaccination against severe covid infection may have been attributable to induced tolerance rather than – or in addition to – induced immunity. Thus, a genetic-vaccination-induced shift from a predominant immune-overreaction failure mode to a predominant tolerance failure mode may have initially appeared as an improvement in disease outcomes. Any further benefit from this hypothetical effect is unlikely moving forward, as at this point nearly everyone has some prior immunity/exposure to SARS-CoV2 which itself should reduce the likelihood of immune overreaction upon future encounters.

Beyond this potential upside, immune disequilibrium has substantial downsides. Autoimmunity can manifest in many ways: chronic fatigue, chronic pain, neuropathy, diabetes, organ failure, etc., and often includes a whole constellation of debilitating symptoms. It is clear that this can be induced by infection as well as by vaccination, but to the extent that vaccination no longer provides any meaningful protection against infection it would seem that the effect of vaccination on autoimmunity risk will be additive rather than protective moving forward.

Spike-specific tolerance will tend to manifest as negative vaccine efficacy: increased susceptibility to the very disease the shots are meant to protect against, except perhaps during a brief period following injection when neutralizing antibody titers are boosted. Indeed it is the high level of reinfection among the vaccinated and boosted that seems to have ignited the recent interest in vaccine-induced tolerance as a possibility.

More general tolerance or immunosuppression may manifest as reactivation of dormant viruses, increased susceptibility to all infections, and increased incidence/aggressiveness of cancer as the innate immune response fails to recognize and attack developing tumors. All of these have been reported, at least anecdotally, in the wake of genetic covid vaccination.

2. In Which the Spike Protein Does Bad Things

The spike protein is a sequence of 1273 amino acids that folds into a complex three-dimensional structure. It resides on the surface of the SARS-CoV2 virus, where it facilitates binding to the ACE2 receptor and fusion with the cell membrane leading to infection. It also functions as an antigen – “antibody generator” – an activator of targeted immune responses that can prevent or attenuate future infections, which is why it was chosen for the genetic vaccines.

Aside from this, however, it is also just a molecule – a complex chemical – that can interact with other molecules in myriad ways. Chemicals can be acutely or chronically toxic, and they are typically assessed for toxicity in a variety of animal tests before being injected into the human body.

I can find no evidence that the spike protein was specifically toxicity-tested in the process of vaccine development. Perhaps it was simply assumed that exposure via infection was otherwise inevitable, so exposure via genetic vaccination wouldn’t be much different. Regardless of the reason, an increasing number of studies have painted a concerning picture of spike protein effects in the human body.

The spike protein has been shown to bind to a number of targets, with potential implications for impaired endothelial cell function, disrupted blood-brain barrier integrity, and neurodegeneration associated with amyloid deposition in the brain.

Among the most common reported adverse events following infection and vaccination, however, have been clotting-related disorders including strokes and sudden cardiac deaths. There are mechanisms by which this clotting may be induced by immune inflammation, but increasingly it appears possible that this may be a direct effect of spike forming amyloid (abnormal protein polymer) structures and/or binding to the clotting protein fibrinogen and triggering it to polymerize into abnormal, breakdown-resistant amyloid clots. These amyloid clots are observed in both long covid and chronic fatigue syndrome, and in addition to forming physical blockages they can be inflammatory and auto-immunogenic. I would not be surprised if the apparent similarities to anti-phopholipid syndrome are ultimately attributed to downstream effects of this abnormal clotting mechanism.

While any effects of spike protein behaving badly can obviously arise following either infection or spike-based vaccination, it seems likely that two-dose genetic vaccination will introduce more systemic spike protein over a longer period of time than the mild SARS-CoV2 infections experienced by a majority of people. Furthermore, as discussed above, if vaccination fails to prevent infection the two processes may be additive, booster injections will be further additive, and if repeated genetic vaccination induces spike tolerance the effect may be greater and more prolonged spike protein exposure during subsequent infections with a resulting higher risk of clotting and long covid/chronic fatigue.

I hesitate to mention the published photos of large rubbery blood clots being found by embalmers, as these seem to dwell somewhere between the realm of lurid unsubstantiated reports and real scientific findings. I will say that if this proves to be an actual novel phenomenon, it would seem likely to me that it is connected to the amyloid-clot-inducing behavior of spike protein in the bloodstream.

3. Viral Evolution and the Alternate Universe Problem

Geert Vanden Bossche has been consistently issuing dire warnings about mass vaccination with non-sterilizing vaccines in the midst of a pandemic, given that this can potentially provide a uniform and robust antibody response across an entire population that the virus can then exploit to develop new and more infectious/more virulent variants – somewhat akin to the manner in which an agricultural monoculture is more vulnerable to pest and disease damage than a diverse mix of crops.

Although Geert has now made several time-bound predictions that have failed to pan out, I do give credence to his broader ideas that interfering in the establishment of natural immune equilibrium with this new virus is likely to alter these coevolutionary processes in a way that is at least as likely to be harmful as it is to be beneficial, to cost more lives over the longer term than it saves.

The problem is that this hypothesis is effectively impossible to test given that we only have one planet, and new variants of SARS-CoV2 spread around the entire globe and rise to prominence over a period of a few months. Looking back from the year 2050, it is entirely possible that the circulating strains of SARS-CoV2 (assuming it is still circulating then, which seems probable at this point) will be more virulent and have caused more deaths than would have been the case had we focused on building natural immunity rather than mass vaccination with novel, experimental genetic vaccines. That said, given that we can never determine exactly how or why a new variant comes into existence, we won’t be able to know with any degree of confidence whether our vaccines made the virus worse.

Some Thoughts and Predictions

Although it is now common parlance to refer to “during the pandemic” as a time in the past, I don’t think this story is yet coming to an end. I also don’t know what the future will bring, though I’m willing to offer some general predictions – any or all of which may of course prove entirely false.

  1. SARS-CoV2 infection levels will rise and fall but will generally remain high over the next year in highly-vaccinated countries, thanks to vaccine-induced tolerance and potentially ADEI (antibody dependent enhancement of infection). Those who have developed spike tolerance but who don’t have the short-lived antibody protection of an injection in the last 1-2 months will experience the highest rates and longest durations of infection.
  2. All-cause mortality will remain elevated and will be roughly proportional to the current rate of SARS-CoV2 infection and ongoing genetic vaccination in the population. If there is a large-scale shift to tolerance or a potential cumulative lethal threshold for spike protein exposure, mortality could begin to rise substantially especially over the winter months.
  3. Rising rates of debilitating symptoms will be attributed to long covid by one narrative and to the vaccines by another. In reality both will be correct to some degree, possibly at the same time in the case of damage caused by increased spike exposure during infection after vaccine-induced tolerance. Hopefully data sleuths like The Ethical Skeptic and El Gato Malo will be able to tease out the differences.
  4. Unvaccinated people will – in general – experience better health than vaccinated people. This effect may not be significant when comparing to those who only received an initial round of injections but will likely be more dramatic when comparing to the boosted and especially 2x-3x boosted.
  5. Official data showing infection rates and death rates by vaccination status will become increasingly difficult to find.
  6. The much-feared crisis of overwhelmed hospitals unable to provide routine essential care may finally arrive this fall and winter, driven by the declining health of multiple-boosted health care workers, the staffing shortage that is affecting all sectors of the economy, and rising numbers of people in need of care.
  7. Interest in additional shots will continue to wane outside of a small circle of true believers. I don’t foresee another push for vaccine mandates unless a new vaccine is released that offers much better short-term protection against infection than the ones currently in use.
  8. Reports of vaccine harms will gradually seep further into mainstream media and consciousness. While I’m hopeful that this will lead to a “turning of the tide”, it is possible that deflection strategies (e.g. attributing harms to long covid instead) will continue to be successful, especially given the sacred and untouchable status of anything called a vaccine within the failing-but-still-dominant religion of Progress.
  9. Immune suppression/general tolerance from repeated genetic vaccination and/or frequent covid infection will lead to increased severity of other infections, and potentially to increased rates of certain cancers.
  10. Viral evolution will be a wild card. We could see a continued trend toward decreasing virulence, or the next immunity-evading strains could also feature increased severity or an increased rate of lasting symptoms. At this point I do not expect to see the “new variant causes mass death” situation that Geert Vanden Bossche has been predicting.
  11. “Classic” severe Covid-19 of the type producing bilateral pneumonia and requiring intubation will remain rare, as we have largely transitioned from an inflammatory overreaction failure mode to a tolerance failure mode. Those experiencing severe or chronic SARS-CoV2 infections will be more likely to present with direct effects of viral tissue damage or spike protein toxicity.
  12. It is entirely possible that most of these predictions will come to fruition and yet the story will be eclipsed by the looming economic convulsions and food shortages that seem increasingly inevitable in the year ahead of us.


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6 Responses to Shapes in the Fog

  1. Jay Pine says:

    Insightful as ever and no disagreement from me, but even in my currently unvaccinated and infection free state, I’ve got a headache. :-/

  2. Christophe says:

    What a fascinating overview. On the one hand, it is amazing how much more we know, after just a few years, about the mechanisms this virus employs to infect human hosts, as well as the mechanisms the genetic vaccines were designed to exploit. On the other hand, it is equally amazing how much we still don’t know after several years of systematic suppression and falsification of any studies that dare to provide politically unpalatable data.

    At this point, the most fascinating unknown I’m trying to tease out of the distorted data is no longer how toxic these various attempts at vaccines will turn out to be, but just how much credibility the world’s current influence peddlers are willing to squander in their attempts to keep that data too blurry to usefully assess. Lots of primates dying or getting disabled would certainly change things, but the futile attempt by the global silverback club to prevent anyone in their tribes from moving beyond denial in their grieving process for their dying worldview promises to shatter every single one of our once-stable systems. The further into abstracted insanity our self-assumed leaders try to force us, the further and more shocking our eventual reversion to the mean (funny how many different meanings that one word has) will end up being.

    At this still relatively early stage in these undisclosed vaccine trials, even were unbiased data made easily available, all we could do would be to hypothesize extrapolations from it. At this point, we would only have 18 months of data available to play with from an at least 10-year trial. The current obfuscated data is bad enough, so I’m certainly not hoping for it to get any worse over the duration of the trial. Well, except to the extent that that worsening might help to flush out the current crop of self-satisfied silverbacks, and ideally flush them all away!

  3. Brian Mowrey says:

    I’m still making my way to the end. But at

    “Suppressing this overreaction – making the immune system more tolerant of the virus – could actually improve outcomes.”

    I was surprised to see the “severe efficacy is tolerance” theory make an appearance (maybe it was already mentioned in your work at eco.). At the same time, my intuitive take on the cytokine storm issue, which I have been too lazy to dig into, appears to be reflected in the review you cited. Namely: the storm is a result of uninhibited viral destruction, resulting (pseudo-) paradoxically from the suppressed reaction to the virus (via the standard coronavirus innate immune suppression toolkit). So I would argue based on that model that severe efficacy *cannot* be tolerance. Immune sensitization to the virus itself results in less net inflammation than letting the virus turn organs into soufflé. OTOH there may be research supporting an alternate model. I would also note my observations about early seroconversion in the paxlovid trial being an incredibly powerful predictor of outcomes: https://unglossed.substack.com/i/52792651/assay-what – So tolerance stricto sensu = more net inflammation. However, tolerance in the context of a polyclonal B Cell / antibody response where the majority of antibodies are still neutralizing can plausibly result in a slow simmer of cellular destruction that never trips a cascade. I’ve been trying to formulate a model for whether this would result in severe outcomes sometimes or not (as in Chudov’s prediction of sudden death via myocarditis etc.).

    And now back to reading your essay!

    • Mark says:

      “Severe efficacy is tolerance” has always been a component of my tolerance hypothesis. I have noticed in your writing that you disagree, and I’m certainly open to the possibility that I’m wrong.

      The FLCCC and other critical care advocates have noted that in severe and fatal cases of covid there is usually a decline in nasopharyngeal viral load even as illness worsens and organ failure sets in. This despite the fact that viral load earlier in the course of infection does seem to correlate with severity. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291003/#!po=48.6014)

      One possibility is that the virus is continuing to replicate uncontrolled systemically even as counts decrease in the nose, or that tissue damage by high viral loads directly triggers the sepsis and ARDS that sets in later.

      The other possibility that I still find more likely is that high viral loads are triggering a secondary hyperinflammatory immune response that is itself far more damaging than the virus itself. So it is the people with the weakest innate immunity and the highest viral loads that are dying, but they are still suffering more damage from the cytokine storm than from viral replication/cell lysis.

      If this is the case I still find it plausible that a shift toward tolerance would engender a decrease in severe illness and mortality, and this could help to explain why the vaccines proved amazingly effective at preventing severe illness even among immunocompromised people, and despite the fact that they had much lower efficacy with regard to preventing infection.

      • Brian Mowrey says:

        Ha – shows how effectively substack has narrowed my intake on theories RE the virus! These days if someone doesn’t hit me on the head with something in my comments, I probably don’t catch it. As such, my heckling on the topic in this essay’s comments is borderline-thread-hijack, so, apologies for that. But I would still like to see more actual substantiation of the theory.

        Really, this comes down to the question of whether viral destruction and spike lead to enough innate immune activation that “cytokine storm” is just an observational description of an overall inflammation / coagulation / fibrinolysis cascade resulting from the virus. Is it a reaction to what the virus has done or and “overreaction” to the virus. Before you bring the shots/antibodies into it, you have to think one thing or the other. The Pretorius et al. work (mentioned in your “behaving badly” section) substantially revises the limited understanding of infection mechanics that obtained when the meme of immune “overreaction” was coined in early 2020. So I call this immune “reaction;” whether it’s overkill and should be modulated (like swelling after injury) or not, it is mandated by the level of damage. And once again the review you link to supports a “reaction” model, even if T Cell sensitization plays a role (but once again this is not an “over” reaction, there is still virus that needs to be cleared).

        For the opposite view, that it is a true “overreaction” – I haven’t seen any support. Perhaps https://www.science.org/doi/full/10.1126/scitranslmed.abm7853 – but otherwise this just seems to be a meme birthed from media “explainers” https://www.yalemedicine.org/news/immune-response-covid-19 , not real research.

        The point here is that the tolerance/efficacy theory totally hinges on this question and yet I never see it discussed. If the cytokine storm is a “reaction” to tissue damage and coagulation, then tolerance of virus is irrelevant. So I would want to see the tolerance/efficacy camp get into this question.

        Secondly, the tolerance/efficacy theory, because it doesn’t apparently credit antibodies with restricting viral reproduction, would predict equal rates of systemic complications. In other words, less cytokine storm, but equal “things the virus does besides that.” This prediction seems to have been rebuked even in a “high-risk” cohort, though obviously healthy user bias could be at work despite the comorbidity-matching https://unglossed.substack.com/p/the-protective-effect – Alternately the tolerance/efficacy theory is acknowledging antibody-limited viral reproduction but assuming this to be irrelevant for reducing the “overreaction”? – how?

        • Mark says:

          Thanks for participating in this discussion. You have about 50% convinced me that the tolerance-severe efficacy hypothesis is without merit.

          In response to your second point, I would agree that the stronger form of that hypothesis – “severe efficacy *is* tolerance” – is almost certainly false, as antibodies will also play a role.

          I’m more interested in the observed phenomenon that as antibody titers wane to the point that vaccine effectiveness against infection drops to near zero, efficacy against severe outcomes seems to be maintained. This, to me, still supports a weaker version of the hypothesis: “vaccine-induced tolerance *contributes to* severe efficacy.”

          The equally plausible alternate hypothesis for this phenomenon is simply that vax-induced mucosal immunity is comparably weak, such that as vaccinal immunity wanes it becomes increasingly useless at preventing infection in the nasal passages but remains effective at preventing infection deeper in the body (thanks to antibody recall and T cell responses).

          Differentiating these hypotheses is hampered by two major unanswered questions:

          1. We don’t really understand the relative contributions of inflammation/cytokine storm and direct viral tissue damage/spike protein toxicity to the manifestations of severe illness leading to death. Hospitals report that the sort of classic severe Covid-19 requiring intubation is much rarer now than it was in 2020-21, but the different tissue tropism of the BA.x variant families is quite likely the largest contributor, with vaccine effects second. Whether or not the cytokine storm is a “reaction” or an “overreaction” functionally depends on whether – on average – it contributes to health (a last ditch attempt to clear a severe viral infection that would otherwise be fatal) or to illness (kicking in once viral load is already in decline and causing tissue damage in excess of what the virus would have caused). It still appears likely to me that this reaction – however apparently justified by high viral load – does on average make things worse, in which case any intervention that intentionally or unintentionally damps down this reaction will improve disease outcomes. One could argue whether a promotion of Th2 vs. Th1 responses by the vaccines should actually be considered “tolerance” (as opposed to just immune training), but to me it is movement along the same spectrum from reactogenicity to anergy. It’s of course possible that *some* movement along that spectrum is a good thing (in which case the degree of spike desensitization caused by the initial injections would – in concert with antibodies – contribute to greater immune equilibrium in an encounter with the virus) while *further* movement along this spectrum triggered by additional injections will lead to stronger tolerance responses (e.g. IgG4 and Treg activation) which then creates a different disequilibrium state in which the immune system is less able to mount an effective viral response.

          2. In 99% of cases we have no idea what the viral load is anywhere in the body except the nasal passages. So we know that vaccination does not reduce *nasal* viral load. If someone has checked to determine whether vaccination results in less culturable virus in the lungs or in the blood during infection, I have not yet seen it. This sort of research would be essential to determining whether severe efficacy of vaccination is primarily attributable to tolerance (changing the nature of the immune response in the context of similar viral loads) or immune training (antibodies/T cells preventing the virus from replicating in deeper tissues).

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