On rare occasions I read some vaccine talk produced by mainstream journalists. It is interesting to see how in light of the continuing series of disappointing vaccine experiments on humans they cautiously begin to balance their remaining critical thinking faculties with the mainstream narrative that dominated their views for so long. The recent article: ‘Updated Covid-19 vaccines boost protection, but may not beat original formula against BA.4 and BA.5, early studies suggest ‘ is one such marvelous example.(https://edition.cnn.com/2022/10/26/health/updated-boosters-omicron-imprint/index.html)
Since I am much better at mastering the science than I am the language, I am going to provide science-based critiques to the big gaps in the immunological interpretation of the data reported on the first bivalent booster studies. I’ll share my comments to the cited interpretations of leading scientists and experts, however I’ll refrain from citing their names as I have no intention to ridicule these individuals—I only intend to point out the immunological ignorance of those still officially referred to as acknowledged key opinion leaders and decision makers in the field. Their immunological ignorance is now inspiring further efforts to fight evil (mass vaccination) with more evil (mass vaccination with updated vaccines)—a recipe for disaster that will certainly end the pandemic the ‘hard’ way. Nature will ultimately teach them how immunology works, and unfortunately not before massive damage is inflicted by the mass vaccination experiment. Before I get to the specific comments uttered by our leading ‘experts’ and cited within this article, I’ll open with a mind-boggling statement made by the journalist to first give a “masterclass” of softs in immunology to these very leading ‘experts’:
“But the hope was that by tweaking the vaccine recipe to include currently circulating strains of theOmicron variant, it would help broaden immunity against those variants and perhaps offer better and longer-lasting protection”
Geert (G): How can one conduct experiments on humans just based on some naïve ‘hope’? Why do scientists produce extensive data on deep mutational scanning without investigating the immunological driver behind the patterns of such reported mutations? If they would only do so, they would immediately realize the abundance of scientific rationale that could substitute for all the hope they put in empirical research on humans.
The scientific evidence clearly indicates that no single updated/ adapted vaccine booster will improve the temporary protective effect conferred by the Wuhan-Hu S-based C-19 vaccines but will instead only expedite immune escape.
Meanwhile, a myriad of reports documenting the convergent mutations in steadily evolving SARS-CoV-2(SC-2) variants unambiguously illustrates that both productive vaccine breakthrough infections and mRNA vaccine-based boosters place immune pressure on more conserved, immune subdominant spike (S)-associated epitopes by recalling immature memory B cells that produce low affinity antibodies (Abs).Of course, the resulting suboptimal pressure exerted by these Abs on these more conserved antigenic domains drives immune escape, first away from the recalled broadly neutralizing (i.e., variant-nonspecific) Abs and subsequently from the broadly infection-inhibiting Abs. This is due to ‘immune refocusing’, a phenomenon that occurs when pre-existing Abs bind to their pathogen-associated target epitopes with low affinity (i.e., not allowing virus neutralization in case of SC-2, for example): see fig.attached at the bottom. In this way, previously immunodominant epitopes expressed on the free-circulating antigen (e.g., spike protein in case of SC-2) can no longer be recognized by the host immune system whereas previously outcompeted antigenic determinants comprised within the same antigen but expressed on infected or transfected target cells will take advantage of the masking effect to recall the corresponding previously primed Abs.
The existence of previously primed ‘mismatching’ Abs is quite obvious in case of breakthrough infections, but how does this occur in case of mRNA booster vaccines?
It suffices to understand that internalization of secreted in vivo synthesized S protein into antigen-presenting cells (APCs) will provide cognate and noncognate T help to immunodominant epitopes on the free-circulating S protein and S protein expressed at the surface of the mRNA-transfected target cells, respectively. Abs to the latter have therefore much lower affinity and are the first to be recalled upon the administration of mRNA vaccine booster doses. As they will subsequently bind (with low affinity) to the immunodominant determinants on the free circulating S protein (i.e., once the latter is released from the mRNA-transfected cell), the subdominant antigenic determinants will be able to outcompete the immunodominant epitopes for assistance from memory T helper cells (recalled as a result of internalization of S protein into APCs) to recall their corresponding, broadly cross-functional memory Bcells. The neutralizing anti-S Abs (NAbs) recalled as a result of the original Wuhan-Hu spike memory(i.e., the ‘hidden’ original antigenic sin) imprinted by the mRNA vaccine have low affinity and are directed at conserved but less immunogenic S-associated domains. So, repeated boosting with mRNA-based vaccines will merely drive the immune system to repeat commitment of the ‘hidden’ antigenic sin. Consequently, mRNA booster injections will expedite immune escape by enabling immune refocusing to be repeated. As illustrated in the figure attached at the bottom, immune refocusing subsequently triggers the elicitation of low affinity infection-inhibiting Abs targeted at more conserved domains. So, regardless of the S version comprised in the mRNA vaccines, the mRNA booster vaccine doses facilitate humoral immune pressure on shared (i.e., variant-nonspecific) antigenic domains that contribute to viral neutralizability and infectiousness. Massive mRNA booster campaigns will therefore accelerate immune escape long before enhanced maturation of the recalled, poorly matured memory Bcells takes place in germinal centers (as equally described in several recent publications).
As mRNA boosters (as well as vaccine breakthrough infections) facilitate immune pressure on variant-nonspecific domains, the type of immune escape they indirectly promote is no longer determined by specific characteristics of the dominantly circulating SC-2 variant. This explains why we’re now witnessing more and more NAb-resistant, highly infectious variants co-circulating in the population.Lastly, as immune refocusing shifts the immune response to conserved domains with very different antigenic characteristics, it is not surprising that ‘mutation spotters’ consider the mutations to reflect ‘large scale’ immune escape.
Here come the expert interpretations or cited comments followed by my critique:
“Immunologists say a vaccine against two strains may not be better than a single strain shot because of a phenomenon called immune imprinting”
G: These immunologists are confusing ‘immune imprinting’ or ‘antigenic sin’ with ‘immune refocusing’. If immune imprinting was responsible for the protective effect observed, one would expect improved protection (even if only short-lived) after the booster dose. This is not the case as each new additional booster has become less and less effective.
“Scientists say imprinting may complicate efforts to stay ahead of new variants as the coronavirus continues to evolve, and it adds urgency to the development of new vaccine technologies to fight the virus” or: “We may need different kinds of vaccine technologies if the virus ever changes so much that it outcompetes our immunity altogether”
G: These scientists don’t seem to realize that the virus only needs about 12 hours to put a new generation (and hence, new immune escape variants to select from) on the globe. What are the new technologies they’re alluding to? They haven’t yet advanced any scientifically sound approach to a universal Coronavirus (CoV) or Sarbecovirus vaccine. Is it so difficult to understand that performing mass vaccination with any kind of CoV vaccine during a pandemic will drive immune escape? Adaptive immune effector cells (typically those vaccines are relying upon to protect) need time to mature and reach sufficient affinity to have optimal neutralizing capacity. Perhaps they were they thinking of ‘mucosal’ immunization? Regardless, the latter will never solve the issue of immune escape either when administered during a pandemic.
“When the US Food and Drug Administration issued emergency use authorizations for new bivalentCovid-19 vaccines from Pfizer and Moderna at the end of August, it did so on the basis of studies in mice and previous human trials with a different two-strain booster formulation. Little was known about the how protective the shots might be in people; full data from clinical trials testing the BA.4 and BA.5bivalent vaccines in humans hasn’t yet been made public. But modeling data suggested that getting the boosters out in September could save tens of thousands of lives....”
G: It is simply unbelievable that experts and regulatory folks largely rely on mice data to conduct new experiments on humans using yet another mRNA vaccine! Have those working for decades in this field not yet learned that mice lie, especially when it comes to immunizing animals with an immunological background that is not comparable to that of the target human population? And when will all these computational scientists and mathematicians finally learn that a model is only as good as its assumptions? As they clearly don’t understand the immunology involved, their assumptions are always wrong and so too are the results of their modeling.
“We can’t say that a few months from now, there won’t be any difference,” he said. “We won’t know that until these individuals are followed for a longer period of time.”
“Clinical trials being conducted by vaccine makers Pfizer and Moderna involve hundreds of people who have had the updated boosters and are being followed for longer periods of time. Data from those studies are still coming”.
G: Clearly, this scientist/ doctor is alluding to the maturation of the elicited memory B cells that has now been repeatedly reported to result from breakthrough infections or booster shots. However, it has been convincingly documented that this maturation process takes several months (4-6 months) before accomplishing full-fledged affinity maturation. Again, the virus is not waiting for this to happen. By the time this occurs the virus will long since have accomplished additional immune escape operations, especially when immune pressure is exerted at a population level.
“...the researchers found that neutralizing antibodies spiked after both shots to about the same high levels, which was good news”
G: Oh really? Why would this be good news knowing that the only effect of these Abs is to drive immune refocusing which triggers large scale immune escape? How many times must I state that if there is one rule that doesn’t apply to immunology it is that more is not always better (in fact, the opposite usually applies)
“Unfortunately, neither one increased T-cell responses very much, and we believe that T-cell responses in addition to antibody responses are important for protection against severe disease,”
G: Some of the top researchers doggedly continue to preach the power of cross-reactive T cells in controlling the virus and taming the pandemic. They seem to have little understanding of the pathobiology and immunology involved in acute SELF-LIMITING viral infections. Maybe some of themare confused by too much HIV vaccine research?
Once again, I am citing just a few of the many articles I’ve written to debunk the critical role of T cells in protecting against SC-2 infection/ disease:
# When anti-S(pike) antibodies against Omicron can no longer sustain the narrative, why not resort to T cells?
# Q&A #09: Do cross-reactive T cells explain mild course of Omicron infection?
# To all those who continue to attribute abrogation of SARS-CoV-2 infection to pre-existing cross-reactive T cells rather than to innate immunity. The devil is in the detail of peer-reviewed publications.
# Cross-reactive memory T cells are associated with (but not responsible for) protection againstSARS-CoV-2 infection in COVID-19 contacts.
# ‘Killer’ immune cells still recognize Omicron variant.... oh really?
“A booster is a booster until proven otherwise and we are in great need of getting more of them in theUS”
G: Yes, and a vaccine is a vaccine until proven otherwise, correct??! This scientist/ doctor seems to be areal fanatic of the concept: the more, the better (i.e., the higher the Ab titers and the more boosters,the better) without asking himself about the immunological mechanism triggered by the boosted Absand the longer-term effects thereof.
“I would be lying to you if [I said] it doesn’t keep me up at night worrying that there is a certain chancethat we may have to deploy another booster – at least for a portion of the population, perhaps olderindividuals – before next September, October,”
G: It seems to me that many regulators would be better off spending their sleepless nights on trying toput the pieces of the immunological puzzle together (or listening to others?!) instead of complainingabout their inability to answer the obvious questions that keep them up at night....
“Both new studies have limitations, but I think when you put them together, they paint a pretty clearpicture that that antigenic imprinting is causing issues here, for sure.” “That’s the reason some strains ofthe flu may hit certain age groups harder than others, too. When viruses look more similar to the firstinfection or vaccine you had, your body tends to do a better job fighting them off.”
”It probably would have been better to update the vaccine by including only the components againstBA.4 and BA.5.” or: “For me, the take-home message is, if you want to boost and provide protection against Omicron, leave the original variant out of the vaccine.” Or: “Imprinting will complicate efforts to keep up with the virus”
G: Given the fact that ‘immune imprinting’ or ‘original antigenic sin’ is one of the oldest and irrefutable paradigms in immunology, why was the ancestral S version made part of the bivalent booster formulations in the first place? But as I explained before, it wouldn’t have made any difference as any version of mRNA-based S protein will entail immune refocusing to other (i.e., subdominant) epitopes.Immune refocusing implies immune imprinting (i.e., ‘hidden’ antigenic sin) but not the other way around.
“It’s possible to break through immune imprinting. Certain kinds of vaccine ingredients, or adjuvants –things that just happen to really wake up the immune system – can do it.”
G: This fellow has forgotten about one key principle in vaccinology: The vaccine is only as good as the antigen! Of course, adjuvants can increase the magnitude and breadth of the immune response, but this will not influence noncognate Th-dependent priming of low affinity Abs to spike protein because the latter are directed against membrane-bound spike protein which is de facto not internalized into APCs, which is a conditio sine qua non for putting adjuvants at work!
Conclusion: Given the deep immunological incompetence of our leading scientific, public health and regulatory experts, one can easily predict that there will be many more plans for empiricism and injecting yet other experimental formulations than there are lucid brains. We should not forget, though, that mankind has never been in control of this pandemic and that this is even less the case as their rational experimentation continues. Indeed, the more man mismanages the pandemic by scientifically irrational immune interventions, the more (and the faster) the virus is evolving towards teaching a lesson in immunology that will hopefully be remembered by the future generation of scientists to come.History, however, will not be as mild as I am with the quotes of those who thought to learn from inconsiderate and dangerous experiments conducted on humans.
Fig.: Immune refocusing (IR) occurs when pre-existing Abs bind to their target epitopes with low affinity (e.g., in case of vaccine breakthrough disease or vaccine boosters in previously mRNA vaccine-primedpersons). Masking of immunodominant S(pike)-associated epitopes allows subdominant epitopes tooutcompete the former for assistance from memory T helper cells. This will enable the subdominant S-associated epitopes to recall low-affinity Abs directed at these epitopes. By placing suboptimal immunepressure on these more conserved antigenic domains, the recalled Abs promote large scale immuneescape. The latter results in natural selection and dominant propagation of a multitude of NAb-resistant,highly infectious immune escape SC-2 variants.
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.