Neutralizing Dr. Bhakdi's attempt at rebuttal

Originale message: https://www.geertvandenbossche.org/post/response-to-dr-bhakdi

Dr. Bhakdi's response (marked in quotes below): https://doctors4covidethics.org/rebuttal-to-geert-vanden-bossches-response-to-dr-bhakdi/

Rebuttal to Geert vanden Bossche’s “Response to Dr. Bhakdi”
Michael Palmer, MD and Sucharit Bhakdi, MD

‍doctors4covidethics.org

‍Some time ago, Dr. Bhakdi published a video presentation [1] which explained that cross-immunity to SARS-CoV-2 is widespread in the population, and that general vaccination is therefore not necessary or appropriate. This was disputed by Dr. Geert vanden Bossche [2]. Here, we rebut Dr. vanden Bossche’s assertions.

In the following, quotes from van den Bossche’s piece are typeset in italics, and our replies are printed in upright font shape.

I have inserted my comments underneath those of these medical doctors. As I am not sure about the role of Dr. Palmer here, I’ve addressed my comments to Dr. Bhakdi only. I have no interest in criticizing people who, like me and others, argue against mass vaccination. It is important, however, that we use the correct scientific justification as anything else will soon or later backfire and be used against us to invalidate our opposition against mass vaccination campaigns. That’s the only reason why I am spending time on countering the alleged rebuttal of these doctors. I’ll start with my summary:

I maintain that Bhakdi’s interpretation of protective population-level immunity is not built on sound scientific arguments. There is no evidence whatsoever that herd immunity, or what he now calls: ‘widespread protective immunity’, relies on cross-protective memory cells elicited by heterologous Coronavirus (CoV) strains (e.g., common cold CoVs). This probably explains why he’s continuously evading my critical comments on his false assumption that cross-immunity equals cross-protection and why his statements attempting to rebut my comments related to this issue are not backed by any relevant reference from the literature. Indeed, none of the allegedly protective mechanisms he’s alluding to are supported by any kind of evidence of acquired, cross-protective effector memory cells. As previously mentioned, if cross-immunity among different CoVs would be protective, we would not be witnessing fulminant outbreaks of the delta variant in several countries.  Bhakdi is simplifying the science down to the level of phantasy. He prefers to ignore some basic immunologic science in an attempt to simplify things and construe interpretations that he can understand himself without having to tap into the different mechanisms that underlie the population’s immune response to the virus. Most strikingly, Bhakdi completely ignores the broadly and universally protective capacity of innate B1 cell-derived oligospecific antibodies (Abs). I can only recommend him to do (a lot!) of literature on these innate, polyreactive Abs. I offer him to start his education on my website where I’ve gathered a number of relevant references from the literature on this very topic.

1. Cross-immunity to SARS-CoV-2 exists and is cross-protective

‍Dr. Bhakdi is confusing all along cross-reactivity (which basically means that antibodies (Abs) or T cells induced by one CoV can BIND similar [conserved] epitopes on some other CoVs) and cross-protection. None of the publications Dr. Bhakdi is referring to has analyzed or claims cross-PROTECTION elicited by other CoVs.

‍Cross-protection is supported by the available evidence:

- A correlation between cross-protection and cross-reactive antibodies has been explicitly confirmed in several other studies [3–6].

It probably suffices to say that correlations are typically not implying a causal relationship

- COVID-19 is more severe in younger children than in older children and adolescents [7]. This is consistent with greater protection of the latter by cross-immunity conferred by past infection with other coronaviruses.

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Indeed, exceptional genetic deficiencies in innate immunity typically become clinically manifest in young children. As such deficiencies become manifest at an early stage in life, older children and adolescents who stayed healthy at this stage continue to be well protected by their innate Abs. This has nothing to do with cross-immunity, let alone with cross-protection.

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- The low disease severity and very low case fatality rates of COVID in the general population further support protection by cross-immunity.

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When you take the population segment that is typically featured by poor functionality of their innate Abs (elderly, people with certain co-morbidities), disease severity and case fatality rates are relatively high whereas the opposite applies to the bulk of the population consisting of healthy people and younger age groups (< 65 years). Again, this observation has nothing to do with cross-immunity, let alone with cross-protection.

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2. Neutralizing activity of SARS-CoV-2 antibodies

‍Again, Abs that bind to Sars-CoV-2 do not necessarily neutralize the virus and prevent it from entering the cell.

‍Apart from the fact that Dr. vanden Bossche erringly equates virus neutralization in laboratory experiments with protection from infection,

On the contrary (!): I am pointing out that cross-reactivity of Abs doesn’t even mean that these Abs can prevent viral entry, let alone they would provide protection!

his above statement applies to all viruses. Each natural virus infection will produce a multitude of clonal antibodies (“idiotypes”). At least some idiotypes will be non-neutralizing; however, other idiotypes typically will neutralize. Moreover, this is true regardless of whether these antibodies are cross-reactive or not. The argument is irrelevant.

Bhakdi doesn’t seem to understand that I am alluding to the affinity of Abs. Cross-reactivity to heterologous antigen (Ag) is based on low(er) affinity interactions of Abs towards immunodominant epitopes. He seems to be considering a natural Ab response a mixture of monoclonal Abs, some of which are neutralizing and some others that are non-neutralizing. This is, of course, an erroneous interpretation as the neutralizing effect of a humoral/ Ab response is determined by the OVERALL effect of the combination of ALL Abs together. Clearly, in case of variants, the overall effect resulting from all Ag-Ab interactions will be dominated by Abs that recognize immunodominant domains. It’s precisely because (CoV) variants, and even more so heterologous (CoV) strains, exhibit changes in immunodominant domains that they become less susceptible, or even not susceptible at all, to cross-reactive Ab immunity!

3. Not all respiratory coronavirus induce cross-reactive antibodies effectively

‍In addition, Sars-CoV-2-induced Abs were only found to cross-react with 2 out of the 4 common cold CoVs (i.e., only for beta coronavirus HKU1 and OC43) and the cross-reactivity was ‘much lower than that observed for the remaining CoV epitopes.’

This is correct. However, whether it comes from some or from all coronaviruses is immaterial to the existence of cross-immunity as such. The study by Nielsen et al. [8] unambiguously demonstrated cross-immunity in almost all test persons who had been infected with SARS-CoV-2.

How can Bhakdi be so sure that the majority of the population has been exposed to the ‘right’ coronaviruses (i.e., beta coronavirus HKU1 and OC43) rather than to the other common cold viruses? But regardless, researchers have only been demonstrating cross-reactivity of anti-CoV Abs without proving relevant functionality of these Abs. Once again, we’re back to the argument that cross-reactivity doesn’t equal cross-protection!

4. Those ghastly variants

‍Furthermore, his statement that people who have built immunity against CoV are automatically protected against all Sars-CoV-2 variants is not true either for exactly the same reasons (i.e., Abs that bind to variants do not necessarily neutralize them and could even be at risk of causing Ab-dependent enhancement of disease; ADE).

‍Dr. vanden Bossche contends that immunity to CoV rests on the presence of neutralizing antibodies that will fail their duty when variants arise. This assumption lacks a scientific basis. It is common knowledge that protection against severe respiratory viral disease derives primarily from cellular immunity.

Where is the evidence for the alleged ‘common knowledge’? And again: where is the immunology? There is no evidence whatsoever that naturally induced, cross-reactive T memory cells are broadly and universally capable of eliminating CoV-infected cells! They can, therefore, not provide population-level protection as Bhakdi tries to make people believe.

Reactive lymphocytes limit viral multiplication at sites of infection.

Limitation of viral multiplication is not sufficient to protect from disease, let alone infection. It could at most mitigate disease, but even bystander T cells could do so! (this is why studies have shown that even immunization with BCG can have a beneficial effect). This is thought to be due to Tc-mediated secretion of immune inflammatory molecules (e.g., cytokines). There is increasing evidence, though, that Sars-CoV-2 is now also developing resistance against a number of these innate immune mediators (see articles on my website).

Antibodies merely play supportive roles in preventing viral spread in the bloodstream.

Where is the evidence for this statement? Is Bhakdi serious in stating that Abs (in general!) have no role to play in fighting the infection at the portal of entry or respiratory tract?

“Variants” (mutant strains) will arise due to “antigenic drift” with any RNA virus that propagates within the human population, and SARS-CoV-2 is no exception. Antigenic drift occurs in minuscule steps and, as is well known, the genetic and antigenic differences between the original (Wuhan) strain of SARS-CoV-2 and any of its variants are vanishingly small relative to the difference between any SARS-CoV-2 strain and the respiratory coronavirus that confer cross-immunity. That such minuscule changes should substantially affect immunity and even promote ADE is not credible.

It seems like Bhakdi missed my point as I stated that Abs that bind with low affinity to Sars-CoV-2 (e.g., such induced by his cross-reactive CoVs) might be suspicious of inducing ADE, precisely because of their weak binding.

Cross-reactive T-cell immunity, which is a pillar of immunological competence against respiratory viruses, has been documented with respect to SARS-CoV-2 since 2020 [9,10]. Antibody response and T cell response are correlated; thus, fixating on the properties of antibody idiotypes only when trying to gauge overall immunity misses the mark.

The mark Bhakdi is continuously missing is that he doesn’t understand that even cross-reactive T cell immunity does not imply cross-PROTECTION!

5. Are the asymptomatically infected doomed?

‍Vanden Bossche insists that the study by Nielsen et al. [8] “does not truly provide information on asymptomatically infected individuals” but that the people referred to in the study must instead have had mild symptoms, and further that “asymptomatically infected individuals do not develop long-lived or mature anti-S [anti-spike] Abs and have not been reported to develop memory B cells or CYTOTOXIC memory T cells. Consequently, previously asymptomatically infected people (i.e., the majority of the population) cannot rely on ACQUIRED immunity for protection against infection or disease.”

‍Unlike vanden Bossche, we are not concerned about the difference between mild symptoms and none at all; quite obviously, both groups of patients were protected from severe disease. More interesting than this quibble is his parenthetical assertion that the majority of the population has already been “asymptomatically infected” with COVID.

This is anything but quibble. Qualifying this as ‘quibble’ merely illustrates that Bhakdi doesn’t understand the immune pathogenesis of Sars-CoV-2 infection. From an immunological viewpoint, asymptomatic infection and the immune effector cells involved are completely different from those coming to play in case of symptomatic infection. The immunology here is very different but Bhakdi doesn’t care as he’s exclusively focused on the common clinical denominator, i.e., protection against severe disease. So, my previous comment related to understanding the immunology that underlies asymptomatic infection, not to gauging clinical symptoms.

He further assumes that such individuals do not develop any immunological memory. Several questions then arise:

1. How was it established that the majority of the population had already experienced asymptomatic infection? Positive PCR tests alone cannot be accepted as proof of this assertion.

Does Bhakdi really think that after the virus circulated in the population for over 1.5 years (including several highly infectious variants), the majority of people who didn’t develop symptoms simply didn’t get exposed to the virus yet?

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2. If any individuals were indeed asymptomatically infected, then what, if not cross-immunity, prevented their infection from becoming clinically manifest?

My answer: Innate, polyreactive Abs capable of recognizing CoV-derived patterns that are shared among all CoVs (presumably even including some other viruses). See reference from the lit. on my website.

3. If these individuals were protected from manifest disease during their first infection, why should we assume that they will fare any worse when infected again? We hope that vanden Bossche will resist the temptation to trot out the fearsome Delta variant in response.

That is exactly the question Bhakdi ought to be asking himself. If folks got acquired immunity thanks to previous exposure to heterologous CoVs, why would they all of a sudden become sick whereas they were well protected during previous waves of this pandemic? He doesn’t seem to have the answer. I have explained on multiple occasions how high infectious pressure can temporarily suppress innate immune defense in previously asymptomatically protected people. My website is full of explanations on how this works and how this renders previously protected people (e.g., younger age groups) susceptible to C-19 disease. More can be found in the articles I published on TrialSiteNews. Sometimes it’s good to read what other people write before attempting to rebut their arguments.

6. Of people and of test tubes

‍In the Danish study [Nielsen et al.] at least nine individuals were unable to fully neutralize viral infection

Neutralization is a function of antibodies or serum samples, not of individuals.

Well, if one considers that full-fledged neutralizing Abs were not found in a number of individuals and if those happened to be the people who were truly asymptomatic, then this becomes highly relevant in that it would clearly prove that protection in asymptomatically infected people does not rely on neutralizing Abs

Clinical immunity may exist even without neutralizing antibodies.

Precisely! The bulk of clinical immunity is provided by innate Abs.

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Moreover, neutralization was determined using a recombinant pseudo-virus that expressed the SARS-CoV-2 spike protein, but none of the other SARS-CoV-2 proteins. It cannot simply be assumed that none of these could contribute to neutralization.

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Where is Bhakdi’s evidence supporting that Abs to proteins other than spike protein have virus-neutralizing capacity?

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‍In addition, it is stated in the discussion [again Nielsen et al.] that ‘some rare individuals have no detectable immunological memory to Sars-CoV-2.’

‍These “rare individuals” were most likely those with low cross-immunity and false-positive PCR tests. The fact that a lack of immunological memory is rare supports rather than contradicts the prevalence of cross-immunity.

How would that work? It is much more plausible that the lack of immunological memory pertains to those who were truly asymptomatically infected as there is no evidence whatsoever that asymptomatic infection induces B cell memory.

To my knowledge, there is no evidence that Sars-CoV-2-induced CD8+ T cells provide cross-protection from common cold viruses or vice versa and this wasn’t even part of this investigation.

Cross-protection from common cold viruses by immunity to SARS-CoV-2 is not the point. We are only discussing cross-immunity in the opposite direction, which has indeed been detected [9,10] and most likely contributes to the clinically manifest cross-protection.

Bhakdi obviously missed the words ‘or vice versa’. Again: cross-immunity does not mean cross-protection!\

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‍7. On herd immunity

‍So, with all my respect for Dr. Bhakdi, the conclusion that herd immunity would already be established and would simply need to be recalled upon exposure to SARS-CoV-2 is not correct. By the way, if this were true, we would not currently be witnessing a fulminant propagation of the delta variant in several countries.

Herd immunity in the strict sense—namely, a high prevalence of sterilizing immunity that prevents a virus from effectively propagating within the population—is problematic with any respiratory virus.

Bhakdi should revisit the definition of herd immunity as herd immunity does not relate to a high prevalence of ‘sterilizing’ immunity. Herd immunity primarily relates to the immune capacity of the population to dramatically reduce viral transmission.  

Dr. Bhakdi was using the term loosely, referring widespread immunity that is sufficient to protect from severe disease.

Herd immunity has NOTHING to do with protection from disease. I am not even arguing about Bhakdi’s definition of herd immunity versus “widespread protective immunity” (WPI) but rather about his false hypothesis that this WPI would rely on previous exposure to other CoVs. That is completely wrong, at least as far as durable protection is concerned!  

The pervasiveness of such immunological protection is indeed apparent from the very low rates of fatality or severe disease in the general population, and particularly among those without co-morbidities. However, we agree with vanden Bossche that it would have been better to use the term “widespread protective immunity” rather than “herd immunity” in this case.

8. Summary

‍With the exception of the above single point of terminology, we see no merit in Dr. vanden Bossche’s response. We maintain that Dr. Bhakdi’s interpretation of the studies he highlighted in his video presentation are fully supported by the available scientific literature.

See my summary at the top

References

1. Bhakdi, S. (2021) Proof that puts an end to the SARS-CoV-2 narrative.

2. Vanden Bossche, G. (2021) Response to Dr. Bhakdi.

3. Dugas, M. et al. (2021) Less severe course of COVID-19 is associated with elevated levels of antibodies against seasonal human coronaviruses OC43 and HKU1 (HCoV OC43, HCoV HKU1). Int J Infect Dis 105:304-306

4. Dugas, M. et al. (2021) Lack of antibodies against seasonal coronavirus OC43 nucleocapsid protein identifies patients at risk of critical COVID-19. J Clin Virol 139:104847

5. Yamaguchi, T. et al. (2021) Immunity against seasonal human coronavirus OC43 mitigates fatal deterioration of COVID-19. Int J Infect Dis (preprint)

6. Yaqinuddin, A. (2020) Cross-immunity between respiratory coronaviruses may limit COVID-19 fatalities. Med. Hypotheses 144:110049

7. Tsabouri, S. et al. (2021) Risk Factors for Severity in Children with Coronavirus Disease 2019: A Comprehensive Literature Review. Pediatric clinics of North America 68:321-338

8. Nielsen, S.S. et al. (2021) SARS-CoV-2 elicits robust adaptive immune responses regardless of disease severity. EBioMedicine 68:103410

9. Le Bert, N. et al. (2020) SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584:457-462

10. Grifoni, A. et al. (2020) Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181:1489-1501.e15

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