Scientists’ molecular stamp collection raises false hopes on outcome of COVID-19 pandemic
The conclusions drawn from scientists’ molecular stamp collection exercises create false expectations for addressing the continuous emergence of SARS-CoV-2 variants, not to mention bringing an end to the COVID-19 pandemic.
All scientists who care about the outcome of the COVID-19 pandemic and understand immunology should read the following publication: Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting.
The scientists’ conclusion that ‘fighting fire with fire’ is the optimal approach to counter the ongoing emergence of SARS-CoV-2 variants is fundamentally wrong. Their interpretation of the data collected through their research raises false hopes for keeping up with the pace of the viral evolutionary dynamics in highly COVID-19 (C-19) vaccinated populations.
The authors have done an outstanding job in demonstrating that repeated exposure to Omicron variants boosts S(pike) variant-specific B cells primed by and targeted at the Omicron variant causing the previous vaccine breakthrough infection. They convincingly show that the neutralizing antibody (NAb) response resulting from this VACCINE BREAKTHROUGH INFECTION -mediated boost exhibits a robust neutralization capacity directed at multiple distinct receptor binding domain (RBD)-associated neutralization domains. In this way, they have substantiated that immune imprinting (antigenic sin) can indeed be overridden through repeated Omicron VACCINE BREAKTHROUGH INFECTIONS or updated mRNA-based COVID-19 vaccine boosters.
However, this does not allow to conclude that immune responses elicited by repeated booster events (i.e., through new VACCINE BREAKTHROUGH INFECTIONS or updated mRNA-based vaccine boosters) will succeed in countering the emergence and dominant spread of new variants, let alone in putting an end to the pandemic!
It is stunning, however, to observe how these scientists entirely disregard a crucial immunological phenomenon known as ‘steric immune refocusing’ (SIR). STERIC IMMUNE REFOCUSING takes place when high titers of Spike protein variant-specific antibodies (Abs) bind to distinct Spike protein variants due to VACCINE BREAKTHROUGH INFECTION occurring after WT vaccination (WT referring to the ancestral, wild-type lineage). As previously explained, high titers of STERIC IMMUNE REFOCUSING-boosted Antibodies directed towards more conserved, cross-reactive epitopes not only specifically bind to WILD-TYP vaccine-specific RECEPTOR BINDING DOMAIN-associated epitopes but also engage in Spike protein variant-nonspecific, high-avidity interactions with repetitive arrays of RECEPTOR BINDING DOMAIN ligands expressed on the surface of free-circulating particles of viral variant.
At high concentrations, these Antibodies fully occupy the targeted binding sites, even on highly antigenically distant Spike protein variants, thereby causing temporary/ short-lived ‘pseudo’-neutralization of a broad spectrum of newly emerging viral variants. At lower Ab concentrations, however, these multivalent interactions confer prolonged mitigation of viral infectiousness. Prolonged mitigation of viral infectiousness favors suboptimal immune pressure on viral infectiousness. This results in highly COVID-19 vaccinated populations exerting substantial immune selection pressure on viral infectiousness. The combined effect of robust neutralization against the previously circulating variant by the boosted Spike protein variant-specific Antibodies , along with immune selection pressure on viral infectiousness, drives the dominant spread of newly emerging, more infectious, and antigenically more distant immune escape variants, as we have seen over the past 6 months. In other words, the highly specific and effective neutralizing capacity induced by the boosting effect is targeted at the infecting variant, not the newly emerging variants. The immune selection of these variants is indirectly facilitated by STERIC IMMUNE REFOCUSING, which inevitably accompanies the recall of WILD-TYP vaccine-induced Antibodies through VACCINE BREAKTHROUGH INFECTION or mRNA boosters.
Because repeated exposure to Omicron VACCINE BREAKTHROUGH INFECTION or the administration of updated mRNA vaccinations not only overrides WILD-TYP vaccine-induced immune imprinting but also triggers STERIC IMMUNE REFOCUSING, double Omicron exposure or ‘doubling down’ on updated mRNA vaccine boosters is not a blessing but a scourge! It is therefore disheartening that these scientists, along with the majority of the scientific community, recommend administering additional (i.e., 2) booster doses of Omicron-based vaccines to individuals who have not received prior Omicron-based vaccinations or have not been previously infected with the Omicron variant.
But how is it possible that, after all this time and money invested in studying the host immune response upon repeated exposure of COVID-19 vaccinated and unvaccinated individuals, the authors draw these erroneous conclusions?
The main reason is that the authors did not offer a correct explanation for several of the generated data. For instance, they failed to provide an explanation for why both the first and second post-vaccination exposures to new Omicron variants recalled cross-reactive memory B cells elicited by WILD-TYP-based vaccination or the first VACCINE BREAKTHROUGH INFECTION with an Omicron variant, respectively. That these so-called ‘Omicron-specific’ memory B cells produce Antibodies that possess broadly cross-reactive potential is illustrated in Figs. 2c,d and Extended Data: Fig. 3a–c.
Based on the increase of Omicron-specific Antibodies and the concomitant rise in the NT50 values for highly immune-evasive variants (e.g., CH.1.1, BQ.1.1, XBB, FL.8 [XBB.1.9.1.8], XBB.1.5, XBB.1.16 and XBB.1.5 + F456L variants) after repeated Omicron infections (see Fig. 2c,d and Extended Data Fig. 3a–c), the authors concluded:
“These results are highly correlated with the plasma NT50 values of the cohorts, which suggests that Omicron-specific antibodies are a major contributor to the increased antibody breadth and neutralization capability after repeated Omicron infection”.
In other words, these scientists blindly assumed that the increased affinity maturation of these Omicron-specific Antibodies (e.g., BA.1/BA.2-specific Antibodies ) after repeated exposure is also responsible for their increased potency against highly immune-evasive, i.e., antigenically more distant, Omicron variants whereas they fail to explain why a broadly neutralizing capacity towards highly immune-evasive variants was already observed after the first VACCINE BREAKTHROUGH INFECTION (see fig. 2 d). Their assumption also contrasts with the well-acknowledged notion in immunology that somatic hypermutation and affinity maturation lead to enhanced affinity of highly specific Antibodies . It is therefore entirely counterintuitive to assume that highly antigen (Ag)-specific Antibodies would exhibit such broad, cross-neutralizing activity. Consequently, I also disagree with their conclusion that the enhanced diversity of Omicron-specific Neutralizing antibody targeting distinct RECEPTOR BINDING DOMAIN epitopes, compared to WILD-TYP-induced monoclonal Antibodies , largely contributes to their broadly neutralizing capability against other Omicron variants. Firstly, it is not scientifically sound to compare Omicron-specific monoclonal Antibodies after VACCINE BREAKTHROUGH INFECTION (and thus, after STERIC IMMUNE REFOCUSING!) with WILD-TYP-induced monoclonal antibodies before VACCINE BREAKTHROUGH INFECTION . Secondly, the broader spectrum of monoclonals directed at neutralizing RECEPTOR BINDING DOMAIN-associated epitopes is likely the result of enhanced ACE2-binding affinity of the more infectious (!) Omicron variants COVID-19 vaccinees had been exposed to. Thirdly, after both the first and the second VACCINE BREAKTHROUGH INFECTION , Ab titers towards viral variants that are more antigenically distant from the lineage causing the VACCINE BREAKTHROUGH INFECTION were low (see Figs. 1a,b, 2 and Extended Data: Fig. 3). This confirms that their infection-inhibiting effect is due to pseudo-neutralization as previously explained.
The authors used ELISA to demonstrate enhanced Omicron variant-specificity of Antibodies recalled upon the second VACCINE BREAKTHROUGH INFECTION . However, they did not conduct ELISA tests on the broadly neutralizing Antibodies to verify whether they also reacted with variant-specific RECEPTOR BINDING DOMAIN epitopes. As previously explained, the mechanism of cross-reactive pseudo-neutralization, which relies on multivalent Ag-Ab interactions, cannot be detected through ELISA.
Furthermore, based on their deep mutational scanning-based epitope characterization of RECEPTOR BINDING DOMAIN-targeting monoclonal Antibodies isolated from repeated Omicron infection, the authors concluded that the Omicron infection history during repeated Omicron infections also introduced Omicron-based immune imprinting. However, they failed to investigate how the NT50boosting effect of repeated exposure or booster vaccination in individuals previously exposed to distinct viral variants (i.e., BA.1 or BA.2) could be reconciled with a similarly high NT50 boost effect for other, highly antigenically distant variants, as illustrated in Fig. 2.
If the authors had investigated the longevity of these broadly cross-neutralizing Antibodies , they would have found that their neutralizing capacity is short-lived. This finding would have led them to understand that the broadly neutralizing capacity of these Antibodies towards new, highly immune-evasive variants cannot be attributed to the interaction of Spike protein variant-specific Antibodies with the monovalent RECEPTOR BINDING DOMAIN.
Despite these observations and discrepancies, the scientists have not yet come to understand that repeated exposure to Omicron variants or updated booster vaccines triggers STERIC IMMUNE REFOCUSING.
It is crucial to understand that, in addition to mitigation of immune imprinting, STERIC IMMUNE REFOCUSING is in the play too.
As the authors overlook STERIC IMMUNE REFOCUSING, they fail to comprehend why the recall of previously vaccine-induced cross-reactive B memory cells upon VACCINE BREAKTHROUGH INFECTION facilitates suboptimal immune pressure on new, more infectious, and antigenically very distant variants, but not on previously circulating variants (i.e., after the first VACCINE BREAKTHROUGH INFECTION ) or currently circulating variants (i.e., after the second VACCINE BREAKTHROUGH INFECTION ). With each successive VACCINE BREAKTHROUGH INFECTION , the NT50 value for a specific variant increases, and the pseudo-neutralizing capacity of the same serum concurrently rises towards more antigenically distant variants. Following the second VACCINE BREAKTHROUGH INFECTION , this cross-reactive neutralization effect will be applicable to new variants that are more antigenically distant from the ancestral strain than those pseudo-neutralized after the first VACCINE BREAKTHROUGH INFECTION .
Why didn’t these scientists discuss the lesson taught by the data generated in the unvaccinated?
As depicted in Fig. 2a and 2b (right panels), prior natural infection (i.e., with the ancestral D614G lineage) does not manifest a robust immune imprinting effect: The re-exposure of unvaccinated individuals to new Omicron variants yielded significantly higher NT50 values for these variants in comparison to the ancestral lineage. It is, therefore, surprising that these scientists did not emphasize the point that vaccination during an immune escape pandemic is highly problematic because vaccination-induced immune imprinting severely compromises the host immune system’s ability to generate Neutralizing antibodies against newly emerging variants. They only bothered about the performance of repeated boosters in individuals whose capacity to generate Neutralizing antibodies against newly emerging variants had already been compromised by vaccination!
Enhanced recall of conserved, cross-reactive memory B cells upon repeated exposure could even entail immune pathology.
The authors demonstrate that Omicron infection after WILD-TYP-based vaccination or previous VACCINE BREAKTHROUGH INFECTION recalls conserved, cross-reactive memory B cells previously elicited by vaccination or previous VACCINE BREAKTHROUGH INFECTION . As antigenic domains that are more conserved may resemble self-antigens, it is reasonable to assume that maturation of Antibodies directed at these more conserved domains mature into IgG4 Antibodies . As the latter are functionally monovalent, they may not only have an anti-inflammatory effect on Ags comprising such self-mimicking epitopes but could also react with monovalent ‘self’ or ‘altered self’ Ags expressed on the surface of healthy or pathologically altered cells, respectively. This likely contributes to the increased incidence of autoimmune diseases and cancers in highly COVID-19 vaccinated countries.
Is it correct to say that mRNA-based vaccines exhibit a more pronounced immune imprinting effect compared to inactivated vaccines due to their higher immunogenicity?
The authors highlight that mRNA vaccines are more susceptible to vaccine-induced immune imprinting compared to inactivated vaccines, likely due to their stronger immunogenicity. However, it is challenging to explain why the robust immunogenicity of subsequent mRNA-based vaccine boosters would not counteract previously established ancestral (mRNA-based) vaccine-induced immune imprinting. The explanation for enhanced immune imprinting conferred by mRNA-based vaccines is thus more likely to be found in STERIC IMMUNE REFOCUSING, as mRNA vaccine boosters trigger STERIC IMMUNE REFOCUSING and, consequently, lead to STERIC IMMUNE REFOCUSING-mediated recall of previously induced Antibodies .
Scientists don’t see the forest for the trees. Their detailed analysis of adaptive viral and immune responses prevents them from realizing why repeated exposure to Omicron leads to ‘inescapable viral immune escape’.
It is reasonable to assert that the authors’ conclusion stating that ‘updated vaccines can counter immune imprinting from wild type (i.e., ancestral) vaccination and elicit strong immune responses against the latest variants‘ is accurate, yet it falls short of addressing the urgent concern posed by new emerging variants. The dominant spread of the latter is facilitated by the effective neutralization of the latest circulating variants and the natural selection of new Omicron descendants. This natural selection directly arises from the collective suboptimal immune pressure that inevitably ensues after boosters with updated COVID-19 vaccines and/or new variant-specific booster treatments in highly COVID-19 vaccinated populations. Due to the escalating immune pressure on its infectivity, the virus will be compelled to elevate the barrier to higher virulence. Consequently, it will acquire the ability to strongly proliferate and spread within the host, overcoming generalized immune pressure in highly COVID-19 vaccinated populations. Ultimately, this process will restore the natural equilibrium between the virus and the host’s immune system.
Conclusion
Whereas mitigation of immune imprinting enables efficient neutralization of the previously circulating variant, STERIC IMMUNE REFOCUSING-mediated mitigation of infection by newly emerging variants drives natural selection of these variants. The combination of both phenomena (via the same repeated VACCINE BREAKTHROUGH INFECTION or updated mRNA booster vaccination) precipitates dominant spread of newly emerging variants.
Consequently, protection of COVID-19 vaccinees against newly emerging Omicron descendants can no longer be assured by Neutralizing antibodies, whether they are vaccine-induced or elicited upon repeated exposure to a new Omicron infection or an updated mRNA vaccine booster. Protection of COVID-19 vaccinees against COVID-19 symptoms or severe COVID-19 disease now exclusively relies on enhanced cytotoxic T lymphocyte (CTL) activity and polymeric non-neutralizing Antibodies (PNNAbs). The more infectious the circulating variant, the more the virus is adsorbed instead of internalized into antigen-presenting cells (APCs). Alternatively, with a more infectious circulating variant, more Polymeric non-neutralizing Antibodies are consumed and fewer Polymeric non-neutralizing Antibodies are produced. This must now rapidly lead to rapidly growing, population-level immune pressure on the enhancing site within the S-NTD (spike N-terminal domain) of dendritic cell (DC)-tethered virions. Any mutation capable of overriding the virulence-inhibitory effect of these Polymeric non-neutralizing Antibodies will quickly result in a massive wave of highly virulent VACCINE BREAKTHROUGH INFECTIONS in highly COVID-19 vaccinated populations.
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