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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 C-19 pandemic and understand immunology should read the following publication: Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting.
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 (VBTI). They convincingly show that the neutralizing antibody (NAb) response resulting from this VBTI-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 VBTIs or updated mRNA-based C-19 vaccine boosters.
However, this does not allow to conclude that immune responses elicited by repeated booster events (i.e., through new VBTIs 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). SIR takes place when high titers of S variant-specific antibodies (Abs) bind to distinct S variants due to VBTI occurring after WT vaccination (WT referring to the ancestral, wild-type lineage). As previously explained, high titers of SIR-boosted Abs directed towards more conserved, cross-reactive epitopes not only specifically bind to WT vaccine-specific RBD-associated epitopes but also engage in S variant-nonspecific, high-avidity interactions with repetitive arrays of RBD ligands expressed on the surface of free-circulating particles of viral variant.
At high concentrations, these Abs fully occupy the targeted binding sites, even on highly antigenically distant S 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 C-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 S variant-specific Abs, 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 SIR, which inevitably accompanies the recall of WT vaccine-induced Abs through VBTI or mRNA boosters.
Because repeated exposure to Omicron VBTI or the administration of updated mRNA vaccinations not only overrides WT vaccine-induced immune imprinting but also triggers SIR, 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.
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 WT-based vaccination or the first VBTI with an Omicron variant, respectively. That these so-called ‘Omicron-specific’ memory B cells produce Abs 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 Abs 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 Abs (e.g., BA.1/BA.2-specific Abs) 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 VBTI (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 Abs. It is therefore entirely counterintuitive to assume that highly antigen (Ag)-specific Abs would exhibit such broad, cross-neutralizing activity. Consequently, I also disagree with their conclusion that the enhanced diversity of Omicron-specific NAbs targeting distinct RBD epitopes, compared to WT-induced monoclonal Abs, largely contributes to their broadly neutralizing capability against other Omicron variants. Firstly, it is not scientifically sound to compare Omicron-specific monoclonal Abs after VBTI (and thus, after SIR!) with WT-induced monoclonal antibodies before VBTI. Secondly, the broader spectrum of monoclonals directed at neutralizing RBD-associated epitopes is likely the result of enhanced ACE2-binding affinity of the more infectious (!) Omicron variants C-19 vaccinees had been exposed to. Thirdly, after both the first and the second VBTI, Ab titers towards viral variants that are more antigenically distant from the lineage causing the VBTI 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 Abs recalled upon the second VBTI. However, they did not conduct ELISA tests on the broadly neutralizing Abs to verify whether they also reacted with variant-specific RBD 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 RBD-targeting monoclonal Abs 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 NT50 boosting 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 Abs, 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 Abs towards new, highly immune-evasive variants cannot be attributed to the interaction of S variant-specific Abs with the monovalent RBD.
Despite these observations and discrepancies, the scientists have not yet come to understand that repeated exposure to Omicron variants or updated booster vaccines triggers SIR.
As the authors overlook SIR, they fail to comprehend why the recall of previously vaccine-induced cross-reactive B memory cells upon VBTI facilitates suboptimal immune pressure on new, more infectious, and antigenically very distant variants, but not on previously circulating variants (i.e., after the first VBTI) or currently circulating variants (i.e., after the second VBTI). With each successive VBTI, 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 VBTI, 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 VBTI.
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 NAbs against newly emerging variants. They only bothered about the performance of repeated boosters in individuals whose capacity to generate NAbs against newly emerging variants had already been compromised by vaccination!
The authors demonstrate that Omicron infection after WT-based vaccination or previous VBTI recalls conserved, cross-reactive memory B cells previously elicited by vaccination or previous VBTI. As antigenic domains that are more conserved may resemble self-antigens, it is reasonable to assume that maturation of Abs directed at these more conserved domains mature into IgG4 Abs. 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 C-19 vaccinated countries.
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 SIR, as mRNA vaccine boosters trigger SIR and, consequently, lead to SIR-mediated recall of previously induced Abs.
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 C-19 vaccines and/or new variant-specific booster treatments in highly C-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 C-19 vaccinated populations. Ultimately, this process will restore the natural equilibrium between the virus and the host's immune system.
Whereas mitigation of immune imprinting enables efficient neutralization of the previously circulating variant, SIR-mediated mitigation of infection by newly emerging variants drives natural selection of these variants. The combination of both phenomena (via the same repeated VBTI or updated mRNA booster vaccination) precipitates dominant spread of newly emerging variants.
Consequently, protection of C-19 vaccinees against newly emerging Omicron descendants can no longer be assured by NAbs, whether they are vaccine-induced or elicited upon repeated exposure to a new Omicron infection or an updated mRNA vaccine booster. Protection of C-19 vaccinees against C-19 symptoms or severe C-19 disease now exclusively relies on enhanced cytotoxic T lymphocyte (CTL) activity and polymeric non-neutralizing Abs (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 PNNAbs are consumed and fewer PNNAbs 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 PNNAbs will quickly result in a massive wave of highly virulent VBTIs in highly C-19 vaccinated populations.
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.
Email: info@voiceforscienceandsolidarity.org
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