Breaking! Omicron Variant And Emerging Sub-Lineages Are Decreasing And Disarming Host Serologic Response By Reducing B-Cell Antigenicity!
Researchers from Tel Aviv University-Israel, The Hebrew University of Jerusalem-Israel and the University of Pittsburgh-USA have in a new study found that the Omicron variant decreases the human host serologic response by reducing B-Cell antigenicity.
The study findings also indicates that the emerging Omicron sub-lineages are also following a similar trajectory of viral evolution and that they are not literally evolving to escape immunity but rather to disarm or hide from host immune response!
It has already been found that the SARS-CoV-2 Omicron variant evades most neutralizing vaccine-induced antibodies and is associated with lower antibody titers upon breakthrough infections than previous variants. To date however, the mechanism remains unclear.
The study team utilizing a geometric deep-learning model found that Omicron's extensively mutated receptor binding site (RBS) features reduced antigenicity compared to previous variants.
Murine immunization experiments with different recombinant Receptor Binding Domains (RBD) variants confirm that the serological response to Omicron is drastically attenuated and less potent.
Detailed analyses of serum cross-reactivity and competitive ELISA revealed a reduction in antibody response across both variable and conserved RBD epitopes.
Subsequent computational modeling confirmed that the RBS has a potential for further antigenicity reduction while retaining efficient receptor binding.
The study team also found a similar trend of antigenicity reduction over decades for hCoV229E, a common cold coronavirus.
Hence the study findings explained the reduced antibody titers associated with Omicron infection and reveals a possible trajectory of future viral evolution.
The key study findings were:
-Omicron breakthrough infection elicits lower antibody response than prior variants
-Deep learning model predicts reduced antigenicity of the Omicron receptor binding domain
-Mice immunization experiments show reduced B-cell immunogenicity of Omicron spike RBD
-Additional mutations could reduce antigenicity while maintaining receptor binding
The study findings were published in the peer reviewed journal: Cell Reports.
The current COVID-19 pandemic has killed more than 6.55 million people globally and infected more than 624 million people according to reported data. (actual figures could be as high as 5 to 6-fold!)
The causative pathogen, SARS-CoV-2 has evolved over the period of time, spawning a number of variants that have shown enhanced transmissibility, virulence, and immune evasion capacity.
The recent variant of concern (VOC) to be detected is the Omicron B.1.1.529 variant, which comprises the most mutations to date.
The study explored the functional relevance of some of these mutations in their ability to escape neutralizing antibody responses. More specifically, the study team examined the ability of Omicron mutations to alter the immune antibody response in naïve individuals.
The Omicron variant has 11 mutations at its receptor binding site (RBS), which is responsible for most serologic responses. Such mutations preserve the ability of the virus to bind to the host angiotensin-converting enzyme 2 (ACE2) receptor while evading neutralizing antibodies that are present after natural infection or vaccination.
It has been found that ACE2 binding is associated with some Omicron mutations, namely S477N, E484K, N501Y, and Q498R.
At the same time, immune evasion has been found to be linked to K417N, E484A, and Q498R mutations. The impact of these mutations is relative to the wild-type serologic response.
The term ‘B-cell antigenicity’ describes the degree of antigen binding to antibodies from B-cells that have undergone affinity maturation. Affinity maturation depends on the occurrence of somatic hypermutations that increase the specificity of recognition and affinity of a given antigen for the antibody in question.
Typically, antibodies often bind to conformational epitopes formed by residues brought together by protein conformation, despite occurring far apart along the protein sequence.
Hence, it is challenging to predict epitopes from the sequence alone or produce a complete map of antibody epitopes.
The study team utilized their new modeling platform, ScanNet, based on geometric deep learning, to predict B-cell and protein-protein binding sites using either the experimental or computational structure.
ScanNet also provides a residue-wise probability score for each epitope called the antigenicity profile.
The high accuracy of ScanNet predictions appears to be higher than many other currently used techniques. An important example is a good match between the antigenicity profile ScanNet created for the SARS-CoV-2 wild-type spike receptor binding domain (RBD) and the experimentally derived antibody hit rate based on the spike-antibody complex structure. Thus, this platform is capable of predicting epitope distribution over the antigens.
The ScanNet platform predicted that Omicron would be associated with decreased RBS antigenicity, whereas Alpha, Beta, and Delta VOCs have a moderate increase compared to the wild-type strain of SARS-CoV-2.
Importantly, the locations of reduced antigenicity in the Omicron VOC were identified.
Interestingly, the study team found that the change in antigenicity was most significant in the most frequently targeted antigens.
As Omicron has 15 mutations that contribute to the change in antigenicity, the study team modeled the structure of each mutation. Over 50% of the mutations were linked to decreased antigenicity, especially Q493R, G496S, and Q498R, while one-third were associated with increased antigenicity. The remaining mutations had no apparent association with antigenicity.
When compared with the 26% reduction in antigenicity shown by all point mutants, the downward trend shown by Omicron appears to be due to evolutionary pressure, with similarly acting mutations displaying reciprocal reinforcement.
A subsequent mouse experiment using wild-type and VOC RBDs was conducted. After inoculation with any of these RBDs, restimulation produced comparable and robust T-cell responses in mice, irrespective of the original stimulation. This indicates a strong type 1 T helper cell (Th1) response accompanied by a robust Th17 response due to the mucosal route of immunization.
The study findings showed that the cytokine interleukin 17 (IL-17) was found at comparable levels in all mice, which suggests its origin from CD4 T-cells that react to specific antigens. In contrast, gamma interferon (IFN γ) levels produced by innate immune cells after non-specific viral stimulation were high.
Upon boosting mice against various VOC RBDs, it was found that antibody titers were much lower in Omicron-immunized animals and 15-fold lower than with the wild type or any other VOC RBD.
This study finding aligned with the earlier predicted Omicron RBD's antigenicity loss associated with its mutational profile.
Although most antibodies target the RBS, which shows extreme variability among VOCs, the other antibodies bind to conserved epitopes. Antibody titers in serum samples from wild-type-immunized mice were comparably high against Alpha and Delta VOCs but less against Beta. The most significant reduction was against Omicron.
These findings agree with clinical findings in humans, thus validating the utility of the mouse model.
Significantly, Omicron-immunized sera contained markedly lower serologic titers against any other VOC but exhibited efficient binding for Omicron RBS. Thus, the Omicron RBS appears highly antigenic, with additional contributions from other cross-reactive epitopes. Cross-reactive antibodies comprised almost one-third of all antibodies detected in Omicron-immunized or wild-type-immunized sera.
It was also found that Omicron-immunized sera had only 6% neutralizing activity against the wild-type RBD compared to wild-type sera against the Omicron RBD. This indicates a conserved spread of antigenic epitopes, with the immune evasion primarily due to the RBS and other conserved epitopes.
Interestingly, Beta-immunized sera had 50% less activity against the Omicron RBD than a 70% loss of activity against the wild-type RBD, with comparable antibody titers in both sets of samples. This indicates that the three shared residues between Beta and Omicron are not responsible for the reduction in antigenicity.
The wild-type sera failed to neutralize Omicron pseudoviruses, despite some degree of cross-reactivity. Omicron sera also did not neutralize Omicron nor wild-type pseudoviruses.
The reduced antigenicity of the common cold coronavirus hCoV229E was observed over time and found to be traceable to RBS mutations, following which there is a pattern of up-and-down fluctuations.
Importantly, this could indicate a phase of adaptation to host antibodies followed by further adaptation through mutations in the immunodominant regions to escape neutralizing antibodies induced by earlier infections. This may predict the course of SARS-CoV-2 in the future.
Lead Researcher, Jérôme Tubiana from the Blavatnik School of Computer Science, Tel Aviv University told Thailand Medical News
, “The study findings are consistent with both the preclinical vaccine trials and clinical convalescent data and provides critical insights into the underlying mechanism of the attenuated host serologic response against Omicron.”
The study team suggest an immune concealing mechanism, rather than an immune escape strategy, with Omicron, which is traceable to a novel mechanism of improved viral fitness.
Hence, this could explain the rapid and persistent dominance of Omicron over Delta. It also agrees with the observations that wild-type sera are more effective against Omicron than Omicron sera from unvaccinated people. Omicron sera fail to neutralize any other VOC. The immune concealing mode of immune evasion is by a marked fall in RBS antigenicity, which may lead to poor affinity maturation and slower antibody response.
The study team said that future work may include analyzing T-cell and Fc effector mechanisms of immunity against Omicron.
The current study provides a greater understanding of how SARS-CoV-2 may evolve in the future and the challenges associated with producing an effective vaccine against this variant.
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