For the reason that onset of the coronavirus disease 2019 (COVID-19) pandemic, attributable to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), quite a few viral variants have emerged. These variants have shown enhanced transmissibility, virulence, and immune evasion capability.

Probably the most recent of those variants of concern (VOCs) to be detected is the Omicron B.1.1.529 variant, which comprises probably the most mutations thus far.

Study: Reduced B-cell antigenicity of Omicron lowers host serologic response. Image Credit: joshimerbin / Shutterstock.com

A latest research paper published within the journal Cell Reports explores the functional relevance of a few of these mutations of their ability to flee neutralizing antibody responses. More specifically, the researchers examined the power of Omicron mutations to change the immune antibody response in naïve individuals.

Introduction

Omicron has 11 mutations at its receptor binding site (RBS), which is accountable for most serologic responses. Such mutations preserve the power of the virus to bind to the host angiotensin-converting enzyme 2 (ACE2) receptor while evading neutralizing antibodies which are present after natural infection or vaccination.

ACE2 binding is related to some Omicron mutations, namely S477N, E484K, N501Y, and Q498R. Conversely, immune evasion is linked to K417N, E484A, and Q498R mutations. The impact of those mutations is relative to the wild-type serologic response.

B-cell antigenicity describes the degree of antigen binding to antibodies from B-cells which have undergone affinity maturation. Affinity maturation is dependent upon the occurrence of somatic hypermutations that increase the specificity of recognition and affinity of a given antigen for the antibody in query.

Antibodies often bind to conformational epitopes formed by residues brought together by protein conformation, despite occurring far apart along the protein sequence. Subsequently, it’s difficult to predict epitopes from the sequence alone or produce a whole map of antibody epitopes.

Concerning the study

The researchers used their latest modeling platform, ScanNet, based on geometric deep learning, to predict B-cell and protein-protein binding sites using either the experimental or computational structure. As well as, ScanNet provides a residue-wise probability rating for every epitope called the antigenicity profile.

The accuracy of ScanNet predictions appears to be higher than many other currently used techniques. A crucial example is a superb 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 able to predicting epitope distribution over the antigens.

Study findings

ScanNet predicted that Omicron could be related to decreased RBS antigenicity, whereas Alpha, Beta, and Delta VOCs have a moderate increase in comparison with the wild-type strain of SARS-CoV-2. The locations of reduced antigenicity within the Omicron VOC were identified. Furthermore, the scientists found that the change in antigenicity was most important in probably the most ceaselessly targeted antigens.

Since Omicron has 15 mutations that contribute to the change in antigenicity, the researchers modeled the structure of every mutation. Over 50% of the mutations were linked to decreased antigenicity, especially Q493R, G496S, and Q498R, while one-third were related to increased antigenicity. The remaining mutations had no apparent association with antigenicity.

Compared with the 26% reduction in antigenicity shown by all point mutants, the downward trend shown by Omicron appears to be on account of evolutionary pressure, with similarly acting mutations displaying reciprocal reinforcement.

This was followed by a mouse experiment using wild-type and VOC RBDs. After inoculation with any of those RBDs, restimulation produced comparable and robust T-cell responses in mice, no matter the unique stimulation. This means a powerful type 1 T helper cell (Th1) response accompanied by a sturdy Th17 response on account of the mucosal route of immunization.

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.

After boosting mice against various VOC RBDs, antibody titers were much lower in Omicron-immunized animals and 15-fold lower than with the wild type or some other VOC RBD. This finding aligned with the sooner predicted Omicron RBD’s antigenicity loss related to its mutational profile.

While most antibodies goal the RBS, which shows extreme variability amongst VOCs, the opposite 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. Probably the most significant reduction was against Omicron.

This agrees with clinical findings in humans, thus validating the utility of the mouse model.

Omicron-immunized sera contained markedly lower serologic titers against some 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.

Omicron-immunized sera had only 6% neutralizing activity against the wild-type RBD in comparison with wild-type sera against the Omicron RBD. This means a conserved spread of antigenic epitopes, with the immune evasion primarily on account of the RBS and other conserved epitopes.

Beta-immunized sera had 50% less activity against the Omicron RBD than a 70% lack of activity against the wild-type RBD, with comparable antibody titers in each sets of samples. This means that the three shared residues between Beta and Omicron are usually not accountable for the reduction in antigenicity.

Wild-type sera didn’t neutralize Omicron pseudoviruses, despite some extent of cross-reactivity. Omicron sera also didn’t neutralize Omicron nor wild-type pseudoviruses.

Reduced antigenicity of the common cold coronavirus hCoV229E was observed over time and located to be traceable to RBS mutations, following which there’s a pattern of up-and-down fluctuations.

This might indicate a phase of adaptation to host antibodies followed by further adaptation through mutations within the immunodominant regions to flee neutralizing antibodies induced by earlier infections. This will likely predict the course of SARS-CoV-2 in the longer term.

Implications

Our study is consistent with each 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 researchers suggest an immune concealing mechanism, quite than an immune escape strategy, with Omicron, which is traceable to a novel mechanism of improved viral fitness. This might explain the rapid and chronic dominance of Omicron over Delta. It also agrees with the observations that wild-type sera are more practical against Omicron than Omicron sera from unvaccinated people.

Omicron sera fail to neutralize some other VOC. The immune concealing mode of immune evasion is by a marked fall in RBS antigenicity, which can result in poor affinity maturation and slower antibody response.

Future work may include analyzing T-cell and Fc effector mechanisms of immunity against Omicron. Nevertheless, the present study provides a greater understanding of how SARS-CoV-2 may evolve in the longer term and the challenges related to producing an efficient vaccine against this variant.

Journal reference:

• Tubiana, J., Xiang, Y., Fan, L., et al. (2022). Reduced B-cell antigenicity of Omicron lowers host serologic response. Cell Reports. doi:10.1016/j.celrep.2022.111512.