Natural selection causes a virus to enhance its evolutionary advantages either by mutations that strengthen its binding with the host cell or by mutations to escape antibody protection. A recent study, published in the Journal of Chemical Information and Modeling, uses an artificial intelligence model to investigate Omicron’s mutations and its infectivity, vaccine escape capability, and susceptibility to monoclonal antibodies.
Study: Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance. Image Credit: Luca9257/Shutterstock
The results from this study call for new strategies to develop the next generation mutation-proof therapeutics, as the study has predicted Omicron to exhibit high infectivity, effective vaccine breakthrough, and almost complete antibody resistance.
Introduction
The latest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Variant of Concern (VoC), Omicron (B.1.1.529), was identified in the last week of November 2021.
Because Omicron is highly contagious and also presents several mutations (32; an unusually high number of mutations) that make it escape the vaccine protection, the current pandemic situation is causing serious concerns. However, a complete experimental evaluation of this new variant might take weeks or even months.
Therefore, in the present study, researchers from the United States have used an experimentally confirmed deep learning model, trained with tens of thousands of experimental data to investigate in silico the impacts of Omicron’s mutations on its infectivity.
Most of the mutations in the Omicron are in the Spike protein, specifically in the receptor-binding domain (RBD). This region plays a vital role in the infection, facilitating the viral S protein’s binding with the host receptor, angiotensin-converting enzyme 2 (ACE-2). Thus it is also the key target of vaccines and antibodies. Therefore, studying the 15 mutations in the RBD of the Omicron may shed light on the nature of Omicron’s infection and response to preventive actions and therapeutic drugs.
The binding free energy (BFE) between the RBD and the ACE-2 is proportional to infectivity. Likewise, antibody binding to the RBD would neutralize the virus. Thus mutations in the RBD causes immediate concerns about the efficacy of existing vaccines, mAbs, and the potential of reinfection.
To analyze how the RBD mutations on the Omicron variant affect the viral infectivity and the efficacy of existing vaccines and antibody drugs, the researchers used a well-tested, efficient and reliable in silico analysis. They used a comprehensive topology-based artificial intelligence (AI) model called TopNetmAb – to predict the BFE changes of S and ACE2/antibody complexes induced by mutations on the S RBD of the Omicron variant.
Main findings
The key 15 mutations in RBD studied in this work are these: S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, N501Y, and Y505H. Additionally, the researchers examined the three-dimensional (3D) structures of the RBD−ACE2 complex and 185
antibody−RBD complexes, including many mAbs. The researchers noted that the positive changes strengthen the binding while negative changes weaken the binding.
They identified that the Omicron is over twice as infectious as the Delta variant due to the RBD mutations N440K, T478K, and N501Y. It may be over ten times more contagious than the original SARS-CoV-2. Omicron may be more infectious than any other variant.
Additionally, they found that Omicron has a high potential to disrupt the binding of the most 185 antibodies with the S protein. This is mainly due to Omicron’s RBD mutations K417N, E484A, and Y505H. This indicates Omicron’s strong vaccine breakthrough capability, especially more than the Delta or other variants.
It is important to understand the antibody resistance developed by Omicron that may affect the healthcare and future development of therapeutic solutions. To this end, they studied a few mAbs, specifically, mAbs from Eli
Lilly (LY-CoV016 and LY-CoV555), Regeneron (REGN10933, REGN10987, and REGN10933/10987), AstraZeneca (AZD1061 and AZD8895), GlaxoSmithKline (S309), Celltrion (CT-P59), and the Rockefeller University (C135 and C144). The researchers provided the specific Omicron mutations that reduce the efficacy of each mAb cocktail.
Notably, the Omicron’s impacts on GlaxoSmithKline’s mAb S309 (PDB ID: 6WPS) which is the parent antibody for Sotrovimab developed by GlaxoSmithKline and Vir Biotechnology, Inc., are predicted to be mild. Because the Omicron-induced BFE changes are from −0.47 to 0.39 kcal/mol, Omicron may have minor impacts on the S309.
The prediction vaccine-breakthrough from this study and recent serum experimental results indicate that Omicron has the highest capability to evade vaccines. The researchers reported that the overall correlation between their prediction and the experiment is 0.9.
Conclusions
The results showed that the Omicron is about ten times more infectious than the original ancestral virus or about 2.8 times as infectious as the Delta variant. The researchers studied 185 known antibody−RBD complex structures. They found out that Omicron has more vaccine-escape capability than that of the Delta variant – nearly 14 times as high (and nearly five folds as capable as Gamma to escape vaccines).
On the antibody resistance, the researchers unveiled that Omicron may completely abolish the Eli Lilly antibody cocktail. Including the monoclonal antibodies (mAbs) from Regeneron, AstraZeneca, Celltrion, and Rockefeller University, the Omicron appears to survive the action of these. Interestingly, the researchers reported that the mAbs from GlaxoSmithKline might not be affected much.
This study suggests the rapid development of a new generation of vaccines and mAbs that will not be easily affected by viral mutations.
