Virus World

Over four years have passed since the beginning of the COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies and small molecules developed for clinical use. However, given the ability for viruses to become resistant to antivirals, it is perhaps no surprise that the field has identified resistance to nearly all of these compounds. Here, we provide a comprehensive review of the resistance profile for each of these therapeutics. We hope that this resource provides an atlas for mutations to be aware of for each agent, particularly as a springboard for considerations for the next generation of antivirals. Finally, we discuss the outlook and thoughts for moving forward in how we continue to manage this, and the next, pandemic.

Published (April 18, 2024):

https://doi.org/10.1016/j.chembiol.2024.03.008

Consecutive waves of SARS-CoV-2 infection have been driven in part by the repeated emergence of variants with mutations that confer resistance to neutralizing antibodies Nevertheless, prolonged or repeated antigen exposure generates diverse memory B-cells that can produce affinity matured receptor binding domain (RBD)-specific antibodies that likely contribute to ongoing protection against severe disease. To determine how SARS-CoV-2 omicron variants might escape these broadly neutralizing antibodies, we subjected chimeric viruses encoding spike proteins from ancestral, BA.1 or BA.2 variants to selection pressure by a collection of 40 broadly neutralizing antibodies from individuals with various SARS-CoV-2 antigen exposures. Notably, pre-existing substitutions in the BA.1 and BA.2 spikes facilitated acquisition of resistance to many broadly neutralizing antibodies.

Specifically, selection experiments identified numerous RBD substitutions that did not confer resistance to broadly neutralizing antibodies in the context of the ancestral Wuhan-Hu-1 spike sequence, but did so in the context of BA.1 and BA.2. A subset of these substitutions corresponds to those that have appeared in several BA.2 daughter lineages that have recently emerged, such as BA.5. By including as few as 2 or 3 of these additional changes in the context of BA.5, we generated spike proteins that were resistant to nearly all of the 40 broadly neutralizing antibodies and were poorly neutralized by plasma from most individuals. The emergence of omicron variants has therefore not only allowed SARS-CoV-2 escape from previously elicited neutralizing antibodies but also lowered the genetic barrier to the acquisition of resistance to the subset of antibodies that remained effective against early omicron variants.

Preprint available in bioRxiv (August 19, 2022):

https://doi.org/10.1101/2022.08.17.504313 

Continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ. 1.1, BA.4.6, BF.7 and BA.2.75.2. Here we examine the neutralization resistance of these subvariants, as well as their ancestral BA.4/5, BA.2.75 and D614G variants, against sera from 3-dose vaccinated health care workers, hospitalized BA.1-wave patients, and BA.5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially the BQ.1 and BQ.1.1 subvariants driven by a key N460K mutation, and to a lesser extent, R346T and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation.

The BQ.1 and BQ.1.1 subvariants also exhibited enhanced fusogenicity and S processing dictated by the N460K mutation. Interestingly, the BA.2.75.2 subvariant saw an enhancement by the F486S mutation and a reduction by the D1199N mutation to its fusogenicity and S processing, resulting in minimal overall change. Molecular modelling revealed the mechanisms of receptor-binding and non-receptor binding monoclonal antibody-mediated immune evasion by R346T, K444T, F486S and D1199N mutations. Altogether, these findings shed light on the concerning evolution of newly emerging SARS-CoV-2 Omicron subvariants.

Preprint available in bioRxiv (October 20, 2022):

https://doi.org/10.1101/2022.10.19.512891 

The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD). The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

Preprint in bioRxiv (May 26, 2022):

https://doi.org/10.1101/2022.05.26.493517