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 

tThe SARS-CoV-2 saltation variant BA.2.86, which was quickly designated as a variant under monitoring after its emergence, has garnered global attention. Although BA.2.86 did not show substantial humoral immune escape and growth advantage compared with current dominant variants, such as EG.5.1 and HK.3, it showed remarkably high ACE2 binding affinity. This increased binding affinity, coupled with its distinct antigenicity, could enable BA.2.86 to accumulate immune-evasive mutations during low-level populational transmission, akin to the previous evolution from BA.2.75 to CH.1.1 and XBB.

With just one additional receptor binding domain mutation (L455S) compared to its predecessor BA.2.86, the JN.1 variant rapidly became predominant in France (figure A; appendix 1 p 12), surpassing both BA.2.86 and the so-called FLip (L455F+F456L) strains. A thorough investigation into the immune evasion capability of JN.1, particularly given its few additional mutations, is imperative.

Published in The Lancet Infectious Diseases (Dec. 15, 2023):

https://doi.org/10.1016/S1473-3099(23)00744-2