By Mariana Bego
In recent months, studies have raised the possibility that certain emerging SARS-CoV-2 variants evolved to escape antibody immune surveillance, elicited by previous infection, immunization, or by monoclonal antibody treatments. It was suggested that although potent, antibodies elicited by vaccines could be less effective against newer versions of the virus.
On the watch for mutations
Investigators from the University of Texas Medical Branch in Galveston engineered several variants of SARS-CoV-2, including one containing the same spike-protein mutations as a variant of interest B.1.351 (also known as 501Y.V2) first identified in South Africa. In their recent article in the New England Journal of Medicine, they suggest that antibodies elicited by the Pfizer/BioNTech vaccine were only partially capable of neutralizing the B.1.351-like virus. Of all the mutations present in B.1.351 spike, they linked the ability of this variant to evade neutralization to only three mutations (K417N, E484K, and N501Y). These residues map to the portion of the spike protein that SARS-CoV-2 uses to adhere to host cells.
Read their article here.
Similarly, research led by investigators at the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, evaluated the neutralization potency of sera from the Pfizer/BioNTech and Moderna mRNA vaccine recipients against viruses bearing spike proteins derived from multiple variants of SARS-CoV-2. Similar to the research described above, they reported that variants carrying mutations K417N/T, E484K, and N501Y, were highly resistant to neutralization. Likewise, cross- neutralization of B.1.351 variants was weak.
Read their pre-print article here.
Why are these mutations so powerful?
In terms of mechanism, researchers from ImmunityBio, Inc. used a simulation software to assess binding between the spike receptor binding domain (RBD) mutants and its human receptor. In a pre-print released earlier this year, they reported that the combination of K417N, E484K, and N501Y results in the highest degree of conformational alterations facilitating binding of RBD to its receptor.
Read their pre-print article here.
Similarly, recent work by a team from the University of Colorado generated several versions of spike with mutated RBD incorporating substitutions found in variants originally described in South Africa and Brazil. They also reported that the RBD mutant carrying K417N, E484K, and N501Y substitutions was able to bind to the human receptors more strongly than the original version of the protein. Interestingly, the mutated version of RBD was not recognized by the therapeutic monoclonal antibody, Bamlanivimab.
Read their pre-print article here.
Where do we go from here?
These studies suggest that a relatively small number of mutations can mediate potent escape from antibody responses. Nevertheless, it is not clear whether these changes make vaccines less effective at preventing COVID-19 caused by the B.1.351-like coronavirus linages. And while the clinical impact of this resistance remains uncertain, these results emphasize the need to continue developing broadly protective interventions to stay ahead of the evolving pandemic.