RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
The study by Bayarri-Olmos et al is an extremely topical exploration of a SARS-CoV-2 variant found in minks that were widely reported in the press in late 2020. The discovery of the variant led to the culling of millions of minks in Denmark, but also led to speculation of potential impacts on human COVID-19. The study, therefore, addresses a highly relevant component of the COVID-19 research spectrum. The authors examine the variant spike receptor-binding domain (RBD), containing the Y453F mutation. Specifically, the preprint examines the RBD interaction with the ACE-2 receptor and its consequent effect on virus neutralization by antibodies elicited by infection or immunization with wild-type SARS-CoV-2. The immunization component is significant because it allows the authors to extend their study to vaccination considerations.
This is a straightforward and brief study. First, the binding properties for wild-type or Y453F RBD and the human ACE-2 receptor are determined. This experiment showed that the mutation Y453F leads to a four-fold higher affinity for the ACE-2 receptor. The next experiment compared the neutralizing potential of human convalescent plasma for both the wild-type and variant RBDs, while the third part of this study compared sera from mice immunized with either wild-type or variant RBD in a cross-neutralization experiment. Surprisingly, given the higher affinity for RBD, the variant RBD was not less effectively neutralized by antibodies elicited by wild-type RBD. This suggests that the Y453F mutation heightens binding but does not lead to immune escape.
In the study, neutralization was measured using an ELISA, developed in the authors’ laboratories and described in another, non-peer-reviewed preprint. The ELISA is essentially an ACE-2 inhibition assay and, in the method preprint, there was a Spearman rank correlation coefficient of 0.92 between the ELISA and conventional PRNT using convalescent sera.
Assuming that, even when comparing heterologous interactions, limiting the assay to the RBD:ACE-2 interaction reflects virus neutralization, then the findings by the authors appear sound, and the authors’ claims are supported by their data. However, if feasible in their laboratories, the study impact would be improved by measurements using live virus PRNT. The impact of the study would be further improved by using also incorporating sera from vaccinated individuals and determining the effect of vaccine-induced antibodies on the neutralization of the mink virus. Finally, the authors’ message that both immunity and transmission be evaluated in variants would be more strongly supported by correlating the increased binding affinity of the Y453F variant with virus transmission.
R. Bayarri-Olmos, M. Idorn, A. Rosbjerg, L. Pérez-Alós, C. Hansen, L. Johsen, C. Helgstrand, F. K. Öberg, M. Søgaard, S. Paludan, T. Bak-Thomsen, J. Jardine, M.-O. Skjoedt, P. Garred, (2021).Vaccine monitoring shows that focused immunization with SARS-CoV-2 receptor-binding domain provides a better neutralizing antibody response than full-length spike protein. Res. Sq.doi:10.21203/rs.3.rs-134388/v1.