New SARS-CoV-2 target could boost immunity against all coronaviruses elife elife
for the benefit of readers; feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Thank you for submitting your article"Evaluation of the highly conserved S2 hairpin hinge as a pan-coronavirus target" for consideration by.
4) The S2 hinge epitope is partially occluded by the S1 domain and access is contingent on RBD up-down conformational switching. The authors should better integrate findings from the various approaches described to help readers understand possible mechanisms for how antibodies bind this epitope. 3) The reader would benefit from better integration of structural, solution , and antibody engineering approaches in the manuscript. This would bring out a more definitive conclusion on the mechanism of targeting the hinge epitope.Reviewer #2 :
Though we do not plan to isolate 3A3-like antibodies from human donors, there is evidence that these antibodies are elicited in infected humans via analysis of polyclonal responses in Claireaux2022. We also know of several studies on naturally occurring S2 hinge targeting antibodies from colleagues that are in preparation. Understanding the therapeutic role of this antibody class is relevant to the study of broadly-reactive S2 antibodies, even if that role is limited.
We also added in line 450 that S2 core-binding antibodies “require further validation” of their ability to recruit effector functions. This is a clear example of the value of pre-prints to stimulate timely scientific collaboration. While Costelloused 3A3 as a tool to probe spike dynamics, here we highlight the original work that identified the epitope.
We have added a new paragraph in the Discussion section to better lay out the complexity of the spike dynamics and how it may impact binding to the S2 hinge epitope:
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