Anyway, these are in a domain that constitutes about 20% of human neutralizing antibodies and are quite possibly somewhat immunologically relevant.
Can you point to where I can find more about this estimate? I’m starting to think of the NTD as more immunodominant than that. E.g., out of 19 potently nAbs isolated here, about half were RBD-targeted and half were NTD-targeted. Here you see similar or more NTD-targeted antibodies in the convalescent plasma of 2 patients than RBD-targeted antibodies (both are outnumbered by anti-S2 antibodies, but I’m—perhaps naively—assuming those are mostly non-neutralizing). Deletions in the NTD also seem to be selected for in response to immune pressure (e.g., in response to convalescent plasma therapy, in persistently infected patients).
In particular, N501Y has already been identified as a mutation that increases the strength of binding to the ACE2 receptor. It also functions as a known escape mutation
I have seen papers exposing large numbers of recovered human serum samples against various escape mutations. When one at a time was presented, only the weakest ~7% of responses (presumably consisting of the fewest antibody types) were affected at all and only a subset of those dropped below likely having an effect. When two escape mutations were added, it went up to about 20%, still biased strongly towards the weaker responses. But again, not all those responses dropped to zero, some just got weaker.
I feel like I’ve seen the paper you’re referencing but can’t seem to find it now. In any case, I’ve also been surprised by other papers showing large impacts of single mutations against polyclonal sera. For example, the 69⁄70 deletions (in combination with the maybe-irrelevant D796H) drop neutralization activity against 3 high titer convalescent plasma samples by >50% (table 1, figure 4C here). Also, several variants—of note, especially E484K, found in the South African variant—seem to drop neutralization activity of convalescent sera, including some that are higher titer, several-fold (Fig 5A here). I used to have more faith in the polyclonal response but I’m starting to question it a bit.
Can you point to where I can find more about this estimate? I’m starting to think of the NTD as more immunodominant than that. E.g., out of 19 potently nAbs isolated here, about half were RBD-targeted and half were NTD-targeted. Here you see similar or more NTD-targeted antibodies in the convalescent plasma of 2 patients than RBD-targeted antibodies (both are outnumbered by anti-S2 antibodies, but I’m—perhaps naively—assuming those are mostly non-neutralizing). Deletions in the NTD also seem to be selected for in response to immune pressure (e.g., in response to convalescent plasma therapy, in persistently infected patients).
Good news — maybe N501Y doesn’t confer escape from neutralization.
I feel like I’ve seen the paper you’re referencing but can’t seem to find it now. In any case, I’ve also been surprised by other papers showing large impacts of single mutations against polyclonal sera. For example, the 69⁄70 deletions (in combination with the maybe-irrelevant D796H) drop neutralization activity against 3 high titer convalescent plasma samples by >50% (table 1, figure 4C here). Also, several variants—of note, especially E484K, found in the South African variant—seem to drop neutralization activity of convalescent sera, including some that are higher titer, several-fold (Fig 5A here). I used to have more faith in the polyclonal response but I’m starting to question it a bit.