Many New S mutations in Delta in US

https://github.com/cov-lineages/pango-designation/issues/188

This was always to be expected as Delta encountered a larger, more densely vaccinated population, but it's still happening with remarkable speed.

There is still no change in the RBD, as I had predicted, but S:L5F is unique. It's in the signal sequence for the S protein and thought to increase viral secretion further. It is a part of B.1.526(Iota).

https://europepmc.org/article/PPR/PPR180476
https://outbreak.info/situation-reports?muts=S%3AL5F

Most of the others are in the S2 subunit, indicating that Delta is taking full advantage of P681R and syncytia.

N1074S appears to be becoming fixed, and it had appeared in no lineage before B.1.617.2. Its increased viability is almost certainly tied to P681R given its position in the S2 subunit.

https://outbreak.info/situation-reports?muts=S%3AN1074S

Q613H never appeared in a really dominant A or B strain, but it was theorized to have worked in roughly the same way as D614G. Its position is conspicuous, but it may be either redundant or synergistic. Very little research has been performed on it.

https://www.biorxiv.org/content/10.1101/2021.06.30.450632v3.full
https://outbreak.info/situation-reports?muts=S%3AQ613H

D936H also never appeared in a really dominant strain, but it thrived in two, only one of which bears P681H, so it's not hard to imagine it's synergistic with P681R in Delta. It's not close to the S1/S2 furin cleavage site and probably plays some other role, and a relatively minor one compared to the profoundly powerful polybasic introduction of H681 or R681, but one which is enhanced by R681.

https://outbreak.info/situation-reports?muts=S%3AD936H

D1139H only occurred in AV.1, but not with extreme conservation. AV.1, a variant of concern to PHE, has P681H, so we can presume P681R+D1139H is synergistic as well as a working hypothesis.

https://outbreak.info/situation-reports?muts=S%3AD1139H

C1253F only did well in B.1.258.3, which has no really remarkable mutations and P681, so it merits special scrutiny if it becomes more prevalent.

https://outbreak.info/situation-reports?muts=S%3AC1253F

There's a big sheer number of mutations here, but given the huge viral loads globally and intense selective pressure of vaccination, this is not really unexpected. More surprising to some may be the lack of mutation in either the RBD or the NTD, indicating that the current set of mutations there is still no pressing need to evade antibody responses better through epitope alteration.

I expect many of these mutations to become fixed and increase infectivity/immune evasion, but they will not cause appreciable antigenic drift, as anti-S2 antibodies are weak and not heavily produced. It's not a very immunogenic region. If I had to SWAG it, it looks like Delta is going to rely more heavily on syncytia for immune evasion and it's getting much better at building them.

Delta is gradually accreting mutations that were beneficial in other strains and could antigenically drift quickly if this mutation rate were achieved in other regions of S. Even without antigenic drift, the vaccines should lose further potency as Delta evolves on its rampage northward as Boreal winter descends.

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