Immune system put pressure on neutralizing epitopes of spike protein
Direct consequence of mass-vaccination
Result of lower neutralizability of the virus
New observations: Antibodies directed to S no longer target the same relative epitopes
S Ab now being directed against non-neutralizing epitopes of the spike
N-terminal domain
These epitopes contrast with localized epitopes in RBD. Less-neutralizing epitopes are more conserved (more shared among variants)
In order for Virus to overcome immune pressure - large-scale immune escape
Hurdle by virus to overcome immune pressure on conserved or non-neutralizing epitopes - many mutations
Current omicron variants are quite different from one another - Why has the immune pressure changed such that it is no longer directed at the RBD, but at the less-variable, more conserved domains within the spike protein (N-terminal)
Immune-Refocusing
Focusing on new epitopes
Rapid breakthrough infections (consecutive) in the presence of vaccinal antibodies which cannot recognize the neutralizing epitopes
Still bind: other epitopes that were not able to provoke a response (due to being out-competed by the other epitopes that the Ab would previously bind to, but are now too differentiated to allow that binding to take place).
These new epitopes will re-call memory B cells that were previously primed for RBD epitopes that neutralize virus
New Ab production for a usage which doesn't neutralize
Putting this epitope under immune pressure will cause selections of mutations that overcome this pressure
Suggestions that antibodies that are recalled have high-affinity for conserved epitopes
Suboptimal immunity which does not neutralize: how does it compensate?
High-affinity can still work to some degree, but it disappears quickly
Newer Epitopes
The way to escape is by changing into epitopes with higher specificity to avoid conserved patterns
Observed selection of mutations that have specific epitopes with lower neutralizability
New epitope, having escaped immune response, will not be well-recognized by pre-existing antibodies
Ab will still bind to the mutated epitope, but no neutralization
Immune system still produces the same non-neutralizing antibodies
Resulting virus will be more infectious
Convergence of epitopes towards more Wuhan-like epitopes, whereas initial variants had epitopes that were very different from Wuhan
New epitopes very similar to Wuhan's specific epitopes, just not those that are conducive to neutralization
Incorporating amino acids that were responsible for enhanced infectiousness of Beta/Gamma/Delta
RBD evolving towards hybrid status - combining several aminos to enhance infectiousneses
