# On the Cusp of Vaccine Schedule
## Introduction
- Immune response of the host
- Fast and large-scale immune escape
- 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