The inability of Delta serum to protect against Beta/B.1.621 virus indicates that, as SAGE predicted, sufficient antigenic drift has occurred since the beginning of the pandemic such that only a bivalent vaccine can provide protection today.


This is not surprising when considering that the two strains took qualitatively different paths towards immune evasion.  Delta increased the distance between two beta sheets in the RBD by 1.5 angstroms, making the energy required for antibodies to inactivate the virus greater.  Beta and B.1.621 directly modified their epitopes and relied on electrostatic, hydrophobic, or other properties to make the antibodies unable to bind.  We do not know how many other qualitatively different paths there are out there, but it's safe to assume, "a lot."

This means we can't just amp up the immunogenicity of the vaccine to compensate for the evolution of the virus.  It must be bivalent as of today.  We will try to find a new target beyond S, which is implausible given the antibody profiles of convalescents, but possible.

However, given today's global case loads and Delta's higher replication rate, the number of strains in circulation doubles over once every month, by a back of the envelope calculation, ignoring any changes to nsp12 and nsp14.  Of course, an increasingly large number of strains is going extinct at the same time, but the rate at which new, successful strains emerge will only increase from here unless we can get R below 1.

You will observe that we were not successful in vaccinating enough of the world's population to prevent the emergence of Beta nor Delta.  Frankly, we weren't even close.  The last mile is the hardest part, as our own efforts domestically clearly demonstrated.  While I anticipate we will improve our distribution networks and our cap and fill capacity, there is virtually no chance of us developing new polyvalent vaccines and administering them quickly enough to catch up to SARS-CoV-2's antigenic drift.

The severity of COVID-19 will increase.  I say this because each successive dominant strain of SARS-CoV-2 has been more deadly than its predecessor, strongly indicating that increased virulence is associated with improved transmission at this level.  Other viruses in its clade are quite deadly(see: MERS).  I would expect to end up, in vaccinated people, somewhere between Delta in unvaccinated people and SARS-CoV-1, with unvaccinated people getting hit with severe shrapnel in the evolutionary tussle.

Whether virulence increases relatively more in vaccinated or unvaccinated people is unclear, though it's likely to be vaccinated just because there's more of them; there will be more forcing pressures on the adaptive immune system, but there are peptides and strategies encoded by the accessory proteins in the ORFs and subunits of S that target both compartments.  There are also antibody-dependent enhancement and immunological imprinting, the former of which has been widely demonstrated in other betacoronaviruses and the latter of which we have largely studiously ignored through our roll-out.  It all depends on what benefits the virus' transmission the most.

I believe we will not suppress the virus through vaccination.  We must develop effective pharmacological treatments, which do not create perpetual immune escape forcings in serial transmission, but which are years off and may do little to ward off long COVID.

Long COVID will be the most impactful aspect of the pandemic in the long term, as hundreds of millions of people have gone from productive members of society to dependents.  We will face labor shortages for years in all manner of disciplines, since fatigue and brain fog are both prominent symptoms.

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