I have the utmost respect for Dr. Gottlieb and have appreciated his
prescience on many issues. He's called a lot of the pandemic better
than most. However, I don't think this will be one of his better
predictions; he got a little unlucky in his timing, as his comments were
before SAGE's findings. Based on them, I'm siding with Larry Brilliant
here.
That
is because infection with Delta will confer limited immunity in both
space and time to variants of the K417N/T/E484Q/K/N501Y sort. These
variants generally don't have great transmission dynamics, but with a
completely different antigenic presentation than B.1.617.2.x, they don't
need to. They just need to be good enough to spread on their own, as
they are effectively not even competing with Delta.
The modeling is a mess. The best study I've found recently was:
Consider, for example, that the level of crude cumulative immunity was modeled in Texas at 70% at the beginning of July.
Since then, their curve has looked like this:
The
old S-protein in the vaccines, fortunately, lies in the nebulous space
where it is still somewhat cross-neutralizing against both Delta and
Beta, although with profoundly reduced efficacy in both(39% VE against
infection with Delta on Israel's latest numbers, where cases are
persistently climbing despite an outdoor and indoor mask mandate, and
some 10-fold drop in nAb activity against Beta, depending on vaccine).
If SAGE's
findings hold, they are a conclusive demonstration that infection by one
strain no longer confers meaningful protection against another strain.
Due to the qualitatively different mechanisms of immune escape,
we'll see more divergence with time -- it's an optimal game theoretical
strategy for strains to avoid cross-reactivity so they can both spread
without interfering with one another.
That low of a VE against infection and
transmission gives Delta ample room to evolve further, and
Beta/B.1.621/etc. don't need to worry about being squished out of
circulation like Alpha was because Delta sera, and presumably a
Delta-based mRNA vaccine beyond the first few months of antibody spike,
is not protective against them. As a demonstration in the opposite
direction, although the numbers from there stink, a large outbreak of
B.1.351 in Bangladesh didn't prevent the rapid subsequent emergence of
B.1.617.2.
NPI's
really are our best shot, and that's why the UK is working on its
contingency planning for this winter. The political cost here and there
will be huge, and non-compliance will probably be, too, which is a
factor in my dismal forecast.
Finally, note that this is not the first time two antigenically distant strains have co-circulated comfortably.
If
I could make one public health move, it would actually be to encourage
everyone to get boosters against poliovirus and mumps. The titers of
the antibodies against the latter strongly inversely correlates with
SARS-CoV-2 disease severity, though through unknown mechanisms; the
antibodies themselves have been identified as non-cross-reactive.
Poliovirus vaccines work by targeting SARS-CoV-2 RdRp, which is much
more conserved than S. IPV is in clinical trials now.
B.1.621 poses a higher risk of breakthrough
infection in people infected by Delta than to people inoculated against
Wuhan-Hu-1 because of antigenic distance and that nebulous sweet spot I
mentioned. It's likely not much higher than B.1.351 and others with
that constellation of mutations. Both B.1.621 and B.1.617.2 probably
pose similar risks of breakthrough infections to vaccinees based on
studies of nAb titers and real-world data from Israel, the UK,
Provincetown, and so forth, while being infected by B.1.617.2 apparently
confers little to no additional immune defense against B.1.621, and
likely vice-versa. This is all modulo the overall infectiousness and prevalence of the strain, so we are likely
to see greater absolute infections of B.1.617.2, probably by a landslide
You can imagine it as being a
bit like a rubber band. We started with it unstretched and built our
vaccines around the center of it. The evolution of the virus has
stretched the rubber band in several directions, and it's stretched
enough such that immunity at one end of the rubber band is now
immaterial to immunity at the other end. The ends are still close
enough to the center that the vaccines will be protective against both,
but it is now shown that the rubber band can stretch far enough that the
distance between points on it becomes too great, and that could
eventually include the distance from the old center to the point of a
novel variant, yet to be identified -- vaccine evasion.
The volume of the rubber band is, of course, the radial phylogenetic tree of SARS-CoV-2.
We're effectively witnessing or have witnessed the emergence of at least 2
SARS-CoV-2 serotypes already, so Gottlieb's hypothesis fails because
it's based on one serotype. Fortunately, our vaccines are not targeted
at either serotype, but somewhere in the middle. The desire to stay at
the middle for as long as possible is probably why there has been no
roll-out of mRNA-1273.351(the Moderna vaccine with a Beta spike protein;
in clinical trials, no EUA, slower than the original) or Pfizer's
attempt at Delta. Either vaccine should fare badly against the other
serotype.
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