VACCINES AND IMMUNITY
My ACE2 cloak hypothesis is shifting a bit. Soluble and membrane-bound ACE2 is clearly not fully saturating all exposed neutralizing antibody sites, and some B cells are binding. Still, ACE2 cloaking suggests that small numbers of virus get fully cloaked.
My ACE2 cloak hypothesis is shifting a bit. Soluble and membrane-bound ACE2 is clearly not fully saturating all exposed neutralizing antibody sites, and some B cells are binding. Still, ACE2 cloaking suggests that small numbers of virus get fully cloaked.
Alternatively to the ACE2 cloaking, the virus still has some shielding mechanisms alternative to that including glycosylation and going from closed to open conformations. In “open” state, ACE2 would bias the thermodynamics of B cell binding to the spike protein...
...and the subsequent antibody-generating response, to be preferential to other sites. Doesn’t mean that B cells won’t stick to neutralizing site at all.
This is in a large part driven by ACE2 existing both as a soluble and membrane-bound protein.
This is in a large part driven by ACE2 existing both as a soluble and membrane-bound protein.
ACE2 binds to the spike protein with sub-nanomolar affinity (~700 picomolar), which is extremely strong binding comparable to the mature antibodies against this same site. This would decrease the “stickiness” of antibodies and B cells (B cell receptor precursors to antibodies).
Other than the ~15x stronger binding affinity for ACE2 with SARS-CoV-2, very little explains why SARS-CoV-1 had much more durable antibody responses than SARS-CoV-2 (see historic data on seroconversion of SARS-CoV-1 patients: ncbi.nlm.nih.gov/pmc/articles/P…).
So, what about vaccines? I’m a bit worried that only 90% or Oxford vaccine participants are generating neutralizing antibody responses. This may suggest that antibodies against the wrong sites are being preferentially generated in many people. This may worsen infection.
Ultimately, the results of neutralizing antibodies being present, along with T cell receptor responses, are promising. I’m cautiously optimistic for the majority of people getting vaccinated having immunity for 6+ months.
With that said, as immunity starts to wane, and in people who did not generate neutralizing antibody responses, we may see some people who got vaccinated (10% or more, potentially) getting more sick with SARS-CoV-2 than people who were never vaccinated. I hope I’m wrong.
The other concern with Oxford’s vaccine is that it’s an adenoviral vector. The second “booster” dose is shown to not induce a strong reaction in patients, however this could largely be due to the immune system clearing the viral vaccine itself.
When people try to tailor the Oxford vaccine to new viruses or mutant strains of SARS-CoV-2, people will carry pre-existing immunity to the adenoviral vaccine itself.
Moderna is showing neutralizing antibody responses as well, though some patients had severe adverse effects to the vaccine. I do worry about persistence of immunity with respect to neutralizing antibodies vs. not in the 6-12+ month period.
Sinovac, in my view, is a bit more promising because it modifies the virus used as a vaccine to have the SARS-CoV-2 spikes on its surface. Oxford and Moderna are getting your body to print out the spikes. Producing spikes on the surface of a particle is more likely...
...to yield a specific response only against the very “tip” of the spike, versus against any epitopes that are on the spike.
Furthermore, I wonder about what sort of glycosylation (sugar modifications) are on the Moderna and Oxford spike proteins, as the virus is glycosylated.
Furthermore, I wonder about what sort of glycosylation (sugar modifications) are on the Moderna and Oxford spike proteins, as the virus is glycosylated.
Changes in glycosylation of the vaccine spikes versus normal virus spikes could alter immune responses, and though this may be benign, it could potentially cause hyper-recognition of the wrong epitopes (immune responsive regions) in contrast to the real virus.
Ultimately, this is why we have safety and efficacy trials, and I applaud everyone’s efforts and the regulatory authorities for fast-tracking based on available evidence. I am cautiously optimistic, however believe that we need to be careful about these potential setbacks.
On another note, we may have a solution for waning neutralizing antibody titers in vaccine development and in infected individuals. Stay tuned.
@PeterKolchinsky offers some similar viewpoints in this thread. I hadn’t reviewed the CanSino data in depth and it looks like their neutralizing titers are even worse. I suspect ACE2 cloaking the pseudotyped virus has something to do with this...
