When the first line of immune defense becomes the last…

Hey guys,

Just letting you know I’ve seen your questions—I’m not asleep at the wheel. Even while traveling, I try to stay alert and keep track of how the virus is evolving.

At this point, things still look pretty much the same as what I mentioned a few days ago. Whether it’s XFG, LP.8.1, or Nimbus, one thing is clear: in highly COVID-19 (C-19) vaccinated populations, the virus is now facing pressure from the innate immune system to hold on to its infectiousness. The adaptive capacity of the population’s adaptive immune response is reaching the end of its spectrum, so the innate immune response is collectively ramping up. But since innate immunity is non-specific, the pressure it exerts on viral infectiousness is a lot weaker and no longer selective. That’s why this kind of immune pressure no longer drives viral evolution by antigen-specific adaptation—it just comes in all forms that, in one way or another, ensure its continued transmission. Hence, we are seeing newly emerging immune escape variants, but predominantly with characteristics that now also let it sidestep or suppress innate immune responses. That’s a serious concern, because it could pave the way for escape variants that gain a huge advantage by sidelining the remaining innate immune defenses in C-19 vaccinees altogether.

For those who’re curious how SARS-CoV-2 has been gaining function in highly C-19 vaccinated populations:
Back when Omicron hit, lots of people with high levels of vaccine-induced antibodies got that infamous razor-blade throat (me included—I caught Omicron just weeks after recovering from Delta). That was likely antibody-dependent enhancement of infection (ADEI), which made the virus more infectious and triggered severe inflammation. Now, we're seeing similar symptoms again, but it seems to be more about the virus being highly infectious on its own, plus weakened innate antiviral responses (especially due to suppression of interferons). The good news (for now) is that the inflammatory reaction following more vigorous infection mostly keeps the infection in the upper respiratory tract—probably because it helps the virus bind to local dendritic cells there. However, from what we’re hearing, it’s not always the case, and in certain regions, the hospitalization rates have already risen quite a bit. What really worries me is that if repeated exposure of C-19 vaccinees keeps compromising their innate immunity, viral replication could get way more intense and long-lasting. That increases the likelihood for a new variant that suppresses inflammatory responses to suddenly dominate in prevalence. If that happens, we’re in trouble: the virus would have a huge competitive advantage—not only already largely resistant to adaptive immunity, but now also able to sideline the innate immune response in large parts of highly C-19 vaccinated populations. That’s when we’d start seeing serious virulence!

So, bottom line:
The virus no longer focuses on evading vaccine-induced adaptive immunity since the host immune system is now increasingly mobilizing more innate immune capacity to restrain the virus. As innate immunity is not targeted at specific antigens, the virus is just sabotaging it broadly—giving itself more time and more room to multiply. And the more abundantly it multiplies, the higher the chance that some random mutation lets it breach that last line of immune defense by shutting down inflammation altogether. Dysfunctional adaptive immunity combined with compromised innate immunity, plus warm weather, is cranking up the pressure in highly C-19 vaccinated populations to keep the virus infectious. Which means—if such a mutation happens, it could spread like wildfire and outcompete all the other variants out there. I don’t know exactly when that’s going to happen, but I have a strong feeling we’ll see it this summer. That said, since the collective immune pressure in highly C-19 vaccinated populations is no longer selective, the diversified mutation patterns we’re seeing now don’t really predict where the virus is headed next.

My advice? Have a solid 3-month emergency plan ready. You might need it if we get hit with a full-blown pandemic resurgence that knocks out key parts of society. In the meantime, just stash the plan in a drawer and live your life.

If you’re vaccinated, make sure you’ve got access to antivirals. f you’re unvaccinated, your (trained!) innate immunity is still your first—not your last!—line of immune defense, and you shouldn’t gargle daily with antiseptics as some medical doctors suggest—that could prevent continued training of your innate immune system! Focus instead on staying healthy: eat well, keep your weight in check, move your body, and get good sleep.