Thread by @PeterKolchinsky

HNY… but first I’ll venture predictions for COVID in 2022+: we retire “pandemic” & welcome new endemic pain-in-the-butt virus. It’s too early to know how much of a pain (worse than flu?) but 2022 could be telling (omicron bad omen). We’ll have benefit of new drugs… but…

…we’re already discovering that monoclonal antibodies can’t be relied upon for long. Omicron has evolved around many of the existing antibodies. There are antibodies that neutralized both SARS1 & SARS2… but seem to not work well for Omicron.

That’s like having a cousin that has less in common with you than you have with a chimp. That’s remarkable. With Omicron, SARS2 showed us a capability most didn’t really think it would exhibit on such a short timescale (I didn’t). And yet, if one theory of how it arose is true…

…that omicron evolved over months in an immunocompromised patient, giving virus time to adapt (accumulating mutations) to low antibody levels, then it may learn more such tricks in the future in a similar way, rendering other drugs obsolete.

For example, 2022 is the year we will see the benefits of direct oral anti-viral drugs, notably Pfizer’s COVID protease inhibitor Paxlovid. It targets the virus’s internal machinery, not the shape-changing external spike protein targeted by vaccines and antibodies.

Not only does paxlovid work on sars2, it should work on any coronavirus, including some unknown future pandemic coronavirus. It reduces the risk of an infection progressing to hospitalization by 85% & death by even more. Imagine having this drug available if COVID-28 hits.

However, 2022 is going to put paxlovid to the test. It’s going to be used in millions, maybe even tens or hundreds of millions. Pfizer has allowed it to be mass produced in other countries by other companies to get it to as many patients as possible. That is noble… but risky.

The trouble w/ paxlovid is that it only reaches adequate antiviral concentrations when dosed w/ another drug, ritonavir (originally an HIV drug). Ritonavir blocks a liver enzyme that breaks down paxlovid, so makes paxlovid last longer in the body.

While Pfizer is careful to package paxlovid in same blister pack as ritonavir so patients are more likely to take them together, who knows what will happen around the world. Eg some may sell paxlovid separately & uninformed patients may take it alone, underdosing themselves.

Whether one takes an antibiotic or antiviral, taking too little of a drug creates conditions under which a pathogen can evolve resistance (as in case of omicron evolving in an immunocompromised patient). So 2022 will tell us how resilient paxlovid is in face of SARS2’s evolution.

If we make it though 2022 w/o news of paxlovid resistance emerging, that’s good. Getting through 2023, better. If paxlovid resistance emerges, we’ll have a new challenge. All current COVID protease inhibitors in development bind in a similar way to viral protease (same pocket)…

…so resistance to one might mean resistance to all. We would therefore need to generate novel protease inhibitors that bind in different ways to protease so that they would still work even if COVID evolved resistance to 1st generation inhibitors like paxlovid.

We could also use polymerase inhibitors (PIs), targeting a different part of internal machinery. Merck’s drug Molnupiravir is a PI (as is Gilead’s remdesivir). Trouble is PIs aren’t as effective as Pfizer’s protease inhibitor, cutting hospitalization/death by 30-50%, not ~85%.

So if we discover virus can become resistant to Paxlovid (in lab it can), then maybe we try combinations w/ Molnupiravir to see if we can prevent resistant from emerging (harder to duck a jab and upper cut at same time). 2022 will be the year we likely try this.

As far as what life will be like, I suspect 2022 will be like now… anxious. Omicron will spike and settle down over next 3-4 months. We’ll then be on look out for next variant of concern and it will come as sure as there are Greek letters after omicron. We’ll soon be reassured…

…that omicron antigens make for great vaccine boosters against omicron. That’s no surprise. Question is whether NEXT variants call for getting boosted with original antigen or omicron antigen. In face of uncertainty, we may see emergence of first dual antigen vaccines by MY22.

No biggie… we vaccinate against flu each season w/ panel of four flu antigens. Two against Flu A strains and two against Flu B. So 2 antigens for covid is cake. Trouble is that we are still dependent on mRNA vaccines; higher the dose, the worse you feel. 2022 may change that.

We’re finally going to get critical mass of data from protein vaccines showing how effective they are as BOOSTERS, not just primary shots. For that, we’ll need control serum from mRNA-boosted patients (instead of HCS controls). If comparable, awesome.

That’s b/c what the world needs most is a well tolerated, effective booster shot that is easily combined with a flu shot that as many people as possible will seek to get annually. mRNA is a big ask given how crummy it makes many people feel, but protein vaccines are easy.

So 2022 gives us several shots on that protein booster goal. If data disappoint, we’re in for years more of mRNA, but unmet need for more tolerable vaccine will keep vaccine R&D going. It’s a matter of when, not if.

As for masks, mandates, quarantine, & testing, 2022 will take us towards new normal. Quarantine is already being shortened for some. Testing will be more available. Masks will have their place. In Asia, pre-COVID, if had cold symptoms, you wore mask & went about your day. Hmm.

Odds are we’ll see vaccine mandates tried to their limit in US. Vaccines are most cost effective way to save lives, unburden hospitals. I bet some plans start charging (some) unvaccinated higher premiums (like smokers). There will be some uproar, then normal. Maybe its regional.

Government mandates will change over time with changing administrations (federal and state), so we’ll have natural experiments that will tell us what works to inform response to next pandemic, as we are learning now.

One key question is role of animal hosts. If animals act as incubators that mix/match SARS2 w/ other CoVs entirely, we may see radically “shifted” strains (think swine flu) worse than merely “drifted” strains like omicron (that has dozens of individual mutations).

Every year w/o radically shifted SARS2 variant emerging from pets (even mice) is reassuring. If happens, then SARS2 will be uncomfortably like flu, which can transform within pigs & birds into something different enough to cause a new pandemic. cdc.gov/flu/about/viru…