28 diciembre, 2021

2021: Where We Succeeded, Where We Failed in Pandemic Year Two

Abraham Verghese, MD: Well, Eric, here we are, with another year of Medicine and the Machine. And for a change, it’s going to be just the two of us catching up about all the extraordinary people we met this year and all the events of the year.

Eric J. Topol, MD: We’ve been through a lot, as has everyone who’s been listening. We’ve been lucky to speak with so many transdisciplinary experts — virologists, immunologists, epidemiologists, you name it — plus, obviously the clinicians. We’ve talked with quite a gamut of people. It’s been helpful for us to learn from others about the toll of the pandemic, along with where we’re heading.

Verghese: I don’t know about you, but I was fortunate to get the vaccine at the tail end of December or early January, and I remember thinking — and this has really been the problem the whole year — that now we’re out of the woods. Right? We thought we were out of the woods. But not quite. We underestimated how difficult it was going to be to get the vaccine to people or to get them to take it. Now the whole year has gone by, and I have a sense of being cheated in some way, as though the outcome of the movie wasn’t what I thought it would be.

Topol: I couldn’t agree with you more. When I got the first shot in December, I thought, this is phenomenal. We knew about the 95% efficacy of both mRNA vaccines, which was of historic note because so few vaccines have gotten to that level of efficacy, no less being produced and tested and validated that quickly. I thought, Wow, we’re going to conquer this. And I believe we would have, if we had been able to quickly contain the virus globally. Had we never gotten to Delta and stopped at the Alpha phase, we would have had it. We would have nailed this and gotten onto an exit ramp and gone to a low level of containment. Instead, unfortunately, we have moved on to these other variants and to Omicron, which can be viewed as the most challenging of all, because of its remarkable growth, its doubling advantage, and immune escape. I didn’t anticipate we would be going into 2022 in this situation. I guess I’m too much of an optimist, Abraham. What do you think?

Verghese: I’m an optimist, too. I was looking at your Twitter feed today and you mentioned the two-drug combination that may well hold great promise. I’d love you to talk about that. Are we guilty of the same hubris that we had about the vaccine?

Topol: That’s a very good point. With the vaccine trials, between Pfizer and Moderna, we tested some 75,000 people, and we had a real readout before the first dose of a vaccine was given (outside a clinical trial) on December 14, 2020. With the oral drug, we have two small trials: a high-risk trial and a so-called standard, low-risk trial. If you look at the results from a standpoint of efficacy, for a pill to be taken for 5 days and reduce the need for hospitalization or death by 89% for the high-risk group and 70% for the low-risk group, it’s pretty remarkable. But we’re talking about a few thousand people, not 75,000 people.

So even though with nirmatrelvir (Paxlovid), the trials are much smaller — we’re talking about a few thousand instead of tens of thousands — the results are pretty striking. Remember, this is a two-drug combo. Nirmatrelvir is the active drug and ritonavir basically extends the half-life of the drug. But to see an 89% reduction in deaths and hospitalizations — there were zero deaths in the active treatment arm for high-risk patients. And in the low-risk group — people with breakthrough infections and no other major risk factors — they had a 70% reduction in hospitalizations and no deaths.

This is very different from the Merck pill. Paxlovid has action against Omicron, so it doesn’t really get buggered up by variants. It’s taking down the main protease, so it arrests replication of the virus. Simply put, it stops Omicron, or the novel coronavirus, in its tracks early, if it’s taken within the first 3 or even 5 days after symptoms. It looks great. The main problem is that we’re only going to have 10 or 20 million treatment courses with these blister packs, these 5-day pills. That won’t hold us, the way it looks right now with Omicron’s ascent in the United States. So it’s good; we need it. But the validation isn’t anything like what we got with the vaccine trials, and it isn’t preventive like vaccines. It works after the horse is out of the barn, when there’s an infection, and that’s a different way to approach and try to tackle this virus, especially the Omicron variant.

Verghese: I’m hopeful that it will make a difference, but clearly it’s going to be used with many other things, including masking and vaccines and boosters and so on. When we spoke with Andy Slavitt, it was interesting how he characterized vaccinations in the United States. Only 14% of the country is effectively vaccinated, if you count booster doses. I think that’s a good way of thinking about it because we have false assurance from two doses — which are as good as nothing, it would appear, at this moment.

Topol: If you look at the neutralization studies — and there are so many of them now, more than a dozen — you see such a dramatic drop-off in the ability to neutralize the virus with Omicron. Two doses doesn’t cut it, and efficacy gets down into the 20% level for protecting against symptomatic infection. So I agree. We’re waning. Instead of being at 60% fully vaccinated, we’re dropping down. As you are well aware, Abraham, we’re already ranked 65th or thereabouts in the list of vaccinated countries, which is unfathomable. If you recall that we had the vaccines, the ingenious work that was done to get there and to get them through to clinical trials — this was a US effort. And here we are, failing in many respects. It’s depressing.

Verghese: It is depressing. In fact, when I was looking back at the list of people we had over the course of the year (actually over 2 years), we’ve had some really colorful, interesting people — everyone from Robin Cook to Walter Isaacson. But we’ve also had a lot of scientific experts, and we always seem to come to this place where there’s the science and then there’s the human, behavioral side. And it strikes me that we haven’t yet brought our best science to understanding human beings and how they operate, and to figuring out how to overcome all the factors that are making us 67th or 69th in the world in vaccine rates. I believe it’s more complicated than political loyalties. It’s about human behavior. I think we have to dig even deeper.

Topol: I couldn’t agree with you more. I have a new respect for the importance of behavioral science, because who would have ever predicted, with a common enemy of a formidable virus, that instead of uniting against it, we would be trying to go after each other? It does seem to me largely politically motivated, but obviously there’s also the anti-science, anti-vax movements, and the conspiracy theories and all that. The science has been formidable. The amount of progress in this compressed period of time is amazing. We could have gone the typical 8 years before we had a vaccine, or we could have gone without ever having a vaccine.

Verghese: You’ve done a good job of listing the scientific milestones. There were so many of them early on, and they continue. Maybe it would be helpful to have a recap of where science has brought us from the moment this virus came on the scene.

Topol: I think a lot of people weren’t as aware of the importance of sequencing the pathogen. If there’s one thing we learned about genomics during the course of the pandemic, it’s that when you sequence a pathogen, along the way you can follow its footprints. Many of those 30,000 letters of the coronavirus genome change, and you can tell spatiotemporally where it is coming from. You can even trace a superspreader and know who patient zero is.

But most important, you can trace the appearance of what is potentially a very serious variant. Or, in the case of the original Wuhan ancestral wild-type virus, that was the one that led to the template for a vaccine within days. I remember how exhilarating it was to talk to Tony Fauci about how, within days of that Saturday sequence being downloaded from the virology site from the Chinese scientists, they were able to turn it around and hand it over to Moderna to get the vaccine made. So sequencing the virus has been a big one. Worldwide, that’s how the South Africans could warn us about Omicron, from their great science. They’ve been leaders in this, no less than the United Kingdom; the consortium there has been exemplary.

The very rapid appearance of monoclonal antibodies was also a big one. That’s been a disappointing story too, because they really worked, but we couldn’t get our act together to give them to people — except in certain places like Florida, where they were using them instead of vaccines, which was absurd. We had people whose lives could have been saved, perhaps, or in people who were very, very ill, their illnesses could have been stopped earlier, but we couldn’t get infusion centers going. And now we’re learning that almost all these antibodies don’t work against Omicron. So that was a great advance that came about quickly, but a disappointment in how we weren’t able to adjust our healthcare system. Starting a new intravenous drug in the midst of a pandemic proved to be quite tough. That’s why I think the pill is much more important.

Other science includes the immunology. We’ve all learned a lot about immunology. It’s been amazing — not just the neutralizing antibodies but also the whole memory B- and T-cell story, and the intricacies of that immune response, whether it’s from infection that sees the whole virus and mounts a response to everything — or the spike protein, a more specific type of immunity derived from vaccination.

One other area that I know both Stanford and Scripps are strong in is structural biology. This has given us the ability now to have a 3-D model of the virus, of all of its binding sites, and the antibodies that bind it, no less the T-cells that bind the virus. This puts us in an incredibly powerful position, to be able to predict what’s going to happen and ultimately develop a pan-coronavirus vaccine, which we need pretty desperately. That is an area that has blossomed during the course of the pandemic and our vaccines benefited, because the introduction of these two prolines in the messenger RNA led to markedly higher levels of antibody production. It was a human-engineered spike protein that led to that, which was a structural biology triumph.

Many parts of the science have been surprisingly vital to the progress we made. But the gaps, and our behavior, as you said, Abraham — that’s what’s holding us back.

Verghese: As we talk about behavior, we are actually talking about human beings. What has struck me this last year is the level of fatigue in the frontline healthcare workers. I’m talking especially about my residents. It used to be that we were the heroes to our residents, but honestly, the residents are my heroes now. They’ve gone almost 2 years, continually masked; their social lives, which at their age are a critical part of their well-being, have been completely disrupted by this virus. They are tremendously overworked. If I go by what’s happening in my hospital, and I think that’s representative of all-comers, all admissions for all reasons are up and people are tired and stressed and ready for a break.

I do a lot of individual ad hoc counseling, where people just show up at my office, and I keep sensing that people are under a lot of strain and many of them are rethinking everything. I sometimes wonder what that’s going to mean for the workforce. I think house staff — and I’m on their side for this — should organize and need to organize better to protect their interests. Some of our hierarchical ways of doing things are getting outmoded because the fact is, these are frontline workers. They’re trainees, but they’re also frontline workers, and they need that kind of respect and attention. We’ve done a lot for physician wellness in the last few years, but it’s never been more acutely needed than at this moment.

Topol: You’re bringing up a vital point here because before the pandemic started, we already had a global crisis of burnout and depression. Then, superimposed on this, we’ve had the stress of the pandemic, where all clinicians were put at risk. This has been just a day in the life of a clinician to be wearing an N95 mask all day, where you feel like you can’t breathe, that you could get COVID from a patient, and all the other stresses involved. This has been tough. On one hand, you see a lot of physicians, young people, rallying. The noble cause has brought out their spirit. But on the other, it’s so taxing and stressful.

Now we are looking at the Omicron story and a whole new chapter of stress on the medical system, one that didn’t support physicians and nurses in the beginning by not providing protective equipment, that didn’t have the testing ready, that had patients coming into hospital with COVID and there was no ability to even diagnose that they had it. What’s amazing is that here we are, 2 years later, and the testing still sucks. You would think that every healthcare worker would be able to do a rapid test every day and have the results in a few minutes so that they know when they come to work that they are in good shape, especially with all the waning of immunity.

We just aren’t getting it right and we’re not prioritizing. It was great to see the healthcare workers be the first tier of the vaccination rollout. That was great. But so many other things have missed our workforce. I’m also surprised that it isn’t compulsory for our healthcare workforce to be vaccinated and at how the courts have not upheld that. What do we need to show that we’re the model for infection control? The latest study showed that only 70% of the healthcare workforce across the country is vaccinated. Isn’t that hard to believe?

Verghese: That’s shocking to me. We’re at 99% or more at Stanford, and I’m sure you are, too, but you’re right — overall, it’s much lower. The other thing that surprises me, Eric, is that we have hospitals that are overburdened and the disconnect between some of the governors, knowing they have a responsibility to the hospital and to the people who work there — the statements they make could overload a hospital when that could be avoided. There needs to be a stronger connection between governance at the political level and hospital welfare. That should matter. You really should not be able to hold yourself proudly if you’re overburdening your hospitals and flying in the National Guard for something you could have prevented. I don’t quite know what the answer is.

It’s been an interesting year and we all have to dig deep and find the resilience and the resources for the year ahead. Let me ask you personally: How are you doing? How have you weathered this year and the year before? How have you changed?

Créditos: Comité científico Covid

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