TWiV 828 COVID-19 Clinical Update #88

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 13 November 2021

pdf of this transcript available (link)

Vincent Racaniello: This Week in Virology, the podcast about viruses. The kind that make you sick.

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From MicrobeTV, this is TWiV, This Week in Virology Episode 828, recorded on November 11th, 2021. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Daniel, do you think you’ll ever come back to ‘The Incubator’ and do a live show again?

DG: I was going to do one. What, last week? But then you were spending time with your wife.

[laughter]

VR: It was a very nice dinner.

DG: Yes. I wonder, maybe either next week, the week after, but yes, no, definitely. I actually like recording there.

VR: Yes, it’s a nice place. You’re welcome anytime.

DG: Anytime you’re not prioritizing your wife and family above me, which –

VR: Is very rare.

DG: Actually, I’ll share this. I don’t know if any of our listeners ever watched the TV series or if you’ve watched it, Stargate Atlantis.

VR: I have not.

DG: There is a scene, it’s getting near the end of the final season and there’s the brilliant scientist, he’s playing you, Vincent. He goes to a dinner and who’s there but Bill Nye and Neil deGrasse Tyson. It reminded me of the time that you stood me up and Dickson for a TWiP so you could hang out with those two.

VR: We never did that.

DG: [laughs] Weren’t you going to head up to the – What is it where they do the star show stuff, the planetarium, and Neil deGrasse Tyson was going to be there and you – [crosstalk] Okay, you’re denying it now, okay.

VR: No, we never did it. We never stood you up. It’s all good.

DG: Because I remember mumbling to my son, “And my PhD is not an honorary PhD, it’s a real one.”

VR: Who has an honorary PhD?

DG: Bill Nye The Science Guy. All right. Let’s get going. Let’s start with my quotation, “He who studies medicine without books sails an uncharted sea, but he who studies medicine without patience does not go to sea at all.” That’s by William Osler. I’m going to plan to throw in a few sea stories as we go forward. Hopefully, that’s a lot of the clinical updates. We got really great dives into the science and the literature and the books. Hopefully, I get to share some of the sea stories about what we’re seeing out there on the high seas of COVID.

VR: Daniel, wasn’t William Osler the founder of modern medicine?

DG: A lot of people consider him the founder of modern medicine. A lot of the things that we do, the bedside teaching rounds, the idea that you can learn all of medicine from really a single patient if you just spend the time, [laughs] it has to be probably a lot of time, but no, really a lot of the modern ideas. Really, modern modern medicine is not sitting at the bedside learning from an eminent physician. It’s actually looking for evidence-based randomized control studies that really guide us forward. I guess I’m going to start. You can tell me if I’m spending too much time on this first part, but I went back to listen to our original TWiV special, coronavirus SARS-CoV-2 and COVID-19 update. That was March 4th.

VR: Wow.

DG: I think we recorded it on Monday and then it got released on Wednesday, but really, it just made me wonder. It actually seemed like we were going to be okay, we were off to a decent start and I went through that episode. We talked about droplet transmission, but we added how if you’re in a closed room with poor ventilation and N95 was recommended, we talked about masks, how they can be great source control, someone coughing, sneezing. We talked about how for 90% of folks, we expected this to be an out-patient disease, but then 10% would end up requiring that higher level in the hospital.

We talked about how critical testing would be because this was so similar symptoms-wise to respiratory pathogens, allergies, really the importance of testing. I talked about incubation time, the time to average onset of symptoms. We talked about telehealth and how we could limit exposures but still manage patients. We even, this way I thought was telling, we talked about vaccination and how potentially one day we could have antivirals targeting the polymerase and the protease. Then we even went on just a few weeks later in Episode 606 to talk about how critical proper evidence-based medicine was going to be to guide us going forward. Here we are, almost two years later.

VR: Incredible.

DG: All right, let’s get right into children COVID. Children at risk for COVID and wearing a mask is less traumatic for a child being hospitalized. Here, I’m going to throw in the first verse of the Robert Frost poem, ”Two roads diverged in a yellow wood. And sorry I could not travel both. And be one traveler, long I stood. And looked down one as far as I could. To where it bent in the undergrowth.” My point with this poem is really the choice now that vaccines are accessible to children down to five years of age. It really is a choice to vaccinate or not to vaccinate. You really have these two options in front of you.

Not to vaccinate is an act of choice as Ben Franklin learned when he lost his son. Choosing not to vaccinate can often be the riskier choice, the road that puts a child at higher risk. By the time that our listeners listen to this podcast, over 1 million children in this 5 to 11 years age group will have been vaccinated. The really nice thing is that we’re not hearing any safety concerns. This is going very smoothly. I think we’re getting reinforced here that the safer of the two choices, the choice not to vaccinate is the unsafe. The choice to vaccinate is a safer choice.

Right now, I have to say the numbers of COVID cases had gone down, they’re starting to go up already. They’re starting to climb and unless there’s some change in the way this virus and human behavior plays out in the next couple of months, this may be as good as it gets. We’re expecting numbers to rise after the holidays. Think about that when you’re making choices. The sooner you protect your child, the sooner you start heading down that less risky path. All right. Testing. This actually lately has been really coming up. What I’m going to say here is it’s really critical.

We’ve been talking about this on national calls and actually, I was on a call yesterday talking about it with our urgent care centers and I’ll be talking about it again next week with some of the other urgent care centers from one of the other groups in the area about how critical a lack of resulting delays is going to be when these oral antiviral pills become available. We still need to wait for the exact wording of those EUAs and part of why I mention this is when those EUAs are written, I am certainly hoping there’s no requirement that confirmation be done with a PCR, that this can be much like the monoclonals if you confirm with a rapid test and we can get people on these pills.

We think that timing is really going to be critical. A lot of the discussions have been with places where the testing will be. Get ready, we want to not have resulting delays. You don’t want to call someone four days later to say, “Oh, you’re now outside the window and the efficacy of this oral medicine has been lost because of problems on our end with getting those results.” We are anticipating at the end of this month, right after Thanksgiving, the post-Thanksgiving surge, that we may have the first of the world antivirals available. As we get into December, a second may be added to this. Think a lot about our testing.

As I pointed out, this started off as an education update for a lot of our clinicians and this is something we’ve got to be thinking about. Time is critical. If a patient calls, if you’re a patient, you want to get that test done quickly, you want to get a result so that then you can potentially take advantage of these oral antivirals, which seem to really work particularly well during that three to five days after onset of symptoms. I want to share a story here because I always share the other stories. This is one of my sea stories. This was a young woman, actually got involved in the case last night. The story was this young woman started to feel poorly Thursday night, let’s give you the timeline. She started to feel poorly Thursday night.

Being a considerate citizen, considerate co-worker, she decided, “I’m going to go get one of these PCRs.” They have these vans around New York City, you can rapidly get a PCR test. The PCR test came back negative, so she thought, “Okay, well, it must be some other one of your viruses there, Vincent, because you own them all.” She figured, “Okay, well, my PCR is negative, I may be feeling crummy, but PCRs are really good.” Weekend went by, got into the next week, and said, “You know what, I’m still not feeling well and my boss is actually now out from work, so why don’t I get one of these tests at home now?” She went ahead, did the test, and it was positive.

VR: Antigen test?

DG: The antigen test. She thought, ”You know what? I’m going to get another test.” She went ahead and got another antigen test, it was also positive. As the story goes, we always hear the story of, ”Oh, I did the antigen test and it was negative. Then a couple of days later I got a PCR and it was positive. Oh, those damn antigen tests.” Just the reality, no test is 100% sensitive. This is a vaccinated woman. She ended up getting COVID and she’ll hopefully ride this out. Hopefully, it will be more than this mild viral syndrome. She’ll finish her 10 days of isolation for the infected and then hopefully get on with her life. Just remember, every test has less than 100% sensitivity, and timing matters and really testing frequency is a critical thing. If the test doesn’t make sense, I think this woman made a smart choice, go get another test.

VR: This young lady was vaccinated?

DG: She was vaccinated.

VR: What do you think about 10-day isolation for vaccinated infected people? Does that make sense?

DG: I would like it to change. I think we’re going to need this science to make, but we’re starting to get this science. We talked about the Singapore study. We talked about the other study. It does look like individuals who have been vaccinated are clearing that viral RNA quicker, about twice as quick as the unvaccinated. It would make sense as we go forward to start looking at shortening isolation for the infected for vaccinated people. My gold standard for me is really contact tracing. If we can show that we’re not seeing transmission past five days of symptom onset in the vaccinated, maybe we can shorten that isolation, which would make a lot of sense because you know what, Vincent?

At some point, I’m predicting the future, you and I are going to end up testing positive. This is here to stay. It’s in the deer, it’s in the cats, it’s in the dogs. We’re going to talk about dogs in a second. But yes, do we keep isolating for 10 days every time someone gets a positive test? There’s a certain point we’ve gotta make more rational decisions. Active vaccination. Never miss an opportunity to vaccinate. Vaccination is how this pandemic ends. The vaccine is the jabs that keep you from getting sick. I’ve turned up my autofocus so I can move a little more and not have that distracting, but here I’m going to tell a hybrid immunity story because we’ve been hearing from the labs.

People get COVID, they get vaccinated, they have this uber immunity, they’re protected, they’ll never get any coronavirus, and so that’s not what we’re seeing out here on the high seas. I just got a call from, actually, it was from the upset concerned father. This was a young woman in her 30s. She had had COVID initially and actually had had quite a difficult time with the initial bout. After a period of time, went on to get fully vaccinated, but then again, last week started to not feel well, and went ahead and had a positive COVID test. They met criteria, went ahead and got monoclonals, but they had a little bit of a tough time here with this.

Just this reality that we talk about hybrid immunity, we talk about a lot of serology studies, but even what we talked about last week, people who get COVID can get reinfected. They can significantly reduce their risk of getting reinfected and getting symptomatic COVID with vaccination, but it’s not zero. It’s a reduction but it’s not bringing it down to zero. Let’s hit a study – the article, “SARS-CoV-2 Vaccine Protection and Deaths Among US Veterans During 2021.” This was published in Science and I think I’ve shared my first ”real job” after I finished my training, actually, I started during my training was working at the VA up in Montana.

Thank you for all these individuals for their service, but part of what I liked about this article was they make a really clear distinction and they even introduced some new TLAs, three-letter acronyms. They introduced VEI, vaccine effectiveness against infection, and VED, vaccine effectiveness against death. Whenever I see vaccine effectiveness, I always want to see what’s that third letter? Is it infection? Is it positive PCR? Is it symptomatic COVID? Is it hospitalization or death? I thought this was nice that in this publication where they looked at 780,225 individuals in the VA system, they reported that vaccine effectiveness against infection, so VEI, declined but vaccine effectiveness against death, VED actually looked like it was holding pretty strong.

Here they talk about for people over 65, they were reporting a VED of 73% for Johnson, 81.5% for Moderna, 84.3% for Pfizer BioNTech. It’s a little bit of a win for Pfizer BioNTech here. We don’t see a lot of those. Now, one of the things I did want to make a comment about here, it fits in is, as I may have mentioned before, I am not seeing much long-COVID in vaccinated people who get infected. We had that one study out there where we heard about a 50% reduction, but that seemed not even as much of a reduction as I’m seeing. We reached out to all our different infectious disease physicians at the different care delivery organizations throughout the U.S.

My friend Paul out there on the West Coast, Michael Almaleh, and a few others, and I’m going to leave them out and get upset that they weren’t mentioned. John Hitt was on the call as well. Really asking, are you seeing much long-COVID in vaccinated people get infected? Really was it silence, we don’t have any in our post-COVID recovery clinic here in New York. This is, to me, really reassuring because that’s one of the things that I worried about. I worry about death, I worry about hospitalization, I worry about people feeling ill, the morbidity, but I have a particular soft spot for people that get long-COVID and for months and months have lost their quality of life, so sharing that sea story.

VR: What’s the numbers here, Daniel? How many patients you’re talking about?

DG: We’re actually talking about millions across the country. We hear just our care delivery organization in New York. We have over 2,000 providers and we have millions of patients. You go out across the country. Actually, UnitedHealthcare covers over a hundred million lives, and on this call, our care delivery organizations across the country. This is, I’ll say a large collection of anecdotes and I look forward to more data on these numbers. Passive vaccination. Remember those monoclonals after high-risk exposures in high-risk individuals? I just had a woman that we took advantage of this today. A woman, renal transplant, had a positive COVID PCR, but it didn’t make sense.

We repeated it, it was negative. We repeated again, it was still negative, but unfortunately, because of that positive test, they were put in a situation where they were exposed to patients actively with COVID. Remember, think of those monoclonals for post-exposure prophylaxis before you let them go on to get COVID. I’ve mentioned that Regeneron has this part of their EUA, but the Eli Lilly product, the Bamlanivimab/etesevimab has this as well. Here, this I thought was really positive. This is a press release and this is follow-up data on some information that we saw before.

On November 8th, the eight-month follow-up data was shared via a press release. New Phase 3 analysis shows that a single dose of REGEN-COV, this is the casirivimab and the imdevimab provides long-term protection against COVID-19. This is the eight-month follow-up data of the study that we read about in The New England Journal of Medicine, the article, “Subcutaneous REGEN-COV Antibody Combination to Prevent COVID-19.” This is getting under the skin, so a subcutaneous injection of the REGEN-COV antibody cocktail. We’ve talked about how this only has a half-life of 22 to 26 days.

We were really thinking, you’re going to have to keep giving these folks this injection every month. But here it was just follow-up for eight months. During this extended time period, there was an 81.6% reduced risk of developing COVID-19 during this follow-up period. Just to give you a sense, how were they catching folks with SARS-CoV-2? They did weekly testing for the first four weeks, and then they followed for anyone with symptoms and if they had symptoms, they would then be tested for COVID-19 or the SARS-CoV-2. 81.6% reduction all the way out to eight months, so pretty encouraging.

Next, moving on to the period of detectable viral replication. The viral symptom phase. This is often where the clinical syndrome comes to light. I’d say the time for monitoring and monoclonals, not the time for antibiotics, not the time for steroids. We can do harm with both of those. Maybe we’re about to get into the time for effective oral antivirals. I’m going to discuss the Pfizer product and jump in if you want to here, Vincent. On Friday, November 11th via a press release, Pfizer announced its investigational novel COVID-19 oral antiviral candidate PAXLOVID that it significantly reduced hospitalization and death based on an interim analysis of the Phase 2-3 EPIC-HR Trial.

Where do those letters come from? Evaluation of protease inhibition for COVID-19 in high-risk patients. There’s actually a lot in that title. This is a randomized double-blind study of non-hospitalized adult patients with COVID-19 who are at high risk of progressing to severe illness. Think of that 10% that we’ve learned about from our monoclonals. These are people who are either above a certain age, above a certain BMI, have certain comorbidities. The scheduled interim analysis showed an 89% reduction in risk of COVID-19 related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset. That was the primary endpoint.

0.8% of the patients who received PAXLOVID were hospitalized through day 28 following randomization. That was 3 out of 389 hospitalized. No deaths compared to 7% of patients who received placebo. That was 27 out of 385 hospitalized with seven subsequent deaths. Similar reductions were observed in patients treated within five days. That was not the primary endpoint, but we saw 1% of patients who received PAXLOVID were hospitalized through day 28. That was within the first 5 days, so 6 of 607 hospitalized, no deaths compared again to 6.7% of patients who received placebo. 41 of 612 with 10 deaths in that group. All right, any thoughts there, Vincent?

VR: The efficacy is a little better than the molnupiravir reported by Merck, which was 50 I believe, right?

DG: Actually, it’s quite a bit better. Yes, it’s quite a bit better. When the Merck drug, when Thor’s Hammer, molnupiravir was – when that data became available, there was a whole discussion like, “This is great. It’s more accessible, but those monoclonals are still winning.” Well, this is 90%. This is actually really, what is a better drug? Potentially, I want both. No, this is pretty impressive. 89%, 90%, this is really getting up there and the whole idea is this may roll out a week or two after the Merck drug. We’re thinking December. Pfizer really communicates well with the FDA, and so the data is being analyzed theoretically as we speak. The key here with the rollout of these drugs is going to be getting those results back in time. You don’t want a PCR that takes six days to get back and by then you’re outside this three or five-day window.

VR: Are they going to be able to make enough doses, both the Pfizer and Merck, to take care of people?

DG: Eventually, yes. The question is, how many doses will be available, let’s say, this December? A few months from now, these are small molecules. This could be pumped out in large quantity. This is going to be something you take twice a day for five days. This is what the drug companies do well. This is a lot easier than making these vaccines. There will probably be shortage, initially. There will probably be some restrictions in the EUA. If these get approved, massive quantities could be produced. Very encouraging I have to say. We keep saying this is truly a game-changer. This is up there with the vaccines.

It’s not a substitute for vaccines. We still want to get people vaccinated. Boy, this is just another great tool to have. All right, and I am going to jump to the, “No one is safe until everyone is safe.” Here, I’m going to throw in another quotation. This is a quotation from MLK, Martin Luther King. I have quoted this fine gentleman before. On March 25th, 1966 in Chicago at a press conference before his speech at the second convention of the Medical Committee for Human Rights, King said, “We are concerned about the constant use of federal funds to support this most notorious expression of segregation. Of all the forms of inequity, injustice and health is the most shocking and the most inhuman because it often results in physical death.”

At this point, I want to tell people, ”Take a moment.” First, I want to thank you, but take a moment and go to parasiteswithoutborders.com. Click donate. Continue to help us get education to the people and places that need it the most. Hopefully, we’re making a difference, but we’re only able to make this difference thanks to you. We’re starting to do better here in the United States, but we need to do much better throughout the world. Throughout the months of November, December, and January, all donations made to PWB are going to be doubled up to get $40,000 to support MicrobeTV with all this great science education that Vincent and the team are doing.

VR: All right, time for some questions for Daniel. You can send yours to [email protected]. Susan writes, “I have a patient with inflammatory bowel disease who’s eligible for the third Moderna booster. She’s on Remicade every eight weeks. When is the best time to give the booster?”

DG: Just for our listeners, Remicade is an immunomodulatory drug. It’s an immunosuppressive drug. It’s targeting the TNF-alpha. Now, Remicade is a monoclonal antibody. We say it has a half-life of about 8 to 10 days. As you get to that eight weeks out, you’re getting to a very low level and then you’re going to re-dose it. You’re starting with a high and it’s coming all the way down.

Most of us have been suggesting that people get their vaccinations about two weeks before the next TNF-alpha inhibition dose, so six weeks after the dose, two weeks before. Some people are getting this every four weeks. You’re going to do it right in the middle there. Yes, that’s usually the recommendation. About two weeks before. We don’t have any great data looking specifically. This is an educated bit of advice based upon the kinetics, based upon the mechanism of this immune suppression.

VR: Chris writes, “Hello, Vincent and Daniel. As a 56-year-old recipient of the single-shot J&J back in March, I’m curious conflicted about the need for a booster. After listening to this week’s Q&A with A&V, I found myself conflicted even more

[laughter]

I’m only an engineer, but I deal with data and statistical analysis every day. Typically, the better data wins the argument or at least moves the conversation in a better direction. My confusion is this. Recently, I’ve been hearing on TWiV or weekly clinical updates or Q&A’s how the single-shot J&J isn’t good enough to quote Vincent in last night’s Q&A with A&V. However, the article, “Durable Humoral and Cellular Immune Responses 8 Months After Ad26.COV2.S Vaccination” attached, published in The New England Journal of Medicine September 2nd, 2021, which I believe was discussed on at least one TWiV, suggests that the durability of the vaccine is very good.

This leads this engineer to the conclusion that in an effort to get us through a pandemic and assuming the goal remains to be preventing hospitalization and death, both I fully support by the way, the single-dose J&J meets the goal with flying colors eight months out. Please correct me if I’m wrong but bring data. I’m all ears.”

DG: Okay. Well, this is great. Here’s the way I’m going to put it. We’re not talking, and I’ll say I’m not talking about J&J as a second dose because of waning immunity. It’s really a lack of getting to that high level that we got with the mRNA. I don’t know how much of these data are circulating in the media and the common press. When J&J was studying their vaccine, they studied it as a single dose. They also had several investigations throughout the world looking at it as a two-dose series. That’s really, I think, what we’re talking about with J&J. It gets caught up in the whole booster discussion that we’re talking about with the mRNA vaccines.

This was really what is going to give us higher efficacy. J&J as a single dose vaccine or J&J as a two-dose vaccine series? Now, the one-dose vaccine actually does quite well above that 50% bar that was suggested was required. When you give it as a second dose, we’ve talked about this, they’re giving us a 94%. Remember, nice wide confidence intervals that the FDA made some comments about. That’s really what we’re talking about with the J&J. It’s we do think a two-dose series is going to give us higher efficacy than a one-dose series. It’s not necessarily about waning, actually. If you look at the T cell response, you look at the antibodies over time, actually, I’m quite reassured by the J&J data.

VR: Quoting from the J&J press release, this is the Phase 3 ensemble trial, which I think you’ve covered here. “75% overall efficacy against severe critical COVID across all age cohorts in all countries in the study.” That’s after one dose.

DG: Yes, which is excellent, actually.

VR: Then with the second dose, it goes up to 100%. I think that’s why you have said in the past it’s a good idea to get a booster. Those are the data, right?

DG: I worry about calling it a booster. I really think it’s, “Take your J&J as a two-dose vaccine series.” The language around boosters and everything I think is more confusing than helpful.

VR: Chris says, ”Don’t let my Racanyelling fool you. All the podcasts in the TwiX family are my all-time favorite ways to spend my commute time. We don’t mind Racanyelling as long as it’s calm and based on science.

DG: Be nice. As long as you’re nice, great to – Having questions, that’s what science is all about.

VR: Ingrid writes, ”My dermatologist prescribed tacrolimus cream for a rash, could the immune-suppressing features interfere with my COVID vaccine or make it more likely I will contract COVID?”

DG: I do not think so. Now, tacrolimus mainly is going to work on your T cells, but it’s not going to really get to systemic levels. I think you’re going to be fine there.

VR: All right. Our last one from Holly writes, ”I’ve searched for an answer to a question about COVID boosters for a specific patient. I have not found an answer. I suspect you might be able to provide such information. I have a couple, ages 84 and 90, both vaccinated in February with Pfizer. In September, they were each diagnosed with COVID-19, neither experienced severe symptoms. They were able to isolate at home.

Because of shortages in Denver, Colorado, neither received monoclonal. Now we face the question of boosters. While they both qualify, is there any reason to consider their September infections as a type of booster on its own? Any reason in folks of such advanced age, not to proceed with a booster? If they should receive boosters, any advice on the best timing?

DG: This is challenging actually. We talked about the studies where someone gets, they’ll say infection-induced immunity. Then they go ahead and get two shots of either an mRNA or the one shot of a J&J and then we’ll look at, for instance, serology or maybe T cell studies. That actually looks quite impressive, but then I think I share it here. A young woman in her 30s, healthy athletic who got infected, got vaccinated, still got infected. We’re seeing that in the studies, we’re seeing this out there in clinical practice. We don’t have as much data on people that got vaccinated, got infection. Is that a boost? Is that equivalent to getting a booster shot? We certainly don’t know.

I think the reason you’re saying you’re coming up not finding much direction here is that there is not a lot of direction here. If these individuals tolerated the vaccines well and you’re looking at boosting them, I don’t think that infection in the interim is a contrary indication in any way. It’s certainly not something we’re seeing a problem. If they had a difficult time with those vaccinations and now you’re on the fence, then again, this is something maybe want to think through a little bit. Has that helped them in some way?

The way I put this together in my own mind and I think I mentioned this earlier, I think at some point we’re all going to get exposed to SARS-CoV-2. It is here to stay as long as we have a number of years ahead of us. There will be a point, and really it’s going to be a question of how many vaccinations are under our belt before we have that exposure? Just add a little bit more confusion to the confusion there. There’s no clear answer.

VR: If they were your patients, they got no bad response to the vaccine, should they get a booster after that infection? Would you give it to them?

DG: I wouldn’t see that the infection would change how I would proceed.

VR: That’s COVID-19 Clinical Update #88 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you, and everyone, be safe.

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