TWiV 910 COVID-19 Update #119

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 18 June 2022

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


VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 910, recorded on June 16, 2022. 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, before we jump into COVID, give us your thoughts on monkeypox. Is this something that worries you?

DG: I’m going to try to avoid using things like “worries me” or “concern.” I’m going to just lay out what we’re seeing and what’s going on. It does look like monkeypox is here in greater numbers than anyone really appreciates. I think that’s the reality. As there’s a growing awareness, there’s going to be a growing number of diagnoses of monkeypox, but I think this is the really important distinction is, “What is monkeypox? What is it clinically? How does it present?” I think I shared with you, Vince, and actually, I’ll share it with our listeners who may listen to the ID Puscast as well.

I was recently involved in helping with a little girl, a three-week-old girl in Ghana who had monkeypox just all over her entire body. That’s the monkeypox that has plagued, I should say, our people in Western Africa for many, many years. It’s a devastating, horrible disease in the DRC, 10% mortality, and the other variant in Western Africa, it’s still 1% to less than 5% mortality there. This disease where you’re just covered in this pox and that’s when it’s being recognized and diagnosed, but what we’re hearing about now is in many cases, grown men, with one or two pustules in their private part areas resolving, nobody is dying in these hundreds and hundreds of cases we’re hearing about.

We hear things about, “Oh, we may be missing cases.” Then, I wonder, “Is it so horrible if we’re missing cases if that’s all it is?” If it’s a self-limited infection, localized a couple of vesicles. I think that it’s important to say that. Monkeypox is here. We had that little girl who got it from a prairie dog in Texas. We had that outbreak in the Midwest. A colleague of mine who may come to work with us just diagnosed a case over in Elmhurst. That’s what we’re seeing. It’s here. It’s a concern. We have vaccines. We have tools to respond. We’re not having people show up like out of a horror movie just covered with poxes everywhere. I’m glad it’s come to people’s attention because you know what? That’s been going on in Africa to human beings for decades now. It would be nice if we actually cared and did something about it.

VR: I think it’s possible. It’s been here for some time, but under the radar, especially before COVID.

DG: I think, certainly, actually, and it was interesting recently something doctor – I don’t know if it was Walensky. It may have been Walensky – but talking about that issue that I often bring up about Occam and Hickam where Occam, you have one thing and John Hickam, you can have as many things as you damn well please, and pointing out if someone comes in and they have these vesicles and you test for HSV and, “Oh, it’s positive.” That doesn’t mean that’s all they got. Often, you get two things at the same time.

This paradigm, I feel like we’re back in the early days of COVID. If you get a positive HSV test, well, that would say to me, “Hey, this person had an exposure. They’re at risk for sexually transmitted disease. We know monkeypox can present this way. It should be in our testing panel,” but right now, we’re like the early days of COVID. You can only get that special monkeypox test if everything else is negative. They have to be mono infections, which we really need to move past that.

VR: That’s a good point. Thank you.

DG: I will start with my quotation. “Ask not what your country can do for you, ask what you can do for your country,” and that’s JFK. I realize I occasionally go in that direction. I figure I should just give him credit for saying that. Over the last two years, we’ve had some very interesting impacts on our society and how we view things. I’m hoping I feel like maybe I grew up when there was a time when people asked, “What can I do to make a difference?” It wasn’t just all about me. I’m hoping we can get back there. I think that’s actually part of moving forward, is us realizing that we live in a community. You could even say it’s selfish to care about the community you live in because you live in that community. Hopefully, as we go through some of these different changes, I’m going to start off with the CDC, no masking on flights. We think about the fact that there are other people on that airplane and at one point, we’ll be those other people on that airplane.

Let’s get right into “CDC Rescinds Order Requiring Negative Pre-Departure COVID-19 Test Prior to Flight to the U.S.” The CDC announced that the order requiring persons to show a negative COVID-19 test or documentation of recovery before boarding a flight to the United States was rescinded effective June 12, 2022. This means that you could have acute COVID. You could be feeling crummy overseas. You could jump on a plane without a mask and then fly right back to the U.S. How do I feel about this? I think that this is the current reality, and it is based upon the fact that the landscape has changed.

We now have widespread access here in the United States where these people would be coming, widespread access to highly effective vaccines, highly effective therapeutics, much better access to testing. This is where things are going, but I want people to start thinking about this on a plane. You may want to now choose to wear high-grade one-way masks, so, using a mask for personal protection on these flights. The CDC is going to continue to communicate updates, but the landscape is changing here.

Children. This is where we’re going to spend a lot of time. This was an exciting week from the youngest among us, as I like to say. First, to start off with something I’ve been saying now for two years. Children are at risk from COVID. Over 1,000 children have died from COVID. The majority of those deaths due to Omicron.

I had a physician who will remain nameless come up to me today goes, “It’s great that the COVID is getting so mild.” I’m like, “What are you talking about?” [laughs] Being vaccinated really can turn this into a mild disease. Getting therapeutics into those high-risk people in the first three to five days can really turn this into a mild disease. Why do you tell me this?” He’s like, “Well, today is day six for me.” I’m like, “What do you mean day six for you?”

As he stands there within about three feet with a loose-fitting mask on, he said, “I got the COVID.” I was on my way to the office, and I said, “When I get there, you may need to give me a COVID test,” and it was positive. I did just fine and I said, “Well, you are triple vaccinated. Oh, yes, but it’s because it’s so mild, but anyway, maybe this gets back to the first part as well. Don’t come within three feet of me with a loose-fitting mask on day six of your illness just because you’re allowed to head back to work.

Let’s continue to realize. Just a reminder. This is actually a contagious disease. You do catch it from others. You do give it to others. Back to the kids. Because this has actually been one of those things as so many people are excited to return back to normal, parents of children under the age of 5 have said, “Hey, what about us? What about our kids?” I’m going to give you a couple different decisions here because we had a decision on Tuesday, but I’m really going to talk about the decision Wednesday.

The first decision on Tuesday was the FDA advisers voting on Moderna’s COVID-19 vaccine for children and teens under 18. That was bringing them down to age 6, but then, we’re going to get to two really important votes that we had yesterday, and I’m actually going to mention a little bit about.  I don’t know if you got a chance to watch this Vincent, or if our listeners got a chance, but I really enjoyed what Paul Offit had to say, and I think this is really important. Two votes they voted, this is the scientific advisory board for the FDA.

This is a vote. What does the science tell us?

Here was the question. Based on the totality of scientific evidence available, the benefits of the Moderna COVID-19 vaccine when administered as a two-dose series, 25 micrograms each dose, outweigh its risks for use in infants and children’s 6 months through 5 years of age. That was unanimously “yes”. Now, this is slightly different. We’re going to get a second vote. Based on the totality of scientific evidence, the benefits of Pfizer-BioNTech COVID-19 vaccine when administered as a three-dose series, 3 micrograms, each dose outweigh its benefits for use in infants and children 6 months through 4 years of age. You notice I turn those from questions into statements because the scientific advisory voted unanimously, but there was a bit of discussion on I think that this was really important, and this is important to communicate to parents. There’s going to be a choice here, between the Moderna and the Pfizer.

There was a bit of discussion about, we really do not have enough numbers to know for certain about efficacy or the ability to compare the efficacy between the two vaccines, but one of the big points that Paul Offit made is that Pfizer-BioNTech is a three-dose series. It was not clear after the first two doses that you are really starting to see separation of the curb, significant protection, or that compelling immuno-bridging data that you get after that third. He was a bit worried, as were other people in the discussion, that it was still going to be viewed as people get one or two doses, and then say, “I’m iffy on that third.” Clearly, the Pfizer-BioNTech in this age group is being recommended as a three-dose. The Moderna is being recommended as a two-dose, but there may actually be a third once we see efficacy in the Omicron context.

VR: What’s the spacing of the doses, Daniel?

DG: Let’s go through it because I think this is important. You get your Moderna and it’s probably going to be June 21 that you’ll have access to that first dose, four weeks later for that second Moderna dose, and then we have this two weeks afterwards, we’ll consider that completed. The Pfizer is, let’s say, get that first dose on June 21. That’s when we’re hoping they’re available. Three weeks later, you get that second dose. Five months later, you’re going to get that third dose. If you’re thinking you want your child to get the vaccine series completed prior to school, you’re pretty much going to have to go with the Moderna on this.

VR: Why are the doses so different on these?

DG: Part of that is that, and this has been the same case with the adults, is it really isn’t exactly the same vaccine. There is a different packaging. There’s a different antibody response based upon how much is in each different packaging system, delivery system. Part of it also was a judgment. People are a little concerned that maybe the Pfizer-BioNTech 3 microgram is a rather small dose, thus necessitating the three-dose instead of the 25 micrograms which is higher, but again, there’s always this balance trying to pick a dose relative to efficacy and safety.

I will say, and I think this is tough, is that we are concerned as we saw with the other is that a certain percent of individuals get that first shot. A lower percent get that second shot and a very low percent get that third shot. Parents, if you’re going to buy into the Pfizer choice, really you’re committing to three shots. If you say, “Maybe two is all I can see,” go with the Moderna because we do want to have these series completed. We want people to be vaccinated based upon what the science shows.

Testing. Actually, this was a perfect lead-in. Vincent primed this. One, use those tests intelligently. We’ve learned over time, that first day of symptoms, see how things go. It’s really that next day that you want to do that test and if it doesn’t make sense, you may want to repeat it the following day. That’s mainly talking about those rapid tests. A lot of folks are doing those at home, but if it doesn’t make sense with a rapid test being negative, go ahead, get that PCR.

The other thing is, as we just mentioned, you can have more than one thing at the same time. When someone comes into that urgent care, when you go to that doctor’s office, you’re not there just to find out, “Do I have COVID?” You might have influenza. Your child might have RSV. There’s many more things out there. A lot of our offices have these quad platforms where they can do that antigen testing and find out for COVID, “Do I have COVID?” Testing for the SARS-CoV-2 viral antigen. “Do I have influenza A, influenza B, maybe RSV?”

Remember, there’s more out there than just COVID. Actually, there’s more influenza seemingly right now than we had months ago. More parainfluenza, more RSV, all the viruses are out of season. Actually, I have to say, I think it challenges to some degree a lot of our thinking. A lot of the things I’ve said over the years, “Well, in the summer, people are outdoors more. The weather’s getting better. The viruses go away.” They seem not to be going away. There may be something about a seasonality pattern, an exposure, an immunity, other things, maybe a little more complicated than we all thought.

Active vaccination. We’ve already touched the big things there, moving this into children, but I will mention a little bit about Evusheld. Maybe we’ll even have a little bit more of a discussion because this is a challenge. Evusheld, this is passive vaccination. This is giving someone those antibodies because we’re concerned they may not be making them themselves, but we’re also gambling, will this continue to work should they encounter one of these new variants in the future? Is this still going to work? What about some real-world data?

Let’s get into Evusheld. The article, “Intramuscular AZD7442 tixagevimab, cilgavimab,” so that may help people remember. Evusheld is a monoclonal cocktail for the prevention of COVID-19. This was published in the New England Journal of Medicine. Just a few things to go into. The pharmacokinetic data in humans indicate that the Evusheld has an extended half-life of approximately 90 days. The dose you get, 90 days later, you’re about half that dose. Another 90 days, you’re down to a quarter. Six months later, you’re about a quarter of what you got upfront.

These are the results from an ongoing phase three trial which enrolled adults greater than or equal to 18 years of age who had an increased risk of an inadequate response to vaccination against Coronavirus 2019, COVID-19. Participants were randomly assigned in a two-to-one either to get that Evusheld or a saline placebo. They followed them for 183 days. That’s about six months. The primary safety endpoint was the incidence of adverse events after a single dose. The primary efficacy and endpoint was symptomatic COVID-19. I love whenever you talk about an efficacy endpoint. What is efficacy here? Symptomatic COVID-19.

A total of 5,197 participants underwent randomization. We ended up with 3,460 getting Evusheld. We have 1,737 in the placebo group. The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1,221 of the 3,461 participants, 35.3% in Evusheld group, 593 or 34.2% in the placebo group, reported having at least one adverse event. Interesting. 35, 34, really about the same. Not higher. People having Evusheld are not reporting any significant increase in adverse events. Credibly well-tolerated. Really jives with our experience.

Symptomatic COVID occurred in 0.2% In the Evusheld, 1%. In the placebo group, they gave us a relative risk reduction of about 77%. When they extend that follow-up to six months, we’re seeing about an 83% risk reduction. Five cases of severe or critical COVID-19, two COVID-related deaths, all in the placebo group, not in the Evusheld’s group.

VR: Normally, Daniel, this is given intravenously, so this is what’s being tested here?

DG: It’s actually an intramuscular injection. [crosstalk] It’s really an easy lift. People basically pull up their shorts or pull down their pants, whatever you want to do. You get a couple intramuscular injections. That’s it.

VR: Now, I think last time, you also talked about a similar trial for therapy, not just prevention, is that –

DG: There was also Evusheld therapy data. This is giving ahead of time, prevention. There was also a post-exposure and actually, people come in. They’ve got the COVID and then you give it. That was about a 50% [crosstalk]–

VR: That was last time. What’s different about this in terms of prevention? Didn’t we already know the numbers for prevention?

DG: We had data from preprints, but this is actually the fully published New England Journal of Medicine article. We get all the data, people can look through it. Maybe we’ll mention it a little bit later to just allude to this, but we do have press release data, and we do have the preprint up there looking at the efficacy of Evusheld with the newer of the Omicron sub-variants and continue to show at least pseudo-viral efficacy so we’re hopeful that’s going to continue to translate. Now, we’re going to get into the exciting part, Vincent. We have the ACTIV-6 results which I’m sure you’ve been waiting for.

If people remember, so ACTIV-6 is that repurposed drug study funded by the NIH. Let’s go through. Posted as a pre-print, we have ivermectin for treatment of mild to moderate COVID-19 in the outpatient setting, a decentralized placebo-controlled randomized platform clinical trial. ACTIV-6 here is looking at repurposed drugs. This is an ongoing decentralized, double-blind, randomized, placebo-controlled platform trial looking at outpatients with mild to moderate COVID-19. We’re looking in that first week during the time of viral replication.

In this part of ACTIV-6, non-hospitalized adults either 30 years of age or older with confirmed COVID-19 experiencing two or more symptoms of acute COVID, they had to be within the first seven days, and they were randomized to either receive ivermectin 400 micrograms per kilogram daily for three days or placebo. The main outcome was time to sustained recovery defined as achieving at least three consecutive days without symptoms.

Secondary outcomes included a composite of hospitalization or death by day 28. 3,457 participants consented to be evaluated for inclusion in the ivermectin arm. 1,591 were eligible for this study arm. 817 received ivermectin. 774, placebo. Of those enrolled, 47% reported receiving at least two doses of SARS-CoV-2 vaccination. It’s split right about half the people were vaccinated, about half the people were not vaccinated.

One of the comments, hospitalization or deaths were uncommon in this cohort. Ivermectin, we had 10. Placebo, we had nine. What did they find? You saw that data right in front of you. One more person in the ivermectin, one less in placebo ended up hospitalized or dead, but that’s not significant. Ivermectin dosed at 400 micrograms per kilogram daily for three days resulted in less than one day of shortening of symptoms and did not lower the incidence of hospitalization or death among outpatients with COVID-19 in United States during the Delta and Omicron variant time periods. Ivermectin not doing much here.

I will say, so this did not go the way the ivermectin folks wanted it to go. We’re already hearing the classic, “This trial was designed to fail,” but I’ll make a couple of comments here. Some of the comments were, “Oh, they gave it within the first seven days.” We all know that you have to give it within the first three days. They did do a subgroup analysis. They looked at giving it in the first three days. They looked at those folks that got it after the first three days. There was no benefit. Timing, getting in the first three – If something doesn’t work, it doesn’t work. It doesn’t matter if you give it earlier or a little bit later. I will say that this was a really good, really solid science. I’m going to agree with the authors who conclude that ACTIV-6 adds to the growing evidence that there is not a clinically relevant treatment effect of ivermectin.

VR: Daniel, there was a previous Brazil study. They look at hospitalized patients and have the similar conclusion.

DG: Yes. This is really just growing evidence. I think it’s one thing, early on for people to have been optimistic about ivermectin, but the science is very clear at this point. It’s not effective, but what is effective? One, Paxlovid. That’s still number one. Eighty-nine to 88% reduction in progression if given in the first three to five days. That’s really what this does. I think we got a little more information this week. I’m going to go ahead and talk about an update from Pfizer on the EPIC Standard Risk, the EPIC-SR. I’m just going to give a little bit of context before I go into this.

A lot of people are using Paxlovid because they’re optimistic. They’re hopeful that it’s going to do whatever they want it to do. It’s going to make people feel better quicker. It’s going to prevent Long COVID. People at Day 8 or 9 are suddenly going to be completely better and they’re not going to have that second, early inflammatory phase to any degree. Let’s be clear. The data is that this medicine keeps people out of the hospital. It keeps people from dying. What about just giving it to Standard-Risk people?

We got an update as mentioned from Pfizer. This is data from the Phase 2/3 EPIC-SR. This is the Standard-Risk patient study evaluating the use of Paxlovid. A number of endpoints did not reach statistical significance. I’ll focus just on the few that did. Treatment with Paxlovid resulted in a nominally significant 62% decrease in COVID-19-related medical visits per day across all patients relative to placebo. It did reduce that a little bit.

An additional pre-specified descriptive analysis showed a 72% reduction in the average number of days in hospital among Paxlovid patients treated in the Standard-Risk. Other, not statistically significant findings included, no Paxlovid-treated patients admitted to the ICU compared to three in the placebo. No deaths in patients who received Paxlovid with one in the placebo group.

I want to bring this, where do we go with this? This is what Pfizer had to say. Due to the very low rate of hospitalization or death observed in the Standard-Risk patient population, Pfizer has decided to cease enrollment in EPIC-SR. We’re really back to what we’ve talked about as far as who should be getting Paxlovid. Paxlovid is for those who are at high risk for progression to severe COVID-19 or those that have risk factors for progression to severe COVID. This isn’t something that everyone needs to get. This is something that you give to people who are at risk. I’ll mention that.

VR: It’s interesting that when you hear about people being hospitalized or dying, those people likely have those risk factors, high BMI, diabetes, et cetera.

DG: Yes, they really do. We are not seeing young, healthy individuals with no risk factors, who’ve been vaccinated end up in the hospital and dying. There’s a type. It’s a person with risk factors. Get your vaccination series, and if you’re at high risk, get treatment. I will talk about why are we always talking about this, but I will talk about it again just because let’s throw some data and science at the rumor mill. The paper “Rebound Phenomenon after Nirmatrelvir/Ritonavir Treatment of Coronavirus disease-2019 in High-Risk Persons,” published in CID.

Vincent and I were on a discussion with these influencers the other night. It was rather entertaining, but there’s a responsibility to being on social media. There was one individual who I think shared, theoretically, they’re a practicing clinician, but they said, “Of the 11 people I’ve treated with Paxlovid during a pandemic,” and I thought, “How can you have only treated 11 people with Paxlovid during a pandemic?” I could do that in a day. We’re in a pandemic. There’s lots and lots of high-risk individuals out there, but the comment was, “Six of those had rebound.” I’m like, “Really? You only treated 11 people and six of them had rebound?”

What about looking at a large cohort? This is a retrospective review of a cohort of 483 high-risk patients at the Mayo Clinic in Rochester treated with Paxlovid. Two patients, 0.4%, required hospitalization by day 30. Rather impressive. Four patients, less than 1% experienced rebound of symptoms which was generally mild at median of nine days after treatment, and all resolved without additional COVID-19 directed therapy. That’s science. That’s a large cohort evaluated, shared. That’s not, “I treated 11 people and I want to be interviewed for the New York Times.” Sorry about that. Remdesivir, that’s number two. I’m a little disappointed here. I was looking at data on Tuesday night. Of people with acute COVID, we’re doing really good. Over 70% of the treatments that people are reaching for Paxlovid, we’ve got a chunk of molnupiravir, really an underutilization of bebtelovimab which we’ll get to next, but about 0.3% was early IV remdesivir with an efficacy of 87%. I understand the operational challenges of getting this out to people, but here is a highly effective, well-tolerated therapy with limited drug-drug interactions, limited issues with renal function. It’s three days. They come in, and it only takes 30 minutes per infusion. We really need to do a better job of operationalizing this. I worry we seem to have just lost urgency in the pandemic.

Number three, that’s our monoclonal therapy. We’re just bebtelovimab as excited as many of us are about monoclonals. We’re still stuck with not really having data. I will talk about a study and this is something that concerned me early on, and actually even had this conversation, I’m going to say, with my youngest brother when he got the COVID. My youngest brother has a number of risk factors. He qualified for monoclonal therapy, and he wanted to ask me, he said, “But you know what? I just got COVID. Here’s my chance to get that natural immunity I heard about if I get the bamlanivimab – “it was back in the days of bam, bam. “Maybe I’m not going to get that immune response.” I said, “You know what? That’s my hope. I really don’t want you getting that immune response. I don’t want you having that second week early inflammatory phase, the pulmonary phase ending up in the hospital.” Here’s the article, “The Anti-SARS-CoV-2 Monoclonal Antibody, Bamlanivimab, Minimally Impacts the Endogenous Immune Response to COVID-19 Vaccination.” We had this issue that once they got the bamlanivimab, now, we’re going to wait 90 days before we vaccinate them because there’s going to be all these problems.

This was published in Science Translational Medicine. This longitudinal serological study evaluated the magnitude and potency of the endogenous antibody response to COVID-19 vaccine in participants who first received a monoclonal antibody in a prevention study. The patients received the first COVID-19 vaccine dose at different time points. It could be as early as 43 days, within that 90-day window that we first talked about. It could be out to 127. The median was about 67 days after that bamlanivimab or a placebo infusion. The majority did not wait the 90 days that had been suggested previously. All the bamlanivimab and placebo recipients mounted a robust immune response to full COVID-19 vaccination, irrespective of age, risk category, and vaccine type.

As they say, and I’m going to agree with this, these findings are pertinent for informing public health policy with results that suggest that the benefit of receiving COVID-19 vaccination at the earliest opportunity outweighs the minimal effect, if any, I added if any, on the endogenous immune response to prior prophylactic COVID-19 monoclonal antibody infusion.

Someone gets COVID, maybe they get those monoclonals. They’re no longer isolating for the infectious. They’re feeling better. Go ahead. Let’s get that vaccine in there. Molnupiravir. Some uptake here, less impressed about 30% reduction. Let’s avoid those harmful things. I am not happy nor is my oncology colleague to have their 84-year-old cancer survivor, high-risk parent go to an urgent care, not a ProHealth, but one of those other ones in the city, and get a Z-Pack during the second day of his illness. That is not what we recommend.

Remember, this is a contagious disease. I know it’s annoying. I know you’ve got COVID and now, you’re having to isolate, but you are contagious when you have COVID. You can spread it to others. That’s how you got it.

The early inflammatory phase. Our real goal is to keep folks out of the hospital. When people end up in the hospital, we are still seeing people die from COVID. I just want to mention the article published in Open Forum Infectious Diseases,  “In-Hospital Mortality Among Hospitalized COVID-19 Patients in the United States.” How did it change in 2021? This is a retrospective, observational study in the U.S. A national sample of 501,671 adults hospitalized with COVID-19, the adjusted in-hospital mortality was 12% in February 2021, 9% in April, 2021. We’re going in the right direction but then we get into September and October of 2021, 16%. That was sort of our early days we were about 20%. Then, we thought we were doing a better job. We got it down to 12; 16% here, we’re seeing in September and October.

I will mention, if you go through, part of these changes has to do with the patient population. When mortality was lower, we tended to have a younger, healthier population. As the mortality increases, you’re seeing a higher-risk population, but just to point out, people are still getting admitted with COVID, nine to 16% mortality. That’s pretty high. Once the folks get there, there are some things we can do but at  this point, the impacts are not as dramatic as the vaccines in early treatments. We got steroids, anticoagulation, pulmonary support maybe remdesivir if it’s early, some immunomodulation with tocilizumab but remember avoiding those unnecessary harmful things.

We are stretching it out today, but there are a few last articles I wanted to discuss. This one is seemingly clinically relevant to a patient I’m currently managing. This was a case report of three patients also published in Open Forum Infectious Diseases, Combination Therapy with Casirivimab/Imdevimab and Remdesivir.” – they’re getting the monoclonal cocktail and a small molecule antiviral – “for Protracted SARS-CoV-2 Infection in B-Cell-Depleted Patients.”

This article described three B-cell-depleted patients with prolonged Coronavirus disease 2019 infection who were ultimately successfully treated with a combination of the monoclonal and the antiviral. Just something to be thinking about as we move forward. I suspect once we have full licensing, we’ll be doing a little bit more of this. Vincent, you’re going to get asked to jump in on this. I pasted in the pretty pictures, but this is the article, “Persistence of Residual SARS-CoV-2 Viral Antigen and RNA in Tissues of Patients with Long COVID-19.”

Posted as a preprint, so this has not been peer-reviewed. Just want to point that out right up front.

Here, in the author’s report, they observed positive staining for viral nucleocapsid protein in the appendix and tumor-adjacent region of the breast, so a tumor was removed but not within the tumor via multiplex immunohistochemistry. They’re going to use RNAscope, which is this commercially available RNA in situ hybridization. I think Rich Condit refers this as RNA hybridization on steroids but using RNAscope both positive sense and negative sense. Replicative intermediate viral RNA was detected. This is this idea that not only are they picking up remnant but this is a suggestion that maybe there’s some active replication going on.

As a single-stranded virus, SARS-CoV-2 has to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, this detection of negative sense, viral RNA, they say suggests ongoing viral replication. They really are. I have to say the figures are beautiful. Vincent, any thoughts on whether this is compelling or not?

VR: I don’t think it’s compelling because the only way you can demonstrate infectious virus is to do an assay for infectivity. We don’t actually know, even though there are negative strands which is good whether there’s infectious virus. They could simply be persisting for long periods of time. It’s rare. These cells aren’t chock-full of these viral RNAs. I would say the relevance is still not clear whether this could fuel Long COVID or not, still remains to be determined.

DG: For me, it’s interesting because if there is replication going on then, OK, our antivirals are going to work, but there’s just remnant, and there could – Oh, it was at some point there was replication before things shut down. There still could be remnant of that intermediate. Guarded optimism, more to come. The article, “Rheumatic Symptoms Following Coronavirus Disease 2019  (COVID-19): A Chronic Post-COVID-19 Condition,” was published in Open Form Infectious Diseases. In this prospective longitudinal cohort study, discharged patients with COVID-19 were interviewed face to face at 12 months after symptom onset. In total, this is a select group, but of these 1,296 of the 2,469 discharged patients, 12% suffered from rheumatic symptoms following COVID-19 at 12-month follow-up. The most frequently involved joints were the knees, the hands, and the shoulders. Interesting enough here, the rheumatic symptoms were independent of the severity of illness and whether or not corticosteroid treatment was given during the acute phase. We certainly see a subgroup of folks with Long COVID with a significant joint issue. Just nice to get this out there in the list of things that we’re seeing that we’re trying to manage. I will close as I like to always do, on, let’s think outside of our own country. No one is safe until everyone is safe. The pandemic continues. New variants continue to emerge.

We still have not done a great job throughout the world with vaccine education, vaccine access. We need to continue to think globally. I want everyone to pause right here. Go to, click on that Donate button. Every small amount helps. We are continuing our Foundation International Medical Relief of Children fundraiser for the months of, well, May is over, we’re in June, and we still have July ahead of us. We’re trying to get up to a goal to donate $40,000 to Foundation International Medical Relief of Children, particularly to focus on reopening our Bududa Clinic in Eastern Uganda. It’s been tough during the last two years.

VR: I think it’s interesting, Daniel, that there are some other viruses that, as you know, cause joint issues, arthritis, like Chikungunya and dengue virus. It is not unique to SARS-CoV-2.

DG: It does remind me of Chikungunya actually, these patients.

VR: It’s time for your questions for Daniel. You can send them to Gabriela writes, “I’m a member of a task force outside the U.S.” Gabriel is from Mexico. “For the use of medications for COVID, next week, we have to explain why we do or why we don’t need to make Evusheld available. The question is whether there is any clinical evidence for efficacy with currently circulating variants in vitro and there is a preprint suggesting that the ADZ7442 is still active against B.4 or B.5 even if activity is decreased severalfold. It’s not clear how to convert the decrease in activity to actual patient protection. The FDA has suggested increasing the dose, but I can’t find information on how, or if that has resulted in the same protection against critical disease or death.”

DG: These are excellent questions. The dose used to be 150 milligrams and with the Omicron data showing a reduction in the efficacy, we actually bumped it up, and now the EUA is for 300 milligrams of each of these. We briefly mentioned this. We get the press release right from AstraZeneca saying that they have in vitro pseudovirus neutralization activity against the variance, and this is actually available as a preprint. There is the preprint, so people can listen slowly and write this down, “Further Antibody Escape by Omicron BA.4 and BA.2 from Vaccine and BA.1 Serum.”

We are seeing some pseudo-virus information and there is the data out of University of Oxford, but this is a challenge because what something does in a pseudo viral assay, what something does in a real BSL-3 viral assay is not always the same. We do need to continue to have post-marketing. I think the data has been, to date, very compelling. An 80%-plus reduction in even symptomatic disease in this high-risk group that can’t potentially protect themselves with the vaccines.

VR: We have a couple of questions about the pediatric vaccines. Stephanie writes, “Looking forward to getting our 4-year-old vaccinated, news articles say we should expect shots June 21. We’re going to be in France all of July. If we get our 4-year-old daughter’s first shot days before we leave, the earliest, we will be able to get her second is six weeks instead of four, do we go ahead with the first shot? Will six instead of four weeks really matter? Will the first shot give our daughter any protection while we’re travelling or should we wait till we return?  I’ll ask our pediatrician, but he’s the one that recommended this podcast. He probably is interested to hear what you think too.

DG: Excellent. The pediatrician can listen and then you should take credit for what I have to say. This is actually a great question. I’m going to base this actually on the small print in what the CDC has pointed out and what the data actually shows. I’m going to encourage you to get that shot, or have your child get that shot, before they go, and then get that second shot, I have no issue with six weeks.

Actually, in the small print, the CDC even says in certain age groups consider stretching out that gap to eight to 12 weeks. We’ve talked about this, that part of putting it so close to three to four, this prime so close is because we’re in a pandemic and we’re trying to get to that point of having protection as early as we can. Let’s take Moderna as a perfect example. If you get that first Moderna shot and you get your second Moderna shot, let’s say six or eight weeks later, you may actually get a little more efficacy than if you had it at four weeks. I don’t see this as a negative. I actually see it as potentially positive.

VR: Hannah writes, “I have a question on behalf of my niece turning 5 in August. Should she get the vaccine ASAP and get two, 4-year-old doses delay, so she gets one 4-year-old dose or a bigger dose two when she’s 5? Wait until she’s 5 to get two bigger 5-year-old doses. My sister trusts my opinion, but I am only a microbiology professor, not a clinician, so I ask you.”

DG: The real advice is go ahead and start the vaccine series now. We’re going to be boosting in the future at some point. I would not wait. I would go ahead and the vaccine dose that someone is eligible for their age, that’s what we recommend going with.

VR: Finally, from Richard, “Do those of us old-timers who are vaccinated against smallpox in the mid-1950s have any immunity against the current monkeypox? I am 72, was vaccinated against smallpox in ’56 at the age of 6.”

DG: We talked a little bit about this on– I think we had a special monkeypox episode. I’m sure we had a special monkeypox episode. At least within the short period of time, we quote this number, 84% efficacy of the smallpox vaccine against monkeypox, but as time goes by, we certainly think that that decreases that protection. The real-life example was when we had that big outbreak about 20 years ago in the Midwest. We had people who had been smallpox vaccinated get infected. We had people who had not been smallpox vaccinated get infected. We saw no difference in the clinical course between the two. I’m thinking that smallpox vaccine from so many years ago is probably not doing much at this point.

VR: That’s COVID-19 Clinical Update 119 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you so much. Everyone, be safe.

[00:47:32] [END OF AUDIO]

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