TWiV 730 COVID-19 Clinical Update #53

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 13 March 2021

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

From MicrobeTV, this is TWiV, This Week in Virology, Episode 730, recorded on March 11, 2021. I’m Vincent Racaniello, and you are listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Update number 53. How’s everything going, Daniel?

DG: I will say I still am optimistic. Here on the ground, things seem to be going in the right direction. Just today, one of the Catholic hospitals where I go, they’ve closed their COVID unit. They no longer have a COVID unit at that hospital. One of the other hospitals numbers have dropped to maybe 20% of where they peaked. Numbers are going down in the hospital. Unfortunately, we still have several people in the ICU, struggling, who probably won’t make it.

One of your shows, I think was Ginger Campbell said, “Hey, if you end up in the ICU, it’s 50/50, if you end up on a ventilator.” I actually say, actually, it’s much more depressing than that. I was reviewing with some of the ICU doctors, single-digit survival this time. Really, we’re doing everything we can to keep people off the ventilators. The people that end up on the ventilators, it really is well under 10% that are surviving in our experience.

Some of the ones that are just tragic, this one woman who’s now out of the ICU, just very vague, and I’m not sure there’s much cognitive function left, so just a tragedy. Talk about how important palliative care decisions are is unfortunately really critical here with COVID.

My quotation. “It is easy enough to vote right and be consistently with the majority… but it is more often more important to be ahead of the majority and this means being willing to cut the first furrow in the ground and stand alone for a while if necessary.” This is by Patsy Mink. In 1964, she ran for federal office and won a seat in the U.S. House of Representatives, was the first woman of color, the first Asian American elected to Congress. I just think that it’s a very appropriate quotation.

It’s easy to group together. I hear a lot of people now— I was just doing a talk for a group at University of Pittsburgh where people are all agreeing, like, “Oh, who could have really seen this coming?” You know what? We warned about this pandemic for a long time. We’re warning that this will not necessarily be the last pandemic if we don’t respond differently.

I know everyone’s all excited and they want to go out there and have their big parties and hug everyone but let’s not let this happen again. While we’re still here, while it’s still fresh in our mind, let’s spend the money now, let’s make the decisions now, let’s get the changes in place so this doesn’t happen again. This has been rotten. This has been horrible. A lot of people have died.

Never miss an opportunity to vaccinate. Never miss an opportunity to test. Never waste a vaccine dose.

Vaccines are getting better, but I’m actually going to start with children and COVID. As we see more adults getting vaccinated, there’s a growing push to get the kids back into schools, getting ready for summer camp and opening many things up for children. The one thing I will say on the ground here is this is not going well for kids. I was talking to my buddy, Dr. Yovino, he’s one of the only adults who calls me Danny, and he can get away with it. He was saying, “We are now seeing its children, growing numbers of children getting diagnosed with COVID.”

Last week we saw the article in the CDC MMWR, Estimated SARS-CoV-2 Seroprevalence Among Persons Aged <18 years – Mississippi, May–September 2020. They looked at serological tests on blood samples collected between May and September 2020 of 1,603 persons aged less than 18. They found on the serological testing 16.3% of these were positive.

They actually suggested that at this prevalence rate over 113,842 of the 698,420 young persons in Mississippi had been infected with SARS-CoV-2 by mid-September. Of note, there’s only been 8,993 confirmed or probable COVID-19 cases reported among young persons to the Mississippi State Department of Health. If you do the math, this means that we’re only catching about 8% of the COVID-19 infections in this young population, meaning that over 90% are going undiagnosed.

In the same article, they referenced the CDC data, suggesting there have been just over three million reported COVID-19 cases in the U.S. in persons aged less than 18. Now, if this is under-diagnosis, instead of three million, that would put us closer to about 40 million cases in children. Even with a prevalence of 16%, it means that over 80% of our children are still at risk of COVID-19. Unfortunately, I think we’re seeing that on the ground here in New York.

One of the things and this was what Dr. Yovino and I were talking about, is that the parents are quite upset because they’re saying, “We were told that COVID was a very mild thing in kids. What’s going on? We were told that children are less likely to die, they’re less likely to hospitalize, they’re less likely to have severe COVID.” I discussed the data coming out of the U.K. that about 10% of the kids that develop COVID, it is not just a mild short-lived disease, but it lasts.

I was just on a call Tuesday evening with our pediatricians. Maybe I was just trying to depress myself, but I wanted to ask them. I say, “I see the numbers in the literature. One of the things that hopefully I add with these clinical updates is, what are we actually seeing? Let’s translate these studies into what we’re seeing on the ground.” Every pediatrician on the call had stories of a growing number of young individuals that they’re taking care of that are suffering.

Just to share a few of these stories with everyone, one was a 16-year-old girl, loves soccer. She got sick with COVID, two, three months ago, but her family wanted to make sure before she got in, she saw the cardiologist, they did an echocardiogram, everything was fine. They said, “You’ve been cleared. We think you’re fine to play soccer.” This is a girl who used to run several miles a day, her life is all about soccer. She tried to play the first game, and she was like, “I can’t run up and down the field.” She’s not going to play soccer this year and she’s devastated.

There was another young woman who had a lacrosse scholarship. She can’t play. There was a boy, this really I found quite upsetting. He had COVID and his teacher called the mom and saying, “What is up with your son? He can’t pay attention in class.” She said, “Yes, he had COVID a few months back, he cannot maintain his attention. He just gets distracted. He can’t keep focus.” I think a lot of what we’re seeing is the kids, when they’re forced either to try to compete athletically, they realize, “Oh my gosh, I am so much diminished from where I used to be,” or they’re asked to do a cognitive task like, “Pay attention and do well in school.”

I worry about this. This is something we’re seeing in the literature. This is something now the pediatrician shared with me. Even something has changed a little bit about the multi-inflammatory syndrome. My colleague and friend, Jay Berger, is taking care of a young individual now who’s in the ICU. Early on, 50/50, with these individuals with the late inflammatory phase ending up in the ICU, now 90% of them are progressing to the ICU.

I’m not sure what to say here other than just we need to be a little bit honest with the parents is that “Yes, your son or daughter may not die or end up in the hospital with COVID and may be at lower risk,” but I’m not sure I’m completely comfortable if one of my children end up getting COVID and maybe having long term complications.

Testing. We saw the first EUA for a T-cell COVID test, the T-Detect COVID test by Adaptive Biotechnologies. This is something a person can go online, click a few buttons, pay a little more money than most of us would like to, and actually get a COVID T-cell test. I’m glad we’re seeing more attention being paid to the T-cells. My PhD was in B-cell biology, but much of my clinical practice and research is focused on HIV, so T-cells have gotten a lot of attention for me over time. A little sad for the T-cells, they were neglected there for about a year, but now they’re getting that attention that they’ve long had because of the HIV epidemic, which still is ongoing.

This is a $150 test that can be done either as an in-home or an in-lab blood draw. Basically, a patient goes on the website, they click a bunch of buttons, and then this test, reportedly compared to the antibody tests, they’re saying this has a greater than 99% specificity, about a 95% sensitivity. This is detecting prior infection with SARS-CoV-2, the virus that causes COVID-19. It’s really a fascinating test.

I was on a call with the same company talking about a study that we’re trying to help them with Lyme disease. I realized as we were talking, I said, “Hey, you’re the same people with the T-cell test. This is the same technology.” It gave me a chance to really drill a little bit down. The technology, they actually have a preprint out there describing it. Preprint is, Clinical Validation of a Novel T-cell Receptor Sequencing Assay for Identification of Recent or Prior SARS-CoV-2 Infection.

It’s a little bit interesting, but let me just explain to our listeners how this technology works and why I think it’s superior to the technology we’ve been using for tuberculosis tests. I’ll throw my disclaimer, they’re not paying me any money for this, nor do I think they will in the future, but I will explain the technology.

Normally, to look for T-cell reactivity to tuberculosis, we do a three-tube assay. The first tube is our negative control. We actually draw up a tube which has some proteins that are specific to mycobacterium tuberculosis, or I should say somewhat specific to the mycobacterium tuberculosis complex, and then we have a positive control with a mitogen, which is going to stimulate the T-cells to produce interferon gamma.

You shake those up, you mix that all around. You have to draw it in the right order. It involves an assay looking at live cells. You need to run this within eight hours. You need to treat these tubes properly. You can’t freeze them, you can’t let them sit too long. What you’re going to do is do an assay that’s going to say whether or not you have specific memory T-cells that are going to be triggered by those proteins and produce the interferon gamma, which is your signature TH1 cytokine. Immunologists can yell at me if I made that too simple. I think that’s a reasonable description.

Now what this does instead, and it’s actually much easier, is you’re going to be doing PCR. You’re merely going to collect a tube of blood. This tube can be frozen. It can be stored. You do a simple DNA extraction, followed by a multiplex PCR that amplifies the rearranged T-cell receptor sequences. Then, this PCR product is popped onto an Illumina sequencing machine and a computer algorithm is going to identify whether the sequences that are specific for targeting or enriched for targeting of SARS-CoV-2 are enhanced. They have a specified threshold. There’s about 4,000 enhanced sequences that have been identified.

This actually is quite a bit easier. You don’t have to worry about having a lab on-site that can do these live-cell assays quickly. How are we going to use this test? I think that’s the other question. I see this personally as potentially something we’ll be looking at in those individuals who we suspect have Long COVID, but either couldn’t get a PCR test upfront or maybe have a negative antibody test and we’re trying to pick up those individuals.

I know this was covered in TWiV 128, but I just want to jump it in here while we’re talking about testing. This was the paper, SARS-CoV-2 Total and Subgenomic RNA Viral Load in Hospitalized Patients posted as a preprint. Excellent discussion TWiV 128. It can’t be TWiV 128. I’m sure the numbers off there-

VR: 728.

DG: [laughs] Have we done that many? Have you done that many?

VR: I have.

DG: I’m really just confirming. That total RNA copy numbers correlate with subgenomic RNA and the PCR is very sensitive. When people have millions of RNA copies when they have CT values in the 20s or lower, that’s probably when people are infectious. It looks like once those CT values are greater than 30, RNA copies are below the level of detection of our rapid antigen tests, 50,000, 40,000, a person is probably no longer infectious. Just nice to get a little more information there.

Active vaccination. I won’t say too much about this, except I am quite intrigued that J&J seems to be coming out as the crowd favorite, at least among a lot of my patients. Even what I was seeing is a lot of individuals at one of the large healthcare systems, about half of them have been vaccine-hesitant. They seem to be more comfortable with the J&J vaccine, the one-and-done, feeling that it’s not this mRNA technology. Exciting to see that. I know I’ve spent a little time discussing the potential impact of vaccination on people with Long COVID.

Passive vaccination. The variants. I hate the variants. David Ho emailed me this week, letting me know that at last check more than a third of the sequences at CUMC have the E484K mutation that at least in the lab makes bamlanivimab and indevimab ineffective. These are one monoclonal from each of the Eli Lilly and the Regeneron cocktails. We’ve already actually started switching our therapies over on the ground here. We’ve tried to switch over to the cocktail therapies with the idea that at least in New York City, in these regions where we’re getting the sequence, about a one-in-three chance that you might be giving a therapy that is not effective.

Also, I got to say this was the week of monoclonals. We got a press release, Eli Lilly and Company announced new data from the randomized, double-blind, placebo-controlled BLAZE-1 Phase 3 study, demonstrating bamlanivimab and etesevimab, together significantly reduced COVID-19 related hospitalizations and deaths (“events”) in high-risk patients recently diagnosed with COVID-19.

Go into a little bit more of the weeds on this. This Phase 3 included 769 high-risk patients, 511 got therapy, 258 got placebo, so it’s roughly a two-to-one match. Events, meaning either hospitalization or death occurred in 0.8% of those receiving the cocktail, 6% receiving placebo, which represented 87% risk reduction with a p<0.0001. This cocktail bamlanivimab and etesevimab together demonstrate statistically significant improvements on key secondary endpoints. There were four deaths total in the trial that were attributed to COVID-19, and they all occurred in patients getting placebo. Nobody who received the cocktail died. That was 0% versus 1.5% in placebo.

This is interesting. Number needed to treat, and what kind of reduction are we doing here? The pricing, in a sense, is targeted to this. You say we’ve got a population with about a 10% risk of dying or ending up in the hospital. We’re able to reduce that dramatically. We know that if a person ends up in the hospital, they have a significant chance of dying, but there’s also a significant morbidity and it tends to be very expensive. I think we’ve pegged it at about $40,000 on average for a hospitalization. They’ve run the numbers on this.

Your number needed to treat has a lot to do with which risk group you’re targeting here.

We also heard from Vir Biotech and GSK. Where are these people coming from? I’ve been watching this in the background, but they released a press release, and I thought this was funny. They promised to post a preprint on the results of their COMET-ICE Study, this is, COVID-19 Monoclonal Antibody Efficacy Trial – Intent to Care Early. What a name? This trial evaluated– this is going to roll right off the tongue— VIR-7831, so VIR-7831, or if that’s a little hard, you can call it GSK4182136. This is a monoclonal antibody.

This is neat actually. It targets a conserved part of the spike protein. They studied this as monotherapy. I’m going to go into what I mean by that. They presented in this press release, interim analysis from 583 patients were enrolled, and they demonstrated 85% reduction in hospitalization or death, p=0.002. Right in that same ballpark.

A little bit of notes about this. This is a fascinating concept, is you find an area on the spike protein that cannot change without disrupting the ability of the virus to basically complete its biology. It’s a required sequence, something that cannot be changed, a conserved sequence. Interesting enough, this epitope is shared with SARS-CoV-1. It’s also an epitope that SARS-CoV-1 can’t change.

Couple other things about this antibody, is that they are using, this as entertaining, a proprietary Xencore Xtend and other Fc technology that allows for higher airway antibody levels and extended half-life. I’m not sure exactly what they’re doing to get it into the airways better, but by changing the Fc– think about it. I always hold up my hands like Nixon and the fingertips are the binding part, but down by my hand, that’s the fragment crystallizable part. You can adjust that and change the half-life. You can potentially have an antibody that instead of only lasting three months, you might give this to someone and protect them for six months. They not only have ongoing efficacy trials such as this, but they also have prophylaxis trials. Can you get this ahead of time?

I did mention the variants and I mentioned E484K. What I was going to say here is I really do not like the concept of variants, and we keep talking about different parts of the world. I like to put this in my mind the way I think about choosing treatment for an individual with HIV. I want to know, what’s the mutation and how does it affect my potential therapy? I hate the E484K because we have evidence that, that decreases the efficacy of the monoclonal bamlanivimab and imdevimab, thus we’re switching over to a lot of the cocktails. Actually, this is going out to our ProHealth doctors, we’ve started sending our patients to the Catholic ERs to get access to the Regeneron monoclonals, the cocktail there. We’ve also been in talks to try to switch over all our UHG programs to using the Eli Lilly cocktail instead of just bamlanivimab, so they’ll be getting the bamlanivimab and the etesevimab because I think we want to stay ahead of this. We don’t want to give a therapy where a third of the time we might be ineffective.

VR: Hey Daniel, for HIV, you do genotyping to figure out what to treat them with. Do you think that’s coming for this?

DG: I actually am hoping we can do it rapidly enough. I reached out to Yossi Steven, and David, and I was like, “By the way, can you create an assay for me?” Because with HIV, we might start someone on treatment, they come back the next week and we have the sequence and then we adjust treatment, but we need to know the sequence now. People may not know this, but this is fascinating. Someone with HIV, when I am designing their treatment, I get the sequence of the reverse transcriptase, the integrase, and the protease and I base therapy on knowing the sequence of the HIV virus that is dominantly affecting them. It’s fascinating.

I think that when we look at monoclonals, there’s two approaches: one is we keep regional surveillance and we use cocktails; the other would be rapid, maybe it’s CRISPR-based, where we can figure out, are those relevant mutations present in that individual? And then adjust therapy based upon real-time answers.

The period of detectable viral replication, the viral symptom phase. Another press release from MERCK. This was MERCK, Ridgeback Biotherapeutics. Ridgeback Biotherapeutics and MERCK Announce Preliminary Findings from a Phase 2a Trial of Investigational COVID-19 Therapeutic Molnupiravir. This is an oral form of a potent ribonucleoside analog. This is an oral antiviral and they reported the results from a multi-center U.S. Phase 2a study. They were looking at 202 non-hospitalized patients. They were giving this within the first seven days of confirmed SARS-CoV-2 infection. The primary efficacy objective was reduction in time to viral negativity as measured by RT-PCR.

They described results of the secondary endpoint, which was a reduction in days to negativity of infectious virus isolated in nasopharyngeal swabs. They actually did this by isolation of Vero cell line culture. I knew that you would like that, Vincent. I actually did some viral culture there. There were basically some encouraging data here. We’ll see, going forward. We’re hoping we can have something like an oral effective antiviral as opposed to where we currently sit with, shall I say, a relatively ineffective IV antiviral.

There were some— Effect of Ivermectin on Time to Resolution of Symptoms Among Adults with Mild COVID-19, A Randomized Clinical Trial published in JAMA, double-blind randomized trial conducted at a single site in Cali, Columbia. They enrolled 476 adult patients with mild disease symptoms for seven days or fewer. This was a one-to-one randomization, either receiving ivermectin 300 micrograms per kilogram per day for five days or placebo.

The primary outcome was time to resolution of symptoms within a 21-day period of follow-up. The median time resolution symptoms was 10 days in the ivermectin group compared to 12 days in the placebo group. Hazard ratio resolution of symptoms, not really significant here. By day 21, 82% in the ivermectin group, 79% of the placebo group had resolved symptoms. They concluded in this study that among adults with mild COVID-19, a five-day course of ivermectin compared with placebo did not significantly improve the time to resolution of symptoms.

They went on to say the findings do not support the use of ivermectin for treatment of mild COVID-19. There are some issues, several issues with this study. Apparently, on October 20th, the lead pharmacist observed that there was a labeling error, and everyone was receiving ivermectin and no one was getting the placebo during this period of time. No virological data, population was very young. There are a lot of ongoing trials. I’m just going to leave this as this did not support the use of ivermectin.

I want to spend a little time in the future when I get more data on fluvoxamine just because I know a lot of people are discussing this, and as we get more data, I’m going to jump in and talk about that. I love the idea of early oral options.

The tail phase and Long COVID. I’m actually going to spend a lot of time. This is a longer section than usual. I know Long COVID is not as exciting as the variants, but the Long COVID population, I feel like I’ve really become committed to this population.

There was a paper, Shane Crotty doesn’t like this paper just as a disclaimer, COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler: Looking for Clarity in the Haze of the Pandemic. This was posted as a preprint. The authors described 1,407 long-haulers that had never required hospitalization for COVID-19. They reported that there were certain characteristics that were more likely to be seen in long-haulers, such as female sex, normal BMI, and these were more likely to become long-haulers. This was interesting. They suggested that as many as 32% of the long-haulers had an initial infection that was asymptomatic.

Certainly, a lot of limitations here, but as one analyzes this paper, it’s interesting. I’m not going to hang my hat certainly on 32%. This is actually something that we’re seeing in clinical practice, something I’ve seen in clinical practice where individuals come in, there’s no clear acute COVID. As we dig in a little, we get a potential exposure that was maybe a few weeks or a month before the onset of these symptoms and then we get a positive antibody test.

I do think, and I would say in my clinical practice I’ve seen people who I certainly feel comfortable diagnosing as long-haulers having Long COVID, who did not have asymptomatic acute illness, but then later on started to develop all the classic symptoms: loss of smell, loss of taste, the hair may have fallen out, the fatigue, the brain fog. I think it will be interesting too, with the T-cell test to see if those people who are serology negative have evidence of a T-cell response.

Here’s the big thing I am getting. We were all getting lots of questions about upcoming gatherings, Passover and Easter. I actually got one text, I thought it was funny. It was a news article. It was a news article on the CDC updated guidelines and the text was, “Is this real or fake news? Are they really going to let people vaccinated get together indoors with people without masks?” I thought it was entertaining, so I’ll hit it here.

As people probably have heard, this was discussed on the last TWiV, we now have the following recommendations from the CDC where they say fully vaccinated people can visit with other fully vaccinated people indoors without wearing masks or physical distancing. Or, they can visit with unvaccinated people from a single household who are at low risk for severe COVID-19 disease indoors without wearing masks or physical distancing.

This is really the part that a lot of people are asking me about. There are certain assumptions here, which I’m going to say, I’m not sure how comfortable I am with these assumptions because what is really someone at low risk for severe COVID-19? I brought up with the children. My son is 15, one of my daughters is 18, the other daughter’s 20. I know there’s a certain idea that we’ll take the 15-year-old who’s on the younger side.

If he got COVID, he loves running, sports are a really big thing for him. He runs a five-something-minute mile as a freshman in high school. If he was not able to do that, that would be a huge blow. I don’t just look at him and say I’m worried about him ending up in the hospital and dying. I’m worried that he might really have Long COVID, that he might have a negative impact. We need to really think about these decisions here. Just putting that out there.

As per the CDC, currently authorized vaccines in the U.S. are highly effective like, “What are we doing here?” They’re highly effective at vaccinated people against symptomatic and severe COVID-19. Also, there tends to be more evidence every day, a growing body of evidence, suggesting that fully vaccinated people are less likely to have asymptomatic infection and potentially less likely to transmit SARS-CoV-2 to others. I think that that’s at least what the CDC puts forward as, “What is the thinking behind this?”

I don’t want to give any specific advice on a case-by-case on TWiV, but I certainly do all day over the phone and in person, but we often get the questions about how do we make things safe? People are going to get together over Easter and Passover much as they did over the Christmas and New Year’s holiday. What are the different factors that can play into your decision? One, being vaccinated. That’s the biggest thing I can recommend. If you have access to vaccination, go ahead and get vaccinated. The vaccination access is improving dramatically and quickly. I hate that we’re on a clock here.

The other is, people who’ve had prior recent infection in the last three months, they seem to be less likely, and that also relates to people who have recently received monoclonals. That’s your lowest risk group.

The other is group size. We know that the smaller the size, the better. If you can keep these sizes small, think about that. We are really getting here to the end of the pandemic. I’ve been saying that for a little while now, hopefully just a little while, but really, we have turned the corner, the numbers are dropping, the percentages are dropping. I think that we’re all hearing that, “Hey, by the end of May, everyone who wants access to a vaccine in the United States will probably have had that shot.” This is the final lap.

Think about that question that I brought up with children. I know they may not end up in the hospital, they may not die, they may be at lower risk for those, but I feel bad when those parents come in and say, “How come no one told me?” Children can get sick. Children can have Long COVID.

Outdoors versus indoors. It’s a beautiful sunny day here in the New York Tri State Area we record. Outdoors versus indoors. Time outside, we now think, we’ve been saying this for a while, the data tends to hold about 20 times safer than indoors. Outdoors is so much better.

Testing. Don’t forget about testing. Testing is not perfect, but as we saw around Thanksgiving, around Christmas, around New Year’s, around Hanukkah, if you test and you pick up people who are positive, you can pull them out. These are layers of making things safe.

Behaviors. Alcohol and hugging. I think that’s what everyone’s looking forward to, drinking alcohol and hugging everyone. These are factors that weigh in.

Community prevalence. You got to pay attention. I have this say right here in Nassau County where I’m out here recording, we’re not doing well and we’re not doing well around kids as far as the prevalence levels. Your local community prevalence, the community prevalence where the people attending are coming from, that impacts the risk.

Health status and risk factors for the attendees. That needs to be factored in. If you’ve got someone who’s undergoing chemo, do you really want to get together now, or do you want to wait until prevalence drops and vaccination is more widespread?

Then of course, the behaviors before and after the event. I know a lot of us are exhausted. We’re done with this pandemic. We just want to “get back to normal.” If you are thinking about getting together for these holidays, another layer of protection is really minimizing your exposures before the event. Consider that if this was a potential exposure, how are you going to behave after the event?

I’m going to finish there, and then I’m going to say, hey, unless you’re driving, drop everything you’re doing, go to parasiteswithoutborders.com, continue to support us. Thank you so much. We are going to continue during February, March, and April to support the American Society of Tropical Medicine. We are hoping to get up to a donation of $40,000 to give to them because we want to help early-career women from low-income parts of the world come to the fall meeting.

Hopefully, that’s going to be safe and this is going to happen because there are a lot of inequities. There’s been a slight shown on the inequities in the world. We want to turn that around in the field of global health and we want to give these young women from these parts of the world an opportunity. Help make that happen.

VR: All right. It’s time for Ask Dr. Griffin, if you want to ask a question, daniel@microbe.tv. First one is from Douglas, who is an emergency physician in California. He says, “You’re very enthusiastic about the use of monoclonals, but my take is that it’s marginal at best for preventing significant complications of COVID-19 with the best data showing an NNT of about 20 to prevent an emergency department visit or a hospitalization and larger studies showing no clinically relevant outcomes. Is there something I’m missing?

I realize the recent press release for bam and etese reported a significant hospitalization or death in patients recently diagnosed. I would assume they did not find a statistically significant decrease in death alone, otherwise, the press release would’ve mentioned it. The IDSA currently does not endorse use of these drugs. While I have been working on getting monoclonals for our Medicaid patients, primarily on the basis of health equity, I’m not sure it’s worth the effort and cost, $1,275 infusion fee that our hospital charges for our uninsured.”

DG: This perfect timing, thank you for writing in now. I got to just present the Phase 3 data. I’ve been hearing that this Phase 3 data was going to come out. Vincent and I actually were on a call on Sunday where people from Regeneron were saying their Phase 3 data’s going to come out. I’ve been getting a lot of personal communication, and actually as the PI on the largest post-EUA bamlanivimab trial, which now I think is going to transform into a Eli Lilly cocktail trial. We’ve been seeing really incredible impact.

Just to give sort of a story on this so people can put it in, we can get some numbers in here, my partner, Anuja Lee, consulted a patient day three of illness. Their son had the COVID. This gentleman comes in dehydrated, hasn’t had anything to eat or drink for a couple of days, gets IV hydration, not hypoxic, high-risk in his 80s, multiple medical conditions. Her advice was, “We got to get this person out of the hospital, out of the ER. Let’s get them the monoclonal cocktail,” because as we just saw from the Phase 3 data from Eli Lilly, really impressive going from, we’ll say, was 6% people moving forward ending in the hospital to less than 1%.

If you look at this individual, he probably has about 20% chance of ending up in the hospital. You reduce that from 20% down to, we’ll say, a 5% or 4%, that’s pretty impressive. What we were seeing out of the MAYO and now, boom, we have this in this Phase 3 trial, nobody receiving the cocktails died. We’re seeing a big mortality reduction. When you look at the cost, basically, I’ve said that’s how they’re pricing their drugs.

They’re saying if you target a population with a 10% likelihood of ending up in the hospital and you can drop that by 75%, now I’m going to say 85%, that makes that $1,000 cost of the monoclonal cocktail makes sense. It actually saves a healthcare system. It saves an insurance company. It saves Medicare and Medicaid money versus the hospitalization.

Also, here we are, this is the most effective therapy that we have. This has a mortality reduction, pretty significant. This has a huge impact on progression. If you interact with people that have gotten these treatments, instead of being sick for weeks and maybe being chronically ill, maybe getting Long COVID, 10% to 20% of the time, we are seeing that these patients at 36 hours are, most of them, saying, “I’d feel tremendously better if they got this in time.”

Instead, the push from the ER doc, from my partner, Anuja Lee, was, “We got to get this person to hospital. We got to start them on remdesivir.” Her response was, “Hey, it’s day three. They’re not hypoxic. By the way, remdesivir, I’m not sure it ever saved anyone’s life.” No, I think the data is really impressive here. I’ve been waiting for this to be– Now it’s out there. I think it’s just a matter of time before the Regeneron joins and we get much more use and appreciation of the monoclonals.

VR: Al is an ID doc in Canada. “Due to the delayed vaccine rollout here from international supply restrictions, our province recently moved to delay the second shot of mRNA vaccines for four months citing U.K. and Israel data for effectiveness after a single shot. Many frontline workers who see COVID patients, including myself, have now had their second shot canceled.

I’m aware of the U.K. and Israeli data. I myself feel like we are playing with fire doing this. Having a large un-boosted population seems like a good way of developing escape variants as well as not adequately protecting frontline healthcare workers. I’m really curious what an outsider’s perspective would be on this as it’s very difficult to voice a clinician’s perspective over a very tightly controlled public health messaging.”

DG: Now, Vincent, this is from Canada, is that right? Did I get that right?

VR: That’s right.

DG: Okay, good. I feel comfortable criticizing the Canadians there, not very violent people. [chuckles] I just want to make sure it wasn’t some nationality that I would get in trouble. That’s exactly my fear. I worry about escape. I worry about selection for variants when you have a low level of antibodies. This is like giving someone half a dose of an antibiotic every other day. You’re basically trying to create selection pressure. I know Paul Bieniasz put out an opinion piece on this and, actually, that is a fear I have. Not excited about that approach.

VR: Miles writes, “My daughter-in-law is pregnant, first time, 11 and a half weeks. Does the lower reactogenicity of J&J vaccine make it safer for her? At what point should she get vaccinated?”

DG: That’s a challenging question, I have to say. I’m very careful to say the best vaccine is the one you that you have access to because if you say, “Oh, but I can get J&J in two months,” that’s not great. If you went in, you say, “Hey, I got either one. I could take the J&J, I can take the mRNA,” there is some suggestion. Pregnant women, you really don’t want them having fevers. Is there a certain advantage? The J&J because of less likelihood of having fever.

There also is two sides to this, I’ll say as far as safety experience. We now have had millions of people get the mRNA vaccines, tens of thousands of pregnant women. They all seem to be doing really well. The J&J platform was used in West Africa down to as young as four months of age, a lot of pregnant women. We have long experience afterward seeing that there were no issues. Really no significant concerns in my mind to any of the vaccines with pregnant women. I think I’m just going to circle right back as I did here to say, a lot of evidence that these are safe, effective. The thing you don’t want to be is unvaccinated during a pandemic, particularly if you’re pregnant.

VR: Last one is from Gary, “Can you tell me what it means that Janssen COVID vaccine protects 85% against severe disease and 100% against hospitalization? I thought severe disease meant ‘requires hospitalization’. What severe COVID does not require hospitalization?”

DG: I think that we need to all use words a little bit better here, a little bit more specific. It’s interesting. We were having a discussion. One of the local hospitals really wants to basically shorten the amount of isolation to 10 days from symptom onset no matter what. I was actually pointing out that the definition by the CDC of severe is someone who requires hospitalization and supplemental oxygen. No. When I say “severe,” I mean they’re on a ventilator, which basically means no one’s going to end up with any more than 10 days of isolation.

If you went through, and actually, this was done pretty well on TWiV, I feel like Rich was struggling with this, how are you using these words if you have a positive PCR and two symptoms? Ultimately what I did is I walked away and said I’m going to forget this confusing terminology and I’m going to ask the really important question, “Day 28, did anyone end up requiring hospitalization? Did anyone die?” The answer was zero in the vaccinated group. So, 100% of preventing people from ending up in the hospital, 100% of people keeping from dying of COVID. In my mind, that’s moderate to severe COVID.

If you can stay in the outpatient setting, if it’s nothing more than the sniffles and a fever and you feel crummy, that’s success.

VR: All right. That is COVID-19 clinical update number 53 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you so much. Everyone, take care and be safe.

[00:44:20] [END OF AUDIO]

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