TWiV 797 COVID-19 Clinical Update #77

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 28 August 2021

pdf of this transcript available (link)

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 797, recorded on August 26th, 2021. I’m Vincent Racaniello and joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Having a good week, Daniel?

DG: I am taking a little time off. I spent some time with my parents, which apparently I announced on The Brian Lehrer Show before telling them I would spend time with them, but it was nice. We’re out on the eastern end of Long Island. I saw whales every day.

VR: Wow.

DG: Even a pod of dolphins at one point, and apparently, my reaction was, “Barnaby, let’s swim really fast so we can swim with the dolphins,” but he is a little slow there.

VR: [chuckles] That’s cool.

DG: Yes. I want to thank you, Vincent, for being willing to record this in the late night here, Thursday.

VR: No problem.

DG: Then tomorrow morning, crack of dawn, I am off to Virginia. My daughters, Eloise, we’re bringing her down, Daisy’s already down there, and they’re starting fall semester at William & Mary, so it’s exciting.

VR: Oh, my gosh. It’s that time already? Wow.

DG: [laughs] It is.

VR: Oh, boy.                                     

DG: All right, right into it. We got a lot today. I didn’t think I would have that much, but, boy. Let me start with my quotation, “When one is young, one venerates and despises without the art of nuances, which constitutes the best gain of life, and it is only fair that one has to pay dearly for having assaulted men and things in this manner with Yes and No.” That’s from Friedrich Nietzsche, Beyond Good and Evil. I was a philosophy major, as some of our listeners may or may not know, and I loved reading Nietzsche. That’s not really where I went with philosophy, but he has some quotes, wonderful quotations, and I think that nuance needs to be the word of science education. Everyone wants these false dichotomies, and we need to avoid those and really focus on the truth.

How are things going? I like to say a single point does not make a line, and I feel at this point we are building on knowledge, so people can take a deep breath and relax. You’re not going to wake up tomorrow morning and find something in the news that changes everything. We are slowly moving in a very positive direction. I mentioned a false dichotomy, so a few weeks ago, Rich Condit picked a paper about false dichotomies of the COVID-19 pandemic, “COVID-19 false dichotomies and a comprehensive review of the evidence regarding public health, COVID-19 symptomatology, SARS-CoV-2 transmission, mask wearing, and reinfection.”

This was published in BMC Infectious Diseases. It’s worth a read. This will be my reader pick right up front. I know that we’ve always tried here on TWiV to avoid this black and white. People want to know, “Is it this? Is it that?” But the truth is a little more nuanced. I think at the end of the day, the inaccuracies of the black and white approaches can backfire and I think people are sharp enough. Definitely, our audience is sharp enough to get educated up to the point where they really understand what they need to.

Children and COVID, actually I’m going to update my quotation. I’m just going to say black and white, children are at risk if they get COVID, and as I’ve been saying for a while now, wearing a mask is less traumatic for a child than being hospitalized. When children were protected and did not get COVID, they could not have a lot of the consequences, but now children are getting infected.

Was listening to the Andy Slavitt podcast this last week and when I heard this number, I was shocked, so I actually had to go check it out myself. 180,175 child COVID-19 cases were reported the past week from 8/12 to 8/19. That’s here in the U.S. Among states reporting, and this was a little disturbing to me– We’ve been saying your child’s chance of ending up in the hospital is about 1 in 100, about 1%, this has creeped up to about 2.2%. If a child gets COVID, so COVID child cases, about 1 in 50 are ending up in the hospital. That’s not what I think we all thought.

We’re down to only seven states that are able to say they have not had a child die of COVID in their state. If you look at the deaths, we’re at about for every 10,000 cases in children, we’re seeing a death, so you can just do the math. As we approach 200,000 cases a week, we’re looking at about 20 children a week dying of COVID. I think that is proper to update this and say children are at risk if they get COVID.

Whether or not people want to blame the delta variant, say this changed something, or just say we are actually now seeing children getting infected, it’s clear children are at risk of death. They’re certainly at risk of hospitalization. We’re seeing rising numbers, and children certainly can have prolonged or long COVID or post-acute sequelae of COVID. I think we’ve moved past that and as we open schools, we need to think about, “What do we do to keep our children safe?”

Never miss an opportunity to test. We did have another preprint looking at the relationship between viral RNA load, Ct values in infected vaccinated, and infected unvaccinated individuals. This was the “Virological characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers.” These investigators looked at 161 infections in fully-vaccinated healthcare workers. The results are still binary, but there’s a sensitivity issue, but it’s viral isolation or not.

These investigators reported that despite similar Ct values, they found a lower probability of infectious virus detection in respiratory samples of vaccinated health care workers with infections compared to unvaccinated health care workers with primary SARS-CoV-2 infections. They also reported that these vaccinated infected health care workers, the Ct values decreased through the first three days of illness.

These investigators concluded the data support that SARS-CoV-2 infectious virus shedding is probably lower in vaccine individuals with infections caused by primarily the delta variant in the study than in unvaccinated individuals with primary infections. They also reported that there were no statistically significant differences in the Ct values between healthcare workers immunized with the four different vaccines. I know the J&J folks always feel like we’re leaving them out, but here they were seeing parity. Vincent, do you have any comments on this?

VR: It doesn’t have the quantitation that I want, right?

DG: Yes, that I want, too. That we want, yes.

VR: That we want, and that’s hard to do, but instead, the paper depends on statistical procedures to draw its conclusions. If you look at some of the comments on the Med Archive site, I think this paper can be helped by some peer review.

DG: Yes, I think that’s fair. What do we want for our listeners– to clarify? We would like to see quantification, not a binary assessment of bio isolation or not. I think the Singapore study paper was the most reassuring to me. Even if you have similar Ct values, it is for a shorter duration. I think we can at least already say a vaccinated person has a lower risk of getting infected. If they are infected, it’s for a shorter period of time that they appear to be infectious, so I am reassured.

Another topic that I get asked about, actually, quite a bit and we had the original peer-reviewed investigation addressing this issue. “COVID-19 Transmission Dynamics Among Close Contacts of Index Patients With COVID-19: A Population-Based Cohort Study in Zhejiang Province, China.” This was in JAMA Internal Medicine. This is really looking at a contact tracing and when are we seeing transmission. This study used a population-based cohort of 730 individuals. These were your index patients. They had received a diagnosis of COVID-19 in China between January 8th and July 30th, 2020, and they had a contact tracing surveillance program.

This was actually quite a massive undertaking. Field workers visited 8,852 close contacts of the index patients and evaluated these contacts for COVID-19 through August 2020, so we’re going to follow a little bit afterwards. Then a timeline was constructed to characterize different exposure periods between the index patients and their contacts. We’re trying to ask this question based on this study, “When are people who are infected, who get infected, when are they transmitting to others?”

The primary outcome was the attack rate of COVID-19 defined as the total number of new COVID-19 cases diagnosed among contacts of index patients divided by the total number of exposed contacts. Secondary outcome was asymptomatic clinical presentation among infected contacts. Relative risks were calculated to investigate risk factors for COVID-19 among contacts and asymptomatic clinical presentation among infected contacts.

Among these 8,852 close contacts of the 730 index patients, contacts were at highest risk if they were exposed between 2 days before and 3 days after the index patient’s symptom onset, peaking at day 0. Compared with being exposed to an index asymptomatic index patient, the risk of COVID-19 among context was higher when they’re exposed to index patients with mild or moderate disease.

This was about a 4.3 adjusted relative risk. Actually, a couple of things we’re getting from this study. One is I think we’re really seeing confirmation that two days before, three days after is really this peak risk. We’re also, and maybe this makes sense, but this is just one study that a person with symptoms appear to be more likely to transmit it to someone than an asymptomatic person. Remember that two days before is the pre-symptomatic period, so we add that.

There continues to be this whole discussion about, “How long do we isolate the infected? Quarantine the exposed? Isolate the infected?” One of the things that people keep asking me is we have data like this, now we have this Singapore study, people who are vaccinated, if they get a positive PCR test and they’re asymptomatic, “Do they really need to isolate for 10 days from that positive test?” We still need more data, but I could see this evolving over time. We’ll keep an eye on this. Vincent, any comments?

VR: This is an interesting conclusion. They say that if you had an asymptomatic infection, you’re more likely to transmit it to someone who’s going to get an asymptomatic infection, right?

DG: I didn’t even go there. I ignored that part.

VR: I find that difficult to understand, right?

DG: Yes. I didn’t go there. The reason I didn’t is what they seemed to be suggesting was this idea of inoculum. They had this idea that if you got a lower inoculum, you might end up with an asymptomatic. If you got a higher inoculum, I didn’t know if that, but, so I didn’t take that as a takeaway. I thought the two days before, three days after.

VR: Yes. I think that’s strong. Yes, I agree.

DG: Active vaccination. Never miss an opportunity to vaccinate and vaccination is how this pandemic gets. Monday, August 23rd, we had the announcement, the U.S. FDA approved the first COVID-19 vaccine. The vaccine has been known as the Pfizer-BioNTech COVID-19 vaccine, and now it will be marketed as, are we ready? Comirnaty. I don’t see that. I don’t see anyone changing–

VR: Horrible.

DG: Who came up with this? No one called me. I remember they used to call me when they were going to name drugs like, “Dr. Griffin, does this make you think of a sports car or a family sedan?” And they had all kinds of ideas. I don’t get this. I don’t see it working. I don’t see my– I don’t even see, personally, me remembering Comirnaty, I think. Anyway, okay.

For prevention of COVID-19 disease, an individual 16 years of age and older, so full licensure is what we’re seeing. We still have the EUA, continues to be available under EUA for individuals 12 through 15 years of age, and they threw in, and for the administration of a third dose in certain immunocompromised individuals still under EUA. That’s not under the full licensure.

Also, the impact of vaccination on hospitalizations continues to be robust. I’m going to throw some information here from the Peterson-Kaiser Family Foundation. 98.3% of people hospitalized with a COVID-19 diagnosis between May and July 2021 were unvaccinated and this cost us an extra $2.3 billion at a national level in healthcare spending. The average personal out-of-pocket cost was $1,300.

Just a couple of things I want to get out here. One is, we’re at a point now where the majority of people that end up in the hospital are the unvaccinated. It’s a huge expense to our country. This is costing us billions of dollars, but also these people, individuals who take the chance and decide to go unvaccinated, they may end up instead of a free vaccine, paying $1,300 out of pocket. I know a lot of the Kaiser Foundation people actually listen to our podcast. I thank you and I appreciate this data, but I want to go in a direction here in a sense to prepare people for what I think we will be seeing in the future.

I don’t want people to keep asking like, “Oh, is this still true? Is it still true that the majority of individuals getting hospitalized are unvaccinated?” Because at some point, I hope the majority of people are vaccinated and thus, it should be pretty rare to find an unvaccinated person anywhere, including the hospital. If we have vaccinated the majority of our highest risk population, that’s the population that even though vaccination is going to reduce that risk, they are the ones that are at risk.

I want to bring up the next article, which was in the MMWR where we’re looking at an area with very high vaccination coverage in the most vulnerable. This was in the MMWR early release, “SARS-CoV-2 Infections and Hospitalizations Among Persons Aged Greater or Equal to 16 Years, by Vaccination Status,” – Los Angeles County, California, May 1-July 25, 2021.

Here, the authors looked at an area with high vaccination rates, as I mentioned, particularly in the highest-risk populations during May 1 to July 25th, 2021. Among the 43,127 SARS-CoV-2 infections in residents of Los Angeles County, 25% were in fully-vaccinated persons, 3.3% were in partially-vaccinated persons, and 71.4% were in unvaccinated persons.

People might look at this and say, “Oh my gosh, we are seeing more infections in fully vaccinated persons,” which I expect. The more we vaccinate, the more we see, but here’s the critical– They reported that unvaccinated persons, people were 4.9 times as likely to get infected. That’s interesting. This is this new superpower, a vaccine protecting us against infection, but here’s the proof of the pudding, 29.2 times as likely to end up in the hospital. Let’s round that 30. An unvaccinated person is 30 times as likely as a similar vaccinated person to end up in the hospital.

I think it’s critical to realize now that vaccinated people, they still get infected. They still can end up with long COVID. They still could get hospitalized. They still might die, but vaccines greatly reduce that risk. I want people to start thinking and don’t keep asking for that number, “What percentage of the people that you’re seeing in the hospital are unvaccinated versus vaccinated?” Because I want that number to change. I want us to continue to vaccinate over a million people a day, which we’re doing again here in the U.S., and I really think we need to focus on getting everyone vaccinated.

I’ve been saying for a while that this pandemic is being driven by people not getting the first two doses rather than people not getting a third dose. The whole booster conversation continues. I’m going to use this as an opportunity to plug TWiV 796, “The Vary Hungry Spike,” with Paul Bieniasz and Theodora Hatziioannou. Can you pronounce that for me?

VR: Hatziioannou.

DG: Hatziioannou. I’m going to work on that because I have to say, I really enjoyed Theodora’s comments. This is a great, really great discussion, in-depth about the booster issue. When you’re done listening to me, go listen to TWiV 796. It is really worth your time. One of the things I will touch on is, “What is the game plan with boosters?” Are we, as Vincent and I talked about last time, are we planning on giving people boosters every six to eight months to keep those antibody levels high to try to boost this new superpower of protection against infection? Are we going to try to do this every fall that we go into, the winter, with our population temporarily boosted? Or is, instead, this a change of our vaccination from a two-dose to a three-dose vaccine with or without periodic boosts?

There was a preprint, “A third COVID-19 vaccine shot markedly boosts neutralizing antibody potency and breadth.” This was posted by David Ho’s group at Columbia, that prestigious university in the Upper West Side of New York City. The idea is that perhaps we rushed that first boost too quickly to get to a level of protection, something we desperately needed in the pandemic, and that if we waited and got a third dose, or a second boost, this might give us a broader and more durable level of protection. We certainly can’t predict the future. The U.S. is moving forward, it appears, with this third dose.

What did they find? This was a heterologous boost. This was, first, the mRNA vaccine, two doses, and then they got the J&J, so they had no vector. They looked at four healthy individuals and they did find that this approach boosted antibody titers. They also reported that the level of neutralizing antibodies against all circulating variants was boosted as well. This is happening, I guess. Vincent, do you have any comments?

VR: Well, really, what’s important is I don’t care about the neutralization titer. I want to know protection against disease, right?

DG: Yes. I think we’ve talked and it’s reassuring, the vaccines are continuing to be really effective, to be honest. I was hanging out with my dad last few days and he’s reading the headlines, which I think are misleading, and he says, “Oh, I just read, oh, that the vaccines are losing effectiveness.” I said, “Dad–” actually, I call him Pop. I said, “Pop, they’re losing effectiveness, against what?” He’s like, “I don’t know, what they’re supposed to do.”

[laughter]

DG: I was like, “That’s the point!” And I’m going to annoy you for a minute because we’re going to go with that– They were studied to protect against disease, death, hospitalizations. This is a new superpower that we’ve discovered and now we’re saying, “Oh, they’re not doing this superpower as well anymore.” That ship has sailed, as they say, but we’ll continue with the education. Now, what about the J&J vaccine? The poor J&J people?

I see a lot of bitterness, people saying, “I was told that the best vaccine was whatever one you could get.” This week, we got a press release from J&J where the company reported interim phase one to a data published in the New England Journal. We went over and discussed that, but in anticipation of the need for boosters, the company conducted two Phase 1/2a studies. The individuals previously vaccinated with a single-shot vaccine, and now they’re looking at giving a booster dose or a second dose of the Johnson & Johnson.

They report that 28 days after the primary single-dose vaccination, this second shot significantly increases binding antibody responses in the participants. The study is apparently going to be posted as a preprint. As we get that data, look through it, and share that certainly.

Period of detectable viral replication. This is when you test positive, this is that viral symptom phase. I like to say the time for monitoring and monoclonal is not the time for antibiotics. I have some good news on this front. I’m going to start with the bad news. We had only been using about 20,000 or 30,000 doses a week when we got to July. We have spiked up to 168,000 doses a week of the Regeneron monoclonal antibody cocktail and demand for Sotrovimab, that’s the other monoclonal from Vir or GSK, that has increased over 300% over the past month. People are getting it, people are getting the monoclonals. People are asking for it. Physicians are making sure patients get it.

Monoclonal antibodies are the most effective antiviral therapy we have for SARS-CoV-2 right now, for people with COVID-19. We also got some preliminary results of the NIH-sponsored Phase 3 ACTIV-2 trial. This is another combination of two monoclonals. They looked at over 800 randomized patients. They gave this combination of—It’s BRII-196, don’t worry, this does not roll off the tongue, and BRII-198. They looked at the composite endpoint of hospitalization and death, this was reduced by 78%.

They had a P-value of 0.00001. These are incredibly effective therapies. I would love to see the move from EUA to full licensure, just like those vaccines, but I do have a little pet peeve as well as this is going. We discussed a couple of months ago, mid-June, the excellent data from the UK RECOVERY trial, where we know that early on when people were given this late in the ICU, it was not helpful, maybe harmful. But if you can give this to individuals early at hospital admission, people that show up, but are still antibody negative, there’s a 25% reduction in mortality.

Actually, if you look through a lot of our trials, that subset always did well. If you look at people who show up without an antibody response, serology negative, there is a mortality reduction. It’s not helpful if the person has already mounted that antibody response, if it’s already late, they’ve been in the ICU on a ventilator for a while. But if you look at the EUA, the Regeneron-COV, so the casirivimab and imdevimab, is not authorized currently under the EUA for patients who are hospitalized due to COVID-19.

That’s a bit of a challenge, and we’ve actually talked about it among other infectious disease physicians. Here, you have a therapy, you have really good data that you can make a difference, that you can reduce mortality, we’re limited. The EUA is restricting us. I know people at the FDA listen, so we would like a little bit of liberalness to use this effective therapy.

The early inflammatory phase. This is right often when people get hospitalized. I think I’ve talked about what I call “the soft admission,” someone comes in with an oxygen saturation of maybe 92%. Here in the New York area, a lot of our ProHealth Urgent Cares, we will start them on oral steroids. A lot of these individuals stay above 90 and can avoid that, what I call “the five-day remdesivir stay.”

Remember, remdesivir’s only benefit was reducing hospitalizations. If you hospitalized someone to give them remdesivir, you’ve failed to do what remdesivir has been shown to do. If we can save that $3,000 drug use, we can save those hospital beds for people who really need them. Not just COVID patients, a lot of individuals that need access to the hospital. Let’s try to make some smart decisions there.

Another thing that is challenging in this area is we are now experiencing tocilizumab shortages in many parts of our country. Mixed feelings here. It’s tremendous that it’s now recognized that patients that have been started on steroids, progress to higher oxygen needs. You can again– seems like a magic number, 25% mortality reduction by adding tocilizumab to the right patient at the right time. Obviously, this medicine is being used, but we need to really make sure we’re giving it to the right people because we are now, with the rising number of cases, with the rising number of hospitalizations, rising number of people who are meeting this criteria, we’re running out of drug.

I am going to jump to, “What is going on around the world?” No one is safe until everyone is safe. I’m going to close on this section. My friend Titus Divali, he’s a physician in Blantyre. Actually, I met him at an American Society of Tropical Medicine and Hygiene meeting. Actually, one that I drove down with Dickson in his Prius and heard all about the hydrogenosome or something along those lines. I think I blocked it out, so that Dickson could tell me the story again because he loves that story. Dr. Divali brought to my attention the article, “Dynamics of SARS-CoV-2 exposure in Malawian blood donors: a retrospective seroprevalence analysis between January 2020 and February 2021.”

There’s been lots of questions about what’s going on as far as COVID in parts of the world where they have limited vaccinations. Lots of speculation on what’s going on, but here, the authors measured the seroprevalence of SARS-CoV-2 antibodies among randomly selected blood donor sera in Malawi, from January 2020 to February 2021. A total of 3,586 samples were selected from the blood donor database.

The seroprevalence approach is really, I think, a very straightforward way to looking at the pandemic, I think, for most of our listeners. If you have the time, this is something you can access as it’s posted, so there’s no paywall on the way. And if you go to figure one, what they did is they looked at each month and what was the SARS-CoV-2 seroprevalence percentage in the blood donors at each time. Basically, by the time you get to this January, February surge about half of 49.7 of the samples are seropositive. You can see this surge over time with a little bit of delay because it takes time there.

Well, I think that’s the big challenge ahead of us is vaccinating the world, and I’m going to remind our listeners, first, thank you for all your support. We are going to continue through the months of August, September, October, all of the donations made to Parasites Without Borders will be doubled. We’re hoping to get up to $40,000 to support Floating Doctors. They’re starting to—FIMRC is starting to do in-person visits to a lot of these areas that they serve, and so thank you for helping us.

VR: It’s time for some questions for Daniel, you can send yours to [email protected]. Our first is from Marsha, whose 38-year-old son has a condition called seronegative spondyloarthropathy, which is related to psoriatic arthritis, though he doesn’t have skin symptoms. His rheumatologist recently recommended he begin taking HUMIRA, an immunosuppressant drug to help relieve the pain and limitation of mobility he experiences. His feet are especially affected, causing pain and difficulty walking. He received two doses of Moderna at the recommended interval reached the milestone of two weeks beyond the second dose on June 1st.

Two questions. “Before beginning to take HUMIRA, could he get an antibody test, quantitative if possible, to determine his existing level of immunity from his two-dose vaccination? Two, before beginning to take HUMIRA, should he have a third dose of vaccine to boost his existing immunity and wait two more weeks before starting HUMIRA?”

DG: There’s a lot in here. For just clarity, this 38-year-old young man has this seronegative spondyloarthropathy. Spondyloarthropathy, think of it as an autoimmune disease. Think of it as an issue where the immune system is triggering this disease, and the way they’re fighting it is they’re using an immunosuppressive drug, HUMIRE, quite popular, that interferes with TNF alpha. This is like, I guess, I’ll say infliximab. Some of those drugs, some of our first biologicals that we used in the ‘90s quite widely.

The concern here is because the immune system is being interfered with, because we are making this gentleman immunosuppress, is he going to fail to have the same robust response that we would like? Well, the tricks is, and I think we’ve talked a little bit about this, is that measuring the antibodies is not clearly predictive of what’s going on, and the TNF alpha is not purely impacting the B cells.

What is the standard and what is the science? This is certainly going to be one of the individuals who will be offered a third dose of vaccine going forward. We do not yet know how much benefit that gives. That science is still being done. We have lots of studies where people have been given a third dose and they measure the antibodies, but we don’t know really what that means.

One of the questions you have here, a real on-the-ground question, is, “Should there be some sort of timing related to the HUMIRA?” Actually, a physician colleague of mine asked me yesterday, same really very similar scenario, also on HUMIRS, so same drug, and it was a question of timing relative to the dose of vaccine. Two weeks is actually a period of time that we often recommend, again, not a lot of science to guide us, really just to understanding of the immune system, trying to separate the immune suppression.

Remember, this drug lasts for quite a period of time, so that two weeks is a question of, “What amount of time is a person willing to be off HUMIRA? My friend, who’s a physician, he’s going to go ahead and miss a full cycle. He’s actually going to stay off for four. It’s going to be two months, so he’s going to skip the one, and then he’s going to go add eight weeks to the next dose.

VR: Next one is from Doug who writes, “I notice you usually talk about the importance of infections after vaccination being classified as either just a positive test or the more important hospitalization or death. However, when you’ve compared the rate of reinfection after natural infection versus the rate of infection after vaccination, you only compared positive tests and did not mention if there’s a difference in hospitalization or death. Are those data available?”

DG: Yes. A lot of people really want a head-to-head comparison. What about people that had a natural infection? What is their risk, six months, seven months, eight months compared to someone who’s been vaccinated? What is their risk of the different outcomes? We don’t have any really great head-to-head studies. If you think about it, it’s hard to do. You need to have a cohort of individuals that have natural infection, a cohort of individuals that are vaccinated.

We have great data on the vaccinated individuals, really tremendous data. On people with natural infection, what we’re seeing is a low risk in the first three months. They actually tend to do okay till about six or seven months. That’s when we’re starting to see this increasing rate of reinfection. What do the variants do relative to that? We’ll find out as we go forward.

I guess what I should say, what we do know, and maybe this is the real question. If you had natural infection, should you just sit back and trust the protection or should you get a vaccine? If you go ahead and decide not to get that vaccine and your buddy gets that vaccine, you are more than twice as likely to end up reinfected than a person who decides to get vaccinated.

VR: Chris writes, “The Times is reporting that Pfizer could be given full approval on Monday, which we just said it was. I have seen a lot of discussion on Twitter with conflicting information from people who all have MD in their bio about whether or not it could then be prescribed off-label for children. Can you clarify the facts here, and if it is possible to use it off-label, how a pediatrician or parent of a kid less than 12 should think about the risks? I do not have kids, but a number of my friends do, and they’re all worried sick about the fall and going back to school.”

DG: Yes, no, this has been quite a discussion in my household, I’ll admit. What is going on here? It’s not being recommended for under 12, and part of the issue is when we look at the ongoing studies, it’s not a safety issue, it’s not an efficacy issue, it’s an information issue. When you start getting younger, small children are not just small adults, they have a different physiology, they are smaller. They may actually end up benefiting from a dose reduction. They may end up with a different dose than what we’re using in adults. Those studies are ongoing. The FDA has added, so that when we do move forward here, the timing is terrible. I admit that.

Now, let’s say someone is 11 years old, and they’re going to turn 12, and they’re a couple of months away, but they’re 100 pounds or 150 pounds. There is a little bit of discretion there, right at the edge, but none of us are encouraging four or five, six-year-olds to start getting vaccinated just because the license has gone. I think there’s going to be a lively discussion here. It is very frustrating as we see a growing number of children getting infected, a growing number of children getting hospitalized, as we’re seeing a couple of kids, two to three, dying a day. This is not great.

I understand a lot of people wanting to be able to move forward. We’ve got to continue to keep those kids safe a little bit longer till we really have the science and knowledge. Even if there is an uncommon side effect, we need to be able to recognize it so that it becomes just something minor or something that we can address rather than it becoming something more significant.

VR: In reality, Daniel, what’s to stop a physician from giving this off-label to a kid?

DG: In all honesty, the majority of therapeutics that we offer to children have never been formally tested, do not have in the package insert. No, this is actually the way medicine works.

VR: One more from Abby, “I have two kids, four and 18 months. Their pediatrician told me that it would be March before they could be vaccinated. I learned that there’s a Phase 2/3 local trial of Moderna vaccine in ages 6 months to 11 years. With community transmission increasing in our area, I feel that their risk of contracting COVID is higher than the risk of the vaccine causing a very negative reaction, but it’s hard to tell. How safe are Phase 2/3 trials? I understand they may get the placebo, but other than that, do you have a sense of the likelihood of severe reactions? As a parent, would you enroll your child in one?”

DG: Yes, maybe I’ll start with the last question. Yes, I would, actually, because we clearly know the impact of COVID. COVID is bad. The vaccines we’ve given these to millions, hundreds of millions of individuals getting down to 12-year-olds. We have ongoing trials looking at younger individuals. If I was looking at having to wait that long, looking at waiting through a winter.

Actually, just to bring this home personally, when the vaccines were rolling out and my son Barnaby was too young to be eligible, my wife actually actively investigated enrolling him in a trial so that he could get vaccinated, get that protection potentially 50/50 sooner. We don’t know if it’s placebo or not. I guess I’ll throw all that out there. Even now, I would say the risk of a problem is incredibly low because we have so much experience, much more experience than we had even when we started the adult trials.

VR: That’s COVID-19 clinical update 77 with Dr. Daniel Griffin. Thank you, Daniel.

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

[music]