TWiV 817 COVID-19 Clinical Update #84

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 16 October 2021

pdf of this transcript available (link)

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

[music]

VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 817, recorded on October 14th, 2021. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: I’m looking at a map of U.S. cases, Daniel, and it still appears to be dropping, right?

DG: It is. If you look at the world, if you look at the United States, it’s on the way down. Regionally, there are some issues. I was just looking at numbers in Minnesota, where some of my friends and colleagues are based, not so good. A lot of people keep scratching their heads, but the big picture’s looking good, some of the local pictures’ not so great.

VR: What fraction of the U.S. population is fully-vaccinated? Two doses, not three.

DG: It’s only in the 50’s.

VR: Okay. What fraction have been infected, do we know?

DG: I’m not sure we actually know. There’s a couple things I think that get into that because what you want to know is, How many were vaccinated then? And then how many of the unvaccinated were infected? Then we’re still trying to figure out the reinfection rate in that population, but then also not just reinfection, but the illness severity in that population because at some point– Yes.

VR: Your head is cut off– Oh no, it’s not cut off, sorry. It was my screen, never mind.

DG: Okay.

VR: Okay, go ahead.

DG: That’s okay. Apparently, I’m also losing a little hair. [chuckles]

VR: Happens.

DG: Yes, that’s what I hear. Let’s go right into the quotation. We got a lot to cover today. Today is an exciting day. I am going to start off with a quotation “Reality is that which, when you stop believing in it, doesn’t go away.” And that’s by Philip K. Dick. I actually really enjoy reading the Philip K. Dick books. Some of his writing is a little bit, you know, I’m not sure my son should be reading them quite yet. Some writers don’t always age quite well.

I actually was listening to one of the other TWiVs where they were talking about the Microbe Hunters, again another great story but boy, when you read it through and they start talking about– It wasn’t really a problem because just the Irish people were dying, but then the British started getting infected. You can imagine sometimes– I’m not sure that ever would have rubbed me the right way, but yes, just during these dark times, it’s nice every so often to get a little bit of a break and read some science fiction.

All right, last time we talked about a lot of meetings and today was the Moderna booster meeting. Don’t worry, I’ll share what happened hot off the press. I called my wife for the update I was like, “Oh Jessica, how’s it going? What are they saying? I’ve been busy seeing patients all day,” and her response was, “You’re kidding? You don’t think I’m actually sitting here watching the Moderna FDA advisory discussion?” but we will get into what happened there.

All right, we’ll start with children. Children are at risk for COVID. I think that’s really clear. As I like to say, “Wearing a mask is less traumatic for a child than being hospitalized.” Where are we with children? I’m going to do my update here. The data most up-to-date was October 7th here in the U.S. This is data made available through the American Academy of Pediatrics collected by the CDC. Over 6 million children here in the U.S. have tested positive for COVID-19 since the pandemic start. Over 23,000 children have been hospitalized and we’ve had 542 children die from COVID.

I think that any of the ideas back before when people were talking about this not affecting children, just to put this in context, because I think that this is going to be part of that decision that parents are going to be making. Is COVID an issue for children? Why am I vaccinating them? I know early on a lot of people talked about, “Oh, we got to vaccinate the children. Herd immunity. Stopping the spread.” I’ve never really been of that school.

As a parent, I’m going to vaccinate my child because I feel like it is in their best interest. Barnaby, as soon as he was eligible, we got him vaccinated. Daisy and Elle are a little older, so they got to get vaccinated a little bit sooner. I didn’t do it for the common good. I did it as a parent because I felt that for them, it was an individual decision that protected them. We are going to get some data. We’re going to hear a discussion on the 26th about the vaccine moving down into the five and up.

While we’re waiting on that, there was another, what I thought was interesting, pre-print posted, “Comprehensive antibody profiling of mRNA vaccination in children.” The background here is that after infection with SARS‐CoV‐2, a significant number of children do not seem to generate a robust antibody response, so we’re quite concerned. Is this going to be a cycle of repeat infections here? Are the vaccines going to work in this population? Is something going on here? Here, looking at the mRNA vaccine response in children, the data was reassuring.

They were able to show robust antibody responses for IgM, IgA, IgG, even after just the first vaccination. And then with the second dose, you’re getting right there up to the levels that we’re seeing in adults after vaccination. A couple logs higher than we see after a pediatric COVID infection. Much better antibody response with the vaccines, much more consistent antibody response with the vaccines. Don’t worry, we’ll touch on the fact that, you know, What about the T cells? What about the protection? It’s more complicated than just one of those antibody levels.

All right, we’re getting more and more uptick with the rapid testing. I think I’ve been mentioning that getting that diagnosis is really critical in a timely manner. Time is an issue here with COVID. One of my son’s friends actually had an exposure, so a high school boy. It took almost a week for a PCR result to come back after that exposure. A child missed a week of school just waiting because of resulting delays. Even here, where we think we have pretty good access to tests, we’re still running into resulting delays.

All right, active vaccination, this is an exciting part. I like to say vaccination is how this pandemic ends. We got data on Novavax, the pre-print “Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.” These are the results from the Phase 3, randomized, observer-blinded, placebo-controlled trial evaluating the efficacy and safety of the Novavax vaccine in adults equal to or greater than 18 years of age. This is U.S. and Mexico, First Quarter of 2021.

Now, here, the participants were randomized into 2:1 ratio to receive two doses of the Novavax vaccine or placebo 21 days apart. The primary endpoint was vaccine efficacy against PCR-confirmed COVID-19. In SARS‐CoV‐2, naive participants starting to look seven days after the second dose. There were 29,949 participants randomized, 19,714 received the vaccine, 9,868 placebo. All moderate to severe cases confirmed in placebo recipients. None in the vaccinated. None of the moderate to severe.

We get that vaccine efficacy of a hundred percent for prevention of moderate to severe COVID. Remember, there’s going to be confidence because once you start giving this to more people, the confidence interval here is 87 to 100. Most of the sequence genomes were variants of concern, the vaccine efficacy against any was 92.6. Let’s hit those numbers again, vaccine efficacy against prevention of moderate to severe COVID, we’re getting 100%. What about vaccine efficacy against even infection? That was 90%.

VR: They actually looked at infection, which they weren’t doing early in the Pfizer and Moderna trials, right?

DG: I think that this is really important. We’ve actually started to, I guess, appreciate and look for what I refer to as the superpower. Something that we really didn’t look for in prior vaccines. One of the issues I have with this “superpower” is we don’t know how durable that is. We don’t think that that’s a durable thing. We think that that’s going to be a window, so we’ll keep getting back to that. I want to say the reactogenicity was mostly mild. This is one of those vaccines that often the placebo and the recipients can’t tell whether or not they got it. We think that this may be better tolerated, less reactogenicity, so that may play a factor here.

VR: Daniel, any idea when they will apply for EUA?

DG: We are told that it’s going to happen by the end of the year. That’s the rumor.

VR: Wow. That’s a big confidence interval.

DG: [laughs] What’s that confidence interval with how many months? October, November, December. [chuckles] They have to apply soon, because the FDA is pretty busy, they’ve got a pretty busy docket.

What about boosters? First breaking news, as we’re recording this, October 14th, the Food and Drug Administration Advisory Committee unanimously recommended giving booster shots of Moderna’s COVID-19 vaccine to people age 65 and older, and other vulnerable Americans. Then the story gets more complicated. We’re going to talk a little bit– there’s two articles I’m really going to go into this week, the first article, “Heterologous SARS-CoV-2 Booster Vaccinations,” preliminary report.

This is under review at the New England Journal of Medicine, but was posted as a pre-print. It is preliminary, not all the data is here. John Mascola, the Director of Vaccine Research Center down at the NIAID, sent this my way, and I expect this to be part of Friday’s discussion. So when this drops Saturday, that’ll be behind us. I think that this is a publication that will get a lot of discussion, but I think it’s important to go a little bit into, “What does this publication show/suggest?”

Just to give people background here, at the end of September on the TWiV COVID update, we talked about effectiveness of the single-dose Ad26.COV2.S COVID vaccine, the J&J. This is a preprint where they were saying a vaccine efficacy of 79% for a recognized infection, 81% for COVID-19-related hospitalizations, just one shot. Then they looked at Phase 3 ENSEMBLE 2, “What if we give that second shot?” Just like we’re doing with the others given 56 days after the first, we got that 100% protection against severe or critical COVID-19, looking 14 days after second shots. That got us up right at that mRNA level.

A couple things I want to point out though, as impressive as this was, J&J tends not to generate a lot of antibodies. We’ve talked about how if you look at a two-dose series of mRNA vaccines using the same units, you’re talking about 3,000-4,000, J&J getting the same efficacy, you’re really only talking about 300. Dare I say, antibodies may not be the whole story.

Let’s go into this new preprint. In this new preprint, and I want people to think about this as we go– I’ve gone through this paper a few times, in the ICU and then with some of the residents on the floor there. I always make a person play a different role. What we’re doing here is, we’re looking at individuals that got either J&J, Pfizer, or the Moderna as the first shot, and then we’re going to give them one of those three as the second shot.

You can imagine, we’ve got the person, the J&J person, they’re wearing their wool hat. We’ve got the Pfizer person, they’re wearing their nice business suit. Moderna person, think of that as your tech person. They’ve got that sharp custom t-shirt on. And then I asked them, “We can now give you one of these three for your second shot.”– We got a little brand loyalty we’re pushing up against here. Here in this study, they are going to look at what– not vaccine efficacy I want to be clear. They’re going to look at how high can we get those antibodies?

We’ll start off with our J&J fellow. Remember, we’re going to get back to what does that mean? Right now, we get to have fun and we get to root for what’s going to happen, and I think Vincent already knows what’s going to happen. We give our J&J person that second J&J shot, they’re now up to that wonderful 100% efficacy, great efficacy as well as the mRNA vaccines, but those antibodies they don’t really go up very high. They stay low. What if we give him a Pfizer or a Moderna? They get up there to these really nice high levels a little bit higher with the Moderna.

Now, what if our individual starts off with Pfizer, and we give our Pfizer, remember this is our person wearing the fancy suit, and we give them J&J, they get really nice high antibody levels. What if we give that Pfizer person a second Pfizer shot? They actually get up pretty high. What if we give them a Moderna shot? It gets up high, but even a little higher than if they got a second shot of the Pfizer.

Now, our Moderna, not to leave them for last, the Moderna person we give them a J&J, nice antibody levels. We give them a second shot of Moderna, nice high antibody levels. We give them a second shot of Pfizer against the brand loyalty here, and we get nice high antibody levels even a little bit higher.

If you’re only looking at antibodies, two shots of J&J doesn’t give you great antibody levels, but we know from the prior data, you get great protection. If you give someone who got a Pfizer or Moderna a different brand, a different formulation, you get slightly higher antibodies if you mix and match than if you do the original. I have to say this is a fun paper, but Vincent, I’m going to pull you into this. What does it mean?

VR: See the problem, Daniel, as you know, is we have no idea what these antibody levels mean. We don’t know what the correlative protection is. The J&J second shot gave great efficacy against COVID, and if the antibody levels, as you say are low, maybe that’s enough to get great efficacy or maybe T cells are also playing a role. I think this focus on antibody levels is misguided frankly. [chuckles]

DG: One of the times when I was presenting this, this is at the end of the day and it was one of the residents. He was thinking about it, and he said, “You know what?” I always love analogies and he’s like, “Think of the antibodies, they’re like the ground troops, but what really gets you out of trouble is the air support.” We’re looking at the ground troops here, we’re interested in the antibodies. There’s a certain role here, but then when you call in those bombers, those jets, that’s what I think we really care about.

I’m not sure that we know what to make of these antibodies. We’re going down this road where we become in the circle echo chamber of talking about antibodies, this is a fun paper, but I’m not sure what it really means. What I will say is there are T cell studies that are being done, so this is preliminary. We’re going to get T cell data, hopefully, we’re going to get some memory B cell data. We’re interested in that. You know what I really care about, Vincent? Can you imagine? I want to know about efficacy.

VR: How about that? The magic bottom line.

DG: That’s really the bottom line. Otherwise, I think we’re assuming we know more than we know.

VR: I think your point about B cells is important. We had a guest on TWiP— By the way, Daniel, not TWiV, IMMUNE, you’ll love it. She works on the immunology of helminth schistosome infections, but she said, “The focus on antibodies is not quite right because it’s really memory B cells, at least with respect to antibodies that matter.” That’s important for sure. I agree, we should be looking at efficacy, not just antibody levels. The other thing is, Daniel, I’m sorry one more thing, I get a lot of questions as you must from people say, “I got this vaccine, can I take this other one?” This answers that question now, “It’s okay, it’s safe, and it works.”

DG: Definitely and I think that’s great that you touched on that, Vincent, is this gives us the safety data was fine. This was safe, there were no concerns, the mixing and matching, when our episode drops on Saturday, this Friday, there’s going to be a discussion about, “Hey J&J, can people get a second dose of J&J if they want?” We expect that to be a yes. “What if they want to mix and match is that okay?” I suspect we’ll see what happens, but this data would suggest it’s fine.

As my mother said, if she got a couple of those Pfizer shots, but now she wants to go with the Moderna Spikevax, it should be fine. There should be the ability, and next year– This is important. What happens next year if they start saying, “We need boosters”? If I want to switch from the Comirnaty camp to join me in the Spikevax camp, it should be okay.

VR: When Amy told me about this, she said, “Now, Daniel can tell his mom it’s okay.”

DG: [laughs] She has to wait. She has to wait till next week.

[laughter]

Now, we are in the period of detectable viral replication, the viral symptom phase. The time for monitoring and monoclonals and eventually maybe something more. Not the time for antibiotics, not the time for steroids. What about aspirin? What about anticoagulants? That question has come up for a while. We have the peer-reviewed article, “Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.”

Do I give the patient anticoagulant? Do I give them aspirin? Is that going to be helpful? Is that going to be a benefit or am I just getting risk without benefit? This is an adaptive, randomized, double-blind, placebo-control trial of anti-platelet, so aspirin, and anticoagulant agents with blinded, adjudication of outcomes of 657 symptomatic outpatients with COVID-19 conducted in the U.S.

The participants are either going to get a baby aspirin, that’s the 81 milligrams once a day, a low dose of Apixaban, that’s one of those oral anticoagulations, anticoagulants, a higher dose or placebo. Then they’re going to look at all-cause mortality, they’re going to look at clots, heart attacks, strokes, hospitalizations. Basically, what did they find? They did not find benefit. There were a few non-major bleeding events associated with the aspirin and the anticoagulation arms about 2% above placebo, so no clear benefit, minor low risk of harm, so more support for keeping those hands in your pocket.

We can certainly do harm during that first week. We can do some positive things in the right patients by getting them those monoclonals. Then, hopefully, we’re going to have oral antivirals on the horizon. On Monday, October 11th, Merck and Ridgeback announced that they submitted for emergency use authorization for molnupiravir. That’s the investigational oral antiviral medicine for treatment of mild to moderate COVID-19 in at-risk adults.

This is based on the data that we discussed last week. So this will be four, it looks like capsules, if those pictures circulating are true, I’ve never actually held the capsule in my hand. Four capsules twice a day, five days. And if approved, how are people going to get this medication? We have heard a little bit, we’re already planning on distribution prior to approval, so maybe that’s a good signal.

The government’s going to be involved, the federal government. If approved, the federal government will allocate a certain amount of pills to each state, and then the states will be involved in distributing these. The hope is these end up in pharmacies, not putting more burden on our hospitals, because ideally an outpatient gets diagnosed, is able to get those pills as soon as possible. We think sooner is the better here, and then we move forward.

Now, what about those monoclonals? A little more data here. People may be feeling like, boy, we’re getting a lot of data on those monoclonals, when are they just going to license them and stop the EUA. Top-line data from AstraZeneca, the results of the TACKLE Study. Now, last week, we talked about this long-acting antibody cocktail for prevention, now this is a treatment, so treatment now.

TACKLE is a Phase III randomized, double-blind, placebo-controlled multi-center trial. It’s got all the right components, and they were looking at the safety and efficacy of a single 600 milligram IM dose. I say sequential, I say it’s actually two shots is my understanding. Looking through the clinical trials, so you’re going to get two shots intramuscular– That’s actually one of the changers here. I want to sort of give, like why do I care so much?

Let’s take a scenario, the patient finds out that they’ve been exposed, that they’re at risk for COVID, they start having symptoms, they go and get a test. I’m going to say it’s Monday. There might be a resulting delay because they’re taking the PCR instead of the rapid. Now, it’s Wednesday, the test comes back positive, a clinician goes online, fills out all the stuff, uploads that test positive results. Within a day they get a call, maybe three days later they get scheduled for the monoclonals. Lots of resulting, lots of delays get built-in.

With an IM formulation, the idea would be the person gets that rapid test, they immediately get the IM injection. We think, again, time really makes a difference. What were the results here, 903 participants randomized 1:1, giving the two separate sequential IM injections, and we saw 50% reduction in the risk of developing severe COVID-19 or death. I want to say well-tolerated, effective, just little more data that the long-acting antibody combo can be of benefit, not only just in treatment, also in prophylaxis. Remember, after this IM shot, we expect this protection to last for 12 to 15 months, so these individuals are going to be followed out for 15 months, so exciting stuff here.

All right, the early inflammatory phase. This is when those folks might start to get hypoxic, enter into that cytokine storm, that pulmonary phase. This might be when they end up in the hospital on oxygen, and one of the mainstays of treatment is steroids. Here was the question of does everyone need steroids? Does everyone benefit from steroids? Is there some sort of granularity here?

This was an article published by my colleagues out at Stony Brook [University] here on Long Island. In the JAMA Network Open, the article “Association of Serum Ferritin Levels and Methylprednisolone Treatment With Outcomes in Nonintubated Patients With Severe COVID-19 Pneumonia.” This is steroids, and you’re looking at a blood level of serum ferritin, which is an acute inflammatory marker. Here, the authors were trying to ask that question, “Do all patients benefit from steroids? Or maybe there’s a subset where the steroids are more effective?”

This was a retrospective, cohort study. Not a prospective, blinded, randomized controlled trial. So we have to keep all the potential confounders of such studies in mind, and we’re going to see that there’s a certain suggestion here that these patients may not have been randomly-assigned to steroids or not. They noted among the 300 patients, 380 patients with the available ferritin data, steroid use was only associated with lower mortality in those with ferritin levels in the highest tertile, so greater than 1,322 nanograms per milliliter.

People not familiar with tertiles, these are not those hard-shelled reptiles, this is when you take your group, and you divide it into thirds, so two divisions. You’ve got one on the left, one in the center, one on the right, and the people in that highest level were the ones where they were seeing the mortality benefit. But here’s a few interesting features: you can’t just take the top line, you have got to actually read the whole article.

If you started to look at patients in the highest tertile, and you compare them to the other patients, they were often not getting azithromycin, they were often not getting hydroxychloroquine, they were more often, about a third of the time, getting tocilizumab. And I think we know if you get tocilizumab without steroids, not great. Looking at the other medications suggested to me, maybe they’re actually being treated by different physicians.

If your physician is giving you azithromycin and hydroxychloroquine, that’s a different situation than a person who’s getting steroids, maybe an IL-6 receptor blocker if there’s an issue. I think that this is interesting. I think ultimately you need a physician, a clinician, making a good decision about your treatment here.

All right, now this is the second article that I’m going to spend a bit of time on, and this was JAMA Internal Medicine, the peer-reviewed original investigation that I have to say I was waiting for this to get published, “Efficacy and Safety of Therapeutic-Dose Heparin vs. Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19, The HEP-COVID randomized clinical trial.”

This is one of those studies that might be important, so I want to spend a little time, a little deeper dive here. A little background, the first author on the study is Alex Spyropoulos, right here in New York at the Feinstein Institute. That’s where Betty Diamond is, I think she was discussed on one of the other TWiV’s shows, the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

Our listeners may remember him, he was not treated particularly favorably in El New York Times piece, “The COVID Drug Wars That Pitted Doctor vs. Doctor.” This gentleman was, if you could imagine trying to do randomized control trials during the pandemic, and there was some interesting dynamics. Early on, it was not clear whether anticoagulants were important or not, and I think more so, what dose of the anticoagulant?

Despite some challenges and I say, Alex is a fantastic gentleman, a great researcher, really well respected. He was able, despite some challenges, to pull together the HEP-COVID trial, this is a multi-center, active control, randomized clinical trial that enrolled patients from May 8, 2020 to May 14, 2021 at 12 centers in the United States. There’s actually a separate trial design paper that was published previously, “Treatment-Dose LMWH (low molecular weight heparin) versus Prophylactic/Intermediate Dose Heparins in High-Risk COVID-19 Inpatients: Rationale and Design of the HEP-COVID Trial.” That was published in Thrombosis and Hemostasis, and they go into a lot more details.

Randomized, pseudo-blinded, active-controlled trial conducted both in hospitals within the Northwell Health system in New York and other healthcare systems in the United States. What they’re going to do is they’re going to stratify the patients into those requiring ICU level care, not just geographic, and those non-ICU, not requiring that level of support.

This is a pseudo-blinded design, so the PIs don’t know what arm the patients are in, but the study pharmacists, they’re aware. The research coordinators are unblinded, so there is a safety aspect, which I actually thought made sense. The patients were randomly assigned 1:1 either to the therapeutic dose, it was enoxaparin, that’s a low molecular heparin anti-coagulant, or the institutional standard prophylactic dose, or intermediate.

What did they find? Well, they looked at the primary efficacy outcome, which was one of three things. Either a venous thromboembolism, so this would be a symptomatic upper or lower deep venous thrombosis, an asymptomatic lower-extremity proximal deep venous thrombosis, a symptomatic pulmonary embolism, a splanchnic vein thrombosis, or a cerebral sinus thrombosis, or an arterial thromboembolic event. A myocardial infarction, ischemic stroke, peripheral or systemic, or death.

Now, they started off screening over 11,000 patients. Ultimately, 253 were included. Here, and I think this is really important, what they were asking here and I’m going to go back to the title because I think this is really critical– They are saying efficacy and safety in high-risk patients. High risk for clotting not high risk for bad COVID. How do they define high risk? They need to have D-dimers they say very elevated, so greater than four times the upper limit of normal or a sepsis-induced coagulopathy score of four or higher, so I think that’s important.

We are saying an individual who has COVID, who’s hospitalized, who is at high risk of a clotting complication, should they get high-dose anti-coagulation or should they be on prophylactic? Basically, what did they find? They did find that there was a significant difference in the non-ICU patients getting therapeutic dose versus the prophylactic dose. What does this add? I think it does add something important and I reached out to Dr. Spyropoulos and was able to get even some more granular data on this.

The current American Society of Hematology recommendations for people hospitalized with COVID-19 is for prophylactic intensity anticoagulation for patients with COVID-19 related critical illness who do not have suspected or confirmed thromboembolism. If they already have a clot, they’re going to be being treated, but the patient’s without that.

I think that this is where this adds something. We have had, as part of that guideline, an individual’s assessment of the patient’s risk of thrombosis and bleeding– it’s important when deciding on anticoagulation intensity. The panel acknowledges that higher intensity anticoagulation may be preferred for patients judged to be at high thrombotic risk and low bleeding risk. Where was the evidence for that? I think that this article is important and adds evidence to support that qualification.

If an individual is judged to be at high thrombotic risk at this low bleeding risk and now we’re looking at using D-dimer greater than four above upper limit of normal, using a coagulopathy grading score, here we have validation that those high-risk patients should have individualized therapy up to full-dose treatment. All right. I know I spent a lot of time, but I think that that’s really an important paper.

The tail phase, just the reminder COVID is not just a two-week viral illness for many people and we have our new PASC, post-acute sequelae of COVID, code U09.9. I think this is important because if people are coding properly, we can identify, we can track, we can really move forward with that. No one is safe until everyone is safe. The WHO, the World Health Organization, announced the launch of the strategy to achieve global COVID-19 vaccination by mid-2022. With the goal of vaccinating 40% of every country’s population against COVID-19 by the end of 2021, only a few months to go. 70% by mid-2022, and this was presented at a press briefing.

The WHO Director-General Tedros Adhanom Ghebreyesus, I think I need Dickson to help me with pronunciation there, but this gentleman laid out the situation, which we’ve previously discussed. Where there are not a lot of vaccine doses getting to these low-income countries. The continent of Africa is less than 5% vaccinated. Now, what is the strategy? The plan is to work with COVAX, the African Vaccine Acquisition Trust, and other partners, to hopefully meet these WHO targets.

Closing there I want to remind everyone through the months of August, September, and in October, we’re about halfway through October, all the donations made to Parasites Without Borders will be doubled, hopefully to get up to a goal of $40,000 to support Floating Doctors down in Panama. I reached out, was actually communicating with Ben LaBrot, the founder, just the other day. Really tough times down there in Panama. Not only with COVID, but all the indirect impacts. Food insecurity, we have children that are really not developing because of limited calories, malnutrition, this is really a challenge so help us help them.

VR: Time for some email questions for Daniel. You can send yours to [email protected]. Rex writes, “You recently suggested the N95 duckbill mask as your preferred PPE, but I can’t find a vendor. I’m retired from a career as a PA, don’t want to annoy my old colleagues for masks. I tried speaking with a rep from 3M, was told they’re only for medical institutions and professionals. The only product I could obtain was an N95 particulate mask they supplied to Home Depot. What can I use that’s available for retail purchase when out and about? I got some KN95s a while back. That vendor is no longer supplying them. I wasn’t sure even if they were genuine. Thanks for your podcast.”

DG: All right. Let me see if I have my masks behind me here, which I do, and I think if people are watching us on YouTube, they can get the visual here. The one in my right hand is the 3M, one that I really like, but again, this is at this point only something that healthcare workers can get.

The other, the particulate mask, this works very well. It is not as comfortable. Remember, I’m wearing these masks often for, well, I guess it was 16 hours a day early in the pandemic– a little bit less these days. These are not as comfortable, this is actually usually what I wear every day. And so you can get N95 masks, they don’t have to be necessarily my favorite N95 mask, but as we talked before, Is this NIOSH U.S.-approved, U.S. manufactured mask?”

The KNs are actually a Chinese standard and they’re not- about 70%, so they really should call them KN70s, I guess, but you can get the N95s and these may not be quite as comfortable as my mask of choice.

VR: Hellen in Baltimore writes, “I’m 76, about to get a booster after two doses of Pfizer. I’ve heard mixing vaccines with different vectors, mRNA, adenovirus, actually gives a more robust response. I’m wondering if something similar might be true with Pfizer and Moderna? If so, I’m thinking I should wait for the third dose until Moderna is approved and perhaps the government will allow that version of mix and match. Although I have little hope that the mRNA plus J&J will ever see the light of day here.”

DG: Well, I think we touched on this, which is great. As we’ve talked about with the boosters, we’re not worried, the sky is not falling. We’re not seeing a lot of loss of efficacy as far as protection against disease, against people ending up in the hospital, about people dying, but people do not want even mild infection. We’re concerned that even just infection is fueling this pandemic, so there is a hope and, I have to say, it’s a hope and I qualify this that getting these boosters is going to really push us down farther. But what really ends this pandemic is those first and second shots, but directly to your question is what we talked about today.

What will have been discussed on Friday before this drops on Saturday is this concept, “Can I mix and match?” If the whole goal is to get those antibodies higher, you’ve had a couple of those Pfizer shots and now you’re hoping to get the Moderna, to get up to maybe that tiny bit higher antibody level. We’ll see where that goes, but that’s what we’re hearing is right on the horizon, so give it a few days and then we’ll have more to say.

VR: Mark writes, “I have a friend who is a college-educated New Yorker who was vaccinated and told me yesterday that medical workers in New York who don’t get vaccinated will be fired and then posed the question to me that these workers who last year were celebrated as heroes will be fired even though there is no proof that they are spreading the virus and that even if they are vaccinated, they can still spread the virus just as well. What does the evidence among hospital workers tell us about spread of virus?”

DG: This is, I think, hopefully we’ve covered this several times over the course, the last few months on TWiV since the data came out from the Barnstable episode. There’s a couple of things that we do, that we do know. People who are vaccinated can get infected, people who are vaccinated can spread the virus to others. There’s two reductions, one is people who are vaccinated seem to be less likely to get infected. That may reduce as you get further out from the vaccine. People who get infected who are vaccinated, and this is the Singapore study that I think we all love, it looks like the amount of contagion and infectiousness is shortened, so people who are infected, it looks like they are less likely to spread it to others, but they still can.

We have those two points of data, less likely to get infected, and less likely to spread it, but you can get infected and you can spread it. The concern in the healthcare settings is these are the highest risk individuals, so if our patients get infected, for them, it’s not just a sniffles, it’s not just a cold, they could actually end up dying. Now, some of our patients are not vaccinated, patients are not required or mandated to get vaccinated particularly some of our seniors, those people are really at high risk. That’s the data, and that’s the concern.

VR: Daniel, I have a colleague in another large Northeastern city whose hospital is in the same situation, they’re about to fire a number of people for not getting vaccinated, but these people are critical for some of the procedures they do, so they’re considering if they’ve been infected to let them go and stay at work even if they don’t get vaccinated.

DG: Yes, this is a challenge. Actually, let’s go down this rabbit hole. One of the things that we’ve seen here in New York is the largest healthcare system, they had to let about 1% of their employees go, so 99% went ahead, but there was a small percent that didn’t. One of the interesting things that’s come up over and over again is, “If I already got COVID, maybe I don’t have to get vaccinated.” This whole concern about maybe natural immunity, and maybe post-infection, gives you some protection.

One of the concerns, and this brings me back to something that we discussed early on, there are people who do not want to get the vaccine and there were actually COVID parties. If you’re a person who doesn’t believe in vaccines and your employer says, “Oh, if you’ve got antibodies, if you have prior infection, you don’t have to get vaccinated.” Some people as we saw, will choose to go out and get COVID. That’s one of our biggest concerns when we start saying like, “Oh, prior infection is an acceptable alternative to vaccination.”

I think Akiko up at Yale made this point very clear. The way to get antibodies then is not through getting infected, that is not a great safe way of doing it. It is a challenge because we’re still working out the science on after you get an acute infection, we think that you are at low-risk of a second infection in the first three months. We know that declines over time, we’ve talked a little about the Oklahoma data where you compare prior infection to the vaccine, and now with this booster, there’s a lot of unknowns here. Yes, the last thing we really want to do is create a scenario where we’re encouraging people to go out and get infected, so that then they can avoid a vaccine mandate.

VR: Our last email’s from Sanjita. “I’m a pediatrician in Texas, an avid listener of your podcast. I haven’t taken a boost or third dose yet as I’m not convinced about the data. I received the Moderna vaccine in December, January, awaiting recommendation on half- versus full-dose. I have two questions for your team. One, if original antigenic citizens are concerned with COVID vaccines, would a new formulation of the vaccine that uses a different antigen of the virus, nucleocapsids rather than spike, be a better way to boost our immunity? I understand we don’t have that formulation yet, but can mRNA vaccines be modified to target a different protein?

DG: The last question is easy, yes. You can basically put in the mRNA for whatever target or whatever protein target you want to go after, so you can do that. I still remember when we were talking about putting all your eggs in the spike basket, that seems like it’s worked out. We’re not sure how much efficacy you get if someone went after just a pure mRNA-type vaccine, but I think, as we discussed a little bit earlier, there’s this data coming out. There’s a lot of discussion.

What is the goal of boosters? The goal of boosters is not necessarily to protect you against severe disease hospitalization. There’s, of course, a hope that this will be a broader more durable response. The rumors and the mumblings are the ideas that the vaccines J&J will probably turn into a two-dose vaccine in the U.S. The Pfizer and Moderna may end up being a three-dose vaccine series much like hepatitis B.

Yes, I think you’re right to say the data is not worrisome, the sky is not falling, we’re getting more and more information as we go forward. It’ll be interesting to see in the coming weeks and months what impact a third dose has on infections and other things, and how even durable that extra little input might be.

VR: The second question, “Why should a young 27-year-old male healthcare worker, my son is a medical student with no underlying health issues and one who follows all MPI religiously, be compelled to take a third dose of Pfizer? Do we have any data on the risk of myocarditis in this age, sex, group after a third dose versus risk of myocarditis from COVID-19 disease after two-dose vaccination?”

DG: I don’t think we’re at the point where it should be something that is compelled. I think it’s reasonable if someone’s over 65, they’re at higher risk, but we’re really seeing, and if you look, even the data that people were worried about from Israel, if you’re under the age of 30, we’re looking at just tremendous efficacy of these vaccines after two doses. I’m not really sure a third dose is required, it definitely shouldn’t be mandated or anything at this point. We’ll see as the data comes forward, I think you should be able to wait and find out what those risks are.

VR: We have no data yet on myocarditis after third doses, right?

DG: Particularly not in people in their 20s, and we have seen that there’s an age-adjusted risk for myocarditis, yes.

VR: That’s COVID-19 clinical update number 84, with Dr. Daniel Griffin. Thank you, Daniel.

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

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