TWiV 823 COVID-19 Clinical Update #86

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 30 October 2021

pdf of this transcript available (link)

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

VR: From MicrobeTV, this is TWiV, This Week in Virology Episode 823, recorded on October 28th, 2021. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today right here at ‘The Incubator’ in New York City, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: This is COVID-19 Clinical Update #86, and the second one we’re recording at ‘The Incubator’ in New York City. Daniel, what is happening with COVID?

DG: There’s a lot going on. Let’s get right into it because we have a lot to cover today, and I’ll say some exciting news. Let’s go right with our quotation and then move forward. “The storm is an artist; the rainbow is its masterpiece.” That’s by Matshona Dhliwayo. I don’t know if I pronounce that correctly. We need to bring Dickson in. I know he has helped me with my pronunciations. It’s one of my challenges in life.

For me, I’m hoping that there’s a rainbow that we pull out of this terrible catastrophe, this storm that we’re in. Maybe actually one of the things I’ll talk about today, I’m going to try to keep bringing optimism when appropriate here. I’m going to start off by just basically saying there’s a lot of bad stuff. We are still in the middle of a pandemic. Don’t let anyone tell you otherwise. It was a bit troubling this week when the WHO came out with an estimate. They were suggesting that approximately 115,000 healthcare workers have so far died of COVID-19.

This is troubling. For a lot of us, these are our comrades, our colleagues. They say this number may actually be as high as 180,000. This may even be an underestimation. Putting this in context, there have been perhaps 5 million COVID deaths to date around the world, over 750,000 here in the United States. This is a small number compared to those bigger numbers, but it’s a huge, troubling number. There was a day last week here in the US when we saw the count over 2,000 people dying in a single day. We are still in a pandemic. I think we need to continue to realize that.

We did have some exciting stuff happen this last week. There was a meeting on Tuesday. I’m going to talk about what the FDA independent advisory committee had to say about that. We have another meeting coming up, a two-day meeting, and this is the ACIP, that advises the CDC. They’re scheduled to have a two-day meeting for the 2nd and 3rd of November. They’re going to be weighing in on what we’re going to talk about, vaccines in kids down to 5 to 11.

Let’s go right into kids because that’s where a lot of stuff happened this last week. As I like to keep reinforcing, children are at risk of COVID. The number of pediatric deaths here in the US has now risen to over 600. A lot of those have been recently lost, and there are a couple dozen kids just this last week. I like to reinforce wearing a mask is less traumatic for a child than being hospitalized. We really need to see how can we keep these kids safe?

This was the vote. This was the question put to the FDA independent committee: based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 vaccine when administered as a two-dose series, 10 micrograms each dose, a smaller dose, three weeks apart, outweigh its risks for use in children 5 to 11 years of age? Put to the members of the Vaccines and Related Biological Products Advisory Committee, the VRBPAC. The response was, yes: 17, no: 0, and one person abstained. It was an interesting meeting to watch.

Actually, a lot of the concerns that they had on this committee was that people would move too quickly to mandates, which actually was also what a lot of public people are concerned about. This is something where the message was, “We feel like this is safe.” About a third of these children have parents that are anxious for them to get vaccinated. This still needs to go through a couple other checkboxes and hoops, and one is what I mentioned. The ACIP is going to be meeting Tuesday/Wednesday of next week. This will be dropping on Saturday, talking about whether or not this is going to be endorsed, recommended by the CDC.

People are already ready to go with this. I think what’s going to happen here is you’re going to see a certain chunk of children who get vaccinated right away. There’s going to be a number of parents who want to wait and see, get a little more safety data on those millions of kids because for some parents, there’s still a little bit of hesitancy. They want to see the safety profile in larger numbers. That seemed to be the message from this committee, is that we’re not saying mandate this, we’re saying give parents who want the opportunity. Once we have more safety data, then there could be a separate discussion about –

“Virological Features of SARS-CoV-2 Infection in Children,” this was published in The Journal of Infectious Diseases. I really thought this was an excellent paper. I’m going to present a couple excellent papers this time as opposed to the normal ones now. I try to only pick ones that I think are important. They collected respiratory swabs on 110 children with COVID-19. They performed quantitative RT-PCR. They did viral culture and reported on direct observation of cytopathic effect, CPE and TCID50. They looked at correlations with age, symptom duration, and disease severity. They looked at whole genome sequences.

They came to a couple of conclusions. One was they said age did not impact SARS-CoV-2. They say viral load. I like to say RNA copy number or recovery of replication-competent virus. Here’s where I’m going to pull Vincent in for a little help. They’re using this term TCID50, and I know that’s been coming up on TWiV a little bit. What is TCID50?

I’m going to try and Vincent is going to correct me, I hope. 50% tissue culture infective dose, this is really a measure of how much infectious virus, like a titer. This end point dilution assay quantifies the amount of virus required to kill 50% of infected hosts produce a cytopathic effect in 50% of inoculated tissue culture cells. In my head, I translate this into PFU per milliliter. The higher the number, the more infectious virus. Vincent, how did I do?

VR: That’s great. It’s exactly right. It’s another way to quantify infectivity instead of doing a plaque assay. In my book, I’d rather have plaque assays. Many people choose TCID50s, and that’s just fine.

DG: Did that surprise any long-term TWiV listeners? No.

[laughter]

Vincent likes his plaque assays. I’ve actually done, and Vincent knows this, but I’ve done some plaque assay. Amy in the lab, she’s much better at that than I am. There’s a skill, there’s a timing, et cetera. Now, what they saw was that the viral RNA levels and the TCID50 had a nice downtrend over the five days post-symptom onset. This goes with what we’ve been describing. There’s a kinetics here of levels of virus, period of time when children are actually infectious. The authors concluded that both symptomatic and asymptomatic children can carry high quantities of replicating SARS-CoV-2 creating a potential reservoir for transmission.

I think the one nice thing I’ll add, drawing the rest of our literature, is that individuals who are vaccinated, we see that level drop off more quickly. It’s dropping off, we think about twice as fast, so really shortening the potential transmission period. There’s some nice graphs. People should go ahead and take a look at this paper. It is open access. “Virological Features of SARS-CoV-2 Infections in Children” in The Journal of Infectious Diseases, and really some nice figures where you get to actually watch the kinetics over time.

All right. The pre-exposure period, transmission, testing. Never miss an opportunity to test. I’m going to talk today about a different type of test upfront. I’m going to talk a little bit about serology or antibody tests. I think that the FDA issued a safety communication on May 19th and this bears repeating. What was that? What was that safety communication? In a sense, it was a scolding, a warning. We’re not listening. That’s why I’m repeating it here. The US FDA is reminding the public and healthcare providers that results from currently authorized SARS-CoV-2 antibody tests should not be used to evaluate a person’s level of immunity or protection from SARS COVID-19 at any time.

I know I get calls all the time where physicians are interpreting these, trying to talk to patients, guiding them based upon serology results. The FDA has basically said, “Don’t do that. We do not have the data. You cannot assume that you know that this is a correlate of immunity.” I’m going to go a little further here, because now that we’re discussing boosters, I’m getting multiple calls every day, and it usually starts with, “I checked the patient’s antibodies and then they want to have a discussion.”

There was a really nice medical news and perspectives piece published in JAMA by Jennifer Abbasi, “The Flawed Science of Antibody Testing for SARS-CoV-2 Immunity.” This article referenced the October 14th publication in the Journal of Medicine, “Covid-19 Breakthrough Infections in Vaccinated Health Care Workers.” If you look at the figures here, there is significant overlap in those antibody levels, even if you look at neutralizing antibody levels. People that have high antibody levels can get infected. People with low antibody levels often don’t get infected.

It is reasonable to look at a population level, but we can’t draw an individual’s serology lab and then tell them what it means for them with any degree of certainty. I think that’s really critical because a lot of people are forgetting this. There’s a bit of hubris here. We think we can look at that blood test and tell our patients something. We’ve been warned by the FDA that science does not support that.

A little bit of exciting – I think this is on the horizon. The US CDC has announced that it is considering test-to-stay programs in schools instead of quarantine. I think here we really have to get past anecdotes and fear and focus on the science. We’ve seen this being done successfully throughout the world. A number of pilot programs we discussed out in Utah, where they safely were doing this. It’s being piloted in a lot of school districts in Massachusetts. Forget about those kids who have a negative antigen test and then a positive PCR test that picks up low levels of viral RNA.

We have lots of robust data that those kids with negative antigen tests are not spreading the virus. What’s the plural of anecdotes? It is not data. We have data here. The kids with positive antigen tests certainly can be spreading the virus. This has been shown to be a very effective, quick way of identifying which kids we do not want to have in those settings. We have to realize keeping a kid out of school is harmful. Our kids have lost tens of thousands of days of in-person education and we now know how to safely get them back to school. It’s exciting to hear that the CDC is looking at this. It’s probably a few weeks off. As this moves forward, I’ll be sure to share updates.

The article that I referenced, again, I’m going to say go ahead, look at the figures, because it’s nice to just see how much overlap there is in those antibody levels between who gets infected and who doesn’t get infected. All right, active vaccination. Never miss an opportunity to vaccinate. My wife was actually heading to the supermarket and asked me if she should get a flu shot or if she should wait and go with Barnaby. I said, “Never miss an opportunity to get vaccinated.”

VR: [laughs] I’m sure she likes that, right?

DG: “Get your flu shot.”

VR: [laughs]

DG: She’s like, “Oh, it takes the same amount of time to get two flu shots as one.” I said, “Yes, but don’t wait.” Barnaby, he got his shot on Saturday after his cross country meet. Remember, vaccination is how this pandemic ends. My public service announcement, please get those flu shots. Not only do flu shots protect you from getting the flu, not only do they protect you from other non-flu-related mortality, but it clouds the issues. You have a fever. You’re not feeling well. You’ve got to go through that whole concern, is it COVID? There’s a lot of, let’s say, problems with getting the flu beyond all the things we normally think about.

All right, back to the COVID-19 vaccines. There continues to be much fear and misinformation around the vaccines. I really thought that MMWR earlier released “COVID-19 Vaccination and Non-COVID-19 Mortality Risk,”Seven Integrated Health Care Organizations, United States, December 14th, 2020-July 31, 2021, was really helpful. Then, there’s something in here that we observed with other vaccines such as influenza, where even if the vaccine does not protect you from death due to that virus, getting sick from a respiratory illness without the protection of vaccine, can increase your risk of all sorts of other things in the following weeks, including things like strokes and heart attacks.

I have to say we look at this on a population level, the 100 million people that have UnitedHealthcare insurance. We look at this. Not only do these individuals who get flu shots have a decreased incidence of in the hospital for flu, but they even have a more significant decrease in their risk of all these other reasons for ending up in the hospital.

Here, it’s asking that same question with COVID. I think a lot of us are concerned that COVID is more than just, do I end up in the hospital, or do I die from COVID? There is a post-COVID impact on our health. This was a huge study. This was a cohort that consisted of 6.4 million COVID-19 vaccinees, 4.6 million unvaccinated persons. They found that recipients of the Pfizer-BioNTech, the Moderna, and the J&J vaccines had lower non-COVID-19 mortality than did the unvaccinated comparison group. This was consistent across all the vaccines.

Who do we think was the winner, because it is a competition? Moderna. The adjusted relative risk of death for people who got two doses of Moderna was 0.34. There was a 66% reduction in non-COVID deaths in people that got the vaccine. People who didn’t get the vaccine, forget about COVID, they were three times more likely to die of something else compared to these Moderna double vaxxers.

I think this plays into what we’ve seen with other illnesses. You need to be looking at the big picture. A lot of people, I don’t know, maybe they’re not that concerned about dying of COVID, but think of all the other things you’re at risk with whatever COVID, whatever SARS-CoV-2 does to our body post-infection. Well, by this time this drops, we will have done our live stream on boosters. People have lots of questions. One of the things that I just wanted was to repeat the amended EUA and clarify one thing that I’ve been getting a lot of questions about.

On the 20th of October, the FDA amended the EUA for COVID-19 vaccines to allow for the use of a single booster dose. Some people feel like this is unfair. If you’re in one of these populations and you had a couple Modernas, you can go ahead and get a J&J. If you had one J&J, you’re only entitled for one other shot. Now, no one is enforcing this, but just to clarify what the exact EUA message is there.

Passive vaccination. I want to remind that remember monoclonals after high risk exposures, it’s not just for treatment anymore, and the REGEN-COV has an EUA for post-exposure prophylaxis. It also has a little bit of a post-exposure prophylaxis dosage clarification, where they say, for individuals in whom repeat dosing is determined to be appropriate for ongoing exposure to SARS-CoV-2 for longer than four weeks and who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination. Initial dose, 600, 600 and then ongoing 300, 300 per month. This is not a substitute for vaccination. This is just another complementary strategy.

All right, this is where it gets exciting if you’re not excited already. Period of detectable viral replication, the viral symptom phase, the time for monitoring in monoclonals, not the time for antibiotics, not the time for steroids. Do we have another potential option on the horizon? We were waiting for these trial results for a while. This week, the results of the TOGETHER Trial was published in the Lancet Global Health. The TOGETHER Trial, I think of it as the recovery trial going on down south of us. This is an adaptive platform. This was, “Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalization Among Patients with COVID-19, the TOGETHER randomized, platform clinical trial.”

Just a little background, because I think this is really important. Fluvoxamine is a, I like to say, not so selective serotonin reuptake inhibitor. Why do I say not so selective? It is a sigma-1 receptor agonist. I want to talk about that part because people are announcing, “Oh my gosh, antidepressants, they treat COVID? What’s going on here?” I do not want people to run out and start giving their patients Zoloft and Prozac and other things, because the mechanism of action that we think, and I’ll go through the data on why we think this more so now than we did even a week ago, is that the sigma-1 receptor agonist may be broadly neuroprotective. It works through an S1R mediated signaling pathway.

We’ll talk a little bit more about this. This may actually prevent that inflammatory cytokine surge. Let’s go through. The TOGETHER Trial is a randomized, adaptive platform trial to investigate the efficacy of eight repurposed treatments for COVID-19 among high-risk adult outpatients. This paper, we’re only going to talk about one of those eight repurposed treatments, and this is fluvoxamine, the not so selective serotonin reuptake inhibitor.

This placebo-controlled, randomized, adaptive platform trial was done among high-risk symptomatic unvaccinated Brazilian adults with confirmed positive for SARS-CoV-2 from 11 clinical sites in Brazil, with a known risk factor for progression to severe disease. It might be age, might be obesity. One of the other ones we’re familiar with. Patients were randomly assigned one-to-one to either receive fluvoxamine, 100 milligrams twice a day for 10 days, or a matching placebo for the same, twice a day for 10 days. 741 participants were given fluvoxamine twice a day, 756 received a matching placebo. They did a great job. The pills looked exactly the same, so they’re all coded.

The trial participants were observed for 28 days post-treatment, with the main outcome of the trial being patients spending more than either six hours receiving physician treatment at a specialized COVID-19 emergency setting, or hospitalization for COVID-19. I hear some people in the distance they’re heading to hospitals. People can hear the sirens. we’re bringing in sound effects.

Now, just a couple nuances here. It’s important for interpreting this paper to understand the distinction between two types of analysis: intention-to-treat analysis and per-protocol analysis. One concern is that with noncompliance, we can end up underestimating therapy. We might want to ask not just about which people were assigned to get fluvoxamine versus placebo, we may actually want to know who actually took fluvoxamine compared to who took the placebo for that period of time.

I like to say one cannot expect a drug to work if people don’t actually take it. That’s the per-protocol analysis. Ask the important question of how effective was this drug in people that actually stuck with the program, took the drug? We’re going to come up to that when we do our analysis. 741, 756 the average age of participants was 50, 58% were female. What were the results?

The proportion of patients observed in a COVID-19 emergency setting, to simplify this, who ended up in the ER or in the hospital, was lower for the fluvoxamine group compared with placebo. This was 11% versus 16%. 5% absolute reduction, but a 60 relative risk – by percent, a 32% reduction in going to ER or hospital. Findings for the primary outcome were larger if we looked at this per-protocol analysis. We actually looked at people that actually took it. Here, a 66% reduction in going to the ER or hospital. If we look at mortality, there were 17 deaths in the fluvoxamine group, 25 in the placebo group that was in the intention to treat.

If we actually went ahead and analyzed the per-protocol population, one death in fluvoxamine, 12 in the placebo. A 91% mortality reduction in people actually taking fluvoxamine. This is an inexpensive therapy. It’s about $4 for those 10 days of therapy in many parts of the world. You’re looking at a number needed to treat of about 20. I think that these are exciting results. It brings maybe our listeners back to that TWiV 766 with David Fajgenbaum, when he talked about the CORONA Project and how we have trials active, six here in the US, have a colleague up at Minnesota, Ken Cohen, who’s doing a trial looking at repurposed drugs.

The exciting thing here is that this may be something off-the-shelf that is less expensive than some of our other options. I do want to point out this drug is not the same as the SSRI. This is not necessarily something that can be swapped out with Prozac or Zoloft or these others. One of the things that reinforced our ideas on mechanism is that the authors saw no impact on viral RNA levels. We do not think this is working as an antiviral. The theory at this point, and there actually are a number of studies looking at this in animal models, is that this mechanism is staving off that cytokine storm. It’s likely via modulation of the signal sigma-1 receptor-IRE1 pathway.

I’m hoping I’m going to test this out to our colleagues, maybe on IMMUNE. They’ll have a special session going through this important pathway. This is an endoplasmic reticulum-based response pathway that ultimately results in IL-6 production. The concept here is you’re starting this early enough and continuing into that second week and preventing that cytokine storm. What this paper gives us is clinical data supporting that hypothesis. We don’t have all that basic biology to work that out. Back to my original quotation, this could actually be giving us insight into understanding and preventing a lot of the tragedies associated with sepsis.

VR: Daniel, this would not be given early during the viral phase, right?

DG: Actually, that’s interesting. It is done during the viral phase, and think of it as immune modulation as opposed to being immune suppressive. When you do this, you don’t have an adverse effect. You’re not allowing or facilitating viral replication, like you might end up doing with steroids, but you have this selective modulation, what we think is preventing that cytokine storm.

VR: Something we tried to do with IL-6, but it didn’t work.

DG: With IL-6, it’s interesting. We’ve been hitting the IL-6 receptors late, but we realize if we go too late – this was the Northwell experience. If you give it to high-risk people right at the beginning of that second week, when they’re just starting to escalate despite steroids, it has an impact. If we wait even 48 hours after they’ve ended up in the ICU, we missed our window. You got to hit the timing on a lot of these things. This was started during that first week. I’d be interested to see where the best timing is. Is this something that you can even start in hospitalized patients when they come in the door and they’re on a couple of liters of oxygen?

It’s a very safe therapy. We’ve been using this therapy. It got FDA approval last century. We use it for OCD. It’s a drug that we have a lot of experience with, a great safety track record. I anticipate a lot more trials going forward. The early inflammatory phase, usually when people get hospitalized, we’re not sure if fluvoxamine might play a role there. As I did say in the interview with Sarah, this is one study we got to confirm before we go forward.

There was a paper that was getting maybe a little too much attention, so I wanted to comment on it. This was “Association of Statins and 28-Day Mortality in Patients Hospitalized with SARS CoV-2 Infection,” published in The Journal of Infectious Diseases. I think this is an example of how we can create a hypothesis based on random care, and then we can decide if we should move forward with randomized care to answer a specific scientific question. Just a spoiler alert, I was not onboard with the conclusions of this group. Let’s go through what was the study.

This study looked at 1,179 adult patients with confirmed SARS CoV-2 and they grouped them into four groups. These are individuals up at Mass General Hospital. Group A, these are folks that came in on statins and they continued those statins. Those are those cholesterol medicines, things like, Lipitor, Zocor, Atorvastatin, and Crestor. The other group came in on those statins and for some reason they stopped them. Then the other two groups, group C, came in not on statins, but was put on them, and group D came in not on statins and was not put on statins.

Most of the groups were pretty big, in the 300-400 range, except for that one where they came in on statins and were stopped, there only 42 individuals in that group. Since this is random care and not randomized care, the groups were quite different in terms of age, race, smoking status, incidence of CAD, diabetes, et cetera. What did they find looking at this random, not randomized care? There really are two important comparisons here.

The first is group A and B, people that came in on statins, and the question of stopping them or not. Then we’ll get to the other group where they came in not on statins. What they’re going to tell us is that the people who came in on statins and had them stopped did worse. There’s a couple of questions that came to me. Why would someone who gets admitted to hospital, who is on a statin for an indication that warrants a statin, why would you stop their statin?

Maybe you’re making a palliative care decision, maybe you’re changing your goals of care, because, even though they’re going to tell us that those patients on whom the statins were stopped had a higher mortality, they were less likely to have their care escalated to ICU, they were less likely to be intubated. The mortality of 16.7 versus 33 suggests that maybe the statins were stopped as part of a goals of care decision along with the same decision not to transfer to ICU, not to pursue intubation. Reasonable to suggest continuing statins, but I’m not sure that I am persuaded that stopping statins was somehow causal in these patients not doing well. It looks like stopping statins was probably part of goals of care.

What about the other, because I think that’s what people are starting to take away from this? Maybe we should put statins on the guidelines. Maybe everyone who comes in with COVID should be started on a statin. The interesting thing here is, apparently, up at MGH, they added starting statins to their COVID 19 guidelines. Here, I was thinking MGH was a haven of evidence-based medicine. Anyway, they got together and decided they should add that to the guidelines. During spring 2020, physicians at MGH created clinical guidelines that recommended starting statin therapy on patients hospitalized for severe COVID-19, but still, about half these folks did not get started on statins. Interesting.

They report that group C, these are the patients who were newly started on statins, that their mortality was 9.6, and group D, where they were not given statins, the mortality was 8.9. I’m not sure I’m convinced that people should be started on statins when they come in. Is it reasonable to go ahead and study this? Yes. Now, I appreciate that they did some fancy statistics with Marginal Structural Cox Models, the Kruskal – Wallis tests for continuous variables, the Fisher’s Exact Test for categorical variables and calculation of hazard ratio estimates. When you actually just look at the numbers without the fancy statistics, I’m not sure the underlying conclusion that we should be putting people on statins was really persuasive.

All right. I’ll get some hate mail from my colleagues at MGH. All right, the tail phase. I like to say COVID is not just a two-week viral illness for many people. People probably know I’m always sensitive to any cognitive impacts of COVID. The research letter, “Assessment of Cognitive Function in Patients After COVID-19 Infection,” was published by a group of authors out of Mount Sinai. This group assessed cognitive function using well-validated neuropsychological measures. They looked at number span forward, measure of attention, backwards, working memory, trail making test part A and B, this processing speed and executive functioning, phonemic and category fluency, language, the Hopkins Verbal Learning Test-Revised, memory encoding, recall, recognition.

In this relatively young cohort, a mean age of 49, they found a high relative frequency of cognitive impairment several months after patients contracted COVID-19. They found prominent deficits in processing speed about 18%, executive functioning 16%, phonemic fluency 15%, and category fluency 20%, memory encoding 24%, and memory recall 23%. I think that this just goes along with – people used to call it brain fog. There’s now a movement to be a little more explicit. These are really cognitive deficits. Not just that your brain is a little fuzzy, your brain is perhaps not working well. Just really tragic.

We’re still waiting for the trials to roll out to try to get answers for these people. No one is safe until everyone is safe. What is going on worldwide? One of the things I like to point out is COVID has hit and damaged things other than just COVID itself. A rather disturbing report published in the MMWR, “Routine Vaccination Coverage — Worldwide, 2020.” What’s going on worldwide with vaccinations; 2010 through 2019, we were doing well. Global coverage with the third dose of our diphtheria, tetanus toxoid, and pertussis-containing vaccines. Our polio vaccine, everyone getting their third doses. They say DTP3, that’s the third dose, or Pol3, people getting that third dose, and the first dose of measles-containing vaccine, MCV1, remained between 84% and 86%.

In 2020, estimated global coverage decreased to 83%, MCV1 coverage decreased to 84%, globally, 17.1 million zero-dose children did not receive the first diphtheria tetanus pertussis dose. This is an increase of about 3.5 million children from 2019. Just not great to see that COVID is not only causing all the damage directly but all this incidental damage.

I will say this is our last episode where we are going to do a shout out and continue to support Floating Doctors. We are really close to that goal. I think we’re going to make it. For the months of August, September, October, donations to Parasites Without Borders, go to parasiteswithoutborders.com, click donate, because we will double that amount. We want to get up to $40,000 to support Floating Doctors and all the great work they do down in Panama.

VR: Time for some email questions for Daniel. You can send yours to daniel@microbe.tv. Mary writes, “I understand that various vaccines can be administered at the same time. What if sometime less than 14 days ago a patient got a COVID shot, now he wants both seasonal flu and SHINGRIX? Should he wait now until the remaining 14 days has passed, or does it mess with the immune system to introduce another vaccine if not simultaneously, and under 14 days from the previous shot? If the patient missed doing it all simultaneously, should they wait? Does it matter if it’s the flu shot, SHINGRIX, other inactive vaccines non-simultaneously less than 14 days? If it doesn’t matter, why is this question on the intake form?”

DG: [laughs] Oh my gosh. I have to say one of the intake forms for the Moderna pod I was working at was whether or not people had egg allergies. Just because it’s on the form doesn’t mean it’s the question you should be asking. Do not miss an opportunity to vaccinate, don’t don’t overthink this. The immune system is exposed to things all the time so if you got that COVID shot it’s a week, it’s two weeks it doesn’t matter go ahead don’t miss an opportunity to get those other vaccinations. Your body’s going to respond well, it’s going to do fine and just because they asked you a question at the intake doesn’t mean it’s a relevant question. It may just be sitting on that form.

VR: Gail writes, “I’m an RN and licensed school nurse working with a preschool population in rural Northern Minnesota. First, I’d like to say I’ve been listening to your podcast religiously for over a year, really appreciate your fact-based information, your quotes and sayings have also been appreciated. They’re great little snippets to use in conversation especially with those who are skeptical about COVID-19 and COVID-19 vaccines. Unfortunately, we have a large proportion of our community who fall into that category. I’m writing to get your opinion on mixing vaccines, I’ve had two doses of Moderna in January and February. I’m eligible for a booster, I’ve listened to you and Vincent and have been questioning the need for the booster at all and at the same time wondering if I should try to get a J&J booster to provide protection in a different manner than the mRNA vaccine. Do you feel this will be a better booster for B- and T- cell production? This is really the answer I’m hoping to hear, as over the past year I’ve come to really respect the advice that you provide on your podcast.”

DG: I think you had all the right points and we’ll have that live Q&A. It’ll actually being recorded, so we’ll be able to go back to that. When it comes to boosters, we’re guessing. I just think we have to be completely honest with that. No one actually knows the right answer to your question. We have different theories. There was that interesting data that was presented from the NIH looking at antibody levels, but we’re not really sure what to do with that. Maybe on a population level there makes some sense there.

We have, as you brought up, some evidence with J&J that you may get more of a robust T-cell response. There may be a more comparable efficacy when this is a two-dose vaccine, the way the mRNAs have been historically. There’s no wrong answer in all honesty. As we’ve talked about several times, the vaccines continue to be incredibly effective at what they were designed to do, which is prevent people from serious disease and keep you from ending up in the hospital and death. They are not a 100%. Only death is that. These are pretty impressive. We’re trying to get more. People are trying to get more. There’s a hope that some degree of reduction in infection can help us move forward in this pandemic.

If you get a vaccine, if you decide to get that booster, whether you get Moderna, Pfizer, or J&J, we don’t know the answer. We’re guessing. These would be the different things that you have to face. If you tolerated two shots of Moderna well and you’re someone who tolerates vaccines well, then, really, any choice. If you’re someone who’s often had allergic issues or problems with other vaccines, then comes the question of do you want to risk switching platforms, potentially having a negative reaction to another platform or do you just stick with what you’re doing?

Maybe you had two shots of Moderna, and that second shot, you had a really rough time. Maybe you’re thinking about switching over to J&J for that. Are you going to get better T-cells, are you going to get better antibodies? We’re guessing so. There’s no bad choice. I had a couple of Modernas. What am I going to do? I might get a J&J as my third shot, but I’m guessing, I have to be completely honest.

VR: Here too is an ID physician at Karolinska University Hospital, Stockholm, and during the last one-and-a-half years been involved in COVID care. I have a question about monoclonals,
“As I understood, vaccinated patients with ongoing immunosuppression like transplant patients are eligible for monoclonals in the US if they’re newly diagnosed with COVID. This is similar at our place even if we do not have a huge monoclonal supply in Sweden. In most of the cases, we do not know the serology status of the patients, if they are converted or not after two or three doses when we have to make the decision on the monoclonal treatment. In some cases, we do, but as you have stated several times, we don’t have the knowledge of the spike antibodies are the key player of protection and at which levels. However, the data are coming and the efforts are made to unify serology response to create some guidelines for physicians. I wonder if you could elaborate more on the subject, that is, if when could you wait with monoclonals if the antibody levels of the patients? I know it’s a tough question.”

DG: Now, this is a great question. It actually came up a couple of weeks ago. I had a patient who was on immunosuppressives. There was actually a nosocomial exposure. They were in the hospital and they got exposed to someone who had COVID. I won’t go into too many details, but that person got another one of my patients infected, that person actually did turn positive. That other patient, I went ahead gave him monoclonals prophylactically. Even though he did end up SARS-CoV-2 positive, he remained completely asymptomatic which was tremendous considering his level of immunosuppression. The other individual there was a different ID doc who got involved in the case and he checked the SARS-CoV-2 spike antibody and then decided not to give monoclonals based upon that. I don’t think again we get back to this issue we’re not supposed to be basing care.

The FDA has told us, “We do not know what those anybody levels really mean. We don’t use vaccination status or serology status against a person when they get acute SARS-CoV-2 and time matters with monoclonals.” We’ve talked about the data where if you get it within the first three days, it’s the most effective. You get it within the first six days, it continues to be less effective. When you get at day 7/8/9, maybe out to 10, the WHO has realized that there’s an extension beyond that so even if they end up in hospital, but they still have yet to mount an immune response, that you still may end up with about 25% mortality reduction. But most of these studies were done in the unvaccinated population. We’re extrapolating, we’re jumping in here. These are incredibly safe effective therapies. From a risk/benefit, if you have access to the monoclonal, it makes sense. It gets to be a much more complicated issue if you’re looking at a limited supply and trying to figure out which patients are going to get the most benefit.

VR: Finally, Nathan writes, “I’m a family physician working full-time at an urgent care center in Santa Monica where we have seen a lot of early COVID-19 infections and even way more testing. I agree with you when you have stated the rapid antigen test is great for detecting a contagious infection as opposed to a PCR test that is best for detecting any evidence of infection whether symptomatic or not. You have also said that the virus is most contagious in the two days prior to symptoms and the first three days of infection. However, I have seen many patients present on day one of symptoms with a negative rapid antigen test and subsequent positive PCR test at the same encounter. How can SARS-CoV-2 be contagious pre-symptomatically with a negative rapid test yet the rapid test is supposed to be best at detecting contagious infections?”

DG: I worry when I hear stories like that. We have really good large studies where we’ve looked at this. I worry then about the quality of the testing. Are you getting a good sample? We had to do some training I know in our Tri-state area when people were first starting to use the antigen tests making sure they were getting a good sample. If you don’t get a good sample, your test is going to be 0% sensitive. You got to get a good sample, you got to actually do it properly, you don’t have to do a deep brain biopsy. You can do an anterior Nares test, properly collected that’s going to be sensitive down to a PCR level of about 50,000. I hear stories like this is where I sorta want to go back – you want to find out, Is it a particular person doing the tests?

Has it been done properly? The antigens are 98% sensitive which means that you’re going to miss 2%, you’re going to miss one in every 50. Am I doing the math right Vincent? You’re going to remember those. You’re going to remember that one in 50 that you missed. If it doesn’t make sense to you, if the person ends up with a negative antigen, you may want to test them again the next morning, and see because again you’re going to have a 2% miss. You got to calculate all that in and you’re going to remember those 2% that you missed.

VR: That’s COVID-19 Clinical Update #86 with Dr. Daniel Griffin. Thank you, Daniel.

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

[music]

[00:47:05] [END OF AUDIO]

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