TWiV 892 COVID-19 Clinical Update #111

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 23 April 2022

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 892, recorded on April 22nd, 2022. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from Washington, D.C., Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Daniel, are you consulting for someone down there?

DG: I’m just visiting, Vincent.

VR: The President hasn’t called you down, has he?

DG: It’s interesting. I did mention to my dad and said, “I’m going to be down at the White House on Saturday.” He’s like, “Oh, I had a meal down there one time back when Bill and Hillary.” And I’m like, “Yes, whatever. Just ruined my story.”

[laughter]

VR: This is update Number 111, Daniel.

DG: It’s tough but let’s get right into it. I’m thinking before as I was putting together I was like at some point these are going to get really shorter. It’s going to be a 15-minute little quick thing but unfortunately, there’s still a lot to talk about. Right to our quotation, our dilemma is that we hate change and love it at the same time. What we really want is for things to remain the same but get better. That’s by Sydney J. Harris. Let’s start with the update. Where are we, cases, hospitalizations. Those of us who are out practicing, I’ll say the clinicians in the audience.

Actually, probably this is everyone in the New York tri-state area is aware of this that the number of new cases is rising. It’s actually rising all across the U.S. Here in New York, it’s continued to rise. In the local area, the confirmed case numbers are above the Delta wave. I mentioned that last time. We’re thinking that with the under-reporting, with the under testing, with a lot of people doing home tests and then not sending those in, testing fatigue, I’ll even say test aversion which I ran into a little bit this week where, “Boy, I feel like I’ve got COVID. I’m pretty sure I’ve got COVID. My dad’s being admitted with COVID, but I don’t want to get tested.”

We are actually thinking there’s really a lot of COVID out there. Here’s a good part. We’re going to talk about this a little bit and Vincent, you jump at any point. We are not seeing a big impact on our hospitalizations even with just these really high numbers of cases. This is like I think the late-night TV show but in reverse. What is going on? Why do we think this is happening? Number One, our current vaccines are incredibly effective at keeping people out of the hospital, keeping people from having severe disease.

Number Two, for those who did not get vaccinated but got infected instead, those survivors, those individuals that have post-infection survivor immunity. For a period of time, they do seem to be at a lower risk of ending up in hospital at a lower risk of dying. This is this whole thing we talked about with flattening of the curve. Individuals who choose not to get vaccinated, choose not to, I’ll say, go the safer route and forego vaccination. We can’t have all these people getting infected at the same time like we’re seeing in parts of China.

This is that risk of trying to go for a zero COVID policy and having it fail. This is a little bit of a challenge here. I would love in a perfect world for everyone to get vaccinated. As we’ve talked about, if we just let everything run free prior to vaccinations instead of the one million dead with the case fatality rate of about 1 to 2%, we’d be seeing four to eight million people dead at this point. We’ve certainly seen examples of countries that I will not mention, where they let things run wild and have maybe three times a number of people dead to show for it based to their neighbors.

We won’t mention those countries because we’ll get hate mail. Third, this is actually the most troubling, but this is actually a reality. The most vulnerable in terms of health social and economics, and ability to keep themselves safe. They’ve already died. Once you’ve died, you can’t die a second time. At least not in the immediate, with reincarnation we’ll throw in some twists there. Also you can’t end up in the hospital and unfortunately, I think this strikes me very personally. Really the number of vulnerable seniors and people with medical issues that died in the nursing homes.

Here in the U.S. I have to say the first wave in New York as now it’s all come out, about half of the deaths were these really vulnerable people in nursing homes and they can’t die again. This has certainly impacted my practice. Fourth we know more. Our understanding of the virus has evolved and that the knowledges have evolved. Hopefully, we’ve done a good job of getting that information out there. Even just masks for instance. I was on the Long Island Rail Road on my way into New York City before I would get on Amtrak.

Most people had masks on, I had a simple surgical mask on but then I was in a different setting, I won’t describe, and I popped on the N95 because I was not in a crowd where everyone else was practicing source control. We’re no longer having to put our groceries in the garage for 48 hours. We have more knowledge about different types of masks. We definitely know a lot more about better ventilation. You almost exclusively get this by breathing in the virus. You want to avoid doing that. We know about testing and actually, we now have the tools to do that.

Fifth, I’m going to say last probably least. We have highly effective treatments for that first week that can reduce progression by 80 to 90%. This is still least. We’ll get to this later but we have Paxlovid, monoclonals. We have early Remdesivir. We have molnupiravir. Maybe to some degree we’ve stopped doing some of the harmful things. We as a medical community, we’re actually doing things we now realize may have actually increased the mortality. That’s just a lesson really learned. The whole idea of the kitchen sink. Kitchen sink killed more people than needed to die.

I need people to think about that. The next time, “Oh, I just don’t want to have not given them what might have helped.” Probably 10% more people died than needed to, maybe even more. I’m trying to be generous there. Right here I want to mention the MMWR early release, “COVID-19 Mortality and Vaccine Coverage to Hong Kong Special Administration Region, China, January 6th, 2022 to March 21st, 2022.” When I was listening to the MMWR weekly podcast, this was one that stopped me in my tracks.

This article gives insight into what happens when after a zero COVID approach, a largely unvaccinated not previously infected population is exposed to the Omicron variant of SARS-CoV-2. Guess, what are we thinking? A lot of people, “Oh, it’s Omicron. That’s so much milder. Darn it. It should be just fine.” I want to point this out. In a largely unvaccinated not previously infected population where it’s estimated that less than 15% of those over 65, had received two vaccine doses where there was a total of over a million cases.

The mortality rate in Hong Kong was among the highest reported worldwide since the COVID-19 pandemic began at almost 4%. It was 3.7%. That’s Omicron. I want people to think about what makes Omicron mild: vaccines.

VR: Daniel, I was out your way yesterday and today. I was at Cold Spring Harbor and took the Long Island Rail Road there. At the meeting, there were a number of people who work on antivirals and they said some even better antivirals for SARS-CoV-2 are coming along and they are going to be game-changers for people who don’t do well with vaccines. I’m looking forward to that.

DG: Oh, that’s fantastic. There’s a couple things we need. We need once a day. Maybe we need a shorter course. I’m not sure we need drugs that don’t have interaction with other drugs. We need drugs that don’t need renal adjustments. We do need better COVID therapeutics. That will be great. A few post-holiday items. Apparently, not everyone listened to TWiV. I was listening to the last TWiV where the abstract that that paper in the journal of the ambivalent studies was presented. Where it was demonstrated that people who listen to TWiV have a lower mortality rate, so lower hospitalization rate.

[laughter]

Apparently, not everyone listens to TWiV, so those who do, please share. We want you all with us but not everyone made the safest of all decisions around the holidays. We’re starting to see a post-holiday rise in cases. We’re starting to see some of these individuals come into the hospital and you could actually tell which holiday they had celebrated by the timing. I’m going to share a couple stories about what I saw and the confusion that’s being created. I think people need to think about these things.

One is a story of this particular grandfather who went ahead and got his fourth shot. He got a second booster on Wednesday, so he would be already for Pesach or Passover dinner on Friday night. Then his niece came over. She had COVID, but it’s OK because grandpa’s got his fourth dose. As he explains to me, “I was feeling pretty good with that fourth shot under my belt.” His son was actually sick and wanted to talk to me. His son thought he might have COVID too but did not want to get tested.

A few things that were really– and I think people can start thinking about this. Friday night was the exposure and yet it was Monday, Tuesday or so that this gentleman came into the hospital. He said, “Boy, that’s really short, Dr. Griffin.” That must have been just a day into his symptoms. He started to feel poorly Monday morning. One, is this concept of getting hospitalized during the viral phase. If you feel really crummy if you’re an older individual, you may feel crummy enough during that viral phase that you’re not hypoxic. You’re not in the early inflammatory phase.

You’re in the viral phase, but just you’re not able to keep stuff down. You’re having abdominal pain, you’re having GI distress. Maybe there’s some vomiting. In the first wave, now that people went back and actually talked to people as opposed to doing all their consults from outside a glass door. About 50% of people had GI symptoms. Sometimes we’re seeing admission during that early viral phase. We can actually jump in with some of our antiviral therapies. Two, and this is something I was asking a lot of people about, I think now we have good science.

There is a shorter incubation from the time you’re exposed when you first test positive and start getting those symptoms. A lot of people have mused that this is prior immunity. This is vaccination. We’re not seeing any evidence that this is the virus seems to have changed over time. This really gives it a fitness advantage if you can quicken the time from infecting a first person to being able to go on to the next. The third, I think this is important: We seem to be seeing a shorter first-week progression to that early inflammatory phase.

It really used to be 7 to 14 days. Our most vulnerable, we would see it about day seven or eight. Maybe younger people might start to get hypoxic day 13 to 14. I started to notice this and I actually checked in with Stefan Muehlbauer. He’s the ED director over at St. Francis Hospital. I think my friend Chris Pascucci, or maybe Patrick O’Shaughnessy had connected us. He sees a lot of these folks in the ER and really was saying, yes, he’s seeing this same shorter time from onset of symptoms to when they start to become hypoxic.

Actually, one of my infectious disease colleagues, Michelle Cho, is seeing this as well. This is actually creating a little bit of a contraction of that viral replication phase, that viral phase, and the early inflammatory phase starting to come a little bit closer together, which may impact our therapeutics.

VR: Daniel, can I–

DG: Jump in.

VR: Why this gentleman thought that two days after being vaccinated, he would be better protected? That’s not how it works.

DG: Yes. I hope our listeners get that. He had been told that he needed to get that fourth shot. He had not been, I think, properly educated on what a fourth shot might or might not do. Actually probably went ahead and ended up with COVID because of a misunderstanding. It takes two weeks. We like to tell people two weeks after whatever that shot is before you’re getting whatever benefit. He had had his three shots, but that fourth shot, and I think we keep having to reinforce this, is that vaccines don’t keep you from getting infected.

If you are sitting there and you have a high-risk exposure, drop that 90% maybe, but that’s not going to keep you from getting infected. Then the vaccines are going to hopefully try to keep you out of the hospital, keep you from getting severe disease and dying from this. I worry about our communication around vaccines. Actually, there was an article, I don’t know if you saw it this week, Vincent, in POLITICO, “COVID Vaccines Concerns Are Starting to Spill Over into Routine Immunizations.”

We really need to keep the message clear and straightforward with regard to what vaccines can and can’t do. Every time we go crazy with like a fourth booster now and not really explaining what we’re talking about and for whom this makes sense. The anti-vax community says, “See, they don’t work. Pretty soon they’re going to be telling us to get vaccinated every eight weeks.” I think we really need to think this through. I didn’t really like that brush-off. I have to say the FDA’s Independent Committee when they said, “Why didn’t you talk to us before recommending fourth shots?”

“Oh, we’re saving you for the important decisions.” All decisions around vaccines are the important decision. I’ll actually say along the same line, what is the data as far as the vaccines go? In 2020, the CDC saw a 15% drop from pre-pandemic levels in state orders for vaccines for children. In 2021, order levels were about 7% lower than pre-pandemic levels according to the CDC. Our miscommunication, not being careful about communication on vaccines, it’s not just affecting COVID vaccines, it’s affecting vaccines. This is potentially a disaster.

Was I on a soapbox there for a second there, Vincent?

VR: It’s OK. We like that.

DG: [laughs] OK.

VR: Just don’t fall off. That’s all.

DG: Yes. [laughs] I’ll be careful. Children are at risk for COVID. Still waiting for vaccines for those under five. We’re hearing maybe June a little bit of discussion about what’s going on there. Maybe I’ll address it next time when we have a little more information about Moderna feeling like they might be ready a little bit before Pfizer and wanting to coordinate that. I’m going to just stay out of that for the moment until I get a little more information. People are a bit excited about the press release from Pfizer.

Pfizer-BioNTtech announced data demonstrating high immune response following a booster dose of their COVID-19 vaccine in children, 5 through 11 years of age. Some concerns we discussed previously about Omicron impacting the protection that we were seeing in this age group. Really just a 36-fold increase in Omicron neutralizing titers following this booster dose. We’ll see going forward durability. I understand this big focus on neutralizing antibodies. We’re going to touch on this again. What we really want to know is efficacy.

Certainly, antibodies are going to bump up when you get a booster, but what does this really translate into in terms of protection? We will see, but we do hear that there are plans for a submission to the U.S. FDA potentially having a three-dose series as a standard, even going down into the 5 to 11-year-olds. I want to put this into context. We keep talking about boosters and every so often I get an e-mail. People, apparently don’t like that. We’re not as excited about boosters as they feel like we should be. Here we are talking about a potential booster in this population.

The vaccine in this age group has been available since November 2021. Only 28% of children in this age group have gotten even two doses. Only about a quarter of the kids have even gotten two doses. In some states, it’s as low as 15%. I think we need to really focus on that 70% of kids who are not vaccinated at all and try to get them just at least those first two doses. I do want to point out, the argument that we’re hearing from the other side is against what I say, “Oh, COVID is not an issue for children. Oh, those children who do, there must be something wrong with them.”

Well, the MMWR early release, “Hospitalizations of Children Aged 5 through 11 Years”-  the same age group – “With Laboratory-Confirmed COVID-19, COVID-NET, 14 States.” This is March 2020, February 2022. Just a few points. There’s a really wonderful graphic. I like when they do that so you can just look at the graphic. What are the three big points? I’m going to really hammer this home. One, 3 in 10 had no underlying conditions. Every time I bring up children, “Oh, it must be kids who have some kind of problems.”

I just want to point this out. This is not an us-them type thing. 3 in 10 of these children who ended up hospitalized, nothing was going on. To all apparent, they were completely normal, healthy kids. 3 out of the 10 ended up in the hospital. 9 in 10, 90% of the kids who ended up in the hospital, unvaccinated. Huge thing we can do there because people hear the first one, they want to throw up their hands. Well, you can get vaccinated. 90% of the children that ended up in the hospital were not vaccinated, and 20% ended up in the ICU.

This is a big deal. Testing. This is actually exciting. Never miss an opportunity to test. This may be getting easier. There was a press release, “FDA Authorizes First COVID-19 Diagnostic Test Using Breath Samples.” This was the performance of the InspectIR COVID-19 Breathalyzer was validated in a large study of 2,409 individuals, including those with and without symptoms. In this study, the test was shown to have a 91.2% sensitivity, 99.3% specificity.

The study also showed that in a population with only 4.2% of individuals who are positive for the virus, the test had a negative predictive value of 99.6%. That actually gives us a sense of where we are now. Meaning people who got a negative test are really probably negative. This seems like a really nice three-minute approach to really screening people out. Really a nice exciting development. There’s actually several companies that are working on this technology and there are beagles who are born with this ability. They just need to be trained up to realize their potential.

Actually, I know that’s big down in the South and up in Canada, but this is really detecting volatile organic compound. I think this is pretty exciting. I’m getting tired of people sticking Q-tips really far up my nose.

VR: You’re still doing that, Daniel, still doing the anterior nares?

DG: I try, but I have to say when I went to Ghana, they were really back in there. [laughs] They were making sure they don’t want to let us dirty Americans come into their country with COVID.

VR: Daniel, does soft drinks affect this test?

[laughter]

DG: I’m glad that you bring that up because that was an issue. People were like, “I know I’ve got COVID,” and they couldn’t get– Finally, they, I don’t know, had a soda and swab the back of their throat got a positive test and celebrated. [laughs] I do not think this is affected by soft drinks, but yes. I do want to talk here in the testing section about this concept that I keep running into of people testing to end isolation early, or testing and not ending isolation until much later.

I know some folks who were previously in academics who are now working for for-profit testing companies seem really excited about everyone testing like maybe even a little bit too often. I’ll have to take back this, never miss an opportunity to test but just there’s a limit. Let’s just talk about what are the isolation recommendations because people seem to have forgotten this. You go ahead, you test positive, the pneumonic, isolation of the infected. Isolation can be discontinued five days after symptom onset, after resolution of fever.

You can’t be taking something that makes your fever go. It has to actually go away on its own. You have to have improvement in the symptoms. Now, taste and smell, this might persist for a while. That’s fine. Now it’s day six, you’re getting ready to go out into the world. You are still considered potentially infectious but at a very low level. We’ve talked about the fact that case-control tracing really puts it within the first five days. You can’t on day four or five do a negative antigen test and then say, “Oh, I can barely see the line. I’m going to go to a big party where they’re going to serve hot cross buns.

Invite Dr. Griffin into a small combined suburban home.” I won’t come. After you leave, wear a well-fitted mask for a period of time, it’s five days. When you get to day 11 you are done unless you are immunocompromised, one of these high-risk individuals. Day 11, if you do one of those PCRs, you do one of those antigen tests. If it comes up positive, you’re not necessarily detecting viable infectious virus. People need to look at the CDC guidelines. I actually think they are reasonable, particularly in someone who’s vaccinated. I don’t know, do you have any comments there, Vincent?

VR: Why are we quarantining people if we have vaccines that prevent severe disease? I don’t understand that any longer.

DG: Quarantine is mostly going away, right? Quarantine for the exposed, isolation for the infected. We’re really mostly doing away with quarantine. This is really this question of a person has tested positive. They’re potentially infectious. I actually think you bring up a good point. If you’re going to be going to an office setting if you’re going to be in there where you might expose someone who’s high risk. I think that’s still the thinking here. We are getting to a point, right. This is going to be a moral, a community. At one point do we– because we don’t isolate the infected with influenza for five days.

VR: Yes, exactly right. We can’t do this forever. There will be a point where there’s just as much SARS-CoV-2 around as there is now and we’re not going to be isolating. I think we’re at that point because we have vaccines that are effective. Are you waiting for 10 more antivirals? I don’t know. I don’t get it.

DG: Actually that might be the issue when we get to antivirals. Are we there with antivirals? Are they accessible? Are we educated? Do people know about those– people who are high risk who should be getting those? Are their clinicians up to speed? Do they have a plan? That might be one of the last little things, but what’s going to change going forward? Not a lot actually other than access. I’ve modified this one. This is my new– Occam was not a physician, but John Hickam was.

[laughter]

OK. For those who don’t get this reference so Occam’s Razor. William of Ockham was a medieval theological philosopher. Occam’s Razor is this principle that they still teach in some of the medical schools that a single explanation is the most likely in medicine. Suggests that the clinician seeks a single diagnosis rather than diagnosing multiple and different ones. Now, John Hickam has his own dictum and his quotation was,”A man can have as many diseases as he damn well pleases.”

John Hickam was a faculty member down at Duke in the 1950s who was later the chairman of medicine at Indiana University. He actually died at age 55 in 1970. He died a young man. An article that I know I’ve talked about and maybe it was in pre-print form, but “SARS-CoV-2 Coinfection with Influenza Virus, Respiratory Syncytial Virus, or Adenoviruses.” This was just published in The Lancet. They looked at over 200,000 adults with SARS-CoV-2 infection who were admitted to the hospital. Almost 10% of these patients had a co-infection.

If you were co-infected for instance, with influenza viruses, this was associated with increased odds of ending up on a ventilator. Actually, co-infection with influenza or even adenoviruses would increase your risks of death. Now that we’re getting all these masks off everyone’s out there, everything’s turned upside down. The seasonality of a lot of stuff is thrown off. We’re seeing a lot of co-infections now. A lot of people come in with SARS-CoV-2 they’ve got COVID, but they’ve also got an adenovirus. They’ve got RSV. They’ve got something else going on.

I’ve even seen common coronavirus and the novel coronavirus in the same person. Maybe just a public service here as people think about what are they going to be doing in the future. I know a bunch of companies are working on combination shots, but think about those flu shots. Hopefully, that’s one of the things people have learned. Flu shots have some protection against infection, but we’ve been talking, what do vaccines really do? What is the goal? They reduce your risk of hospitalization. They reduce your risk of ICU admission.

They reduce your risk of death. We have multiple studies demonstrating this. As I like to point out, about 90% of people who die from the flu are unvaccinated. When my patients get the flu and they muse about, “Why do I keep getting these flu shots? I just got the flu.” My one-liner to them is, “Did you die?

[laughter]

If you didn’t, the shot is working. Keep getting your shot. When you get the flu shot and you die, OK, then call me up and complain. Then you can stop getting your flu shots.” This is the big thing. I think you were just mentioning the mask are coming off. I like to point out to people you go into that bathroom at the restaurant it says everyone has to wash their hands. No, it doesn’t say everyone. It says only the employees. I guess the rest of us can go back and eat our meal and touch everything. Make smart decisions.

If you’re in a crowded place, if you’re a high-risk individual, if you don’t want to get COVID. One-way masking with a higher quality, the N95, the K95s can protect you. Please keep washing your hands. Active vaccination, never miss an opportunity to vaccinate, the jabs that protect you from getting very sick. Still lots of discussions about boosters and variant-specific upgrades. I like the Paul Offit editorial in the New England Journal of Medicine, you guys discussed it on one of the other TWiVs which was great.

“COVID-19 Boosters, Where From Here,” I do think we’re getting a little bit lost there. Let’s talk about what everyone asks me every week. Not a week goes by with people saying, “Yes, it’s great, Dr. Griffin, you keep telling me this, but I want the new improved.” What about the Omicron specific? What about the variant-specific? Moderna announced a clinical update on their bivalent COVID-19 booster platform on April 19th. Actually, there was a little manuscript available as pre-print, but it wasn’t initially, but then it became. The preprint safety, immunogenicity, and antibody persistence of a bivalent beta-containing booster vaccine. These were the results of a phase 2/3 study, evaluating the safety and immunogenicity of the bivalent vaccine candidate mRNA-1273.211. We’ve talked about this before. Basically, what is this vaccine? It’s the mRNA-1273, that’s our “Original Coke” version. Then they’re going to add an equal amount of beta variant spike protein-coding mRNA. It’s a 50 microgram, 50 microgram. They’re doing these boosters about 8 to 10 months, almost 9 to 10 months after the initial primary series.

I’m going to interpret their comments a little bit because what I found was these results indicate that bivalent booster vaccines can induce potent and durable antibody responses providing a new tool in response to emerging variants. I stuck in the show notes here and we’ll have a link to this, one of the figures where you can actually see the pre-booster, and actually, day 29, so we’re a little bit early, but OK. You can look at the different, whether you using the 123.211, so this bivalent booster. You can look at across the different– so ancestral, gamma, alpha, beta, which looked pretty good.

It looked like we were going in the right direction here. I know a lot of people are going to want multivalent, they’re going to want a new improved vaccine. People, when it comes to boosters, I suspect that most people will have a choice. This may be more appealing to consumers but also demonstrates that you can put multiple mRNAs in there and still go ahead and actually get a good response. Did you have any comments on this, Vincent?

VR: It’s not any better than the 1273 alone, it’s marginally better, but really the question is to echo something you brought up earlier, what about efficacy against severe COVID? This is just antibody levels which we keep doing over and over again and we don’t know what they mean. I don’t care about your antibodies, I want to know if this protects people any better than 1273? If not, put it back in the freezer, please.

DG: I guess it could be a marketing. If you want to pay $10 extra, you could get this as an option, and then if it’s $10 extra, people assume it’s better. [laughs]

VR: Right.

DG: Where was the T-cell data?

VR: No, forget about it.

DG: They wanted to claim it was higher antibodies but I just left that out.

VR: I think that it’s marginal, right?

DG: Yes. it was marginal.

VR: The real issue is, what does it do for disease, and they’re going to have to do– This is a phase 2/3, right?

DG: Yes. We’ll get some efficacy data from–

VR: Hopefully, we will. Yes. They’re not going to put a beta vaccine out. This is going to be some other combination, which they’re going to have to retest, right?

DG: Isn’t that interesting? They have in here ancestral, SARS-CoV-2 with the D614G in there. Then they add the beta. Then they test it against gamma, alpha, beta. It is interesting like are you going to eventually have an alpha, beta, gamma, Omicron, ancestral because you can put a lot in there. We have a Prevnar 20 now where we have 20 different antigens for our– You can put a bunch in there, but yes, I think that was the big thing. It wasn’t clear to me that it was actually better that it warranted this upgrade. I think that’s what people–

I think this may be a miscommunication. There’s been so much discussion about when do we get upgraded vaccines? We really got lucky here, the original vaccines are tremendous.

VR: In that TWiV though, you mentioned, we looked at that, and the advantage of having a variant-specific booster are minimal, at least in that mouse model. I’m just not convinced that we need to do it at this point.

DG: I’m not sure when it comes to severe disease where we’re talking, probably, growing evidence to support this as very T-cell mediated. I was wondering about the Peter Hotez, he’s got this just the receptor-binding domain saying, “I don’t know.” Then I was thinking, “Well, there’s a bunch of T-cell epitopes in there,” so maybe even that is going to be durable with different variants.

VR: Didn’t Pfizer test an RBD-only mRNA early on and decided it wasn’t as good as the full spike, so I’m not sure what Peter is thinking frankly?

DG: Yes, Pfizer didn’t go down that route. They did test it in mice. People are not mice, right?

VR: Yes.

DG: What did they say, mice are not humans, monkeys lie–

VR: Mice lie, monkeys exaggerate and ferrets are not humans.

DG: [laughs]

VR: There are limitations, but yes.

DG: We’ll see if the mice are lying, but they actually tested the multivalent boosters in a mouse model, this is preprint. “Low-dose Bivalent mRNA Vaccine is Highly Effective Against Different SARS-CoV-2 Variants, a Transgenic Mouse Model.” One of the things that I found exciting about this was that the mice did die. This has always been an issue with some of the models. I felt bad when I was excited that the mouse died, but you need to know this stuff. The low-dose bivalent mRNA vaccine that contained half the mRNA of each respective monovalent vaccine induced comparable neutralizing antibody titers.

We’re fine with that. “Enrichment of Lung-Resident Memory CD8 T-cells, Specific CD4 and CD8 Responses,” and fully protected transgenic mice from SARS-CoV-2 lethality. None of the ones that got this actually died. The bivalent vaccine significantly reduced viral replication in both beta- and delta-challenged mice. Sera from the bivalent mRNA vaccine immunized Wistar rats, so we got rats now, also contain neutralizing antibodies against Omicron BA.1 variant. The data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines are a feasible approach.

I’m not sure they’re better, again, but we’ll leave that. That may be a marketing issue, I’m not sure.

VR: Daniel, the key here is that if you put the ACE2 as a transgene with a very highly active promoter, then apparently, that makes the mouse die because if you–

DG: Or is susceptible to death, I guess, after the exposure to virus.

VR: Yes, as opposed to other transgenic models with– For example, if you have a lower activity promoter, they don’t die. Or if you use a mouse-adapted virus that is binding to mouse ACE, they don’t die either, but here, because there’s so much ACE apparently, maybe it lets more virus in, I don’t know.

DG: Interesting. It would be nice to know in these studies, like you want to have the FC transgenic mice as well, so they have the full immune response. Passive vaccination. I actually get to talk a little bit about Evusheld today. I’ll get to the charging issue in a moment, but let me just talk about the article “Intramuscular AZD7442 Tixagevimab, Cilgavimab For Prevention of COVID-19.” This was published in the New England Journal of Medicine. Eligible participants were either 18 years of age or older.

They had, I think this is important, increased risk of an inadequate response to COVID-19 vaccination. Let me just say that again, increased risk of an inadequate response to COVID vaccination. They weren’t testing people, they weren’t checking antibodies levels, we do not know what those mean. They weren’t saying, “Oh, your antibody levels are too high, we’re excluding you.” They just looked at patients that were at high risk of not getting a good response. Remember, it’s not all just about the antibodies, there’s a whole immune system here.

These are the results of an ongoing multi-centered double-blind parallel-group, randomized placebo-controlled trial looking at the safety and efficacy of a single dose of Evusheld for pre-exposure prophylaxis. A total of 5,197 participants underwent randomization received one dose or placebo. It was a two-to-one, and so we have 3,460 in the Evushelds group. 1,737 in the placebo group. Symptomatic COVID occurred in 0.2% of the participants in the Evusheld group, and in 1% of the participants in the placebo group.

We’re seeing a relative risk reduction of almost 80%, so a 76.7% reduction. Extended follow-up out to a meeting of six months showed a relative risk reduction of 82.8%. That’s symptomatic COVID. Five cases of severe or critical COVID-19 and two COVID-19 related deaths occurred all in the placebo group, zero in the Evusheld, which is twice as big a group. Really, really compelling here. A couple of things I want to show, and one is that editorial. I know there are places that take these high-risk people.

They don’t give them Evusheld because they’ve done some antibody test and decided that they’re not going to give them this protection. We don’t know what those antibody tests mean yet. Maybe there’ll be some subgroup analysis in this data in the future, maybe that’s the right thing to do. To deprive someone and then they end up getting infected, they end up dying, I’m not sure we have the data. That certainly doesn’t follow FDA guidance on using those serology tests, none of them are actually approved for that purpose.

The other thing, and I think this is a little tricky, and I want clinicians to know about this. A lot of times a patient can go to a place that’s in-network so to speak. They can get this Evusheld with limited out-of-pocket expenses. There’s a bunch of VIP groups out there, a bunch of people charging upwards to about $1,000 to give an individual Evusheld. I’ve actually had this happen recently, where what you’ve got to do is call around, figure out where that person needs to go. People should not be paying $1,000 or failing to pay $1,000 not getting Evusheld because there is this price something going on.

VR: There Daniel, one of the participants at this meeting, came up to me and said, “Tell Dr. Griffin, it’s impossible to get Evusheld.”

DG: Yes, tell that participant to call my office, I’m going to give you the number right now. 516-656-6500. I will make sure they get Evusheld, it is not impossible. You just need a clinician who’s willing to do what it takes. It may take a little bit of work, and I’ll do that work, but we all need to be doing that work. That’ll come up a lot. If you also can’t get Paxlovid, call my office, we will make sure it happens. I’ve given up on sleep. I’m just not doing that anymore. I’m just making sure people don’t die of COVID. [laughs]

Period of detectable viral replication, the viral symptom phase. Time for monitoring, and antivirals, monoclonals, enrollment in clinical trials. Not the time for doing things harmful, not the time for giving steroids in that early period and increasing their chance of progression. Not the time giving them zinc and giving them GI distress or doxycycline or azithromycin. We don’t treat viruses with antibacterial agents. Let’s go into what we do. We have updated guidelines from the World Health Organization that I’ll refer to as we go through.

Number One, right, Paxlovid. We’ll get to that. I had people tell me even in the New York City area, “Oh, Dr. Griffin, it’s impossible to get Paxlovid for our patients.” Again, call my office, it is not. We are getting Paxlovid to patients here on Long Island. We’re getting Paxlovid to patients in New York City, in Connecticut in New Jersey in the whole tri-state area. It may take a little bit of work, but there are therapeutic locators, we’ll share them in the show notes. Again, I’m going to start being more available because it seems like this is a problem.

These are out there sitting on shelves. Now this is not true in some parts of the country and unfortunately, I have some colleagues out West. I won’t mention the state Montana Idaho, but where you actually look at the look at– there’s no doses. It’s actually crazy. It really is difficult. I do acknowledge that at this point it can be tough getting this. The WHO now has endorsed Paxlovid, strong recommendation for the use of nirmatrelvir, ritonavir in patients with non-severe illness at the highest risk of hospitalization. This is that early period, first three to five days.

Based upon risk factors, you don’t wait to see if they get sick. If they wait until they get sick, you missed your window, but they are not recommending it in people who are low risk. Number two, monoclonal therapy here in the U.S. it’s bebtelovimab out to day eight, and monoclonals are also endorsed by the World Health Organization in this early period. Number three, remdesivir, right? We have three-day early IV data. This is compelling. Once they end up in the hospital, I’m not sure how much we’re doing.

Given early on the first five days about an 87% reduction in progression. We now have updated World Health Organization guidelines, finally endorsing remdesivir but for this indication for this timing. Conditional recommendation for the use of remdesivir in patients with non-severe COVID-19, that’s early, at the highest risk of hospitalization. Antivirals work when there’s viral replication. They don’t work if you wait and give them after the fact. Then molnupiravir, that’s our last option, only a 30% reduction in progression, so less impressive.

No renal adjustments, no drug interactions. Be careful with those women of childbearing ages, you want to get that negative pregnancy test. This is also in the WHO. This has been in there a little bit longer. Conditional recommendation for the use of molnupiravir in patients with non-severe COVID-19 at highest risk of hospitalization. Not much new for the early inflammatory phase. As I like to point out once people end up in the hospital in the early inflammatory phase, limited options. Remember, sometimes particularly our older, more frail may end up in the hospital during that viral phase.

Just because they have trouble keeping stuff down, they’re feeling so crummy and they’re not doing well at home. During that early inflammatory phase when the oxygen gets below 94%. You don’t need to run them up and down the back stairwell. This is a resting oxygen level, we’re trying to make them hypoxic. Steroids at the right time in the right patient. Anti-coagulation, sometimes we’re adding tocilizumab. That’s still we’re waiting for a full licensure review on that. Now I’m going to actually put a couple of things together, Long COVID and the rest of the world.

We are potentially going to have some trials looking at antivirals and the treatment of Long COVID. Looking at the theory is there viral persistence, but no one is safe until everyone is safe. The article, “Global Prevalence of Post-COVID-19 Condition or Long COVID: A Meta-analysis and Systematic Review.” Authors really did a lot of work here. They started by searching PubMed, Embase, and iSearch looking for post-COVID-19 condition prevalence at 28-plus days from infection.

They initially screened nearly 4,500 articles, narrowed it down to about 50 studies, and then ultimately included 41 in the meta-analysis. Really a complex bit of analysis here but what takeaways can I share? There appears to be a global issue with long COVID though there are some differences in regional prevalence estimates. They’re estimating that 200 million individuals have been impacted by long COVID. While fatigue is the most common symptom, this was actually followed by memory problems. The cognitive issues. That can be devastating.

We’re going to finish here before we go to e-mails. I want everyone to pause the recording right here go to parasiteswithoutborders.com. Click the donate button. We’re almost to the end of April when this drops, is I think one day left. We’re so close to our goal of getting to $20,000 so we can donate $40,000 to the American Society of Tropical Medicine and Hygiene. Priority will be placed on scholarships for females from low and middle-income countries travel award scholarships so they might attend the 2022 meeting in Seattle, Washington.

VR: Time for some questions for Daniel, you can send yours to daniel@microbe.tv. John writes, “Thanks for your update at the end of TWiV where you mentioned you’re on a call about Long COVID research. Three months have passed since my Omicron infection, and my Long COVID symptoms have not subsided despite being fully vaccinated and boosted. From my perspective, I just don’t understand why big pharma doesn’t have a single clinical trial for a drug like antivirals to treat Long COVID.

Why hasn’t the NIH or CDC developed a diagnostic test for persistent virus microclots, auto-antibodies? So many of us are stuck with no treatments, and no clinical marker to support a diagnosis.”

DG: Yes. John, there’s supposed to be this organized effort the RECOVER project. I will say from a personal standpoint, I’ve been talking with the leadership at UnitedHealth Group. Our plan is hopefully, in really just another week or two here. Reaching out to Pfizer trying to put together a randomized placebo-controlled trial looking at antivirals in people with long COVID. We really need to test that theory can these individuals benefit from that. When we get that up and running, hopefully, the TWiV listenership and I know Survivor Corps already stepped up and said they would be interested in helping us recruit.

I think this is an important question, is viral persistence part of this? Can an antiviral impact this? It’s one of those if no one else is going to do it, which seems to be what’s happened so far. I’m going to jump in and try to make this happen. Thank you, John, and gosh, sorry that you’re still having issues.

VR: Kevin writes, “I was wondering why the current recommendations are to only give either Paxlovid or monoclonals instead of giving both? Just curious seems like there’s a 10% progression rate with either why not get disease progression down to 1%?”

DG: No, I think this is a good point. Right now we’re under EUA, so we’re restricted. If you had someone who’s really high risk, for instance, you might actually think it might make sense to look at giving both. I actually had a patient recently in the hospital and Jai Ballani, he’s one of the docs who kind of came up through the ranks. He’s now an attending there at the hospital and I started the patient. They were like day two of illness. Started them on Remdesivir, and then he was concerned about the kidney function.

I did comment that the kidney function was improving. Coincident was starting Remdesivir but he didn’t want to continue. We ended up giving this patient monoclonals instead, rather than completing the Remdesivir. There are certain patients who maybe it makes sense. Anyone who tells me, “Oh, don’t worry Dr. Griffin, we’ll never get drug resistance,” I worry about that because I was burned early on when I used to think that might be true with the monoclonals, but we’ve gone through the alphabet with those.

VR: Abby writes, “I’m a pediatric urgent care clinician in New York, Connecticut. Couple of points. One, based on my experience with my daughter and husband, having a year of severe Long COVID, I wholeheartedly disagree with the idea we should not use Paxlovid, assuming there’s enough supply. I’m certain, we are breeding loss of confidence in medicine by showing such a deaf ear to those suffering with Long COVID and saying, ‘Wait for the data.’ This is a desperate situation. I’m caring for kids with a year over of severe fatigue, memory loss, regression, et cetera.

FYI, Mount Sinai, long COVID clinic recommended 6 to 12 months of aspirin. I’ve reviewed these studies. I don’t think it tells us not to use it for Long COVID.” Why don’t you address that first, Daniel?

DG: Let’s start with that. I think this actually goes back to what John was asking, is people desperately want to know. It’s one of those things where people think, my gosh, Long COVID might get better with Paxlovid. We need to know and I do understand the concept of, oh, compassionate just give it to people and see, but we really need to see and know. Every time you give individuals medications, we’re not sure what the long-term impact is going to be. We’ve certainly well-intentioned caused harm as I talked about some of the early approaches to COVID-19 here in the states, actually throughout the world.

We really need to know the answer to this because boy, if it can help people with Long COVID, then we should be giving it to people with Long COVID.

VR: Point two, clinically I am seeing at least a 30-to-40% false-negative rate with rapid testing. I have many families all symptomatic where only one, two, or three out of five people test positive. Or where a patient gets tested with symptoms and only tests positive on rapid and/or PCR after three to four consecutive negative tests. Sure, I think some inaccurate testing can be user error, but most seems to be an overreliance and overselling by everyone to the public on how accurate these tests are. There is such a push to get back to normal. We want to believe the tests are infallible and this is far from true.

DG: I think that this is a good point. When I do my weekly talks with the urgent care physicians in the tri-state, we always talk about the subtleties of testing at when do you test and who do you test? It is tough because we will be having more at-home testing technologies in the future. I think we’re maybe asking a lot of people to understand what that means. If you have a family, let’s say everyone is sick, everyone has symptoms. One person tests positive, the other people test negative, you don’t take those people who tested negatives with consistent symptoms and say, “Oh, go out in there in the world, go to that hot cross buns party.”

We use clinical judgment and assess to our pretest probability and use that to interpret the test results. This is actually a big challenge and I agree wholeheartedly with you here.

VR: Finally, so far with B2, I’m seeing a longer lag in transmission than with Omicron post-exposure. I’m seeing a wider window two to seven days than with Omicron, which seemed more like two to three days. I’m curious what others are seeing.

DG: We’re still seeing that short that two-to-three days like I was describing the gentleman who got exposed at Pesach. Then we just started to get our Easter admissions yesterday. We’re still seeing this short two to three day. We’ll keep track of that. I actually wish there was better surveillance. I mean, I hate to have to like keep asking everyone, what are you seeing. As we know, what is it? A confirmation bias? Our ability to remember. I wish there was really a better tracking system here, so I could quote a study instead of having to pool my colleagues.

VR: The plural of anecdote is not data?

DG: Yes, exactly.

VR: That’s COVID-19 clinical update, Number 111 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you, and everyone, be safe out there.

[music]

[00:55:08] [END OF AUDIO]

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