TWiV 936 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 17 September 2022

pdf of this transcript available (link)

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick. [music] From MicrobeTV, this is TWiV, This Week in Virology, Episode 936, recorded on September 14, 2022. I’m Vincent Racaniello. You’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello everybody. I am in New York. Where are you, Vincent?

VR: Today I am coming to you from Little Rock, Arkansas, the birthplace of the Clinton Movement if you remember.

DG: [laughs] I remember that, I do. All right. We’ve got a lot to cover today. We wouldn’t think at this point, but yes. Let me start with my quotation. “Franklin’s illness gave him strength and courage he had not had before. He had to think out the fundamentals of living and learn the greatest of all lessons, infinite patience and never ending persistence.” That was Eleanor Roosevelt speaking about her husband and his struggle, which is going to bring us right into what we’re going to spend quite a bit of time today.

Polio, now for those of you not in New York, for those of you in New York this week New York’s Governor Hochul declared a polio state of emergency in New York after the virus was detected in a Nassau County wastewater sample. People wonder why it wasn’t enough that it was up there in Rockland or Orange or even in New York City. I think it’s because I live here in Nassau County and she knew it was hitting home so, thank you. Now [laughs] just to be clear, there are likely hundreds if not thousands of cases of nonparalytic polio right now in our region. Just before I make it complicated, it doesn’t need to be complicated. Understanding polio I think is a little easier than understanding COVID.

I’m sure Vincent might take issue with that, having spent 40 of his years delving into the complexities of polio. Why do I say there are perhaps thousands of cases of polio out there, nonparalytic polio? It’s because there are three types of polio and people take notes, type 1, type 2 type 3, pretty easy. Right, no Greek. You don’t have to be in a fraternity or sorority to count. Type 1, we estimate that about one in 200 among unvaccinated cases, results in paralysis. Type 3 probably similar, one in about 300 maybe, but type 2, that’s what we’re talking about currently. It’s about one in 2,000 before you see a case of paralysis. We’ve already seen a case of paralysis up there north of the city. We also are seeing it all these different districts. How does it end up in the wastewater?

Someone is infected, they’re shedding this from the gut. They’re flushing it down the toilet. If they don’t wash their hands well it’s on their hands potentially getting into food stuff, infecting other people, potentially ending up in pools if they’re not adequately treated. That’s why we say that we estimate there is lots of ongoing transmission. I’m going to hit a couple articles. Also Vincent, I’m going to pull Vincent in because he’s the guy to have pulled in on this topic but let me start off with the MMWR, “Detection of a Highly Divergent Type 3 Vaccine-Derived Poliovirus in a Child, with a Severe Primary Immunodeficiency Disorder – Chongqing China, 2022.” Now, they start with a little bit of background and I want people to think about this as I want to suggest that this is implications beyond just polio.

Let me start by just reading the beginning of the report. Oral polio virus vaccine has proven to be highly effective in the global effort to eradicate poliomyelitis, because of its ability to induce both humoral and intestinal immunity, ease of administration and low cost. Sabin-strain OPV, oral polio virus, contains live attenuated virus and induces immunity by replicating in the intestinal tract, triggering an immune response that clears the vaccine virus. However, among under vaccinated communities and persons with immunodeficiency, OPV mutations that arise during prolonged replication, they’ll think about prolonged replication, can result in the emergence of genetically divergent neurovirulent, vaccine-derived polio viruses.

That’s what we’re currently dealing here within the U.S. In addition, OPV has resulted in rare cases of vaccine-associated paralytic poliomyelitis among vaccine recipients or their close contacts. That’s that one in a million, that’s why we’re not doing that here in the U.S., maybe there’s other implications. They go on and to say that one challenge that we have mentioned – but that I really want to shine a light on here is something they refer to as immunodeficiency-related vaccine-derived polio viruses.

An issue here is that people with immunodeficiency can have prolonged excretion of the vaccine derived polio virus. They can potentially see community transmission of these genetically divergent infection, infectious polio viruses. What is this report? In this report, we hear that a boy aged 1 years old ,born in Guizhou province, was initially admitted to a children’s hospital at age 6 months, with persistent diarrhea, daily fevers, diffuse, red papular rash and lymphadenitis, so inflammation, swelling, tender lymph nodes. He received a diagnosis of severe combined immunodeficiency. During his hospitalization, stool specimens were obtained on February 28, March 1, 2022, sent to the Chinese CDC, the CCDC polio laboratory, for testing in accordance with WHO recommendations. Four isolates obtained and tested by real time, reverse transcription-polymerase chain reaction were identified as type 3 poliovirus.

Genetic sequencing of the viral capsid VP1 coding region, indicated that the four isolates diverge from the type 3 Sabin strain by 22, 23, 22 and 24 nucleotides so, 2.4% to 2.7%, and shared 15 nucleotide substitutions. They conclude by saying integrated systemic poliovirus surveillance, including AFP environmental – I’ll add wastewater here and iVDPV, that’s your immunodeficiency related vaccine-derived poliovirus, surveillance is critical to detecting and containing all polioviruses and helping to achieve and sustain a world free of polio. Right, here is what I’m going to ask a question. Vincent and I can have a little discussion here. We’re about to talk about the fact that poliovirus has been detected in wastewater samples in all these counties. Has it been there for a while or did we just start looking?

VR: I would say that it’s been there for a long time. We just started looking because we’re looking for SARS-CoV-2 in wastewater, the system is in place. I’ve been calling for 10 or 15 years to be looking for poliovirus and wastewater. Why is that? In 2000, the U.S. switched from oral polio vaccine to inactivated polio vaccine and the assumption was all these OPV-derived viruses would go away, but you don’t know until you look. At that point we should have started to look in wastewater for OPV-derived viruses. Now in every person who gets OPV, every person, one of the things they said in this article is that sometimes it reverts. No in every person who gets OPV it reverts and is neurovirulent. The fact that only one in one and a half million kids who receive OPV get gets paralyzed is really amazing, because all the virus they shed after a couple of days is neurovirulent.

Now in the U.S., we have OPV coming from other countries where they still use OPV. That’s been happening since 2000 when we switched to IPV. We had to start looking in 2000, for these viruses in sewage. This has been a big, big mistake and in this article they say environmental surveillance is important. It’s always been important. I would say, wherever you look in the U.S., you’re going to find polioviruses in wastewater. I think they’ve been around for many, many years. We’re just looking for it now and we’re finding it. Now in the end Daniel, if you get vaccinated, this is not an issue. It’s an issue for eradication, for sure because I don’t think we can ever stop vaccinating, but in terms of danger to the public, just get vaccinated and you can ignore the poliovirus in the waste water.

DG: Very simple message. Just get vaccinated and I have to say, our TWiV is – I have to say – is doing something. It was actually my cousin Peter Gates, who’s in the financial sector. I was talking to him about this announcement and he’s a TWiV listener for the last two years. That was one of his first questions. Have we just started surveillance? Has it been there for a while? Did it just appear? People are listening, people are learning. I’m glad to hear that we’re educating the public up, but on September 9 we had a New York Department of Health announcement on polio. I want all the clinicians to listen because there’s actually something buried in here that is important, and I’m going to say changing what we need to be doing.

We hear poliovirus detected in wastewater samples from Rockland County, Orange County, Sullivan County, New York City, and now Nassau County, where I’m actually sitting right now as I record. All New Yorkers who are unvaccinated, including children by 2 months of age, those who are pregnant, and people who have not completed their polio vaccine series previously should get immunized right now, not in a few weeks, right now. Really simple message. If you are vaccinated, this is not a problem, in accordance with CDC and they go on to talk about the polio immunization schedule. The children, they’re getting three doses and then they’re getting that fourth.

That first dose should be given at 6 weeks through 2 months of age, so right, early. Another dose at 4 months, another dose at 6 to 18 months, and then boom, that fourth dose at somewhere between 4 to 6 years of age. To go to our public schools here in New York, you are supposed to do this. You got to check a box. My child got their polio vaccine unless you have a “Religious or philosophical or medical exemption.” I want people to be thinking about, what philosophical or religious exemption suggests that you want to expose your child to the risk of ending up paralyzed for their entire life?

The other thing they talk about is if you are an adult and you’re not sure if you’ve been vaccinated, go ahead, get vaccinated. Interesting enough, they throw a couple of things in here, and in a sense, these are really translations of things we’ve said before, but this is actually the part. Everyone, listen, if you’re a clinician listen closely. At this time, the following New Yorkers who have previously completed their polio vaccine series should receive a one-lifetime booster dose of IPV.

Who are those folks? Individuals who will or might have close contact with a person known or suspected to be infected with poliovirus or such person’s household members or close contacts and healthcare providers, all of us, nurses, aides, MDs, DOs, and NPs, PAs, healthcare providers working in areas where poliovirus has been detected, Rocklin County, Orange County, Sullivan County, New York City, Nassau County, and then they go on, even urgent care emergency departments, that’s EMS, neurology, virology lab workers, and individuals with occupational exposure to wastewater. This is really something – for a while the recommendation has always been, we suggest lifelong immunity, but if you’re going to be in a place where polio is endemic, ouch, that’s here, then you might consider getting that booster.

VR: I have a question, Daniel.

DG: Go for it, Vincent.

VR: There’s been one case of paralytic polio in New York. What are the individuals who have contact with a person known to be infected? Well, it’s zero. It’s zero.

DG: The other, which is really interesting, is: What changed? This has probably been here for all time. It’s we just started looking. Have we seen people in their 80s and 90s? Have we seen people our age who were vaccinated as kids, now they’re getting – Is there lifelong protection from the four shots series? Probably, but you know what? We’re all into boosters, Vincent. Vincent, we’re into boosters. You can’t be anti-boosters.

VR: Well, listen, as you know, Daniel, I’m critical of SARS-CoV-2 boosters. I’m critical of this because as you say, we have had this poliovirus around for ages, and nobody’s gotten paralyzed, except this one person in New York who was unvaccinated. This doesn’t make sense to me. What would’ve been good, would’ve been to monitor wastewater all these years and say, “Look, folks, we have poliovirus in the wastewater. You’re still not getting polio if you’re vaccinated, so the vaccines do last forever.” Or maybe we don’t find poliovirus in most wastewater, and that’s why people are not getting paralyzed. It could go either way. We don’t have any data on that, and that’s why CDC has dropped the ball here. They should have been looking.

DG: Yes. I think that’s big, and we’ll get to this. What is the big problem? Who’s at risk? It’s the unvaccinated. We make a difference by vaccinating the unvaccinated. This little bit of obsession with boosters. maybe I’ll echo Paul Offit, I worry that we might be losing our way. Let me move on to a health alert, and this is actually tied right in, I thought this is where it fits. “Severe Respiratory Illness Associated with Rhinoviruses and/or Enteroviruses, Including EV-D68, Multistate, 2022.” Now, are you familiar with this EV-D68 there, Vincent?

VR: Just a little bit, Daniel. We happen to have worked on it for the past eight years. This has been Amy Rosenfeld’s project, as you know.

DG: Yes. We’re very familiar with this. I don’t know if the public is, so let’s just raise awareness here. Healthcare providers and hospitals in several regions of the United States notified the CDC, Centers for Disease Control and Prevention, during August 2022 about increases in pediatric hospitalization in patients with severe respiratory illness who also tested positive for rhinovirus and/or enterovirus. Rhinovirus and enteroviruses can have clinically similar presentations and are indistinguishable clinically from one another. They’re also indistinguishable on a lot of our multiplex assays that we use in clinical settings. We get this report rhino/enterovirus. It’s not one thing with a horn at one end and entero at the other. It’s actually just an impact of the – but no, I have to say, what’s come away with these assays is people call, “Oh, I’ve got the rhino enteroviruses if it’s a new species or something. Concurrently pediatric acute respiratory illness, sentinel surveillance sites are reporting a higher proportion of EV-D68 positivity in children who come up with the RV/EV positive compared to previous years.

Although this primarily causes acute respiratory illness, this virus has been associated with acute flaccid myelitis, that paralytic manifestation that we’re familiar with polio as a rare, but very serious neurological complications. Just a little bit of a heads-up public service there. All right.

VR: One quick comment, Daniel. If you get a rhino/entero-positive on your BioFire, the only way you can tell if it’s a rhinovirus or an enterovirus, like D68, is to sequence the sample. Only special labs are doing that, but at Columbia, they have tons of rhino entero-positive samples and they don’t know if there’s enterovirus D68 in any of them. Secondly, the paralysis associated with EV-D68 is exceedingly rare, much rarer than polio and only 700 or so cases have been reported in the U.S. alone since 2014 when we started seeing a lot of EV-D68. There have been a lot of news reports about this new poliovirus, but it is far less prevalent than poliovirus. It’s not a fecally transmitted virus. It’s a respiratory virus, so it’s very different, and Amy is working on that assiduously in her lab to try and figure out how that works.

DG: I think those are critical comments, one, and I think maybe people listening should realize this. We are hearing about this because there’s a sentinel surveillance network with certain sentinel surveillance sites, but in general, when your child comes in with a respiratory illness, we usually don’t even spend the money to do a multiplex. They charge $800 to do these, which is a little ridiculous. Then even when that money is spent, you don’t necessarily get the breakdown that this is EV-D68. Again, we don’t have great surveillance, and I think that’s something we should be thinking about with the money we spend on national security, this is a national security issue, knowing what’s out there, knowing what’s going on, doing a better job of surveillance.

All right. Monkeypox, as I’ve been saying for a while, monkeypox is not a gay disease or African disease, monkeypox is an infectious disease. Following our trackers, we have some good news. The MSM, men having sex with men population, really have done a great job of behavior modification, so things are really going well in that community, but we’re seeing problems outside of that community, as we previously mentioned. Remember this is predominantly through contact, no sex required. The only way you’re going to make the diagnosis is if you actually send off that test. Remember, two of those swabs putting in liquid mediums, sending it off refrigerated or frozen for testing.

Vaccines, we’ve got them, and we heard that the NIH has started enrollment in its trial testing, the intradermal administration of the JYNNEOS vaccine. This is a public service announcement. The trial will enroll more than 200 adults across eight U.S. research sites, and then participants will be assigned to the different study arm where you’re going to see one arm is just going to get the standard approach. One arm is going to get one-fifth done intradermally. A third arm is just going to get one-tenth intradermally, so seeing if we can even stretch them a little bit further. Hopefully, we’re going to get some information here about the response as well as safety and tolerability. Next one.

VR: Daniel, how are we going to assess efficacy if we don’t have a control arm?

DG: I’m a little bit disturbed but they’re going to look at peak immune responses induced in recipients. Yes, yes. Whack yourself in the head. We have no correlates of immunity here as we’ve clearly discussed. We need efficacy trials. Those might be test negative observations after the fact as we have a growing number of people vaccinated. Yes, we also need to. Let’s not make the same mistake we just did. We need correlates of immunity. If you’re going to look at what you think is a correlate, you need to show that it’s actually a correlate.

Treatment. What about treatment? As promised the NIH announced that a Phase 3 clinical trial evaluating the antiviral tecovirimat also known as TPOXX is now enrolling adults and children with monkeypox infection in the United States. Study investigators aim to enroll more than 500 people from clinical research sites nationwide. We’ll include a link for those interested in enrolling in the STOMP trial. This is study trial A5418, Study of Tecovirimat for Human Monkeypox Virus. You could get a STOMP when you study tecovirimat.

I don’t know where the O comes from “monkeypox.” This is a study. It’s NIAID-funded. Who can join? Really incredibly broad. They actually have different groups. I was speaking to, Jason Zucker, who’s been on one of our podcasts, who’s a med-peds infectious disease attending there at Columbia. Actually, he and I have spoken quite a bit recently. Actually, Columbia is one of these sites. My friend Jason Zucker has been really helping us initially with getting access to TPOXX and now he’s actually going to be involved in running this trial.

We’re actually going to get data. There’s actually going to be a placebo arm in the nonsevere. The severe pregnant high-risk individual, they’re all going to get treatment. There’s also going to be a placebo-controlled arm. These would be people who normally wouldn’t get access. One of the big things for clinicians out there with this trial is even if you have a person with nonsevere disease, just think about the pain, think about the duration of isolation and infectiousness. We’re going to be getting data on that. We’ll leave a link but it’s and get more information there. Catchy link. Yes, we can’t just keep treating people with a drug that may or may not work. We need to know what we’re doing. It seems so silly to have to say that, right Vincent? [chuckles]

VR: Is there a control arm in this trial, Daniel?

DG: Yes, there will be a placebo, there will be a control. We’re actually going to get efficacy if you can imagine that. If someone is in the control arm and they progress and become severe, there will be a crossover. We’re not being completely heartless. Was I considered a research purist or something last time, something like that? Let’s move on to COVID. Children, COVID, and other vulnerable populations. As we’ve been saying for a while, children are at risk from COVID. Boy, vaccines can get confusing when it goes down to children.

We’re actually going to leave a link in our show notes to help people navigate. What is your age, is this your primary series, is this a booster? I was actually talking to a friend of mine, Jay Berger, the head of our pediatrics here. We’re now Optum. We’re now 2,100 physicians in the tri-state area and he’s head of pediatrics, still head of infectious disease. We’ll see if that lasts. He had actually sent out a cheat sheet, asked me to go through it and see if he had it all right. My response was that if they ask internists to do something with this much complexity, there’d be mutiny.

Those pediatricians they’re just so patient. Well, let me bring up the correspondence, “Effects of Vaccination and Previous Infection on Omicron Infections in Children.” This was recently published in The New England Journal of Medicine. I have to say, there are still lots of people out there who think it’s a much better idea to just let kids get infected than enjoy the benefit of vaccine-induced protection. Maybe there is more in here than just that. These are the results of looking at a large cohort study over a six-month period when the Omicron variant was dominant, so very timely.

They report on the protection conferred by the Pfizer-BioNTech vaccine. Actually, we get information on previous SARS-CoV-2 infection against infection and disease. I’m not even going to talk about infection because I just don’t care that much. I know that’ll get people a little bit upset. What I care about in these kids is, how do they do? Do they end up in a hospital? Do they die? Is there something about the vaccine or prior infection that protects them against hospitalization, severe disease, and death? I do acknowledge we’re not talking about Long COVID here but let’s go through, what did they actually find?

We’re going to ask two questions. One is, how effective were these vaccines for those endpoints during Omicron? Then as mentioned, if a child survives an infection, how much protection do they have from that experience? A total of 15 hospitalizations and zero deaths were noted among 273,157 vaccinated children. We’ve got a quarter million children vaccinated, post-vaccination, we only saw 15 hospitalizations. We saw zero death. We’re seeing complete 100% protection against death.

We’re seeing an incredible limit in the number of hospitalizations. This is really impressive. Actually, I have a figure here and I’m going to encourage people to look at figure 1. Not only do we see something in infection also conferred significant protection against hospitalization. There’s overlap here. I don’t want people competing here, which is better, but it’s actually encouraging. It’s not great because as we’ve seen, getting that protection from infection carries the risk of Long COVID, which as we’ll continue to talk about, is lower post-vaccine.

It also carries the risk of all those thousands of children who ended up in the hospital. We also lost over 1,000 children, getting infected with COVID is not without risks, but just to share this information.

VR: Daniel, this is the original SARS-CoV-2 vaccine and these kids are infected with Omicron. The original vaccine is still doing a great job.

DG: And only two doses, going strong. I think that’s something we’re going to keep hitting on. When I got another article I’m going to bring up later is that there’s all this press about, oh, vaccines and waning. As we’re going to continue to talk about, I do, Paul Offit and I, probably same page with it’s really a three-dose vaccine now that we have Omicron, but don’t ask me to come back next week with the data showing three is better than two. because we are really seeing durable protection against severe disease with these vaccines.

We’re going to get that. I’ve got another article. The next we’ll talk about is that pre-exposure period. As I like to say, have a plan. We’ve been talking about what should be part of that plan. We’ve talked about vaccination. We’ve talked about passive vaccination. Also, I’m doing an unbranded awareness campaign where Pfizer is making these gifts and movies for me, Vincent. It was-

VR: Very nice.

DG: Our social media thing is coming to fruition. It’s non-branded, it’s just raising awareness about what puts you at risk and the importance of having a plan. I’m actually hoping this has an impact. We’ll see next week.

VR: Daniel?

DG: Yes.

VR: I have a great story for you. One of our listeners, Doreen, has been listening to you for two years and she had a plan with her physician. She said, “I want to do this.” A couple of weeks ago, she woke up one day, she tested positive. She had symptoms in the morning. She tested positive by rapid antigen, called the doctor, by 2:00 PM was on Paxlovid.

DG: That’s excellent. That’s what we’re talking about and we keep hitting on this. Five-hundred people a day are dying. I was on a call with – It was, All Things Considered, one of these NPR shows. The question was, who are these people? Well, 300, 60%, those are unvaccinated. That’s really simple get vaccinated. What about the other 200, predominantly older adults, predominantly over the age of 75, predominantly people who did not get treatment in that first week? I keep repeating the majority of those people dying, they don’t need to die. These are preventable deaths and so have a plan. [chuckles] Active vaccination. Never miss an opportunity to vaccinate and vaccinated people still get infected. They are just less likely to die or have severe disease.

The paper, “COVID 19 Associated Hospitalizations Among Vaccinated and Unvaccinated Adults, 18 Years or Older in 13, U.S. States, January, 2021 to April, 2022,” published in JAMA Internal Medicine. These are the results of a cross sectional study of U.S. adults hospitalized with COVID 19 during January, 2022 to April, 2022. During Omicron variant predominance. COVID 19 associated hospitalization rates where 10.5 times higher in unvaccinated persons and 2.5 times higher in vaccinated persons with no booster dose. We’re actually seeing a little bit of an impact there. That’s where I’m drawing my “it’s now a three shot series.” Compared with unvaccinated hospitalized persons, vaccinated hospitalized persons, were more likely to be older and more likely to have underlying medical conditions.

I’m going to keep hitting on this, the effectiveness of vaccines over time. The paper has that right in the title, the paper, “Effectiveness of COVID 19 Vaccinations Over Time Prior to Omicron Emergence in Ontario, Canada: Test Negative Design Study,” published in Open Forum Infectious Diseases. This study addresses what I think is really an important question. How well are the vaccines doing with regard to protection against severe disease and death? Should we be worried? Which is what we hear every day, is protection really waning like we keep hearing? These investigators included 261,360 test positive cases, about a quarter million test positive cases and 2,783,699 individuals as the test negative control.

How was the vaccine efficacy against severe outcomes all the way out to 240 days? After two doses, it remains stable at 98% for severe outcomes. Actually there’s a really nice figure that people can look at over time. There’s a lot of discussions about, when that second dose was given, different dosing intervals over time, this is pre-Omicron, so I will say I do buy into the now three doses is what the primary series should be, sounding very similar to polio here. This is actually incredibly reassuring.

All right. “Nasal IgA Wanes Nine Months after Hospitalization with COVID 19 and is Not Induced by Subsequent Vaccination,” was posted as a preprint. Just a little background here but I think this is really important. Another one of those that got tweeted out there, maybe a little too quickly, wondering how authors can, how people can read this that quickly. Most studies focus on circulating antibody levels. IgG but not much information on mucosal, antibody levels such as IgA. I think our listeners are getting familiar with this distinction. Now we have this hope that maybe there’s a way to get high enough levels of immunoglobulins IgA on mucosal surfaces that will really have a robust defense against infection and maybe even onward transmission. I talk about this as the superpower of vaccines, that it’s not a typical promise. It’s not what we expect, but we’re now starting to ask the question. Is it possible?

As I’ve repeatedly pointed out, I think that individual whose last name rhymes with “Lavitt” may have missed this when he wasn’t listening. Vaccinated, people still get infected, but vaccines protect against severe disease. I want people to have two questions in mind. One, is there a level of mucosal antibody that provides protection against infection? If there is such a level can we induce and maintain this level? I think it’s worth looking at figure S1 where we see the IGG and mucosal, IGA levels collected prospectively from 446 adults following hospitalization for COVID-19.

Here we have infected and then mostly vaccinated. 89% of these individuals are vaccinated. You can actually see the IgG goes along. You can actually see when the vaccines came out, the IgG goes up, follow this a long time. If you look at the nasal IgA response it starts to go down after nine months and you really don’t see much of a much of a response to vaccination. What do these levels mean? What do they correlate with? We don’t know. It is this comment about the current vaccines are not necessarily boosting those IgA levels.

VR: Even if you could boost them, Daniel, the levels are always going to go down. We do not keep high levels of antibodies either in our serum, in our tissues or in the mucosal surfaces. If you’re thinking about making an IgA-inducing vaccine that keeps the levels up forever, I would say it’s a lost cause.

DG: I worry about that and I, actually, I worry and I don’t know when Paul Offit is going to be on, but I do worry about this losing our way our-

VR: Two weeks.

DG: Yes, two weeks, I’m looking forward to that. This issue, are we really thinking that you just give, enough vaccines, you’re finally going to prevent infection and transmission in a durable way. I think this is just more information along that lines.

Now passive vaccination, and I know for folks that are immunocompromised, well a lot of them are not getting Evusheld. Remember Evusheld is passive vaccination. This is giving people those antibodies. I wasn’t too happy when I read the pre-print, “Resistance of SARS CoV-2 Omicron Subvariant, BA.4.6 to Antibody Neutralization,” posted out of David Ho’s lab here at Columbia. Just to give people a little background, what is this BA.4.6, people keep making these rosy predictions about the winter and they say, oh, unless there’s a new variant.

Well, there is a new variant by the way. It’s already up to 20% in the Midwest. It’s up past 10% in our local region. SARS coV-2 Omicron sub variance, BA.4.6., B.A.4.7 and BA.5.9 have recently emerged. As mentioned, BA.4.6 appears to be expanding even in the presence of BA.5. It’s actually starting to really pick up ground. There looks to be a fitness advantage here. Compared to BA.5, these new subvariants harbor mutation at R 346 residue in the spike, like a protein, there’ll be a test on that.

They found that the authorized combination of tixagevimab and cilgavimab, so the Evusheld, completely lost neutralizing activity against BA.4.6, BA.4.7 and BA. 5.9.It did look like bebtelovimab retained efficacy. So ,concerning there.

All right. Now we’re going to move into the early viral, upper respiratory nonhypoxic phase, right? That first week. Vincent, I’m going to put you on the spot. I mean, the notes are right in front of you. This is like the cheat sheet. I was saying, Vincent, perhaps by now you can run through the order of recommended therapy. You get diagnosed with COVID, what’s number one?

VR: Paxlovid.

DG: What’s number two?

VR: You have to have your doctor ready, make sure your doctor’s ready. Number two is remdesivir.

DG: Number three and four?

VR: Number three, just bebtelovimab, and number four, molnupiravir. I really didn’t have to look at that because you’ve been saying it enough that I got it.

DG: Should we do harmful things to our patients just because it makes us feel like we’re doing something, should we give them high dose vitamin C or zinc or colchicine or chocolate flavored horse paste or some antibiotics because no one wants to go home without that? No, let’s not.

VR: No, we shouldn’t do things that are going to harm your patient.

DG: I mean, that should be simple, do no harm. It’s amazing that needs to be in your oath. Apparently, without that you would just go ahead and do that if it would fill your coffers. Second phase, we’re trying to avoid this. We’re trying to minimize this as much as possible that second week, the early inflammatory lower respiratory hypoxic phase, that’s when we have immune modulation steroids, anticoagulation, pulmonary support may be remdesivir if we’re early enough and remember, avoid those unnecessary antibiotics and unproven therapies. Remember this is not a linear disease we have the first week we have the second week. Then during that third or fourth week, we can have these rebound issues, whether or not you get treatment.

That could be due to clotting issues, due to other infections, secondary infections, that could be due to a secondary inflammatory wave. We need to keep our eye out for that. Low and behold, we make it past four weeks and we move into the late phase. Couple articles here as we close it out. The article, “Persistent Circulating SARS CoV-2 Spike is Associated with Post-Acute COVID-19 Sequela,” published in CID. This is a retrospective pilot study looking at plasma samples from adults that developed acute COVID, or PASC, so those who did didn’t get PASC. In this cohort of 63 individuals, 37 had been diagnosed with PASC. The investigators looked at SARS-CoV-2 antigens and a panel of 10 cytokines.

They reported using optimized ultrasensitive, single molecule array, assays, SIMOA, that could detect either SM, S1M spike, or N nuclear capsid in about 65% of the patient’s diagnosed with PASC several months after SARS-CoV-2 infection. Just to narrow this down, make it a little simple, spike was detected in 60% of PASC patients and not detected in any of the non-PASC, COVID-19 controls. They didn’t find any differences looking at the cytokines. Now I want little caveat here. Everyone like stay seated, before everyone interprets this data to support their own hypothesis, I want to say that this is interesting, and we need to understand what this means.

This is a pilot study, as I say that right in the title. Is it more generalizable, is this evidence of a reservoir, ongoing active viral replication, antigen that’s not cleared? Just to say that as they point out this is a pilot study, so hopefully, we’ll get more information here. The article, “Impact of COVID-19 Vaccination on the Risk of Developing Long COVID and on Existing Long COVID Symptoms: A Systematic Review,” was published in eClinical Medicine. The authors initially searched published articles and preprints and identified 2,584 studies. They eventually narrowed this down to 11 peer-reviewed studies and six preprints that were ultimately included.

Six studies and n of over 17 million individuals, investigated the impact of vaccines before SARS-CoV-2 infection, so vaccine infection Long COVID design. Overall vaccination was associated with reduced risk of odds of Long COVID, with preliminary evidence suggesting that two doses are more effective than one, still waiting to see about three. Eleven studies, this is 36,736 COVID-19 survivors, investigated changes in Long COVID after vaccinations. This is vaccination as a therapeutic. Seven articles showed an improvement in Long COVID symptoms, at least one dose post vaccination while four studies reported no change or worsening after vaccination.

All right, so I will finish up with no one is safe until everyone is safe. This situation is going to come to some sort of an end, as we’re seeing there’s tremendous potency to these vaccines for preventing severe disease and death. There’s tremendous potency to some of our early treatment tools. We’re also seeing that people who did not die during that first infection as we discussed, we’re acknowledging, we’re seeing that there is protection, boy, what a risky way to acquire that, but no one is safe until everyone is safe. We keep seeing examples of this. Let’s just focus on what’s going on here. Let’s continue to think about the rest of the world. This is when I ask everyone to pause the recording right here, go to and click “Donate.” We are not supported by any big companies. This is all grassroots.

It’s your donations that make this possible. If you enjoy this science-based education, help us continue. We are now doing our Floating Doctors fundraisers. During the months of August, we’re now into September and October. Donations made to Parasites Without Borders will be matched and doubled up to a potential donation of $40,000.

VR: It’s time for your questions for Daniel, you can send them to Daniel at Larry Writes, “Hi, Dr. Griffin. I heard you on Brian Lehrer last week, and I tuned into the latest TWiV podcast. Thank you for what you do. I thought that you said on WNYC, that it is actually preferable to get the flu vaccine and the new COVID bivalent booster at the same time. Is that what you said? If yes. You never got the chance to explain why that is. My partner said she read an article saying the opposite that you should wait a week between the two. Can you clear this up for me?” Why don’t you take that part first?

DG: Let’s start with that. If people listen, I was on the Brian Lehrer show and Brian’s a brilliant guy. I always enjoy, and they always fact-check. I’ve been texting back and forth with the producers of the show. they’re always fact checking. They always want to make sure that the information shared is accurate, reliable. That was the question. Should you wait, should you space out? The current recommendation is to get that flu shot and that COVID shot at the same time. Moderna was actually working on trying to get it in the same syringe. People don’t want to be poked twice. When I do go around and get my booster, when it becomes a little bit convenient, I can do it right here in town.

I’m going to try to get both at the same time. Other vaccines though you might want to space out. There was – not a question that came up here, but came up when an educational thing – what about monkeypox? What if you’re getting your monkeypox vaccine? Situations like that we’re going to prioritize the monkeypox vaccination and we’re actually going to delay that booster.

VR: Now, just a word on these fact-checking things, Daniel. I’ve been a fact checker, they call you up and they read you something and they say, is that right? They say, yes, so maybe the person is wrong. It’s only as good as the person they’re asking. I don’t put a lot of stock in fact-checking, but it’s important to do it, I agree.

DG: It’s funny whenever – Maybe it’s the habit of mine. Whenever I’m asked to fact check, I always respond with references with-

VR: I think that’s good stuff.

DG: I’m like, this is the truth. Here’s the reference that supports why I say that. I think that’s important. What is it? We talk about the Delphi consensus, where a bunch of people get together decide they’re oracles and then spout expert advice with no data, no science behind it.

VR: All right. Continuing with Larry’s second reason for writing. “You make a very good point about not using Twitter or what your partner read online to determine your health decisions, but I feel that the way you advise people to consult with their primary care doctor doesn’t reflect the current state of medicine. I just turned 63. I’m very healthy. I live in New York City. I would love to have a 30-minute sit down with my PCP to discuss a COVID plan, but doctors, these days are limited to 15 minutes and that’s if you can find a doctor. You say, if your PCPs not up to the latest info or doesn’t return your calls, go find another.

I’ve been on Obamacare for recent years. Maybe New York City market is unique, but none of my regular doctors will accept an Obamacare insurance plan. They feel that if they accept them, they’ll be inundated with patients, for which reimbursement is low and prevents them from having time to see other high-paying patients. When I had to search for a doctor, it’s hard to find one who will accept new patients. Again, maybe this is different in other parts of the country where doctors have little choice, but to join the one or two networks in their smaller market.

But I urge you to take this into account when you advise people to simply phone their doctor or go in for a long consult, it doesn’t happen very often that a doctor returns a call, much let sits down with you for 30 minutes. All of which is to say, when I hear authorities advise listeners on the radio to check, to see if their doctor is in network, it’s like being told that the check is in the mail. I believe that if you acknowledge some of these difficulties in your remarks, they would be more effective because they would be better reflecting what listeners are dealing with daily. Thanks again, for being such a clear and reliable communicator.”

DG: I think this will be a plug for our Optum tri-state network. This is really – we’re physician-run, we’re physician-led, we take the time and I think if you get a chance to speak to – actually Vince and I just saw one of your neighbors. We’ll try not to violate any HPI. We make a point and again, that’s why I keep telling patients to find a doctor who will take the time because it makes no sense financially. o send all this money to the hospitals when I consider it a failure if someone ends up in the hospital. We want people to have a primary care provider. Those primary care providers should be properly reimbursed.

Patients should actually have the time to have those discussions. If you can spend 20 minutes with a patient and keep them out of the hospital, keep them from dying. Once they die, they’re not paying those premiums. They’re not coming and visiting you anymore.

It doesn’t even make financial sense, our current model, but I do acknowledge that the system is broken and we do need to improve it. That’s hopefully why I continue to provide this resource, hopefully giving you the information so when you do have that shortened abbreviated visit, you’ve got the information you need to make that a valuable use of everyone’s time.

VR: I think we ought emphasize Daniel, that you’re not being reimbursed for this weekly hour of your time.

DG: Wait, what?


VR: Oh, sorry about that.

DG: No, I am not. It’s a privilege.

VR:  OK. Robert writes: “Thank you so much for your excellent weekly COVID reviews. Please keep them coming. My question involves Paxlovid and potential drug-drug interactions because Ritonavir’s inhibition of CYP3A4, it’s reported that after its discontinuation at five days for Paxlovid, 80% to 90% of the CYP3A4 inhibition resolves within three days. Because of this, I was under the impression, and have been recommending to my patients to hold drugs that require CYP3A4 for elimination, such as apixaban, cholesterol meds, et cetera for a total of eight days. I hear some of my Pharm D colleagues note this however. I do not hear this recommendation expressed by many of my clinical colleagues or experts. Can you set us straight on this? Thank you.”

DG: One of the links we actually leave in our show notes every time is the link to the They recommend five days and then another five days. Let’s say, you are on that statin, you stop it for the five days, you stop it for another five days. They’re acknowledging and giving this guidance. Again, I think that that’s an educational challenge. Well, this say it right here, if you’re going to stop a drug while you’re going to be on this medicine that’s going to interfere with the liver metabolism, that doesn’t go away right without last dose. It’s five days while you’re on it, we recommend another five days for safety, and then you go ahead and resume this on the medications.

VR: Harry from Auburn, California writes: “My wife, Shirley, is post-polio from her September 1948 illness. Our GP doctor states there is no risk factor from post-polio regarding COVID. They also state they know of no association. Is there any known post-polio risk factor for COVID that you know of? Hoping to get your input.”

DG: When I went out to practice in Colorado, where I was – practiced for about a decade, Fort Collins, Colorado, really a lot of individuals there with post-polio. My biggest concern would be those folks that have an impact upon their respiratory capacity. Other than that, there are no specific signs that I’m aware of post-polio and the COVID risks.

VR: Finally, Ana writes, “I’ve been listening to your updates in other TWiV podcasts since I discovered you during the first year of the pandemic. You’re an incredible resource. Thank you for keeping us sane and informed. My 10-year old daughter had two doses of Pfizer’s spaced three weeks apart, the second in December 2021. In May this year, we unfortunately all got COVID. My question is, how necessary is it for her to get a booster since now she has both vaccine and infection-derived immunity?”

DG: I think this is a great question. We’re learning over time. One of the things we’re learning, I think we’re acknowledging, is that it’s not great to get infected with COVID without the vaccines. But once you’ve had the vaccines, once you’ve survived a case of COVID, as we saw, as we discussed in our article today, there’s significant protection against severe disease. That’s what we’re hoping to generate here.

This isn’t that you’ve got to rush out. Again, just to go back to that first, have that discussion with the pediatrician. Is there an urgency here? There isn’t much of a downside to getting that booster, but is there much more of an upside, try to accomplish what we think we may already be achieving.

VR: That’s TWiV Weekly Clinical Update with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you, and everyone, be safe.


[00:53:29] [END OF AUDIO]

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