TWiV 974 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 14 January 2023

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 974, recorded on January 12, 2023. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: Still have trouble remembering it’s 2023.

DG: [laughs] You’ll have to script that. I’m going to put in my script. Hello everyone, so I don’t start saying hello everybody, or forgetting my opening line.

VR: All right, Daniel, what’s up today?

DG: Well, we have a lot, and I actually, two quotations, special treat today, maybe special treat, you all can tell me. “There is no such uncertainty as a sure thing.” That’s Robert Burns, Auld Lang Syne, so people might remember Robbie Burns. Also, “I am not a person of opinions because I feel the counter-arguments too strongly.” That’s Mary Shelley.

Right up front, I wanted to acknowledge how so many are having a tough time, but wanted to take a moment to specifically talk about physicians. Recently a few physicians have shared with me their frustrations. One dropped the compliment after venting for a straight 10 minutes without interruption: “You must be a real physician because you just let me vent for 10 minutes and did not interrupt me once.”

As we heard from our medical society here in New York, 62% of doctors reported suffering from burnout up from 40% in 2018. The majority of doctors this last year have reported that they feel burnt out. More disturbing to me is a separate report found that 1 in 10 physician surveyed had considered or attempted suicide in the last year.

Just listen, if you’re having a tough time out there, reach out. A lot of us went into medicine. We want to be there to help people. Your colleagues are right there next to you. If you’re having a tough time, reach out. I know it’s been a tough time. Things have changed quite a bit since I started to practice medicine, which is even not that long ago.

All right, let’s get right into Ebola. The Ebola outbreak, which erupted in Uganda, that was recognized in September 2022, has been officially declared over, officials said on Wednesday, Wednesday of this week, on the 11th, the outbreak had spread to nine districts, including the capital, Kampala, raising fears of its snowballing across the East African region. It was the worst Ebola outbreak in Uganda in more than two decades.

Second deadliest in the country’s history with 142 confirmed cases. According to the World Health Organization, it takes 42 days, twice the maximum incubation period, for an Ebola outbreak to be declared over. No new cases were reported on Tuesday, the 42nd day. There was a celebration back there in Uganda.

All right, polio. I don’t know if people who are watching or if Vincent, you recognize this is my polio bow tie.

VR: I do, the color. Yes, I can tell because I have a tie like that actually.

DG: See the Rotary International symbol there?

VR: I do. In fact, I have it right here. Let me get it.

DG: [laughs] This is great.

VR: Let me interrupt.

DG: For those of you that are listening right now, Vincent has left the set. He’s getting something, he’s returning now. I feel like I’m a sportscaster and now he is.

VR: Now, if we were on CNN, we wouldn’t be allowed to do that because they’re on a tight schedule.

DG: They wouldn’t let you do that and out it comes. You know.

VR: See, there it is. It’s a regular tie.

DG: Vincent, that’s the same, that’s my bow tie, but then I modified it so very similar.

VR: I don’t have a Rotary on it though.

DG: Oh, yes. You got to pay extra. Sorry about that.

VR: This is Infectious Wareables, right? Is that what you got?

DG: Yes, Infectious Wareables. We shop at the same place.

VR: I think someone gave it to me.I don’t usually, you think it could go on this turtleneck here? Would that work?

DG: Well, while you do that, let me start talking about polio. I really want to keep polio on people’s radar and it’s going to be on your radar by the way. You’re going to be hearing more stuff. A new batch of wastewater samples have turned up positive for polio in Orange County. Did I pronounce that correctly? Orange. Orange. The finding.

VR: Depends where you’re from. Either way.

DG: The finding comes after six weeks of negative results for the virus in wastewater testing throughout downstate New York. It’s actually interesting, if you look at the, is this almost looks like a heat map of like red and positive and then negative, and then you get the red again. Two wastewater samples were positive. According to New York State Department of Health. One sample was collected from the Herriman sewage treatment plant. One sample was collected from the Middletown sewage treatment plant. The strains in the two positive samples were genetically linked to a Rockland County case of paralytic polio discovered in July 2022.

VR: This is interesting because it’s not clear where, was this in someone who didn’t go to the bathroom for six weeks? No, that’s not likely. It’s not a reintroduction because it’s linked to the case from July, right? It’s not another introduction. It’s something, somehow, some kind of circulation here that we just didn’t see. Maybe someone visited this area, used the bathroom, and that’s it. Very curious.

DG: It’s interesting, right? They’re genetically linked to the Rockland County case. It’s interesting and I think another, I was chatting with Amy Rosenfeld today. I think you know Amy there, Vincent, she used to work at Columbia,

VR: I do.

DG: Just about, we really don’t do a lot of surveillance here. One of the, there’s a public health benefit to surveillance, on my soapbox here. A lot of times, you have these conversations, but why am I bother vaccinating my children? Why are we getting vaccinated for polio? It’s not even a thing. It is a thing. It’s here. I think that if this is out there, if people are aware, helps us with our discussions encouraging people to get that protection from vaccine.

VR: No, these viruses that are in wastewater could paralyze you. They’re revertants of the vaccine. They’re not attenuated, so you should be vaccinated for sure.

DG: Influenza is a little bit on the way down. It’s still higher than it’s been in several years, but that is leaving the opening here for COVID. I wanted to start by correcting a mistake I made last week and I got lots of, actually, they were reasonably kind emails, tweets, DMs, et cetera. Thank you. Actually, that’s one of the great things, right, is we get a pretty significant peer review here whenever we say anything. Let me go back to what was the response. Katie writes, I recently had COVID-19, and because I am breastfeeding, I was told by my GPs nurse that I should not take Paxlovid. I’m vaccinated and boosted, but no bivalent booster and I don’t have any risk factors.

Then she goes on. I had said this is reasonable, but let’s actually go through, because she opens up a bigger question, is what about a high-risk individual? You’ve got a high-risk individual. Is it safe? Is it OK? Are you told not to give Paxlovid during breastfeeding? I should have taken the time and I’m going to acknowledge that I didn’t take that moment to click on the FDA package insert to verify.

If you look in section 8.2 under lactation, and I’m going to go through this, because I think this is a good chance for me to highlight that this is not a contraindication and that this is something that is a risk-benefit in breastfeeding when a person’s breastfeeding, there are no available data on the presence of nirmatrelvir in human or animal milk.

The effects on the breastfed infant or the effects on milk production, a transient decrease in body weight was observed in the nursing offspring of rats administered nirmatrelvir. They referenced data. Limited published data reports that ritonavir is present in human milk. There’s no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Paxlovid and any potential adverse effects on the breastfed infant from Paxlovid or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

Then they mention the data, which is the pre and postnatal developmental study. Body weight decreases of up to 8% were observed in the offspring of pregnant rats administered nirmatrelvir at maternal systemic exposure, approximately eight times higher than clinical exposures at the authorized human dose. No body weight changes in the offspring were noted at maternal systemic exposure, approximately five times higher than clinical exposures at the authorized human dose of Paxlovid. I should also say that the American College of Gynecology, ACOG, is also on board with the use of Paxlovid in high-risk individuals who are breastfeeding, referencing these same points. As a correction to my previous comments, it really is a risk-benefit consideration and breastfeeding is not an absolute contraindication to use of Paxlovid.

All right, a compelling piece with lots of photos in The New York Times about what is happening in China with a focus on Shanghai. What exactly is happening? Why are things so bad? I’ll leave a link into this article but I just think one of the challenges is that there were a lot of ideas, people had certain ideas about Omicron and now it’s so mild, that this will be fine, lots of people can get infected, it’s not going to be a problem and the other thing is going to be a challenge is we’re probably not going to get the information on the ground. We hear stories of crematoriums going all the time, we hear of places where people are buried, et cetera, just to sort of throw that out there.

The other topic that hits home on the growing evidence that SARS-CoV-2 is here to stay. National Geographic did a nice piece, COVID-19 is more widespread in animals than we thought. So far, the virus has been detected in more than 100 domestic cats and dogs, tigers, lions, gorillas, snow leopards, otters, spotted hyenas, a binturong, not sure what that is, a coati, where’s Dickson when you need him, a cougar, a domestic ferret, a fishing cat, a lynx, a mandrel, a squirrel monkey, wild black-tailed marmosets, big hairy armadillos, a leopard, as well as mink, mule deer, white-tailed deer, and we do not even do that much wild animal testing, so this is likely just the tip of the iceberg.

All right, I always like to mention children are at risk from COVID and Long COVID and the challenge, someone’s asking me this recently, we used to get really good data on a weekly basis, on a monthly basis, how many children are hospitalized, how many children are dying secondary to COVID. We’re not really getting great data there, I just want to point that out. Let’s move right into the post-exposure period, that testing, have a plan. We talk about this ahead of time, talk to your provider.

If you don’t have a provider, we acknowledge that, we’ve talked about how some of the pharmacies have created options. Here in New York, there’s actually a number you can call but what can we do to keep ourselves safe from any variant under the sun? Non-pharmaceutical intervention. Masks protect you against every variant. The science favors mask use and suggests a hierarchy with N95s offering the highest level of protection; ventilation, almost exclusively respiratory spread, so keep that HVAC fan turned on and let’s talk about an article.

I do not think there’s any partisan divide on the topic of clean air, maybe there is, the article, “Increasing Ventilation Reduces SARS-CoV-2 Airborne Transmission in Schools: A Retrospective Cohort Study in Italy’s Marche Region,” am I doing that right?

VR: I think it’s just ‘Marsh.’

DG: OK, in the Marche Region, published in Frontiers in Public Health, it’s retrospective. Here, they looked at more than 10,000 classrooms of which 316 were equipped with mechanical ventilation. They used ordinary and logistic regression models to explore the relative risk associated with the exposure of students in classrooms. They reported that for classrooms equipped with mechanical ventilation systems, the relative risk of infection of students decreased, at least by 74%, compared with the classroom with only natural ventilation, reaching values of at least 80% for ventilation rates of greater than 10L, and then they give some units of which I am not familiar.

From the regression analysis, they obtained a relative risk reduction in a 12% to 15% for each additional unit of ventilation rate per person.

VR: Daniel, it’s 10 liters per second per student.

DG: All right, actually I’m familiar with that, liters and students and seconds. All right. Continuing on my theme of improved ventilation. The article, “Use of Carbon Dioxide Monitoring to Assess Ventilation at a National Infectious Disease Conference,” was published in Clinical Infectious Diseases. Three of the authors carried around these handheld CO2 monitors and as one might expect, there were high levels in rooms with greater than 90% of posted capacity. I actually ordered one for myself, so I’m excited to start monitoring this. I actually ordered the one they used in the study, so this is going to be great.

VR: What are you going to do with this, Daniel?

DG: I’m going to monitor.

VR: OK.

Daniel: I’ll report back. I’m very excited. This will be another excuse for me to not have to eat in crowded restaurants. All right, people may have heard the report that COVID-19 environmental surveillance looking at wastewater from planes in Malaysia recorded 96.5% of samples were found to have the Omicron variant of SARS-CoV-2 virus. Very interesting to try to interpret this. When we are told to take off those masks because they want to see our smiles, gives me a little pause but let’s think about this more. We know that people continue to stay positive often for weeks.

If this same result is found in one year or two years, how do we interpret this? Does this mean that 96% of planes have someone transmitting the virus, as one colleague suggests, is my buddy Jay Berger, perhaps this is an underestimate because how many people are even using the airplane lavatories for a long haul instead of the before and after some of us prefer. Is 96% of people using the lavatory on the flight putting positive in there? What if we look for flu or RSV, or polio or dare I suggest we actually do some quantitative work. I don’t know, did you run across this, Vincent? This is circulating in the mainstream.

VR: Yes. Well, I think that just being positive isn’t enough to be transmitting, right?

DG: I’m not sure what to make of this.

VR: You can be positive for weeks, but it may be at a level that you’re not really infecting anyone and what’s on the airplane, it doesn’t have to be very much in again, low levels of virus. I’m not so concerned about this, frankly.

DG: It’s hard to hard to make but it does make for a great scary headline.

VR: You’re right, let’s look for some other viruses, we will find them all, and then what?

DG: Then I’m never flying again, I guess. All right. COVID active vaccination, we’ve got a bunch here, which is great. More on boosters, with the preprint, “Effectiveness of the Bivalent mRNA Vaccine in Preventing Severe COVID-19 Outcomes: An Observational Cohort Study,” posted on The Lancet preprint server. This is data from the Clalit Health Services. As excited as we want to get, all the qualifications, this is a retrospective, observational cohort approach, looking at Israel’s largest state-mandated health service organization. Let’s start with the methods.

These are the results of a retrospective cohort study that included all members of Clalit Health Services, aged 65 and over, eligible for as they say, a bivalent booster but at this point, really many parts of the world, you can just say booster, because that’s the only option. Hospitalizations and deaths due to COVID-19 among participants who received the bivalent vaccine, were compared with those who did not, no placebo control. We’re not going to basically get compared to those that did not get a vaccine, compared to three or four.

A Cox proportional-hazards regression model, with time-dependent co-variables, was used to estimate the association between the bivalent vaccine and COVID-19 outcomes while adjusting for demographic factors and coexisting illnesses.

What did they find? A total of 622,701 participants met the eligibility criteria of these 84,314, so 14%, only 14% received a bivalent booster during the 70 day study period. This is not a lot and probably rather similar to what we’re seeing in the U.S. Hospitalizations due to COVID-19 occurred in six bivalent recipients giving us an adjusted hazard ratio of 0.19; death due to COVID-19 occurred in one bivalent recipient, so for death and adjusted hazard ratio of 0.14.

This is the headline we get. Based on this data, the bivalent booster maybe reducing progression to hospitalization by 81% and risk of death by 86%. To be completely transparent, we’re talking about a baseline risk of hospitalization in this study of 0.055% or 1 in 2,000 and this is people 65 and over, and the baseline risk of death without a booster of 0.01% or 1 in 10,000.

The absolute risk is really small, we’re talking about, numbers needed to boost in the range of 2,000 maybe to prevent a hospitalization, maybe in the range of 10,000 to prevent a death. When you look at the 81 and 86, you come like, oh my gosh, how can anyone not tell everyone to run out and get a booster when you see these numbers? But you’ve got to ask, we start doing the math if you’re 10,000 and this is two months, protection at this point we’re seeing for two months. You could actually see this little tail where things start to tail off a little, so yes.

VR: This tells me that not getting the booster is really good also, right?

DG: Well, I guess what I’m going to say, is getting those three shots is really good.

VR: Yes.

DG: People who’ve got three shots are really in a good place, and we’re still recommending boosters for high-risk individuals. I think you look at data like this and when people start saying, if you’re 19 and you’re fine, and you had COVID, and do you really need, I think this gives us some context. You don’t want to overpromise with vaccinations. You don’t want to overpromise with the boost, you want to be honest about what you can be offering.

VR: The other thing, Daniel, as you said last week, we spent $5 billion on this bivalent booster. It may well be that if we still use the old booster, that would’ve had the same effect. We don’t know that, we might have saved a lot of money, and this is 70 days, and as you say, it’s beginning to tail off, maybe in 140 days. there’s no more protection than people who didn’t get the booster. I think you can’t use this to say that a good strategy is to change the booster every six months or so.

DG: This is a huge challenge, and it’s not just a scientific challenge. There’s a motion here, there’s, are you an anti-vaxxer? You’re not recommending that everyone gets. It’s a very sensitive topic, and despite that, I think we do have to be honest to what the science is telling us. It’s going to be a meeting right, later this month to talk about what happens next. I just think we have to be really honest about, don’t just throw out this 81% reduction and 86%. You see that and you’re like, oh my gosh, wow, and then you’re like, OK, what’s the actual risk reduction, not the relative.

And now, what about mucosal immunity? Have we heard a lot about mucosal immunity? I think so.

The article, “Seven Month Duration of SARS-CoV-2 Mucosal Immunoglobulin-A Responses and Protection,” was published in The Lancet Infectious Diseases. I do suggest spending some time on this, including the supplemental data. I actually spent quite a bit back and forth looking at supplemental data and the figures going from the text to the figures. There’s really a lot in here, but I found Figure 1A the most interesting.

Here, they report the association between mucosal IgA concentrations at the 75th percentile or higher at enrolment. They use the British here with only one “L” in enrolment. A reduced risk of symptomatic ba.1, ba.2 or ba.5 breakthrough infection remained over an eight-month follow period with a hazard ratio of 0.55. Really much due to this initial risk difference, so you can really see the line separate and then they follow the same slope.

VR: This is after infection, because that’s what gives you mucosal immunity, not vaccination.

DG: Yes. It’s really interesting, they have a lot, and this gets challenging when you’re looking through the figures, and they do try to break this out with, is this coming from systemic IgA and then leaching across, is it being made locally? There actually is some data that really supporting the idea that this is being made locally in mucosal surfaces secondary to stimulation. This is a challenge, like, how do you keep yourself from getting COVID? You get COVID, OK, that’s interesting, so just throwing that out there.

VR: What is the measurement here, this is protection or disease or what?

DG: This incidence of symptomatic ba.1, ba.2, ba.5, so symptomatic, yes, and then they follow it over weeks.

VR: Well, as you know, the challenge with these respiratory mucosal infections is they’re very quick and you don’t get a great mucosal response. It doesn’t last for very long and in fact, they’re so quick, they’re in and out, they’re transmitted, and the immune response is lagging behind. It’ll be very challenging to vaccinate and solve that issue.

DG: Yes. No, I think that I was listening to the Amy and Vincent Q and A last night while driving to see my son compete in his indoor track meet. I mentioned that, Amy and I had talked about this really a long time ago. I think this is interesting. There recently was an article by three eminent older white male, anyway. This is a basic clear challenge. It’ll be interesting to see if it’s something that we can figure out how to get past. I joke like, hey, the way to keep from getting COVID is to get COVID, but maybe there’s some way to induce this mucosal protection for some reasonable period of time.

Then actually not get COVID by not getting COVID, so all right, moving into the COVID early viral upper respiratory non-hypoxic phase. Number one is still Paxlovid at some point, I’m going to stop mentioning this by name. Hopefully people will get this in, what does it take five times or 50, but little news on this front, Walgreens launches the free Paxlovid delivery services with DoorDash and Uber convenience ensures greater COVID-19 treatment access to all Americans this winter.

I think this was announced a little bit back, but I just ran across this. I’m waiting to open up my DoorDash app and have, I might have COVID choice in the title. I think this is actually going to be go to the Walgreens and then they’re going to coordinate with the others here.

Hopefully, they’re going to train the DoorDash and Uber convenience folks to drop off that Paxlovid and run away so that they don’t end up getting COVID. All right, if you can’t get Paxlovid, number two is that early, three day remdesivir and then we really are limited molnupiravir last and least. Then let’s not do anything harmful, I had a gentleman recently in the hospital, and this was his third bout of COVID. I was trying to figure out, like, see, I had it the first time early on. You did OK, yes, second time you did it, you’re fine. What happened this time? He said, well, you know what, this time I called up my primary doctor. I told him I felt like I was coming down with something.

I told him I had a COVID test and he called in a Medrol Dosepak and I’m like, OK, now I understand why I’m seeing you in the hospital. OK, so let’s not do that.

COVID early inflammatory, lower respiratory hypoxic phase .I know Vincent, if you remember when we talked about the data on sabizabulin. Well, on January 10, Veru announced the appointment of David D. Ho as chairman of the Infectious Disease Scientific Advisory Board. As COVID is here to stay and we are seeing close to 3,000 deaths each week, it’ll be interesting to see if this microtubule disruptor ends up in our toolbox for COVID-19. Currently, we’re still using steroids, anticoagulation, pulmonary support, remdesivir within the first 10 days, immune modulation. I mentioned that tocilizumab now is FDA approved for this indication.

Please update those electronic systems. It’s not e-Way, you don’t have to fill out all those forms, so thank you. All right, moving into COVID, the late phase Long COVID. The article, “Long COVID Outcomes at One Year after Mild SARS-CoV-2 Infection: Nationwide Cohort Study,” was published in the BMJ. I’ll be a little critical of how the media is covering this, but let’s actually talk about what this study has to say or shows us. These are the results of a retrospective nationwide cohort study that used electronic medical records from Israeli nationwide healthcare organization.

This study was performed to determine the clinical sequelae of Long COVID for a year after infection in patients with mild disease and to evaluate its association with age, sex, SARS-CoV-2 variants and vaccination status. COVID-19 infection was significantly associated with increased risks in early and late periods for anosmia, dysgeusia, it had hazard ratio of 4.59, pretty high, cognitive impairment, 1.85, dyspnea, 1.79, weakness 1.78, palpitations 1.49.

Now hair loss, chest pain, cough, myalgia, respiratory disorders were significantly increased during the early phase. Now, the spin is mainly positive and I think that’s consistent with other studies with what we’re seeing. Unfortunately, not for everyone and not for all the issues. They have a nice figure where they actually look through some of the complaints. As far as losing your sense of smell, far as things not tasting right, most people, that’s getting better. As far as chest pain, actually, by 12 months out, the incidence of that report is very similar to baseline.

Some things for instance, so weakness, that continues to be elevated hazard ratio. It really seems like it gets better and then comes back. Unfortunately, we see that. Cognitive impairment, so memory impairment, concentration. Again, we see that persisting out over time.

Some things get better. I think the spin on this was, most people are going to be better at a year. That’s true, 95% of people are going to be better at a year, but you still have that chunk of individuals that continue to suffer and that’s real. I was going to tell a brief little story that was poignant this week. I still have a few patients that got sick early on, so March 2020, and still continue to struggle with Long COVID.

This is a healthcare professional, I’ve been taking care of, hadn’t been able to see me for a few months because of some health insurance issues. It was nice to check up on them again. When we last talked, they were in a dark place, but they were doing quite a bit better. They were fairly emotionally labile. I was talking to them a little bit about whether or not they were emotionally labile always, whether it was just that when something was upsetting they were just, more easily brought to tears.

I suggested that they watch the movie Old Yeller. I don’t know if you’re familiar with Old Yeller. I figured this is a good one, find out if they cry at the right times. Of course, I told a little spoiler alert at the end, that dog gets rabies and has to be shot. She said, “That’s OK. It’s not a spoiler. I won’t remember.” I said, “Well, then you might want to write down the movie because I don’t think you’re going to remember the name of the movie.” At the end, before I said goodbye, I said, “Do you remember the name of the movie?” She said, “Oh, yes. Big Yellow.” I said, “Yes. Look at your sheet of paper.” (Laughter)

VR: Very good.

DG: Today, she just texted me, “I’m not sure if I want to watch that movie, I hear they shoot the dog at the end.” A little bit of joking here, but just to really point out. Here’s a high-functioning individual, a healthcare professional who now almost three years later is having the cognitive impairment that I just described. Not everyone gets better.

VR: Is there any association with first infections, vaccination? Do we see a difference in these rates?

DG: Speaking in general, pulling together what we know, we do know that individuals that get COVID after vaccination are less likely to get Long COVID so that’s very reassuring. Individuals that get vaccinated after they start to develop Long COVID have shown a reduction in the development of Long COVID or the persistence of Long COVID. That’s actually one of the first things we’ll do is ask someone, have you been vaccinated? If they’ve not, we’ll recommend they go ahead.

The interesting, this is a little bit of challenge, the sooner after the infection you get that vaccination if you’re unvaccinated, the more effective it seems to be as far as reducing your Long COVID symptoms.

VR: Do we know if Paxlovid has any impact on Long COVID?

DG: We talked about one study suggestion that there might be about a 25% reduction. We don’t know. I think that’s an important thing for us to follow and know. That would be a pretty reasonable indication. Anything we can do to prevent the millions of individuals that end up suffering post-COVID. At this point, we don’t know. That’s not an indication for Paxlovid. We’ll see if it ends up being an indication.

VR: Oh, one more question. This came up on the live stream last two weeks. There’s a certain risk of myocarditis in young men with mRNA vaccines. If you get boosters, does the risk, is it cumulative, or additive or with each booster, is it the same amount of risk?

DG: It seems to peak with the second dose, so it’s not cumulative. We tend to not see it that much with the first dose, we tend to see the peak with the second dose. It’s interesting. We see a lower rate at the third dose, but there’s also a selection or people who had issues with the second vaccine, are they just not getting that, they’re removing themselves.

VR: Thank you.

DG: Let us finish off with low-middle-income countries. I like to remind everyone, no one is safe until everyone is safe. This has repeatedly been something we say. I do want everyone to pause the recording right here go to parasiteswithoutborders.com and click “Donate.” Even small amount helps. We’re getting down to the end here. For the rest of January, donations made to Parasites Without Borders will be matched and doubled up to a potential maximum donation of $40,000, from PWB to MicrobeTV, where maybe we’ll print up one of those big checks, Vincent, that you can carry to your bank.

VR: That’d be cool. We could take a picture, we’ll send it to The New York Times. In these final weeks, if you would like a copy of Principios de la Virología autographed by all the authors, all five authors, if you donate $5,000 or more to Daniel’s campaign parasiteswithoutborders.com, we’ll give you one of those books. Just shoot me an email if you do that, vincent@microbe.tv. Now it is time for your questions for Daniel. You can send them to daniel@microbe.tv.

Taryn writes, “Should I get a second MMR dose for my toddler? We live in the U.S. but not in Ohio, still wondering what you think. Also, do you have any knowledge as to how many of the children hospitalized with measles have had only one shot? I’ve seen data on the number infected with only one dose but not the number hospitalized.”

DG: Interesting. People are aware. We had a pretty significant measles outbreak in Ohio, a number of children ended up in the hospital. I think the question is here in addition to the normal MMR routine, should people be getting an extra dose? I think there’s also coming up, there was a recent PNAS article about waning mumps protection. Should we be doing, an additional dose in that? At this point, it wouldn’t be a widespread recommendation for you up there in Canada. Is it where it is?

VR: In the U.S. Somewhere in the U.S. but not Ohio.

DG: We’re not making this as a general, across-the-board, everyone get another shot. This really was an outbreak triggered by people being not adequately vaccinated.

VR: Peter writes, “I just received my fifth COVID vaccine. I noticed on the insert, it says effective in preventing COVID and that’s from the CDC Moderna factsheet. Your team has always suggested otherwise. It doesn’t prevent infection, it prevents hospitalization and death. What’s wrong here?”

DG: [laughs] Something’s wrong there. It’s a pretty high bar, this whole idea, and we keep bringing this up, the fact that for pathogens that really, basically stay outside the body. They’re in the lungs. Pathogens, they are on mucosal surfaces, triggering these responses that don’t have viremic stages, that have a really short incubation period. It’s really hard to maintain for any period of time protection against infection.

There is, as we saw, for a transient period of time, you’re going to get a reduction in infection. We were not, but people were a little bit too sloppy with their language early on. Think of the vaccines, the main thing they’re doing is they’re preventing disease as opposed to infection.

VR: Severe disease and death mainly.

DG: That’s the main protection and that’s actually the durable impact that we’re seeing. As we talked about, we mean death, we mean hospitalization, and we actually mean Long COVID.

VR: Leona writes, “You have quite a following in Southern Oregon. I’m certain it makes a difference in the care of our community. I was recently asked if vaccines contribute to the development of new variants of SARS-CoV-2. It seems this has been in the news recently. What’s your understanding of the impact of vaccines and the formation of new variants?

DG: Actually it’s a great question and this is where words matter, how you say this because there’s this whole movement out there that the only reason we have variants, or we have variants is because of vaccines. Vince and I have talked about this quite a bit. Vince, you’re going to, hopefully, jump in on this. The whole idea is that viruses change over time. That’s intrinsic to viruses. They love to have these quotations or these titles, where they talk about, mutating viruses. Viruses mutate. That’s the deal.

What they’re doing is they’re mutating to have whatever fitness advantage is required under that selective pressure. Here in the United States, 97% of individuals have some level of immunity. The big pressure here is for immune evasion. Now go to a place like China that we’ve discussed, where there’s not a lot of immunity in the population. There’s less pressure there for the immune evasion. There can be different pressures there.

There’s always going to be different variants. There’s always going to be different pressures. In a vaccinated and a previously infected population, the fitness pressure driving those variants is for immune evasion. It’s not for more serious disease, it’s not for milder disease. It’s for something that makes the virus more fit. Vincent, if you had any comments.

VR: I think any kind of immunity will select an evasive variant. It could be vaccine or it could be natural infection. In the U.S., over 90% of people have some kind of immunity from vaccination or infected, that’s going to select for variants. It’s not just vaccination that does it, as you said.

DG: There’s nothing. I think that’s interesting. There’s this special idea that when people bring this up, “Oh, if we all just got infected, there’d be no problem.” Immunity is roughly immunity. Immunity puts this pressure.

VR: One Ruthie writes, “I’m a public health nurse, so immunizations and education about those is my job. I was listening to a podcast with Dr. Stanley Plotkin. He said something I don’t understand, or maybe I misunderstood. He said that mRNA vaccines don’t stimulate very good long-term protection, so that needs to be worked on. My impression was that antibodies wane with time, but we still have fairly good protection against serious disease. I also thought there wasn’t much research on B and T cell responses to COVID vaccines. What am I missing? I want to make sure I’m sharing correct information.”

DG: This is good. Vincent, I’m going to ask you to jump in and fact-check what I have to say here. There’s this whole idea that we’ve talked about, I joked that Amy and I discussed this back when we were in preschool together, that infections that are mucosal, that don’t have viremic stage, that have short incubation periods, that it’s going to be pretty hard to develop a durable protection against infection.

We’ve also talked about the fact that antibodies contract over time. That’s what happens. There’s suddenly this idea where people are putting these two together and saying, “Oh, it’s all because of mRNA vaccines.” Antibodies don’t contract more quickly after an mRNA vaccine, after maybe say a Novavax, a protein-based vaccine. Antibodies contract at a certain rate.

A lot of people are throwing this out. They’re saying, “The problems we’re seeing with COVID, the problems we’re seeing with infections like this without a viremic stage with a short incubation period, it’s all because we’re using mRNA vaccines. If we only used a more traditional vaccine, we’d have more durable protection.” I don’t think that’s the case. I don’t think this is something intrinsic to mRNA vaccines. Vincent?

VR: I think, long-term protection, so far, the vaccines are working well against severe disease. We don’t know how long that’s going to last. It probably won’t last 40 years like poliovirus and measles and smallpox. It’s already gone a couple of years, so it’s not bad, but how much longer? I don’t know that Plotkin knows. Nobody knows how long it’s going to be, so we just have to see. So far, you’re right. We do have protection against severe disease and I don’t know how long that’s going to last.

DG: Actually, it’s a good point that you bring up there, Vincent. When they say it doesn’t provide long-term protection, but actually, as we’ve shown repeatedly and I think we just saw in another study, even people that didn’t get that booster, these vaccines are providing pretty significant, pretty well to point, durable immunity up to now against severe disease, against death, against hospitalizations. Are they able to keep antibodies at a high level? No, that’s just not what antibodies do. I’m not sure there’s really any validity to what he’s saying about mRNA vaccines.

VR: I also think that long-term. It depends what you mean by long-term. It could be 30 or 40 years. We have no idea. We’re not there yet. We’re only at three years. I don’t think three years is long-term, Daniel, right?

DG: No. Now that you’re 70, the metric of long-term changes.

VR: That’s right. By the way, there is a lot of research on B and T cell responses to the vaccines. In fact, we’re going to have Daniela Weiskopf on TWiV tomorrow. She works at the La Jolla Institute for Immunology and works on T cell, so we’ll hear more from her.

DG: Now, does she work there or they all surf? I think they all surf. That’s where I learned to surf at La Jolla, so hopefully, we’ll hear …(laughter)

VR: Well, she publishes a lot, so I think she does some work. Our last one –

DG: She watches everyone else surf.

VR: This last one is from Judy. “My mom is in long-term care with dementia. No other underlying health conditions, besides beginnings of dysphagia. She’s 88. I did what you suggest that I contacted her doctor and pharmacist to come up with an action plan. She’s fully vaccinated. Her pharmacist said she qualifies for Paxlovid. However, the challenge is Paxlovid shouldn’t be crushed, and this is how her medications are administered. Just wondering if crushing them would be beneficial, or what would you suggest our plan B should be?”

DG: This has come up before, actually. I think, this was a question that was asked, very similar question on one of the Friday TWiV deep dives about, can you crush Paxlovid? In the EUA, in the package insert, et cetera, here, actually, EUA, FDA document, they say, “Do not crush,” and then they don’t tell you why. It’d be nice if they told you why. Is it because it’s enteric-coded? It is because they’re using these new nanoparticle technology? They don’t really actually tell us, but basically, the package insert is, “Do not crush.” They don’t tell us why.

Yes, crushing Paxlovid is not recommended. Unreliable serum levels if you do that. If you cannot swallow the Paxlovid pills, then what you’re going to want to do is move on to number two, which is going to be your remdesivir option.

VR: Remdesivir intravenous, right?

DG: Yes. Just three days.

VR: Judy says, “Love your bow ties.” That’s TWiV weekly clinical update with Dr. Daniel Griffin. Thank you, Daniel.

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

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