TWiV 883 COVID-19 Clinical Update #108

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 2 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 883, recorded on March 31st, 2022. 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: Daniel, this is update number 108, and we’re apparently at booster number four, aren’t we?

DG: Yes, we were going to just jump right to booster number eight, but no, don’t worry, we will talk about boosters. I’ve been getting a bit of a deluge about that, so we will get there. I was just sharing with Vincent, just as I’m about to record, the power in the entire area where I record went down so I have a long extension cord, it’s about 50 feet long, snaked in here, so I think it’s going to work, but we’ll see.

Let’s get right into the quotation. “Science is the search for truth, that is the effort to understand the world. It involves the rejection of bias, of dogma, of revelation, but not the rejection of morality.” That’s by Linus Pauling. I like this. The ideal is science is about discovering what is real, what is true, not about what we want to be true, but actually what is true. Nice to maybe remind people, that’s what science is. I try to keep opinion as much out of this as possible and share the science. I know some people feel like, “But Dr. Griffin, what should I do?” I’ll give you the science if you want that little extra what should you do, then you probably need to schedule an appointment and then I’ll give you that last push.

My purpose here is to share with you the science, the knowledge to help you make the decision that’s best for you. Where are we this week? We are back to boosters, this time we’re talking about shot number four. I have to admit, I got such a deluge of text emails, calls, actually, so much I was in the Brian Lehrer Show this week. Actually, I was thanking Brian for having me on because this way I could talk to a million people all at once.

Hopefully, we’re going to do that here on TWiV as well, answer all those questions, and yes, I’m going to tell people, listen to TWiV, stop texting, and we’ll go into what’s going on here. On March 29th, Tuesday, the US FDA-authorized a second booster dose, a fourth shot, of either the Pfizer-BioNTech or the Moderna COVID-19 vaccine for older people, certain immunocompromised individuals. Let me just run through the update, because the distinction I want to make right up front, this is about access, there’s no recommendation in this change, and so we’ll talk a little bit about that. I’m going to hit the three bullet points because there are things that are not in here and there are things that are in here, so let’s go through.

Number one is the broadest statement. A second booster dose of the Pfizer-BioNTech COVID-19 Vaccine or Moderna COVID-19 Vaccine may be administered to individuals 50 years of age and older at least four months after receipt of a first booster dose of an authorized or approved COVID-19 vaccine. Pretty broad right, really saying we’ve got access for a lot of folks 50 up.

Then a couple of others, this is the immunocompromised. A second booster dose of the Pfizer-BioNTech COVID-19 Vaccine may be administered to individuals 12 years of age and older with certain kinds of immunocompromise at least four months after receipt of a first booster dose or any authorized or approved COVID-19 vaccine. These are people who have undergone solid organ transplant, who are living at conditions that are considered to have an equivalent level of immunocompromise. This is pretty significant, immunocompromise.

Then they go on really with the third point be very much along, a second booster dose may be administered at least four months after the first to individuals 18 years of age and older with the same certain kinds of immunocompromise. That’s what they have to say, but what is it based on? People got pretty excited about a preprint “Second Booster Vaccine and COVID-19 Mortality in adults 60 to 100 years old” posted on Research Square as a preprint, and the top headlines were pretty dramatic.

Let’s go through because if this is going to be the data that people are going to be looking to when they talk about this, what do we have here? For starters, this was a retrospective cohort study where they looked at eligible people that got a booster and compared them to eligible people that did not get a booster. A big confounder that they even point out is really what they are actually comparing is a group of poor, mostly Arab, mostly ultra-Orthodox populations to a wealthier Israeli population. I think you can just stop right there because we already know who does better.

COVID-19 is a disease where we see inequity, we see the impact of behavior, and we only looked for a 40-day period that began seven days after boost in the population that got the fourth shot. If you move past the flaws, you’re looking at minimal incremental benefit I’m going to quote Paul Offit, I just listened to the most recent TWiV earlier today where Paul’s wife actually wrote a letter. What does Paul have to say about this? “This study, while it offers the only evidence, is deeply flawed. The participants all volunteered to get a fourth shot, and are likely to be people who are naturally careful about their health.”

First, I’m not going to take much from this study, but I am going to talk a little bit about, where are we? Are we really needing this? Should people be worried? Are the shots not working? I’m going to follow up this with the discussion of the MMWR early release. This just came out: “Effectiveness of Homologous and Heterologous COVID-19 Booster Doses Following 1 Ad.26.COV2.S” –  so the Janssen, the J&J –“Vaccine Dose Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults. VISION Network, 10 States, December 2021–March 2022.”

We’re going to be talking about the vaccines. Here we get the data on vaccine effectiveness of different vaccine approaches. It’s here in the US, this is our data. This is published, this is not just a preprint. They’re looking at the different vaccine approaches including boostering strategies and we’re seeing during the Omicron variant dominance. This is all about disease, not infections, so they’re looking at emergency and urgent care visits and then hospitalizations.

This study included 80,287 encounters among patients with COVID-19-like illness seeking care at EDs, emergency departments, urgent care facilities, and 25,244 hospitalizations among patients with COVID-19-like illness. We don’t have all the data I want, but we have a bunch of data here, so let’s look at the vaccine efficacy against visiting the ED or the urgent care. If you got two doses of J&J, about a 54% reduction. If you got one J&J and then in mRNA, it went up to 79%. If you got three mRNA doses, you’re already at 83% reduction.

Important really here, we’re talking about someone seeking medical care because they have symptoms. We’re not necessarily talking about someone who’s very ill. They’re going, they say, “I don’t feel well, I want to get tested,” so what about hospitalizations? Here, we’re actually talking about someone who is sick enough that they’re going to end up getting admitted to the hospital.

Vaccine efficacy after three mRNA doses against hospitalization 90%. Just paused there for a moment just to repeat that for everyone, right? During the Omicron, you got your three doses, you didn’t get your fourth, you’re already at a 90% reduction. What if you got a J&J and one mRNA, not quite as good, 78%. What if you went with just two J&Js, 67%. What if you just got one J&J, OK, 31%.

You stop there and put this a little together. Vincent, I’m pulling you right in, don’t worry. Three mRNA vaccines, you’ve already got a 90% reduction. I don’t think going into this, we ever thought we were going to be able to have numbers like that. Sure, if you only got one J&J and you’re 31%, I think it makes sense to do something there. Throwing an mRNA is going to get you up to 78%. Thrown a J&J, only 67, so boy, if you had one J&J, I’m going to go ahead and say get an mRNA on top of that J&J, we’re now getting better data to make that recommendation.

But three mRNA doses, we’re at 90%, numbers are going down, your risk of exposure, your risk of infection, is now really the right time to be recommending that people run out and get a fourth dose, or should maybe this be a discussion we have come next fall when we’re expecting numbers to start to rise? Vincent, people know where I stand here so far. What are your thoughts?

VR: I think as you’ve pointed out and Paul Offit pointed out, and I’ve read the Israelis preprint yesterday, it’s clearly flawed. We’re talking about a difference in a few hundred deaths, to base US public health policy on that, I think is embarrassing. I don’t understand why the FDA did it. They did it without an advisory board meeting, as you know, and it’s only for the mRNA vaccines. If it were so important to get a fourth dose, they would recommend it for the other vaccines as well. I think this study emphasizes that you don’t need a fourth dose.

I really like the emphasis on hospitalization, because as you say, visiting an ER, it’s just too squishy, as I would say, it’s not a solid– I would love to have deaths, I think that would be the best thing, but 90% is amazing. Most vaccines don’t get close to that. Even 78% is pretty darn good. I always tell people, this is what we have right now. These are the vaccines we have. This is the best it’s going to get and it’s pretty darn good.

DG: Yes. I think it is actually pretty impressive to be at 90% with the mRNA through Omicron, when we were worried about immunization. Yes. If you’re like me, I’m going to use myself as example. I’m trying to get my BMI down to that ideal level, so 50s, no significant health issues, BMI reasonable. Am I going to run out and get a fourth dose? No. My parents, am I going to say you got to run out? No, I’m not actually.

There certainly are people who are going to say, boy, what’s the downside? These vaccines are incredibly safe. They now have the option of going out, but boy, there’s nothing scary here. The vaccines are continuing to work incredibly well. I will say, ask your doctor if a fourth shot is right for you, and in most cases, there’s going to be no urgency because these vaccines are still doing a fantastic job.

All right. Children, COVID, vulnerable populations. I mentioned last time when I was recording that I would be on a call with my colleagues in Hong Kong. I did that right after we recorded. It was Thursday night for me, Friday morning. Really tough seeing what’s happening in Hong Kong. Some of what was communicated was upsetting with regard to the vulnerable populations. Apparently, a lot of the physicians in Hong Kong were telling their patients who are 65 and older, “You’re a little too frail for vaccine. I think we should avoid that.”

I’m in shock. That’s the group that is so clearly a no-brainer for the benefits of vaccine, that’s your target population. To be telling someone who’s over 65, you’re too fragile for a vaccine, but apparently, you’re not too fragile to get COVID and die from COVID, that just didn’t make any sense. Clearly, as we talked about last time, when you look at individuals who have not been exposed to Omicron before, you look at these children who are unable to get vaccinated, we are not seeing any significant decrease in intrinsic severity of Omicron. We are seeing, unfortunately, that’s in these vulnerable populations. Yes, very tough out there.

I have to say looking at some information that just came across my desk today, so to speak. If you look at counties throughout the US, if you look at the youngest population of individuals that are eligible for vaccines, the under 12, in about half the counties in the US, you ready for this, Vincent? Less than 10% are vaccinated.

VR: Wow.

DG: Yes. Here we are. Do we want a fourth dose? Well, what we really want is that first and second dose in so many other people. The variants we talk about, they’re not going to come out of someone who didn’t get that fourth dose. They’re going to come out of populations where no one got that first dose, particularly populations that don’t develop a nice robust response and are going to get repeat infections in that background of partial immunity, so not great there.

All right. Testing. Never miss an opportunity to test. We got to keep doing that. We’re falling down a little bit here, I have to say. Our test positivity rate is up to 3% in our immediate area. I just got the ProHealth stats the other day. That means we’re not testing enough. A lot of people are testing at home, so boy, that 3% is probably even worse than we think it is because a lot of people are coming in for a confirmation of a positive test. A lot of people are not getting tested.

What I will say, MMWR, early release use of at-home COVID-19 tests. I still remember the days when there was discussion about whether or not these were a good thing or not. We’ve moved past this. This was really a report looking at the use of that at-home COVID tests. We saw a really dramatic increase in the use of the at-home test during the Delta period. It was about a 5.7% of folks reporting using them. When we got into Omicron, it got to be greater than 20%. This coincided with the increased availability. This winter holiday season, the Omicron prevalence. Nice to see those increase, but I’m a little worried that people seem to be dropping off the other side. Don’t forget this lesson. How do you know if you have COVID or not? You do a COVID test.

All right. The pre-exposure period. Some couple of exciting things in here, I will say. Perhaps I sound like a little bit of a broken record, but Vincent, you told me it’s OK to repeat yourself, so I will do that again. The article, “Time of Exposure is Critical in a Highly Sensitive Model of SARS-CoV-2 Transmissions,” published in PLOS Pathogens. Here, the authors are using a golden Syrian hamster model to look closely at transmission, and really, nothing surprising but reinforcing the time of highest viral load is the highest time of transmission.

They did two PFUs with inoculation on Vero cells. We’re not talking about RNA copy numbers, we’re actually talking about viral load. Also, timing is really critical. Right in those early days, that’s when we’re seeing the highest risk for transmission. Either way, I found it a little hard to get through the figures. It would be nice if the figures are less challenging to decipher, but no, just really, really reinforcing what we know about transmission.

The other thing I want to talk about, and this has been I think a science communication challenge, but the impact of air quality and the indoor transmission issue. We now have expert guidance from the Environmental Protection Agency with two pages of recommendations that codify the best practices on ventilation, air filtration, air disinfection from academic experts and federal agency of the last two years. Then you go to that second page and there’s all these links where you can go and look at what you might want to be doing in your particular situation.

It’s nice to see this moving forward. I was in a call with a camp this week, still doing those pro bono camp guidance calls. We’re about 90 days out from summer or so. One of the topics that came up was what were the implemented improvements in the indoor air quality. Trying to keep those air exchanges, trying to keep those indoor settings as safe as possible. We also have an update on if you want to prevent someone from getting COVID-19, do you give them a COVID vaccine, or do you give them a tuberculosis vaccine?

[laughter]

DG: I had an idea on where this might go, but published in CID, we have “Efficacy of Bacillus Calmette-Guérin Vaccination” – so it’s a BCG vaccination – “Against Respiratory Tract Infections in the Elderly During the COVID-19 Pandemic.” Basically, BCG-vaccination had no effect on the incidence of respiratory tract infections, including SARS-CoV-2 infection. Actually, it was even a little bit of a trend going in the wrong direction, but I won’t mention that so, yes, that’s not really- We have effective vaccines for COVID, so that’s what we should be doing.

All right. Active vaccination. You know this gets tricky, so go to the CDC page and keep updated, and don’t just look at the table, for the clinicians out there, read all the little fine qualifications down below. Is it three to four weeks? Is it eight to 12 weeks, depending on age groups, there’s a lot of fine print now. Make sure we’re giving our patients the best possible information, but I always like to extol the benefits of vaccination for pregnant individuals in terms of this being a much safer choice for the mother, the unborn child, and then the lasting protection.

We have the original investigation, “Association of SARS-CoV-2 Vaccination During Pregnancy, With Pregnancy Outcomes.” This is a really large safety study, population-based retrospective cohort study that included 157,521 deliveries in Sweden and Norway, SARS-CoV-2 vaccination during pregnancy compared with no SARS-CoV-2 vaccination during pregnancy. They found that vaccination during pregnancy was not associated with any increased risk of any adverse pregnancy outcomes, so very safe. This is a huge, huge cohort where they’ve looked very closely at this. Not only is getting vaccinated during pregnancy associated with benefits, but it is not associated with any adverse issues.

This next one I really like. I guess it hits my immunology bone. This is “mRNA-1273 and BNT162b2 COVID-19 Vaccines Elicit Antibodies with Differences in Fc-Mediated Effector Functions.” This is looking at the Moderna vaccine, looking at that Pfizer-BioNTech vaccine. This was published in Science Translational Medicine. I like here that they’re actually not just looking at the neutralization, but they’re looking at the Fc, so that stock mediated antibody function. This is where the antibodies not only can neutralize, not only block attachment and entry of the virus, but can actually pull in some of those other immune cells, those neutrophils, those natural killer cells. They actually saw a little bit better with the Moderna vaccine, as far as Fc-mediated antibody functions.

I’m going to ask you, because I just listened to the most recent TWiV, and I think you might have ideas. Because the mRNA is pretty similar, could this be something related to the packaging perhaps?

VR: Yes. In the paper we did on TWiV, they found a big difference in the ability of the lipids that make up the packaging to stimulate cytokine production, which is important for how well a vaccine does in inducing immune responses. We know there are differences between Moderna and BNT, so maybe this is in part explaining this. It’s quite interesting.

DG: Yes. I have to say though, Vincent, when I talk about this- this is what I talk about around the house, so maybe you would enjoy that.

VR: I would.

DG: Then my wife is like, “Well, now I got three Pfizers, I want a Moderna. I want that better Fc-mediated antibody function,” so I have to reassure her that she’s fine. There is probably a subtle difference, but boy, the Pfizer and the Moderna vaccines, three of those, that’s pretty impressive stuff.

VR: Yes.

DG: Yes, so my wife’s not going to run out and get a fourth shot either. Passive vaccination. I just keep Evusheld up there in mind. I really don’t think people are utilizing this. There’s a lot sitting on the shelves. There’s a lot of vulnerable high-risk people out there, so go to the COVID-19 therapeutics locator. We’ll put those in the show notes. Find these therapies. They’re sitting on shelves. Let’s try to get those from sitting on shelves out there to actually helping people. All right, time for some hate mail, Vincent.

[laughter]

VR: Well, let me guess. It’s either hydroxychloroquine or ivermectin.

DG: Correct. We are now in the period of detectable viral replication, the viral symptom phase, the time for monitoring, monoclonals, antivirals, enrollment in clinical trials. I say not for steroids. Steroids, the timing matters. You don’t do it during this first week. You might do it in certain people during that second week. This is not when you give antibacterial agents for a virus. We’ve talked about not helpful to give Zinc, GI upset, not helpful to give aspirin. Now, we actually have the published “Effect of Early Treatment with Ivermectin Among Patients with COVID-19,” in The New England Journal of Medicine.

These are the published results of the double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2 positive adults recruited from 12 public health clinics in Brazil. Patients who had symptoms of COVID-19 for only up to seven days, they’ve got to be within the first seven days, yet have at least one risk factor for disease progression. The individuals were randomly assigned to either receive ivermectin once daily for three days or placebo.

I’m going to say right up here upfront, when they initially were going to do this trial, it was just going to be one day of ivermectin, but some of the groups that are, I will say, optimistic or have been optimistic about ivermectin, weighed in, so the trial was actually modified to look at a three-day dosing in accordance with the recommendations of those groups. I’m going to get to those groups in a minute.

This is a trial that has looked at other interventions. It’s looking at other interventions including fluvoxamine. We saw the data on that, it was encouraging. They’re looking at metformin, but I’m just going to focus on the ivermectin results here. We have 1,358 patients randomly assigned to receive ivermectin, so 679 there, placebo 679 there. The initial trial, as I mentioned, was going to be one day, but this is just the results of the three-day dosing. 14.7% percent of the folks in the ivermectin group had a primary outcome event as compared to 16.3% in the placebo group. This gives us a relative risk of 0.90, but a credible interval range of 0.70 to 1.16. Of the 211 primary outcome events, 81 were hospital admissions.

Findings were similar in several ways of trying to look at this. I also want to point out too, they broke it down in figure 2 into looking at folks that got it within the first three days versus those that got it day four to seven. Actually, there was a trend going in the wrong direction if you got it within the first three days, so not something you would expect to see if you are optimistic about the role of ivermectin in this context. No significant benefits of ivermectin seen with regard to primary or secondary outcomes.

It’s nice to actually get a chance to look at the data as opposed to– That was a nice interview that was done, but nice to actually see the data of this well-done randomized controlled trial. Remember, this is the same trial that gave us some encouraging data on fluvoxamine. When that was shared, people were very excited and applauding the work. Now that same person is being demonized and vilified by certain groups claiming they’re a– What is it? A shill for big pharma? You can’t have it both ways. This was a well-done, good trial. If you’re going to claim there’s any benefit of ivermectin, boy, it has to be pretty darn small. This study does not provide encouraging data with regard for the use of ivermectin in the treatment of COVID-19. Vincent, any thoughts?

VR: Not surprising. This is really what we’ve been hearing informally for a long time, and it makes sense. This is a compound for parasites.

DG: Yes. It is tough, right? It’s interesting. I know the rhetoric is, “Oh, this was a study destined to fail, designed to fail, big pharma wanting to keep us from getting our wonderful life-saving medicine,” which I hate to say it, but some people now want me to give it to their family members to treat heart failure, to treat testicular pain. It’s not a wonder drug. It’s a great drug for parasites. This trial was funded in part by UHG, which their goal, they would love to find a cheap generic repurposed drug that kept their patients out of the hospital, that kept their patients alive and paying those premiums, so yes.

VR: Well, I think also, Daniel, it shows. Ivermectin in cells in culture will inhibit virus production at somewhat higher levels than therapeutically used. It just goes to show that being active in cell culture doesn’t translate to results in people.

DG: Yes. I think that’s unfortunately true, yes. What does work? Let’s move to those things where we have some good science. Paxlovid, and again, I want people to go to the COVID-19 therapeutic locator, there’s lots of Paxlovid out there. I keep hearing, “Oh, it’s hard to get.” It’s not, I have to say. I’ve looked around the country at different sites using the locator. There are thousands of doses sitting there on shelves, so look at the locator. I’m directing this at clinicians, but patients, advocate for yourselves. If you’re not sure, there’s a COVID-19 drug interactions checker. We can put all this in the show notes. Find out where’s that Paxlovid, run through what’s the kidney function, what other drugs are they on.

The next monoclonals, really moving, and I have to say right here in the New York area, moving completely to the bebtelovimab for our monoclonal treatment. We are up to greater than 85% is now the BA.2, the Omicron stealth variant around the world, greater than 55% in the US, so BA.2 is now the dominant variant, and bebtelovimab is the preferred agent. Again, there’s lots of this sitting around not getting used, so you don’t need to use a monoclonal with questionable efficacy when you have bebtelovimab.

Remdesivir, we still have the early three-day outpatient treatment and molnupiravir if you have issues with kidney function or drug interactions or other things, and tons of molnupiravir out there, so think about actually getting these to your patients. If you’re a patient, think about advocating for yourself. OK, the early inflammatory phase. I’m going to return to this and that whole issue of aspirin, but remember this is when we say this is when steroids might be the right time in those patients where your oxygen saturation is less than 94%. Some literature that maybe you can even get a little bit more fine-tuning by looking at your C-reactive protein.

What about platelets? What about aspirin? I’ve been seeing all over the mainstream media that there was some exciting stuff about, “Association of Early Aspirin Use with In-Hospital Mortality in Patients with Moderate COVID-19,” published in JAMA Network Open. This was a cohort study that suggested there might be benefit, and then they go ahead and conclude, you know what? A randomized clinical trial that includes diverse patients with moderate COVID-19 is warranted to adequately evaluate aspirin’s efficacy in patients with high-risk conditions, we have that and we talked about it last week.

That was the paper, “Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients with COVID-19, a Randomized Clinical Trial,” where we did not see a benefit. We got the one article, the punch line before we got the joke, and the punchline is that when you do a proper trial, you’re not seeing benefit here. We continue to recommend against using antiplatelet agents, against using aspirin.

What about prone positioning? This is where we ask these patients, a little bit of tummy time, we want you to lay on your belly. We have discussed that you can actually see in real-time some pretty significant improvements. What about a good study telling us that what we’re doing is helpful? The article, “Prone Positioning of Patients with Moderate Hypoxemia, Due to COVID-19: a Multicenter Pragmatic Randomized Controlled Trial,” so COVID PRONE, published in the BMJ. There’s a really nice introduction. A lot of times, reading introduction really gives us a flavor and a context. Here, there’s a nice bit of background where they talked about how prone positioning was introduced, became a part of clinical practice back in the 1970s.

Early uncontrolled trial suggested that there might be some benefit here in COVID-19. Really, what happened here? [chuckles] They had trouble getting people to actually prone. Ultimately, those in the proning group were only proning for about two and a half hours a day. They finally gave up from a futility standpoint. It’s really hard to show benefit of an intervention when you’re actually not able to get your treatment group to participate in the intervention. Really, really tough, that we couldn’t get this data.

I was pretty excited to see the results of this, and I have to admit this had to be pretty frustrating for the investigators, not able to really get those folks prone, not really able to get the evidence to tell us what’s going on here.

VR: Daniel, what? The patients don’t want to lie on their belly, is that the problem?

DG: Yes, people don’t want to lie on their belly. You can think about it, it makes sense. You’re feeling sick, you’re having trouble breathing, you’re running a fever, everything hurts, you just want to get comfortable, you really don’t want to lay on your belly.

[laughter]

VR: Understood.

DG: It takes an incredible amount of commitment, really from nurses, to be honest, being there, encouraging them, family members when possible, because sometimes we do this outside the hospital. It takes a lot of resources, not money, but resources, as far as a person really working to make this happen, so yes. I will cut right to the end. Long COVID, where I have to say I’m a bit optimistic, I’m seeing this discussed more in the mainstream media. I’m starting to hear more studies coming out, so I am optimistic that we’re hopefully going to be moving from putting Band-Aids on the symptoms to having some real evidence-based understanding and interventions going forward.

What about the rest of the world? No one is safe until everyone is safe. Here is where I’m going to pause and tell everyone to stop their recording, go to the Internet, go to parasiteswithoutborders.com, click on that Donate button because we’re continuing to support the American Society of Tropical Medicine and Hygiene. February, March, and April, things seem to be going pretty well here. We’re trying to get up to our goal to make a potential donation of $40,000 to ASTMH. Main focus is going to be scholarships for females from low- and middle-income countries so that they can come to the annual meeting, so they can get support so we can hopefully address that. Thank you for all your support to date.

VR: Time for some questions for Daniel. You can send yours to [email protected]. Katie writes, “My son just turned five in February, received his first of two Pfizer vaccines. The pediatrician recommended he returns in three weeks for the second dose. However, I have heard you talk about the more effective timing between dose is a little longer. When I asked the pediatrician about it, I felt like I received a canned response about what the CDC recommends. I, of course, want to do whatever is going to be the safer and more effective option.

Just a little background, my son has recurrent croup that has landed him in the ER twice in the last few months. He tested negative for COVID both times, but positive once for RSV and positive for the common cold the second time. Of course, my fear is how his body would react to actually getting COVID. The other complication is that his two-year-old sister has a rare form of cancer, so we have to protect her as well by the rest of the household getting vaccinated. Given our situation, what would you recommend as the best timing between doses? Due to a scheduling conflict, his second vaccine is actually scheduled four weeks out from his first, instead of three weeks.”

All right, so that’s the first part, and then we’ll do the second question. Go ahead.

DG: Yes, wow, this is reminiscent of when I said, it’s important to read the small print, not just look at the tables. Yes, when you look at the tables, you go to the CDC page. We have a cdc.gov, vaccines, COVID-19 schedules, or tells you, you can look at the different ages where it discusses primary series and whether or not a booster dose is yet recommended. The 5 to 11, right, two doses. Then you look at the table that says dose 1 and dose 2 separated by at least three weeks.

Then you go to the fine print for the folks in the 12 to 17. That was the fine print because this was the age where we we’re seeing an increased incidence of myocarditis. If you go to the very bottom, small print of this page, we’ll try to share this in our show notes, the CDC, straight out of the CDC, they say, an 8-week interval may be optimal for some people, including males 12 to 39 and they talk about how this can reduce the risk of myocarditis. They also actually say vaccine effectiveness may also be increased with an interval of longer than the three to four weeks. This is fine print, I’m sharing this here, and so, kudos for listening to TWiV, hopefully, this is helpful.

At that younger age of 5, we have some concerns, I will say some concerns about getting better efficacy if you wait a little bit longer. I guess maybe concern isn’t the right word. Yes, there is always that issue of, boy, while you’re waiting you don’t have that extra protection you’ll get once you get that second shot, but we’re in a period in most of our country where the case numbers are low. In most areas of our country, that metric would make sense delaying out to that eight-to-12 weeks before you get that second shot in the primary series.

VR: Katie wants to know what is MIS-C. Is this something you get from the vaccine or from the virus?

DG: This is an inflammatory syndrome that affects all of the organs, can lead to decreased heart function. You can get kidney failure, a sepsis shock-like. It is associated with the disease. We have not seen any credible association with vaccinations. I’ve reviewed a lot of cases looking at this, so I could say that with, say a high degree of confidence.

VR: John writes, “What would be the optimal timing for an mRNA booster in pregnancy given the following situation: My friend is a 32-year primiparous woman with an uncomplicated pregnancy at 21 weeks, had two doses of an mRNA vaccine prior to pregnancy and got a mild case of COVID just before she was to get her booster at 8 weeks. She recovered from the mild COVID, had only mild reactions to the two vaccines doses. Given she’s had three exposures to spike through two vaccines and one infection, what is the best timing for her booster? Our COVID prevalence in rural Wyoming is finally very low and her habits make her exposure risk low.”

One could argue that putting off the dose until, say 36 weeks, might afford her with better protection for the fetus and newborn rather than an earlier dose, say next week, in which antibody levels might be waning by the peripartum window. Also, although the robust MMWR report shows no evidence of preterm delivery, a hypothetical advantage of waiting until 36 weeks might also be less implications should there be a high fever or reactogenicity trigger preterm labor. Your thoughts.”

DG: Wow, so John, are you a physician because this is very sophisticated. Yes, I’m going to concur, but let me go through what I’m concurring with. At this point, we’ve got the two vaccines under the belt. That’s good stuff. You also talk about low prevalence, so we’re feeling pretty good for the coming weeks. Really, maybe the question here is what’s the best timing based on the science we have, based on the understanding of immunology. It probably is that third trimester. It’s probably at least two to three weeks before delivery.

This gives a chance, not only for the antibodies to go up, which can be transferred, but there’s also a transfer of cellular immunity. Not only transplacentally, and I think we’ve maybe talked about this in some of the immune episodes, but there may even be some transfer in the breast milk as well. Yes, the timing, if you’re going to lay this out and say when’s the best time for that booster, it’s probably going to be in that third trimester, it probably going to be that two-to-three weeks before delivery. If it’s going to be a normal, spontaneous vaginal delivery, you’re guessing on that due date, so use that in your metric.

VR: Jen writes, “My 83-year-old mother with multiple comorbidities received her first booster mid-November, was positive for Omicron on January 23rd. Receives sotrovimab on January 25th. I’ve read two think opinions. Some say no need to wait for vaccination booster after sotrovimab infusion. Other places are saying wait 90 days. My mom is raring to go to get her second booster, but only 60 days have passed since her infusion. Should she wait until April 25th, 90 days since her monoclonal infusion or can she get her booster sooner?”

DG: Well, I’m going to make this simple and just focus on updating the old information. Early on, there was a recommendation of waiting 90 days after monoclonal therapy. That’s gone. We no longer have that in. Forget about the monoclonals. Once a person is past the 10 days isolation for the infected, once they’re feeling better, vaccination is fine. Now an 83-year-old woman with multiple comorbidities, talk to your doctor about that fourth shot. This is one of those people that it might make sense. There’s a low downside, potentially an upside.

VR: Jen writes that because she listened to your weekly updates, she knows exactly what to do when her mother tested positive.

DG: That’s fantastic.

VR: Megan writes, “I am 32 years old, thin and healthy. I had 100 micrograms of Moderna in August and due to my reaction, I waited to get another dose in December, four months later and only received 25 micrograms. My antibody level in January was over 2,500. I’ve had chronic lymphocytopenia for many years. My earliest labs available are 2016 or ’17. My absolute lymphocyte count fluctuates between 1 and 1.4. Both my lymphocyte percentage and neutrophils are normal.

Through listening to TWiV and reading articles about B- and T-cell immunity, I started to piece together that my counts are not that different from some of my cancer patients. I work as a part-time nurse in a small cancer clinic. Usually, their lymphocyte count is better. I recently saw an immunologist and I was not deemed immunocompromised because I made antibodies to the vaccine and clinically/symptomatically, I’m healthy, not getting extra infections.

We don’t know why I have this. My mother has ankylosing spondylitis, no immunosuppressive medication, and has the same counts as me. Google search will bring up countless studies on lymphocytopenia and a severe or bad prognosis with COVID. I’ve looked through cases and studies and it’s with counts that are not that low, even one where patients aren’t doing well or dying. Everybody seems to drop, but I’m already normally in that risk zone. How far will my lymphocyte count drop?

Three years ago, I was hospitalized with norovirus and my ALC was 0.6, the only time it’s gone below 1. Am I at risk for a bad prognosis? I need someone who understands immunology and has been at the COVID bedside. Dr. Griffin, would you be able to explain what lymphocytopenia looks like in a COVID and how that affects the outcome? As it stands, I don’t qualify for treatments like Paxlovid and I’m terrified to rely on my immune system. Does vaccination help? I can’t get boosted until May or June.”

DG: I’m not sure that you don’t qualify in all honesty. Let me go through this because this is a complicated email, so make sure everyone’s listening to what we’re talking. Lymphocytopenia. This is an individual whose lymphocytes, white blood cell count, is low and the major lymphocytes that we see, you know, circulating when we do our WBC, our white blood cell count, are going to be B cells and T cells. I think hopefully our listeners are all up to speed on the importance of T cells in addition to B cells.

Doing that antibody test, and this is something we actually routinely do to assess B-cell responsiveness to vaccine, is we’ll look at antibodies post-vaccine. Not necessarily saying, “Oh, we suddenly know what those antibodies tell us about COVID,” but saying those antibodies tell us something about your B-cell responsiveness to vaccine challenge. We historically have done this with Pneumovax, with the polysaccharide pneumonia vaccine.

When you describe having a low number of lymphocytes, particularly when you describe when it’s dropped in the past, I would have concerns and remember Paxlovid is sitting on shelves. We’re not talking about you taking it from some other deserving person. You would be someone who, despite being 32 years old, despite being thin and healthy, I would have concerns when you describe this chronic lymphocytopenia. I would say consider yourself a potential candidate for Paxlovid. Talk to your immunologist about this. Talk to your primary physician about this.

VR: That’s COVID-19 clinical update number 108 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you very much. Everyone, be safe out there.

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