TWiV 837 COVID-19 Clinical Update #91

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 4 December 2021

pdf of this transcript available (link)

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick. From MicrobeTV, this is TWiV, This Week in Virology, Episode 837, recorded on December 2nd, 2021. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today here at The Incubator in New York, Daniel Griffin.

Daniel Griffin: Hello, everyone. Hello, Vincent.

VR: Hello, Daniel.

DG: [laughs] We can actually see each other.

VR: We’re doing this TWiV and a TWiP, so Daniel thought he would come in and do it here, which is great, because that’s what The Incubator is for. This is Clinical Update #91, Daniel. Boy, have things exploded in the last week.

DG: Yes. The amount of communication I have gotten this last week is quite extraordinary. Let’s jump in because we have a lot to cover. Today, I’m going to be engaging Vincent quite a bit because I think there’s a lot of unknown. There’s a lot of interesting news. Let’s start off with my quotation, “A man should never be ashamed to own he has been in the wrong, which is but saying, in other words, that he is wiser today than he was yesterday.”

I’m not sure exactly who this should be attributed to. Apparently, this was in a Jonathan Swift compilation. It may have actually been properly attributed to Alexander Pope. This will give our listeners a little bit of research. You can expand and look up something other than COVID-related– I have to say, this whole last two years have been quite humbling. When I saw this quotation, it was making me think of the early days when the monoclonals were being developed and we had this idea that we wouldn’t have to be that worried about variants, but as we’re going to see today, we are going to be talking about a new variant.

As far as my update, I will say, numbers here in New York, as predicted, after Thanksgiving, after all the travel, after all the get-togethers, number of cases has increased– Well, from about 5,000 or 6,000, up to about 10,000. Number of folks in the hospital has pretty much doubled and we’re expecting that to keep rising. Things are not great here in New York, things are not great in the country, and things are not great around the world.

I wanted to start by talking about the two bits of news that people probably want us to be talking about. The first got a little bit overshadowed by the second, but let’s talk about molnupiravir. On Tuesday, November 30th, the FDA expert panel voted, not unanimously, in a split vote, 13 to 10, so barely went ahead with this to authorize molnupiravir. Lots of discussion. I don’t know if people got a chance to watch this, but lots of discussion about the risks of birth defects if this is used in pregnancy, possible generation of new viral variants because of the mechanism of action. There was also an update on the data. I think that also put a little bit of a wet towel, if I think– I’m terrible with expressions, but maybe that is an expression.

Merck and Ridgeback Biotherapeutics provided an update on the move-out. Remember, we had the MOVe-IN, which got stopped, but this is the MOVe-OUT patient study. Data was available for all enrolled participants, 1,433 in this study population. Molnupiravir reduced the risk of hospitalization or death from 9.7% in the placebo group to 6.8% in the molnupiravir. Only seeing about an absolute risk reduction of 3%. Not quite as exciting as the top-line results. Only seeing a relative risk reduction of 30%. There were nine deaths in the placebo group, one in the molnupiravir group. The adverse event profile in the upfront acutely remained consistent, so remained to be a well-tolerated medication.

At the FDA advisory committee, there was a little bit of concern about how effective this medication actually would be when this came out. We’re talking about a number needed to treat here of 33 to keep 1 person out of hospital. With a price tag of $700 per treatment, we’re talking about over $23,000 just to keep one person out of the hospital. At least we still have PAXLOVID, which will be reviewed later this month. We’re hoping that’s a little bit more compelling when we get the final data and all the background here.

What about Omicron? However you want to pronounce that. This variant already has its own Wikipedia page. I’m a little jealous there. Just right up there– What do we know? What do we not know about Omicron? I’m going to actually self-fertilize, I guess I’ll say. The most recent This Week in Virology episode with Vincent and the gang, I think there was a really good deep-dive, not only to Omicron, but also into some of the ideas that, hopefully, I’m going to rope Vincent into talking about today.

We do know that this variant has a number of changes in the spike protein, a number of amino acid changes. Someone gave me a hard time because I claim that what was bothering me most about the new variant was that people kept referring to mutated proteins, and mutations really have to do with DNA and RNA. They said, “Really, Dan, that’s what’s bothering you, the terminology?” [chuckles] Why can’t we just say nonsynonymous mutations leading to amino acid changes in the protein? Isn’t that so much simpler than talking about a mutated protein? Apparently not.

Some people have, I think, gotten quite upset about Omicron. Part of it is what I think was really well-discussed in the last TWiV, is people have been looking at some of these amino acid changes in the 1,273 amino acid long spike protein. They’ve seen that there’s a K417N, which some data suggests may be associated with antibody release. The E484A, which again, may be associate with antibody release. We’re starting to worry about some of our monoclonal antibodies. I’ll talk a little bit about those. The N501Y, does that improve ACE2 binding? The P681H, is that involved with immune evasion of the interferon system and improved replication through an impact on the furin cleavage site? What are the questions? I’m going to pull Vincent in on this.

In my mind, there are five important questions. I’m going to say right up front, we do not have these answers yet, but we will get these answers. One, and this is probably one of the most important questions I’ll say here at home in U.S., but this is going to be different in different parts of the world. Will this variant have a fitness advantage over Delta? As we’re recording this, we know that there was an identified individual in California. There was another individual who came from Minnesota to New York City to an anime conference. I kind of like anime, so I’m sorry to hear that, that those conferences are now risky affairs.

There are already a couple identified cases here in U.S., but will it have a fitness advantage? I was talking to my wife a little bit, going through the amino acid changes. That’s what we discuss around the dinner table. It’s really hard to look at individual amino acid changes and then put that all together in the soup and see what it will translate into. Will it have a fitness advantage over Delta? That’s going to be a real-world experience. That’s something we’re going to see in coming weeks when both Delta and Omicron are in the same populations.

The second is, can we figure out how effective our vaccines will be with Omicron? I think a lot of people care about that. There’s been a big push now, the idea that, “Well, maybe if you get that third dose, that booster, that’ll not only get your antibody levels higher, but it’ll broaden the repertoire.” We’re going to get an answer to that. A couple of the ways that we can look at that one, is there is serum from people that have been vaccinated once, twice, three times? You can actually look at that either in a pseudovirus or in a real BSL-3 setting and see is evidence there? Again, we’re going to actually be able to observe over coming weeks, are we seeing infection rates in the vaccinated compared to the unvaccinated?

The next, and I think this is something that a lot of people have brought up, if you were infected before and you’re riding on your, we’ll say viral-infection-induced immunity, are you less protected when it comes to Omicron? The WHO did release a little bit of data on that, suggesting that you are less protected. Just another push to, even if you had infection before, go ahead, get those vaccines.

The next, and this I’ll talk a little bit about because we’re starting to get some information here, is will our monoclonal antibody cocktails still be effective? Let’s go through which ones we’re using and what we have information about. Based on some of the amino acid changes, we are quite concerned that the Eli Lilly cocktail, that’s the bamlanivimab-etesevimab, will not be effective here as we saw it lost effectiveness with Beta.

The Regeneron cocktail, we do not expect this to become completely ineffective, but we do think this will have some impact. Regeneron has already intimated that, but we’ll get the data on that. Sotrovimab, that’s the Vir GSK product, that was actually a product that was developed targeting what they like to say is an invariant. Well, David Ho said there’s no such thing as an invariant section of the spike protein, I tend to believe him. We’ll say an area that is more difficult to vary. They’re already announcing that they think that sotrovimab, the GSK-Vir monoclonal antibody, will continue to be effective in the face of the variant. That’s lab data. We’ll have to see real-world efficacy data.

I’m particularly interested in the AstraZeneca long-acting antibody therapy, because that will probably be considered for a pre-exposure prophylaxis indication this month. That I have not heard about. Adagio, that’s another company that has a bunch of monoclonals, which are also purported to be variant-proof. I don’t know if proof is the right word, but designed to continue to have efficacy in the case of variants. We’ll see.

One of the tough things here in the U.S., and maybe this is a wake-up call for us, the U.S. does not do a lot of sequencing. We’ve sort of been sitting here in the dark. I feel like this was the early days of testing. The U.S. was sequencing fewer than 1% of specimens earlier this year. Now, it’s running those tests on maybe 5% to 10% of samples. That’s regional, California does a great job, but we really need to get more in-line with other nations as far as the amount of sequencing we do, so we can track going forward if there’s any changes in real-time what’s happening.

Vincent, I’m hoping you and I can talk a bit about how these amino acid changes might change things. Before we do, I’m going to throw in a preprint, because we’ve gone way too long without discussing the latest literature. There was a preprint, “P681H mutation in the Spike glycoprotein confers Type 1 interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant.” I thought this was an interesting paper where the authors are using lung epithelial cells and suggest that if you put in this P681H amino acid, that you confer this fitness advantage. I thought in the context of the TWiV you just did, maybe you’d have some comments about how good are we at looking at amino acid changes in the spike protein and predicting phenotype.

VR: Well, this is a very hard question. In fact, the paper we did on Tuesday’s TWiV illustrates that where they tried to look at Alpha, Beta, and Delta variants in the lab, and asked, “What gives these fitness advantages in the world?” Because we don’t know. What we know is that one displaces the other because it’s more fit, but we don’t know why. The most remarkable result, that all of those variants reproduce equally well in cells from the human respiratory tract, which is what you should be looking at. That is exactly what you should be looking at.

DG: Shouldn’t we be looking at vervet monkey kidney cells?

[laughter]

VR: This is exactly right. Then they tried to look at syncytium formation and didn’t really learn anything from that. The quest for understanding fitness is going to be a long one. Certainly, if you’re resistant to Type 1 interferon, and it’s not complete resistance most likely, it’s a partial resistance, that would confer some fitness advantage, I would guess, in a population, because that’s independent of adaptive immunity and it’s not going to matter if you’ve been infected before. That could be interesting. We’ll see if this pans out. A lot of these preprints never make it. [chuckles]

DG: That is true. [chuckles] Sometimes it takes months to get from the preprint to something, which actually looks quite different when it finally sees the light of day. There’s a couple things that I wanted to bring up too. Vince and I, we briefly alluded to this, and it was this issue about the importance of B cells versus the important of T cells. Will T cells save us all? How important are B cells? There are a couple papers that caught my attention. One was, “Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance Physician Registry.” Big deep breath. What was that all about?

One of the things that we have been noticing is that individuals, who for some reason or other are on B cell depletion therapy for treatment of a disease, tend to have really bad outcomes. They tend to be at significantly-elevated risk of severe COVID-19. We are seeing that individuals who do not have B cells to protect them are about four times as likely to end up with severe COVID-19 disease. We don’t do a lot of T cell depleting therapy, so it’s hard to see in humans.

The next paper that I wanted to put in front of people’s eyes, I guess. [chuckles] Anyway, direct everyone’s attention to, was a paper called, “Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques.” Here, what they’re going to do is they’re going to deplete the T cells from the rhesus macaques and then they’re going to go ahead and study what happens. They’re going to deplete either the CD4 T cells, the CD8 T cells, both T cell subjects, and then they’re going to go ahead and there’s going to be infection.

They’re going to look at a number of things. Peak viral loads were actually similar in all groups with resolution of virus in the T cell-depleted animals only slightly delayed compared to that in controls. That surprised me a little. I’ve always thought in my mind of antibodies really critical at preventing infection jumping in early, but then I was expecting the T cells to jump in. If they didn’t jump in, I was expecting to see more severe disease.

Now, going on, the T cell-depleted groups developed virus-neutralizing antibody responses, class switched to IgG, but when re-infected six weeks later, the T cell-depleted animals showed amnestic immune responses characterized by rapid induction of high titer viral-neutralizing antibodies, faster control of viral loads, reduced clinical signs. Interesting. These results suggested that while T cells may play a role in the recovery of the rhesus macaques from the acute SARS-CoV-2 infections, their depletion was not necessarily resulting in severe disease.

The authors here were suggesting that T cells were perhaps not as critical in the resistance of the macaques to severe COVID-19. They actually go on to say in their conclusion neither prime CD4, nor CD8 T cells appeared critical for the immunoglobulin class switching, the development of immunological memory, or more importantly, protection from this second infection.

Now, along these lines, and I’m going to pull Vincent in here quickly because I’m hoping he’s excited to discuss this further, but there is a T cell vaccine. This was this paper that was just published in Nature. “A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity.” This vaccine, COVAC-1, is a peptide-based vaccine candidate. It’s composed of SARS-CoV-2 T cell epitopes derived from various viral proteins.

The goal is to introduce SARS-CoV-2 T cell immunity to combat COVID-19. These are Phase 1 open-trial data. We have 36 participants, they’re aged 18 to 80. They received one single subcutaneous dose of the vaccine. Now, there’s going to be a primary and a secondary endpoint. The primary endpoint, safety analyzed until day 56, immunogenicity in terms of COVAC-1-induced T cell response was analyzed and followed up until month three.

They report that there were no serious adverse events, no Grade 4 adverse events. I thought this was a little interesting. Expected local granuloma formation was observed in all study subjects, while systemic reactogenicity was relatively absent or mild. People were not feeling crummy. They weren’t getting that, “Oh, my gosh. I’m out for a day or two,” like we see with, I’m going to say our B cell, our mRNA targeting vaccines. It was really more of a local reaction. SARS-CoV-2-specific T cell responses were induced in all study participants.

Now, what we’re going to see next is we’re actually going to see them looking at the Phase 2 trial. Who are they going to test this in? They’re going to be testing this in patients who have a B cell or an antibody deficiency, where it doesn’t look like we can get them that protection through an antibody induction. Maybe we can get it through a T cell induction. I’m waiting to see this. I’m curious. I do not honestly know. Clearly, we’ve had incredibly impressive results with our monoclonal antibody therapies. Particularly, we give this within the first three days and we’re seeing very few people progress. Pretty impressive. But what is the role of T cells? I don’t know.

VR: You know Sette and Crotty have said that T cells are very important for protecting you against severe disease. That makes perfect sense. They say that, in fact, there have been some people lacking B cells who’ve been infected and they recover. They don’t die. But then Sette did say, “I still don’t want to be without antibodies because I think the two together are very important.” This is very interesting. I’m not sure I’d want a T cell-only vaccine. I would like a mixture.

DG: I want everything. I want my soup, my salad, my main course, and my dessert. It is interesting. As I pointed out, people with B cell depletion, they’re at higher risk, but they’re not all dying on us. We’re still getting most of these folks through. Interesting.

All right. Children, COVID, and mental health. Children at risk of COVID, unfortunately, we’re seeing a spike in the number of cases, it’s not a pun on the spike protein, in children getting COVID, in children having difficulty with this virus.

I’m going to refer to this as a disturbing publication on the viral RNA levels in the youngest among us. The article, “Infants Younger Than 6 Months Infected by SARS-CoV-2 Show the Highest Respiratory Viral Loads.”This was published in JID, Journal of Infectious Disease. The authors analyzed the viral RNA copy number from 45,318 SARS-CoV-2-positive nasopharyngeal swab samples obtained in Buenos Aires, Argentina. If they need some volunteers to come down to Argentina, let me know. I hear it’s a beautiful place.

They found that infants younger than six months of age had about 32 times as much viral RNA as your average adult and about a thousand times as much as children aged seven months to four years of age. There looks like there’s this peak in the first so many months of age. It brought for you, Vince, and you can actually see these really cool ORF1 CT value plots.

VR: As you say, it is PCR RNA, so it’s not clear if they’re making more infectious virus. That would be concerning. Until we look at that, I’m not sure what this means.

DG: I made sure to translate it from their– They say viral loads. I like to be honest. This is RNA copy number. We’ll have to see how that pans out. Perhaps the good news in this section is the publication, “Secretory IgA and T cells targeting SARS-CoV-2 spike protein are transferred to the breastmilk upon mRNA vaccination.” This was published in Cell Reports Medicine. In this study, the investigators collected 23 paired samples of breastmilk, pre-vaccination and after first, and second, mRNA vaccine administration.

I think this is interesting. In the teaching of immunology, we usually just brush past the importance of breastfeeding, we talk about transfer of IgA, but not only do you get transfer of IgA, we also get transfer of IgG, and there actually is a transfer of cellular immunity. I think this is something not necessarily on everyone’s mind. People have looked and said, “Yes, there is IgA, there are antibodies in the breastmilk, but it’s just not a lot.”

Here in this study, they were able to show, not only these high levels of antibodies in the breastmilk, but they were also able to show that in addition to the transfer of antibodies, there was actually transfer of spike-specific T cell. One more reason for us to encourage women who are thinking about getting pregnant, women who are pregnant, women who are nursing, to go ahead and get those vaccines. You’re not only protecting yourself. Great way to protect the youngest among us.

All right. Testing. Never miss an opportunity to test. The publication, “Analytic Survey in Patients Presenting To the ED With Suspected COVID-19, the ID NOW Point-of-Care Assay Based on Nasopharyngeal Swabs Had 98% Sensitivity and Specificity Versus RT-PCR.” I love when the title just has everything in there. This was published in the Journal of Clinical Virology. In this study, they used the ID NOW, which is a rapid molecular test. Yes, the same one they use at the White House. This uses a nicking endonuclease amplification reaction or NEAR.

It’s interesting technology. I won’t go too much into it, but basically you’re nicking away one of the double strands, creating a single-strand DNA. Really isothermal, so staying without the heat cycling and getting amplification pretty quickly, giving you results in less than 15 minutes. I say less than 15, because sometimes someone who really has a lot of viral RNA, you’re getting results in just a few minutes. If it comes up closer to 15, there’s actually a quantitative aspect to the timing of your results.

Here’s critical. The nasopharyngeal swabs were directly tested with the ID NOW COVID-19 assay. When you did that, you swab the person, the machine’s ready to go, you pop them straight in there. Your sensitivity was 98% specificity. 97.5%, so not 100%, but pretty darn good when compared to the RT-PCR. What if you took those and then you just let them sit around, transported them to the lab, tested them later? Your sensitivity’s going to drop down to 62.5%.

This is really a point-of-care test. Incredibly effective at preventing spread, of detecting folks. Within 15 minutes, you’re picking up 98% of those folks in the ED and able to act upon that. This is great, but you know what, if you’re positive and you just continue to go about your life, then this is not helpful. I think we had some issues with the use of this machine when people tested positive and did not necessarily comport themselves appropriately after the fact.

The publication of another scoring system, “External validation of the QCOVID risk prediction algorithm for risk of COVID-19 hospitalization and mortality in adults: A national validation cohort study in Scotland.” This will be one for when our colleague joins us later for TWiP. This was a huge data set. This comprised 5,384,819 individuals representing 99% of the estimated population in Scotland. They created an algorithm, and then they recalibrated over time. There’s a planned Version 3 that’s going to include vaccination status. No surprises here.

A very complex system. There were 36 different variables. I believe this is something that you might want to plug into at EMR. I think that the mass scoring system we talked about before where you look at age, you look at your BMI, you look at kidney disease, diabetes, immunosuppression, those give us a lot of what this system validated; 36 variables. It’s nice to see that we can predict ahead of time. This is a good reminder. Even those folks who are vaccinated, and we’re going to get to that in Version 3 here, if they get infected, if they’re over the age of 65, if they have other things going on like diabetes, kidney disease, obesity, they’re at solid risk of ending up in the hospital. Still, people we want to jump in and do something about.

Active vaccination. Never miss an opportunity to vaccinate. Jabs that keep you from getting sick. We’re going to see over the coming days, hopefully by next week, we’ll have some update on how well the vaccines, how well the boosters do when it comes to Omicron. Don’t forget about passive vaccination. Don’t forget about those monoclonals for post-exposure prophylaxis. We’re waiting for the pre-exposure submission and EUA. This is going to be interesting. As I talked about, this is where we’re going to be asking the question of, “How well do these work if Omicron becomes something that we need to worry about?”

I was talking to some physicians yesterday. They were feeling a little bit uneasy with the limited amount of sequencing we do. I know at one point, I had some discussions with a couple of these companies about developing point-of-care testing, because we would like to know if we’re going to be using these potentially highly-effective, highly-expensive therapies. If we’re actually doing the right therapy for the right variant. As mentioned, we are thinking that the Vir-GSK sotrovimab is going to continue to be effective, we expect the Adagio to continue to be effective. There will likely be some hit to the Regeneron effectiveness, we’re waiting to hear results on that, and AstraZeneca, that will be very important to know.

Long COVID, PASC. Now, one thing I like about the term PASC– This actually created a little bit of controversy. I think of PASC as an umbrella term and long COVID is just one thing that falls under that umbrella. Now, there was an article, “COVID-19 Post-acute Sequelae Among Adults: 12-month Mortality Risk.”I think this actually shed some light on why it’s important, why it’s meaningful, to have such a large umbrella term.

Here, they looked at the risk of death over the next 12 months post-discharge if someone had been admitted with COVID. They looked at 13,638 individuals. People probably remember my reaction to the clap-outs, the idea that when they leave the hospital, it’s all better now. My commenting, for so many people, this is not necessarily true. Here, when they look at the 12-month all-cause mortality risk for patients with severe COVID-19 compared to COVID-19-negative patients, the hazard risk for death was increased 2.5 times. If you had mild COVID, the hazard risk was still 1.87. The very interesting thing is the majority of the deaths, 79.5%, were from causes other than respiratory or cardiovascular.

There’s something this virus does to the system. We are seeing in our individuals that end up hospitalized, not only this significant increase in death over the next year, but an increase in the new diagnosis of diabetes, cardiovascular disease, strokes. This is a situation where it is so much better to get the vaccine than the virus. Before we get to emails, remind everyone throughout the months of November, December, and January, donations made to PWB will support MicrobeTV. MicrobeTV is now a 501(c)3, so you can go right there as well.

Because MicrobeTV is now doing this virology textbook, if you donate $1,000 or more, let us know so we can go ahead and get Vincent to send you a virology textbook with a little bit of a signature and an inscription in there. Send us your address, so we know where to send that. If it’s overseas, send us a phone number as well, because PWB will even cover those shipping costs to get those books out to you so that a little bit more money can stay in the coffers at MicrobeTV and they can keep producing this great content.

VR: That counts for donations made to Parasites Without Borders as well, right?

DG: I guess we’re adding that now.

VR: That’s very good.

DG: If you send $1,000 or more to PWB, let us know if you want one of these textbooks. I’m sure everyone does.

VR: Sure. Doesn’t everyone?

[laughter]

All right. Thank you, Daniel. Now, it’s time for some email questions. You can send yours to [email protected]. This one is actually from the last TWiV, from Holly. We could not answer it, so we said let’s give it to Daniel. “I had the Moderna vaccines in January and February 2021. I had the lymph node response with enlarged painful axillary and clavicular nodes that lasted a few days. Fast forward to August and September, I was bit and stung while outdoors, both resulted in significant reactions with severe swelling, itching, redness, lymph enlargement, overall cellulitic appearance. Both required steroids to treat and I was given an EpiPen just in case. This never happened to me before. I’ve talked to two other people who have had similar reactions to bites since vaccination. Perhaps it’s coincidence, perhaps it was a murder hornet. In the research, you have reviewed and– personal experience. Is this a potential vaccine reaction? Yes, I reported it to VAERS.”

DG: We’ll do this backwards. We’ll start with, Is this something where there’s much literature? No, actually. Why do I know that? It’s because, actually, several people have had this experience. That always prompts me to go through as, Is this something related? Is there something about the vaccine that’s making people a little more sensitive, shall we say? Actually, there have been a few. It’s anecdotes at this point. People have reported they seem a little more sensitive to things. I don’t understand the mechanism. I’m not sure if people are just noticing this more, but yes, I look forward to this being more investigated. I’ve actually heard a few stories.

VR: She also wants to know, “Do you think we should have any reservations in getting a booster because of this?”

DG: I wouldn’t. Again, it’s a risk-benefit. If you said, “Oh, boy. I got this shot and I got vasculitis, or I developed this psoriasis vulgaris,” or something like that, Guillain-Barré, then I would say, “Okay, now let’s have a conversation.” Having a slightly stronger reaction to a sting, to a bite, I think in the scheme of things, it’s fine to just go ahead.

VR: Adrian writes, “My family is planning to attend a large, but intimate gathering of families, over 100 people, at the end of the year with dancing and singing.” I think you should go also, Daniel. Sounds good.

[laughter]

“Everyone will be vaccinated. It’s required to present a negative PCR taken within 72 hours of the event’s start or a negative antigen test the day of the event. The group will be together for five days and nights. I’m 50 without any known risk factors. I got my second Moderna six months ago. Should I rush to get a booster before the event? What about my 19-year-old daughter or her 16-year-old sister? Is the boost available to them? In your discussion of timing, it seems that longer than three to four weeks between the first two doses would’ve been better. Is this reason to believe it might be better to wait longer for a boost?”

DG: There’s a lot in there, Vincent. There’s a lot to unpack. The first is, it still frightens me, I don’t know if people have the same reaction. When they see a movie and all these people are gathered together and they’re not wearing masks, I start to squirm a little bit. I don’t think I’ve psychologically fully-recovered from the fact that we’re in a pandemic, and we still are in a pandemic, and numbers are rising.

It is challenging, COVID-19 it’s not going anywhere. This is here to stay. A lot of people are starting to try to make decisions about what are they going to do. People like being together. They like having these intimate events. 100 people? That’s going to be a lot of people being very intimate. How do we make things safe? You went through, I think, some of the good things here. Vaccines are huge. They’re really good at reducing your risk of infection. That’s the new superpower we’re excited about. They’re really good at reducing the risk of severe disease, but we’re not reducing it to zero. We’re still talking about our older individuals with medical problems still being at a solid risk of ending up in hospital.

The testing. I think people are getting a little bit maybe more savvy with regard to this. I’m not sure how excited I am about a PCR 72 hours prior. It’s really that antigen the day of the event that I’m most excited about, and maybe an antigen test the day before, the day of. You start adding up. PCR is at $200 a test, or even $150 a test, versus an antigen test at $10. I’d rather have multiple antigen tests.

Other things to think about is ventilation. How much of this venue is going to be in a closed indoor packed setting without good ventilation versus an area with more open ventilation, things like that. People are going to want to make personal decisions. If you are a 19-year-old healthy individual, vaccinated, you are very low risk. Then the other side, if you are 90 years old, and you’re carrying a little bit of extra weight, and you have some medical problems, the calculus is going to be a little bit different. I think that people can start doing things like this, but it isn’t going to be in the comfort level of everyone and there are ways to make this safer.

VR: Should they get boosters, Daniel?

DG: One of the things that we think about boosters– I’m looking forward to the Paul Offit discussion about this. Boosters are recommended. Broadly, we do think, we do hope, that they’re going to for at least for three to four months reduce your risk of infection. We really don’t have much data on the impact on moderate to severe disease, but it’s a reasonable choice and it is recommended.

VR: Finally, will masks make a difference when people are together for such a long period of time?

DG: Masks make a difference. We talk about a reduction, but then reduction of 10 hours, 100 hours. When you get to a certain point, it becomes almost like a household transmission setting where if someone is there and someone is infected, you’re going to see transmission. The mask can only reduce it for a limited period of time.

VR: Finally, Amy writes, “My seven-year-old received her first vaccine yesterday. I have a question regarding timing for the second dose. All I keep hearing is how here in the U.S., we give the second dose too quickly, which many believe led to a decreased response. It’s seeming like countries that delayed the second dose are doing a bit better. What are your thoughts?”

DG: This always brings me back to my middle daughter, Eloise. We always say, “Eloise, you already have an A, why are you going for the A-plus?” She’s gone for the A-plus. Particularly in younger individuals, we are seeing really impressive data. They’re already at the A-plus, it seems like. I’m not sure that there’s a grade above the A-plus. I think three to four weeks is fine. I think we’re getting really excellent results there.

Now, in our older individuals, 65, 70, 80, we probably would get a little better response if we delayed it. I think what you’re mentioning, there is science and there’s experience to support lengthening that first to second dose. A lot of the logic, and I think you have to ask this question, “What is the prevalence? What is the risk?” Because as we see, once we moved from the original variant to, let’s say the Delta variant, that first shot just isn’t giving you that much. That second shot is really getting you up to that high level. Now that we’re doing a third shot six or so many months later, I think you’re getting– Some people might say that was the properly-timed second dose.

VR: That’s COVID-19 Clinical Update #91 with Dr. Daniel Griffin. Thank you, Daniel.

DG: All right, thank you. Everyone, be safe.

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