TWiV 843 COVID-19 Clinical Update #93

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 18 December 2021

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 843, recorded on December 16th, 2021. 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, how have been the cases and so forth in your hospital?

DG: I think things are not good. Things are not good locally, things are not good nationally, things are not good globally. We’ll talk a little bit very soon here about what’s driving that, and what we’re seeing. Let me start off with my quotation because we have a lot to cover. Can you believe this? We’re two years in and the firehose continues. I’ll start with my quotation. Almost an answer to your question, I was thinking of quoting Sylvia Plath. I was feeling in that kind of a mood, but her stuff was so dark. I decided instead to go with Mary Shelley, it was brighter. [laughs]

“No man chooses evil because it is evil; he only mistakes it for happiness, the good he seeks.” I think as dark as this is, with, well, here in New York State over 10,000 new cases a day. Here in our country with some days getting close to 2,000 deaths per day. This is dark. This is very upsetting. I know we’ve become divided, at least if you look at social media. We’re really the un-United States of America, but I think we have to find common ground, because we have tough times ahead.

The numbers are rising, and just this week, I got alerted from one of our local systems that we have a severe shortage of monoclonal therapy. And at least locally, at this one institution– well, it’s not just one, but this network of institutions, they’re no longer offering Post-Exposure Prophylaxis (PEP) with the monoclonals, and they are restricting use only to either unvaccinated, not fully-vaccinated, or individuals not expected to mount an adequate immune response as defined by the CDC, or age greater than equal to 65.

This is tough. I certainly have had patients in the past who have thought like, “It’s okay if I get COVID. I’m going to go, I’m going to get my monoclonals. I’ve done all the other things.” Well, this might not be an option.

VR: Daniel, I assume most of these cases are in unvaccinated people.

DG: That’s interesting. Most of the cases that end up in the hospital are in the unvaccinated. I’m hoping at some point, the majority of cases will be in the vaccinated, because we have clear evidence that a vaccinated person who gets infected is at lower risk from where they started. You take a healthy woman in their 30s, fully-vaccinated, we’ll figure out what that means at some point. If they get infected, we expect them to do quite well.

The college students, we’re talking about 20-year-olds, healthy. We expect them to do very well post-vaccination. What we worry most about is people who are older, people with comorbidities. Even if they’re vaccinated, as we’ve discussed, they still can end up having troubles. Now, the other, we’re going to talk about omicron. It’s been several minutes and we haven’t mentioned it yet. How are we doing locally with omicron? Because, of course, that’s driving this current pandemic, Vincent. No, I’m joking about that.

VR: I was wondering what you were saying.

[laughter]

DG: I just want to get us– Make sure Vincent was awake there. I have to say, across our country, this is still dominantly delta, but the CDC breaks down the U.S. into different regions with regard to variant tracking. Our region, locally here, is region two. This includes New York, New Jersey, and Puerto Rico and the U.S. Virgin Islands. Not sure how they clump us all together there, but that’s region two. The data on variants is always a little outdated because the person gets diagnosed, the virus gets sequenced, then we get the news.

We have news for the week ending December 11th. This is old, but we were already over 13% in our local region for omicron. I’m hearing that we may be up in the 30s the time we get data for the current week we’re in. This current trajectory puts omicron as the dominant variant. Well, before the end of January, if not sooner, and with all the travel, we’re expecting region two to be cross-pollinating the rest of the country. It is seeming that there is some fitness advantage here. I like to use the terminology fitness advantage because we actually care.

When people talk about transmissible, I’m not sure what they mean. As we saw with delta, there was a shorter time from exposure to the time you would transmit to the next person. That’s important for us to know, clinically. Is it about immune evasion? Is this going to be something we don’t see in people who get a third shot, but do see in people who had a prior infection? The immune evasion question is going to be important for us. Is there a lower inoculum? We still talk about this. When we have contact tracing, 15 minutes, within six feet, we talk about indoors versus outdoors, it’s five minutes, so we need to get a sense of that as well.

Is there a longer transmissibility period? We’re still using the same isolation of the infected for 10 days. I think we’ve talked about before with the vaccinated, I’m not sure we need to be doing that for as long, but then the question comes, with omicron, is it longer? By the time we get to day 11, is it fine to send that individual to a Christmas party with the elderly parents? Lots for us still to know. I know a lot of our local physicians keep asking me, “How can I go ahead and find out?” If I’m going to recommend that this patient goes for monoclonals, which we’re going to get to in a minute, as far as efficacy, how do I know whether I have a patient with omicron?

The shortcut, people have probably heard about the S-gene target failures, or the S dropouts, and I was listening to a recent TWiV where Dickson asked about this, and it made me realize a lot of our listeners probably don’t know what an S dropout is. I think Dickson is really good at picking up those things where you’re like, “You know what, if Dickson doesn’t get it, I bet our listeners don’t.” Here’s why I just want to give everyone a little quick three-sentence primer on this, and that’s a perfect turn of phrase, primers. When we do these PCR tests, what we’re actually doing is we’re using these primers, and they’re short sequences of DNA, and they allow us to amplify relatively specifically certain sequences, certain target sequences.

Each of these sets either contains primers that are specific for nucleocapsid, or open reading frame one, or the RdRp, the RNA-dependent RNA polymerase, or maybe the spike, and most of the assays are using two or three targets. Let’s say you’re running a test where you’re amplifying nucleocapsid, ORF1 and spike. What happens is the nucleocapsid ORF1 come up, but the spike doesn’t come up. That alerts us to something that we saw initially with the alpha variant, now we’re seeing with omicron. There’s enough of a change in the genetic sequence coding for spike that you get this S dropout effect, which is actually good.

People, “Oh, why don’t we change those spike primers?” Actually, better to have this dropout, which alerts us earlier. Unfortunately, then things get sent to Wadsworth, we can sequence about 100 or so a day, the data flows back, doesn’t really ever get back to that clinician and the specific patient. That’s the S dropout behind the scenes here. Why do we care as clinicians? Well, we care in part because we want to know, “Do those monoclonal antibody therapies work with the ominous omicron?” There are really a number of papers, so I can’t share them all.

I was enjoying the recent TWiV, where it was some discussion about this little deeper dive than I will give our listeners today, but thanks to Dr. Sargam Raja Mahat, a CVS pharmacy manager who sent a link to the preprint, “B.1.1.529 escapes the majority of SARS-CoV-2 neutralizing antibodies of diverse epitopes.” I thought this was a complicated, but really interesting investigation, where they are able to use unsupervised clustering to classify the different neutralizing antibodies into six epitope groups.

For instance, what they do is they have a Group A and a Group B, and these might be neutralizing antibodies like one of the Eli Lilly or maybe one of the AstraZeneca, and these are binding to their receptor binding domain in an up configuration. Then you’ve got ones in the Group C and the Group D. Again, a different one of the Eli Lilly, one of the Regeneron, and they’re binding to the receptor binding domain regardless of their up or down confirmations, and you’ve got Groups E and F. Basically, let’s cut to the chase. There’s a couple things that we’re concerned about here, and one of the reasons that I asked our listeners to send stuff my way is I wanted to know about EVUSHELD.

EVUSHELD is this new pre-exposure, long-acting antibody developed by AstraZeneca. We have this big question, “If we give people EVUSHELD, give them this passive antibody biclonal protection that you give twice a year, will EVUSHELD protect people against omicron?” We also want to know, “Will Regeneron work, will the Eli Lilly work?” Let’s start off with EVUSHELD. EVUSHELD, we talked about before. This is tixagevimab, that’s AZD8895, co-packaged with cilgavimab, AZD1061. The tixagevimab is in Group B, so it’s binding to the shoulder of the receptor-binding domain and it appears to be very sensitive to changes at 486, 487, 476.

Cilgavimab AZD1061 falls into Group D, and this actually is more sensitive to changes at the receptor-binding domain right shoulder towards about 309. Unfortunately, what we are seeing here summing up all the data they have available, it looks like the Eli Lilly cocktail, the Regeneron cocktail, the AstraZeneca cocktail are all escaped by omicron, while the Vir GSK, that’s the sotrovimab, and actually, another one people are not familiar with, the DXP604 out of the BeiGene group, these still function but there may be some reduction in efficacy. Not the news I was hoping to hear.

All right. Very similar data that “mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant.” In this investigation, they’re looking at mRNA booster immunization. In this investigation, they reported a near-complete lack of neutralizing activity against omicron in polyclonal sera after two doses in convalescent individuals as well, but mRNA booster immunizations in vaccinated and convalescent individuals resulted in a significant increase in sera neutralizing activity against omicron. That’s the little bit of good news, a little more like maybe the boosters are something that is going to help us in this situation.

All right. Children and COVID. This is good news. We heard from the CDC director Rochelle Walensky, no concerns about myocarditis with nearly five million children vaccinated. I think this is something that a lot of people have had their eye on and there was a nice recent Nature publication looking at myocarditis. It really looks like this lower dose that we’re giving to the younger individuals is working out well. We’re not seeing concerns with myocarditis. I think this just speaks to the importance of thinking about your target population for the jab. Pfizer looks like it is a safer mRNA choice in younger individuals, particularly with respect to the myocarditis risk.

That being said, case rates are rising in children and vaccination rates are dropping, so not great to hear. I do think it’s important to be thinking about how we approach kids coming in with COVID-19. As we talked about last time, if you’re thinking about monoclonals, particularly in areas where we think the monoclonals are still effective, the Eli Lilly product was dropped down to newborns, so we still have that as an option. Timing does matter, and so I want to share a story that– Even though I try to take a little time focusing on what my wife says is my non-paying activities, I still get lost of calls, and so this is my timing matters reminder.

One of my colleagues reached out to me. Actually, it was just today. This is a story of a 15-year-old girl. She starts to feel poorly, goes ahead and gets a PCR that is positive for COVID-19. Symptoms start Sunday. A little bit of a resulting delay, but now we’ve got this positive PCR, we got it yesterday. This 15-year-old girl has juvenile idiopathic arthritis. She is on immunosuppressive therapy with methotrexate and REMICADE, so both T cell and B cell function deficient, and has a high risk for bad outcome. The physician goes and there’s a way for one of our local large health care systems to submit an application online to get this individual set up for antibody infusion.

They get approval today, but they’re not scheduled for their appointment until Saturday, the 18th of December. Not really a great solution. That individual actually went to one of our local places where they could get it today rather than waiting. Remember, as we’ve gone through those studies, those delays impact the efficacy of monoclonal therapy. Even though we say you have a 10-day window, the first three days is the most effective, the next six days continue to be quite effective. If you get past day six, your efficacy drops in half compared to giving it in those first six days.

All right, testing. Never miss an opportunity to test. Maybe there’s some subtle nuance to that that we can talk about, Vincent, but I’m thinking that this article will be quite popular with some of our TWiV listeners. The article “SARS-CoV-2-specific memory B cells can persist in the elderly who have lost detectable neutralizing antibodies.” That was published in the Journal of Clinical Investigations. All is not lost if those antibodies are low. Here, these investigators studied a cohort of elderly care home residents, median age of 87. I think that’s going to go ahead with elderly there.

They were comparing these and looking also at staff. The staff had a median age of 56 years. They’re very young. These individuals had all survived COVID-19 outbreaks with only mild or asymptomatic infection. These are those folks with so-called viral infection-induced survivor immunity, and the cohort was selected to enrich for a high proportion who had lost their neutralizing antibodies specifically to investigate the reserve immunity from the SARS-CoV-2 specific memory B cells. They looked at individuals who had basically lost their neutralizing antibodies, and what they’re going to do here– This is interesting technology. They’re going to use a receptor binding domain tetramer.

This is basically going to be two things stuck together that are going to tag those class-switched memory B cells. They basically found that those spike receptor-binding domain-specific memory B cells were detectable in the majority of these individuals who had lost those neutralizing antibodies. They also found that functional spike S1 receptor binding domain-specific recall was detectable by ELISPOT in these individuals. I thought that this was encouraging. All is not lost.

I’m going to talk a little bit where in testing, I’m talking about serology testing. What about those serology tests? What about using them for reinfection? I had, I think, a sophisticated patient discussion this last week, and this was this whole discussion about what about individuals who have been infected before, how do they know about their infection risk, is this being tracked?

I did want to share that the CDC is tracking this information. There’s actually a page, “Science Brief, SARS-CoV-2 Infection-induced and Vaccine-induced Immunity.” We are interested in how people who’ve been infected before are doing. There’s a quote I’m going to take from there and I’m going to share a story: “Multiple studies have shown that antibody titers correlate with protection at a population level. However, data are presently insufficient to determine an antibody titer threshold that indicates if an individual is protected from infection.” At this time, there’s no FDA-authorized or approved test that providers of the public can use to reliably determine whether a person is protected from infection. They also have a section, “Comparison of infection and vaccine-induced immune responses.” This is evolving. It’s being tracked. We are interested. We are hoping that people who have been infected before are less likely to get infected again. Actually, I’m going to briefly touch on an article on that, but let me share a story.

I got this call earlier today, busy day. This is a woman who is a healthcare worker. She was initially infected in March 2020, so right in the early days. Had COVID then for the first time, but she decides instead of getting vaccinated, she’s going to track her antibody levels. She’s testing them regularly, they continue to be very high. As my wife asks, “Who’s paying for all those antibody tests?” “I guess our insurance companies are.” She’s feeling good. She’s got this high level. She decides not to get vaccinated. She is planning on getting pregnant, but she is going to an OB and doing in vitro fertilization.

The day before that in vitro fertilization appointment, she isn’t feeling well and she is required to get tested by the OB. Lo and behold, despite her very high antibody levels, she ends with COVID this second time. She goes, she gets monoclonal antibodies. I’m not sure what the indication was, but she does because she’s not pregnant at this point. Now, 90 days pass, but she’s still tracking those high antibody levels. She’s now pregnant. She somehow gets an OB to write her an exemption letter saying that because she is pregnant, she shouldn’t get vaccinated. Now, today I get a call because she, again, tested positive for COVID.

I just want to point out, and this is a perfect example because people want to go ahead and they want to draw those serology tests. They want to feel like if those levels stay high, they’re not going to end up getting reinfected or infected post-vaccine, but clearly, as we keep sharing here, we are seeing and we are getting this reported in the thousands, reinfections, re-reinfections, and now even re-re-reinfection. Fourth infections in less than two years. This looks like this young lady has had her third infection in the last two years.

Active vaccination. “Protection against Covid-19 by BNT162b2 Booster across Age Groups.” Now, this is exciting. We are in that, “Never miss an opportunity to vaccinate. Vaccination is how this pandemic ends.” In this study, the authors extracted data from the period from July 30th to October 10th, 2021 from the Israeli Ministry of Health Database. Here, we have 4,696,865 persons 16 years of age or older who had received two doses of the BNT162b2 at least five months earlier.

For the primary analysis that comparing the rates of confirmed coronavirus disease, COVID-19 severe illness or death among those who had received a booster dose at least 12 days earlier with those who had not received a booster. This is a two-dose versus the three-dose. This is becoming interesting in my mind because they’re not going to just look at vaccine efficacy against infection, but we’re actually getting to vaccine efficacy against hospitalization and death. Let’s start off. As expected, the rate of confirmed infection, the vaccine efficacy against infection, was decreased by a factor of 10, but what about the rate of severe analysis?

Here, we are seeing a reduction in the boosted group by a factor of 17.9 among those 60 years of age or older reduced by 21.7 among those 40 to 59 years of age. Really interesting. Among those 60 years of age or older, mortality was reduced by a factor of 14.7 with that third dose. As exciting as this is, I want to add the qualifications– This is a very limited window. We don’t know how long this extra protection might last. Vincent, do you have any thoughts? Are we all going to get shots every four months?

VR: The problem with this is when you get the booster, you have high antibody levels. Yes, you’re going to prevent infection and you’re going to prevent severe disease, of course. The real question is if you wait six to eight months after that third dose, when your antibody levels have contracted, of course you’re going to get infected most likely. Then at that point, what the disease looks like is really important, not right after the booster. That doesn’t seem to make a lot of sense to me.

DG: I think this is a challenge. We’re in the middle of a pandemic, we’re trying to make on-the-fly public health decisions, and there is this real issue that I like to keep returning to, “Who is getting infected?” Let’s say you got infected before and you get reinfected. Oh, my gosh, you’re crying foul, those people. Menace to society, not getting vaccinated. A person gets vaccinated, oh, my gosh, they get infected again. Another menace to society. One of the articles I’ll spend a little more time on next week, which I just had a chance to look over today, was “Duration of SARS-CoV-2 Natural Immunity and Protection Against the Delta Variant: A Retrospective Cohort Study.”

I don’t like to call this natural immunity. I’m not sure where that got coined. I don’t know how natural it is getting infected with SARS-CoV-2 and all the other things that come with that. I like to refer to what it actually is. It’s post-viral infection survivor immunity, because remember, we still have a case fatality rate in the U.S. of 2%. People complain about the vaccines and whatever side effects they might have, but the infection has a 1 in 50 mortality rate. That’s not great. There’s also a hospitalization rate, a long COVID rate, and all the rest. Here, we’re just looking at survivors. These are people who survived.

Initially, it was encouraging with regard to the reduced risk of reinfection, but then I got to the point where, what about how do these people do? If they do get reinfected, are they less likely to end up in hospital? Are they less likely to go to ICU? What about mechanical ventilation? What about death? That’s where I was actually quite concerned. Here they reported that the severity of illness in terms of those parameters; hospitalization, admission to ICU, mechanical ventilation, and death were similar for the reinfections compared to the primary infections. Remember, we already lost our most vulnerable.

In this reinfection, a 7% mortality was observed in survivors of the first infection. A wake-up call. I know a lot of people say, “Oh, I had COVID before, I know it.” That was like, “Well, none of these people died the first time and 7% of them died with a reinfection.” I think that that’s just another argument for what can I do to reduce my risk of getting infected and reduce my risk of a bad outcome?

The period of detectable viral replication. We’re still saying the time for monitoring and monoclonals. Will the oral antivirals ever come? This is where I like to say, “Not the time for antibiotics, not the time for steroids.” We’re waiting to let early inflammatory phase before we think about steroids. This is a virus. It does not respond to antibiotics. Another helpful article– and I think I’ve got to keep reinforcing this. The article, “Azithromycin in patients with COVID-19: a systematic review and meta-analysis,” was published in The Journal of Antimicrobial Chemotherapy. Here, the authors went through– ultimately included 16 studies, five were randomized control trials, 11 were observational. They were looking at a total of 22,984 patients, and can you guess? No significant difference. No benefit to treatment with azithromycin.

No reduction in hospital admission, no reduction in clinical severity, no reduction in need for ICU, not the time for antibiotics. Now some, I think very– I thought this was positive news. On Tuesday, December 14th, Pfizer announced the final data for all high-risk patients enrolled in the EPIC-HR Study. We have 2,246 patients. This confirmed the results of the interim analysis for PAXLOVID, and showing a reduction in the risk of hospitalization or death by 89% if given within three days, 88% if given within five days of symptom onset compared to placebo. No deaths were seen in the patients that were treated. There were deaths, unfortunately, in the placebo group.

There’s a second ongoing study. We heard just a little bit of a hint. This is the EPIC-SR. This is looking at standard risk as opposed to high-risk adults. Here, there was a 70% reduction in hospitalization. No deaths in the treated population. We also got a little bit of data on decrease in viral load at day five. Approximate ten-fold decrease in viral load at day five relative to placebo. We’re seeing this in both the EPIC-HR, that’s the high-risk, and the EPIC-SR, that’s the standard-risk. Really indicating or supporting the concept that there is robust activity against SARS-CoV-2. What I’m hoping here, this could impact that isolation period.

If you’re getting a ten-fold reduction, maybe we can start saying things once you’ve been on this medicine for so many days, you don’t have to isolate for the full 10, but this looks like a potential way to keep people out of hospital, keep people from dying. I am looking forward, by the way, FDA, if you’re listening, we’re anxiously waiting for your thoughtful due diligent review. The last one in this section, “Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19.” This was published in JAMA.

Now, what people in the hospitals are aware of and maybe our listeners are not, is we’ve really switched over in how we provide ventilatory support. Early on, there was this whole push, early intubation. I think a lot of the discussion was about protecting healthcare workers, but we have really tried to push intubation mechanical ventilation down to an option of last resort, and we’ve started using a lot of these high-flow nasal cannula modalities. This was a randomized clinical trial that included 220 patients with severe COVID-19. The patients were randomized to high-flow oxygen therapy versus conventional oxygen therapy.

What this high-flow nasal cannula involves, is giving oxygen through these prongs that go into the nares, the nostrils, but they’re larger and we can really deliver high volumes of oxygen this way. They reported that the rate of intubation and mechanical ventilation for those treated with this high-flow oxygen therapy was reduced to 34.3% versus 51%. About a 33% reduction in progression to intubation. Very encouraging and really consistent with what we’re seeing. We are really able to keep people off those ventilators, which is tremendous at all levels.

All right, the early inflammatory phase. I said there was going to be a lot today. This is that time when, usually, when people end up hospitalized, and another rather influential publication “In non-critically ill patients with COVID-19, therapeutic anticoagulation improved survival to discharge without organ support.” This was published in Annals of Internal Medicine, and it’s got it all right there in the title. These are the results and we’ve talked about, these trials of the adaptive multi-platform randomized control trial, so the ATTACC, Anti-thrombotic Therapy to Ameliorate Complications of COVID-19.

The active for a multicenter adaptive randomized, controlled platform trial of the safety and efficacy of anti-thrombotic strategies in hospitalized adults with COVID-19. REMAP-CAP, that’s the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia. The authors report on 2,244 patients who are hospitalized with COVID-19 and did not need ICU-level care. This is a distinction. We’ve talked before about people in the ICU, the recommendation for prophylactic because we see increased bleeding in that setting, so here we’re looking at using therapeutic in patients outside of the ICU.

Here, they actually are finding an adjusted odds ratio, where people are doing better outside the ICU using therapeutic as opposed to prophylactic. That will potentially be a change. We’ll have to wait and see what the guidelines do with this new information. I want to talk a little bit about long COVID in people who have been vaccinated. That’s one of the things we’ve talked about. People who’ve been vaccinated are less likely to get infected. They appear to be less likely to get long COVID, there appears to be some therapeutic impact to getting vaccinated, even if you’ve had COVID before and the vaccination comes afterwards.

I think I shared that story recently of a young lady who ended up getting COVID despite two vaccine doses, this is still back in the days of delta. This was an individual that, we think, may have gotten it from exposure to an infected boss. Now this individual is about two months out, and now she and her roommate both got infected, are having significant hair loss. Unfortunately, though it is reduced, we are still seeing long COVID despite vaccinations.

No one is safe until everyone is safe. From the Center for Infectious Disease Research and Policy, so that’s CIDRAP, the article “Africa’s COVID-19 numbers surge, but hospital cases remain low.” This article refers to information from the WHO Regional Office for Africa. This is the organization out of University of Minnesota with Michael Osterholm as their executive director. Interesting information. Let me close there before emails by reminding everyone that during the rest of December, also through January, donations made to PWB will be doubled. We are going to give a, I’m going to say a minimum of $40,000, at this point, to support MicrobeTV and all the great work they do, all the great work they help us do as well. Thank you so much for everyone who continues to support our work.

VR: Daniel, this past week, we’ve seen closings suddenly of many universities as students test positive, and they’re sent home quickly so they don’t have to quarantine on campus over the holiday. What’s your thought about that?

DG: I have a lot of thoughts. One is, this is the doomsday scenario. Let’s take 500 students who have COVID and let’s send them back home across the country. Let me share an interesting story. This is a young lady and she is being sent home from Cornell. I, of course, get looped in. She has the minimal, she’s like, “Maybe I’m congested, maybe I have, but I’m not really sure.” Before she goes home, she goes and she does a rap and it’s negative. She goes and does another rap the next day because she wants to make sure it’s still negative, but they require that she gets a PCR test.

She goes, gets the PCR, and then she even on Tuesday morning, when she gets home, she does a rapid before she interacts. Then she gets a call later that day that the PCR is positive. This is one of these interesting issues of, is she really contagious? [crosstalk] I don’t think she is. I think if you keep having negative rapids every day, I think that PCR is just picking up some small amount of RNA, and this poor girl is now as-per-the-rules going to isolate in her room for 10 days and not interact with her family. I don’t think that makes sense scientifically.

VR: Daniel, they don’t give you the Ct values, do they?

DG: It’s really hard to get them.

VR: Because I’ll bet hers is in the high 30s, and we know that you’re not likely to be contagious. I think all of this testing, PCR testing, in particular, without Cts is not really a good plan – especially with so many people vaccinated. And you’re having all these mild, asymptomatic and who knows what they are, they’re just exposures with a bit of RNA in there. They’re not meaningful. I think closing all the colleges is ill-advised in my opinion, but nobody asked me, so. [chuckles]

DG: Yes, I wouldn’t mind if they somehow said, “We’re only going to run the PCR to cycle 30 or 35,” whatever it is. You have to just stop. Don’t go out, some of them are running the machines to like cycle 44. I’m like, “What are you doing?”

VR: I agree, I agree. Time for some email questions for Daniel, you can send yours to daniel@microbe.tv. First one is from Theresa, a nurse in Canada, “I’ve had two doses of AstraZeneca. Over three months, I could not get the mRNA vaccine, due to anaphylactic reaction to PEG. The talk about the third dose leaves me wondering what I can get in Canada, they’re only offering mRNA vaccines. How about AstraZeneca? What is the literature on that?”

DG: This is a great question because sometimes I feel like we’re a little too mRNA-centric, if that’s a thing. There was earlier this month in The Lancet, a really nice article called– and it was the findings of the COV-BOOST, C-O-V-B-O-O-S-T, we’ve probably talked about that at some point. This is where they’re looking at people that got a couple doses of AstraZeneca, then got a third dose. They’re boosting, but there’s also a bunch of combinations there similar to another paper we talked about. It does look like a third dose of the AstraZeneca can get you this boost, and they do.

They look at antibody levels, they look at neutralizing, they look at T cells as well, imagine that. It’s really good data. I would, I think, in a person who’s in a situation like yours, where they’ve had two doses of AstraZeneca, they’re trying to decide if there’s any potential benefit for boosting. We have been boosting people who have immune compromise now that we’re talking about a lot of these vaccines turning into three-dose series, there is some data surrounding that.

VR: Brian writes, “My question for you, I was diagnosed with a case of shingles four-and-a-half weeks ago as a mild case, however, my symptoms aren’t quite completely gone yet. There’s still a bit of a rash on my chest, some minor back pain. I’d like to get my COVID booster now, but I’m concerned it might cause a shingles flare up. Any advice?”

DG: This is a great question. I know we’ve touched on this before. What we certainly saw with first doses of the vaccines was an increased rate at which people would develop shingles. What is shingles for our listeners? You get chickenpox as a child. The chickenpox virus, we’ll call it that, is held dormant by your immune system, there’s a dynamic process. The stress of the immunization, actually, was associated with an increase in shingles that we saw. We’ve actually talked to a lot of people about getting their shingles vaccine before that boost, but if you’re still going through the primary series, I think it’s actually fine for you to go ahead.

We’re not really seeing with that second shot that your shingles will suddenly get worse. That would be my advice. In general, we probably should have known that these vaccines were coming, we should have given everyone their shingles shot before. At some point, you should get a shingles vaccine because even after having shingles, the SHINGRIX, the modern shingles vaccine, is going to significantly reduce your risk of shingles in the future.

VR: Jennifer writes, “Last year, there were newspaper articles concerning the hypothesis that a vaccination against measles, mumps and rubella, MMR vaccine, may conclude in a less strong COVID infection. What do experts say about this? Could this be true as COVID vaccines seem to have a limited time range for being effective? Could MMR provide a longer lasting effect?”

DG: Yes, I’m going to pull you in on this, Vincent. I am familiar with “natural infection” with these viruses having these broad impacts on the immune system, but I’m not certain that there’s any reliable evidence that the MMR vaccine is going to have a detrimental effect, but Vincent, do you have any?

VR: As you know, there was some idea that MMR and perhaps oral polio vaccine might give you a few month respite from COVID mechanism unknown, but I have not heard of any additional data since then.

DG: Okay. All right, we’re on the same page. That’s always a good thing.

VR: Yes. Courtney writes, “I’m so excited to hear about the new preventative monoclonal from AstraZeneca. I had a severe vaccine reaction this past spring to Pfizer. I developed POTS and an exercise intolerance that’s left me wheelchair bound. At the time of vaccination, I was already a long-hauler from a presumed infection I had in March 2020, but I was much higher functioning than I am now. My doctors have advised me against any more COVID vaccines. Monoclonals seem like a great option for me. I’m just curious if there’s any chance I could have another worsening of my condition from it. What is the difference in mechanism between this and the mRNA vaccines? I seem to be incompatible with all things COVID.”

DG: Yes, so this, the troubling times right now that we have omicron on the horizon. This is actually the perfect scenario where we talk about this, where someone cannot really tolerate, where we don’t feel like we can get them adequate protection with vaccination. This was really, you are a part of that target audience individuals, just like– or in your situation. Now, here’s the challenge. We do know that we have good evidence that the long-acting antibody combination, the AstraZeneca, the EVUSHELD, is really effective against the [unintelligible 00:42:05], the alpha, the beta, the gamma, the delta, we don’t know.

We have concerns that it’s not going to provide protection against omicron, but here’s the thing that’s still out and we’re still trying to get this data. I really sort of– word of caution because it takes time to get this data. We do not know about the severity of this variant. There’s a lot of optimism that maybe it is milder. If you can get protection against more virulent at once and it does turn out this one is milder then this still might be an option, but I always say it takes time for people to die. It also takes time for us to see the impact of this on people who are not protected, people who are immunocompromised.

If you see infections in people that were just recently infected with delta, if you see infections in people that were just recently vaccinated, if you see infections in young college students and they all do well, we would hope that is the case. We’re still waiting to really know how virulent this variant is, and when that data is available, I will definitely share it. I’m not a person to throw darts at the board and just hope. I’ll share when we actually know.

VR: That’s COVID-19 clinical update, number 93 with Dr. Daniel Griffin. Thank you, Daniel.

DG: Oh, thank you so much.

[music]

[00:43:39] [END OF AUDIO]

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