What is the data on COVID-19 vaccines? + FAQ

Welcome back to Depth of Anesthesia. This is a podcast that critically explores our clinical I'm David Hao and I'm an anesthesia resident at the Massachusetts General Hospital. Anesthesiology News has two new podcasts called On the Case and Ask the Experts. You can listen to both of them on the Anesthesiology News Presents channel. We're going to be doing a very special episode today that's all about the data behind the COVID-19 vaccines.

Our guest today is Dr. Adam Flachik. Dr. Flachik is one of our senior residents here at Mass General, and he completed his internship in internal medicine at the Mayo Clinic. Prior to that, he spent time at the Paul Ehrlich Federal Institute for Vaccines and Biomedicines in Germany, where he worked in preclinical development of novel vaccine candidates. Dr. Flachik, welcome to the show. Thank you for having me today, and thanks for that very kind introduction, David.

Dr. Flachik, can you tell our listeners a little bit more about yourself and your background? Sure. I'm currently a CA2 resident. I come from Toronto, Canada. I completed my graduate studies at McGill University. where I studied host pathogen interactions and immune mechanisms of viral and fungal infections.

As you kind of alluded to, I subsequently went on to Germany. And worked in preclinical development of peptide-based proof-of-concept vaccine candidates for allergic diseases I'm really looking forward to this to this discussion and your expertise because I think a lot of the information here is going to be valuable to not only our listeners, but their patients and maybe even family members. So let's start with where we are right now in the landscape of COVID vaccines in the United States. So as of February 26th. 2021, there are currently three vaccines approved for emergency use authorization in the United States, with two further vaccines going to submit their phase three data for approval in the coming weeks to months As of March 16th, we vaccinated approximately 21.7% of the population who had received at least one dose.

And approximately 110 million doses were administered in total. This is both a very exciting time as we have a new arsenal against COVID. but also an exciting time in vaccine development, as many of these new vaccine candidates are relying on either new or repurposed innovative vaccine technologies We're obviously in an unprecedented period of time with the pandemic, and I imagine there might be some challenges to some of the vaccine trials that are ongoing. Yes, so traditional vaccine development is usually on the order of ten years from preclinical studies to final approval and manufacturing Um getting a vaccine through the full, although shortened, clinical trial process in 9 to 12 months is completely unprecedented. Traditional vaccine trials go through a very kind of linear sequential process where you have the preclinical trials in the lab setting, usually in animal models.

Followed by the phase one trials where you have safety and dose testing. You subsequently have phase two trials where you do small scale efficacy trials. And finally you have the very large phase three trials and thousands of participants looking at efficacy. Vaccines are extremely risky and expensive business for pharmaceutical companies. There's a very high bar for safety, and the attrition rate can be high as well. companies often require multiple different candidates with repeat trials prior to getting approval.

During this pandemic, however, clinical trial phases have been executed simultaneously instead of sequentially. So as you may have seen in the New England Journal of Medicine and the Lancet, phase one and two trial data is often reported together, and phase two and three data is often reported together as well. The greatest challenge, however, has been optimizing the manufacturing process. So once large vaccine developers had established a likely Canada in preclinical trials, they immediately began manufacturing and producing doses despite not having approval guaranteed for their product Nonetheless, we see that this continues to be a problem and shortages continue to exist worldwide. So it sounds like the new pandemic paradigm has really compressed the entire process and many of the steps that were occurring over the process of maybe years are now you know happening in the order of months and really being executed in parallel.

One term that I do hear frequently when it comes to COVID vaccine development is EUA. Can you tell us a little bit more about this? Yes, so um EUA or emergency use authorization is an FDA term, and verbatim it is the use of an unapproved medical product or unapproved use of an approved medical product to diagnose or treat life-threatening disease caused by public health emergencies such as COVID-19 when there is no adequate approved available alternative So basically, under normal circumstances, the FDA requires approximately six months of safety data for a vaccine candidate to be approved Oftentimes, however, this can be years of data. For example, the recent Shinrix vaccine actually had an average of 3.1 years of follow-up data per participant in their clinical trials However, for emergency use authorization this threshold was decreased to only two months for COVID nineteen.

And the logic behind this is that the majority of vaccine adverse events occur within the first six weeks following vaccination. Luckily, we are now seeing some more substantial data coming out from our current vaccine efforts, post-emergency use approval, which continues to show the safety of these vaccines Now assuming that a vaccine has successfully navigated all these challenges that you've discussed, what actually makes for a successful candidate? So of course uh a vaccine needs to demonstrate both safety and efficacy in phase two and three trials. However And the most challenging portion is generating a long-lasting immune response, which is comprised both of neutralizing antibodies as well as memory T cells A good vaccine also needs to be easy to manufacture and at a low efficient cost.

And finally, a vaccine should be thermally stable or at least have an easy way to transport so that it can be used worldwide. And now that we do have a number of good vaccine candidates and larger numbers of the population are being vaccinated, a concept that I hear about often is that of herd immunity. What is herd immunity and how does that work? Yep. So herd immunity basically refers to population immunity or vaccinating those who can be vaccinated to protect those who cannot.

Um scientifically it's defined by the infectivity of the disease or the R naught or basic reproduction number. So If we take measles, for example, it is a very infectious disease. The R naught number of measles is on the order of 12 to 18. This means that one infected patient will theoretically transmit the disease to 12 to 18 other persons. Therefore, to achieve herd immunity to measles, we actually need to vaccinate. or have natural immunity to disease in 95% of the population, meaning that only 5% cannot receive the vaccine.

Uh for the original COVID-19 wild type virus, which was responsible for the first uh wave of infections in the United States, it's estimated that the R naught or basic reproduction number is approximately two to three. So we would need approximately 50 to 67 % of the population to be vaccinated or to have natural immunity to the virus to achieve a herd immunity. However, what we're seeing now is there are many of these new emerging strains worldwide and they appear to be more infectious than the original wild type virus. And now many experts believe that the herd immunity threshold is probably on the order of eighty percent. Interestingly, the serial prevalence of antibodies, so the prevalence of people who have natural immunity, quote unquote, in the American population and a study in January 2021 showed that the serial prevalence was approximately 14%.

Therefore, we still have quite a ways to go to achieve herd immunity in this country. And for those patients or people who are able to receive the vaccine, is there an immune response that would be an ideal response to the vaccine? An ideal immune response to vaccination is characterized by three components. So the first, and we probably mostly heard about this one, is a long-lasting neutralizing antibody response to the pathogen The second is a long-lasting CD4 helper T cell response. So if we can remember back to our immunology days in college.

Helper T cells help B cells produce antibodies while creating an appropriate inflammatory milieu to clear the virus. They come in multiple different flavors as we're finding out, but the most common types are TH1 and TH2. So TH2 CD4 T cells, as you can remember, are responsible for clearing helmths and parasites, and they're responsible for allergic diseases However, to clear a virus, you want a strong pro-inflammatory TH1 type of immune response. And this is often characterized by the cytokines interferin gamma, TNF alpha, and IL-12. Finally, and often the most difficult long-lasting immune response to achieve following vaccination is the cytotoxic CDAT cell response.

So CD8 T cells are memory T cells as well that directly kill infected cells so that the virus is unable to replicate and spread further And where are we at currently with respect to emergency use approved vaccines in the United States? Currently, we have three approved vaccines for emergency use authorizations. These include the Pfizer BioNTech mRNA-based vaccine, which was approved December 11th, 2020. We have the Moderna mRNA-based vaccine approved December 18th, 2020. And finally we have the Janssen Biotech or the Johnson and Johnson DNA Virovector vaccine, which was Recently improved February 26, 2021.

I think a few other interesting vaccine candidates to mention are the AstraZeneca or Oxford DNA viral vector-based vaccine, which has been in the news quite a bit lately, and will be submitting their phase three data to the FDA in the coming days. and the Novavax peptide-based vaccine, which will be submitting for emergency use authorization in April or May Perfect. So I think the stage is set for us to start diving into the data on the individual vaccines. And let's start with the first vaccine to be approved, uh the Pfizer vaccine, which is the one I got. What can you tell us about this vaccine? So until the fairly recent past, nucleic acid-based vaccines, or those based on mRNA or DNA, had been very challenging as mRNA and DNA are not stable extracellularly and often require a vector or some kind of delivery system to get into the cell.

The Pfizer or BNT162B2 vaccine is an mRNA-based technology which takes an mRNA that encodes the full-length SARS -CoV-2 spike protein Which is currently believed to be the key viral component leading to viral binding and infection It takes this mRNA and it surrounds it by a lipid nanoparticle that allows the mRNA to be transported into the cytoplasm. Phase two and three data, which was published by Pollack and Al in December 2020 in the New England Journal of Medicine, of a large-scale placebo-controlled observer-blinded clinical trial of forty-three thousand participants. With a primary endpoint of preventing laboratory confirmed COVID-19 at 17 seven days post-second dose of vaccine, demonstrate an overall efficacy of 95%, which is absolutely fantastic. The participants of the trial were generally 16 years of age or older, and they relatively represented the youth U.

S. ethnic demographic. However, the largest criticism of this trial was that only twenty one percent of participants were noted to have any prior stable chronic medical conditions, and the investigators were able to exclude anyone who they deemed to have quote unquote unstable disease. The vaccine, as most of us know, is given as a two-dose regimen, 21 days apart. It has a very acceptable safety profile. Which I'll talk about later, but as most of us know, it usually leads to a local or kind of mild, moderate systemic effect, usually lasting for up to four to eight hours.

Interestingly, people who are generally older or above the age of 55 did not experience these uh mild or moderate systemic effects And only four serious events were reported in the trials. These included shoulder injury, auxiliary lymphatopathy, paroxysmoventricular arrhythmia, and leg paresthesias So it sounds like all in all a very promising vaccine. You did mention that this vaccine is an mRNA-based technology, and I've heard concerns in the popular media about the safety of mRNA vaccines considering they are new and quote unquote untested technology. How exactly do mRNA vaccines work and is there any potential risks that we should be concerned about? So mRNA vaccines work by entering the cell cytoplasm?

When they enter the cytoplasm, they are translated using the cellular machinery into a peptide or a piece of protein. This peptide is then presented on the cell surface and this is recognized by the immune system and this is what leads to the long-lasting immune response What's really important to note and should be highly emphasized to patients is that these vaccines are non-infectious, non-integrating. meaning that the mRNA never actually enters the nucleus, and therefore there is a very, very low risk of causing insertional mutagenesis Which is one of the primary uh things that patients are often concerned about. And as I understand it, there were a number of studies performed looking at the immune response to the Pfizer vaccine.

What can you tell us about that? So as someone who worked in immunology, I think the immune responses vaccine was the most exciting. There were a few trials uh specifically looking at uh serum in participants from the phase one dose finding trials One trial was by Sahin and Al in Nature in September 2020. And what they found was that there was a very long-lasting neutralizing antibody response. In addition, when they did flow cytometry and looked closer at the peripheral immune cells in these participants, they found that The CD4 and CD8 profiles matched exactly what I described of an ideal vaccine immune response.

So the CD4 cells were generally TH1 in nature. They produced quite a bit of interferon gamma. And the CD8 cells were killers and produce interferon gamma as well. These are both highly beneficial in providing long-lasting immunity to this viral infection And I think what's also especially interesting about this vaccine is that we also have a large observational study from a mass vaccination campaign in Israel to back this vaccine up. What can you tell us about how this study was conducted and what the findings were?

Yes, so the goal of the study was uh real-world conditions. And as you alluded to, it was a very large observational study of almost six hundred thousand vaccinated individuals matched to unvaccinated individuals in It was published by Dagan and Al in February 2021 in the New England Journal Medicine, if you'd like to check it out. And it appears that in the real world, the vaccine did provide a similar efficacy of 94% against symptomatic COVID-19 infection Interestingly, it appeared to provide a 92% efficacy against any documented infection. So it means that people who had asymptomatic disease also seemed to be protected ninety-two percent of the time. The study found that the efficacy was not dependent on age and those above the age of seventy seemed to have a similar efficacy.

And interestingly, following even a single dose, they found that at two weeks, approximately an efficacy of 62% existed. However, one mildly concerning aspect of the study was that those with multiple medical comorbidities generally were found to have a smaller or lower efficacy to the vaccine And as you mentioned, this data is obviously particularly meaningful because it was conducted in a more or less real-world setting. And so some of the findings are quite uh externally valid. The next vaccine that we'll now chat about is known as mRNA 1273 and is manufactured by Moderna. It's the second vaccine that I think uh U.

S. healthcare professionals were acquainted with What can you tell us about this vaccine? Yes, so the Moderna vaccine is again a full-length mRNA vaccine encoding the SARS-CoV-spike protein encapsulated by a lipid nanoparticle In the phase three randomized observer blind and placebo controlled trial of over 30,000 individuals, which was published by Baden and Al in February 2021 in the New England Journal. The Moderna vaccine was found to have an overall efficacy of 94.1% at preventing symptomatic COVID-19 disease at 14 days post-second dose of vaccine. Again, this vaccine had a very similar acceptable safety profile. However, 88% of participants did note a local injection site pain.

With up to seventy-nine percent of participants having mild to moderate systemic effects, which lasted up to two point nine days And the third vaccine that we'll now chat about is the newest to receive EUA, and it's definitely unique from the prior two vaccines which we've just discussed. in that it is a DNA viral vector vaccine. What can you tell us about the Johnson <unk> Johnson vaccine? Yes, so as you alluded to, the Johnson <unk> Johnson vaccine is a DNA viral vector vaccine. Um the big difference is that this vaccine is based on a previously approved technology known as advac adnovirus. platform. It was previously approved by the European Medicines Agency for Ebola virus.

This vaccine encodes the DNA for the spike protein. which is integrated into an adenovirus or common cold virus , which is replication incompetent. It is then delivered to the patient or participant. where it is taken up into the nucleus and transcribed into a mRNA and then translated into a peptide and similarly like the mRNA vaccines it is presented on the cell surface. The randomized double-blind placebo-controlled trial, 43,000 individuals, demonstrate an efficacy of 85 % at preventing moderate or severe COVID-19 disease at 14 days post-vaccination. This trial was quite different from the others in that one, it was only a single-dose vaccine. And second, it was quite a international, very diverse trial.

It was performed in eight different countries However, what made it a particularly strong trial was that 51% of participants in the trial reported having a comorbidity associated with a risk for severe COVID-19 disease And therefore, this might explain the lower efficacy observed at 85% compared to the Moderna and Pfizer vaccine Further, looking at the immune response, where they looked at phase one and two A data, they found a positive neutralizing antibody response in 100% of participants at 71 days post-vaccine, so quite a long Neutralizing antibody response. And what is important to note is that the viral vector itself does not actually integrate into the genome. However, there is one potential downside to viral vector-based adenovirus vaccines , in that an individual could theoretically already have immunity to the adenovirus.

That is being used, and therefore the adenovirus vaccine would be rendered incapable of inducing an immune response to the DNA segment that it is delivering Another vaccine that's come out relatively recently and has actually caused a lot of controversy, I'd say, is the Oxford vaccine. It sounds like there's been some concerns about the safety of this vaccine, so what can you tell us about this one? Yeah, so similar to the Johnson <unk> Johnson vaccine, the Oxford vaccine is based on an adenovirus vector. The phase two and three data for the original approval in the UK and Europe was actually based on pool data from multiple different studies in the UK, Brazil, and South Africa. They looked at 24,000 patients and found an efficacy of 63 %.

Um interestingly, they had to readjust their trial midway through and ended up giving a second dose. Therefore, most participants actually received their second dose 69 days after their first. And that is why uh in the UK and Europe this vaccine is given 12 weeks apart. This vaccine is not currently licensed or license for EUA in North America. However, they are submitting their data in the very near future.

There's some controversy on this vaccine being approved in the over 65 age group. In Europe it appears to be approved. However, in certain jurisdictions, such as in Canada, it's not being approved in those over 65, and this is mostly based on the lower efficacy. The largest advantage of this vaccine, however, is the cost. So an average dose of the Oxford vaccine costs approximately $4 as compared to $20 to $40 for all the other vaccine doses, and it is very easy to store at regular refrigerator temperatures.

And it's likely that this vaccine will be the one that will be vaccinating uh parts of sub-Saharan Africa which do not have uh easy access to very cold refrigeration systems. My understanding of some of the controversy is that there's a fear of a potential link between this vaccine and blood clots. Has this actually been substantiated by the data that you're aware of? Yeah, so it's very interesting. Over the last several weeks, there have been multiple reports of uh the Oxford vaccine causing thrombosis.

Um one to two weeks post-vaccination, um which has led to unfortunately a few deaths in Norway This has resulted in the vaccine being pulled in multiple countries in Europe. However, honest on analysis of the data, the WHO as well as the European Medicines Agency found the vaccine to be safe. However, they are issuing a warning. saying that certain rare types of blood clots may occur in those with a baseline low level of platelets Um the US study that I alluded to recently, which included 21,000 participants and is submitting for approval in the coming days. found no increased risk of thrombosis or thrombotic events in any of the participants in the study. The study data isn't yet published, and I'm interested to kind of see what they found when looking at it a little bit more closely.

Definitely sounds like we have a couple more vaccine candidates that we should be on the lookout for in the coming months. Moving into a slightly different category of immunity, I do want to touch on convalescent serum. This was I'd say touted very early on in the pandemic. And I wanted to ask you if there were any studies looking at whether or not it was actually efficacious as a strategy for generating immunity. As you alluded to, so initial observations were that if you took serum from a COVID-19 recovered patient and gave it to a critically ill patient, you could provide a type of passive immunity However, a recent study out of Argentina of 228 patients in the ICU by Simona Vision Al in November in the New England Journal of Medicine. showed that there was no improvement in the clinical status of thirty days with no mortality benefit When you mount a natural immune response to COVID-19, you actually produce a large variety of neutralizing antibodies to every portion of the virus.

And it's thought that only a very small portion of those antibodies is actually directed against the spike protein, which appears to be the most essential in causing infection. And it is probably for this reason that these covalescent Sierra studies have not panned out. Um, although this topic still remains controversial. However, I think this kind of opens up something interesting in that it lends some credence to a potential for a monoclonal antibody against the spike protein as a potential treatment. However, this is uh outside the scope of the podcast.

Another concern that you've discussed with respect to her generating herd immunity is that of the emergence of variants uh worldwide. What do we currently understand about these strains and what is the impact? Yep, so the SARS-CoV-2 virus is under a significant evolutionary pressure. Which leads to the emergence of viral variants. So there are two kind of main variants circulating at the moment that we hear about.

So there's the B117 or the UK variant. and the B1351 or the South African variant. They have been circulating in the United States since December and January respectively. Interestingly, the large study, the observational study from Israel, mentioned that the UK variant did appear to be a fairly dominant circulating strain at the time of the study and they still found a ninety four percent efficacy, which is reassuring. However, um two studies, uh in vitro studies by Liu and al and Wu and al in February in the New England Journal of Medicine, looked at the neutralizing capacity of serum from Pfizer and Moderna trial participants. What they did is they took the serum put it on a agar plate with virus and found uh what the neutralizing capacity was When they looked at the UK variant, they found that there was only a slight decrease in its neutralizing capacity compared to the wild type However, when they looked at the South African variant, two-thirds and 6.4 fold decreased neutralizing capacity was noted with the Pfizer and Moderna trial participants serum, respectively.

Dr. Flachik, thank you so much for such a comprehensive and really data-driven rundown on the of the current landscape of vaccines. I'd like to shift gears now and really apply that data-driven approach towards some of the commonly asked questions that we may encounter as healthcare professionals from patients. family members, or even our own colleagues. Vaccine hesitancy is understandably a persistent barrier, and I do hope that your approach will help inform our listeners. To start off, what is our role as perioperative healthcare clinicians in the vaccine landscape? Yeah, so vaccines are usually administered to healthy people, and therefore it's very essential to maintain a high level of ethical imperative and public trust.

Um, as you said, unfortunately there is a very high level of vaccine hesitancy. It's a significant problem. And we find that a study done last summer of 13,000 people in 19 countries found that 71.5 % of participants would very or somewhat likely take the uh COVID-19 vaccine. However, that means that up to 30% of people were unwilling to take the COVID vaccine. And my guess is that a fair number of that percentage would probably be unwilling in part due to concerns about potential side effects.

Considering how rushed the entire process was compared to standard vaccine development. So what is the data on the actual side effects that people have encountered thus far with respect to these vaccines? So as many of us who have received the vaccine, we know that there are very common local injection site reactions. So almost 85% of participant in the Pfizer. study reported either pain, swelling, or redness at their injection site. And then 78% of participants reported feeling feverish, having fatigue, headache, or chills.

So these Local and mild systemic effects were quite common, generally lasted for two to three days. What's interesting is they do seem to be worse following the second dose, and as patients or participants were older, uh these were less common. There also initially appeared to be a concern for Bell's palsy following vaccinations, um, with three cases noted in the Moderna trial. However After some consideration, the FDA appears to believe this is an acceptable background rate for Bell's palsy. Um and we'll probably see a little bit more data on that uh as more people are vaccinated.

All vaccine adverse events um must be reported by healthcare providers to the vaccine adverse event reporting system or VARS, and this is a requirement by law. And finally, there is a countermeasures injury compensation program, which is a program that provides compensation to any individual who may be harmed by the COVID-19 vaccine. However To date, I am unsure if anyone has made use of this program. However, it is available Another concern is that of anaphylaxis. What's the actual incidence of anaphylaxis with the data that you've seen so far?

Yep, so the FDA has a very specific kind of definition for anaphylactic uh reactions or allergic reactions. So they are symptoms of high, swallowing, wheezing, respiratory distress within four hours of vaccination. Um all the trials excluded any individuals who had any prior history of anaphlaxa to any of the components in the vaccine, and the Pfizer trial went even further to exclude anyone who had any allergic reaction to any vaccine in the past. Two big reports by the CDC in December and January with post-approval monitoring. Looking at 1.8 million doses of the Pfizer vaccine and 4 million doses of the Monera vaccine, found that there were 21 and 10 cases of anaphylaxis reported respectively.

This works out to about one in one hundred thousand persons for the Pfizer vaccine. What is reassuring though is that Seventy to ninety percent of these cases occurred within 15 minutes of vaccination. So as all of us remember. There is a 15-minute observation period following vaccinations and it is for this reason to detect the majority of anaphylactic reactions Now, is there a population of people who should not be vaccinated? Yes.

So any person uh with a history of severe immediate allergic reactions to any of the ingredients in the vaccines. Um so specifically in the mRNA vaccines, they are both stabilized with polyethylene glycol and polysorbate. Any person who has any reaction after the first dose should not receive the second dose. Finally, I think it's important to mention a prior history of Dion Barret syndrome or Bell's palsy are not contraindications to vaccination And what if you're pregnant? The WHO and the CDC state that pregnant and lactating women may choose to receive the vaccine. but they should balance the risks of exposure as well as their own comorbid risk factors before making that decision.

Both agencies caution that there is no data currently available in pregnancy. All the trials that were performed in the United States excluded pregnant women from their trial data. However, there are a few kind of reassuring data points. So animal models of pregnancy were used in preclinical trials and did not reveal any concerns. And it's also estimated that as of a couple weeks ago It is likely that approximately 20,000 pregnant women likely received the vaccine, nonetheless, in the United States, and so far no red flags have been noted.

In the large observational Israeli study, Um 1,500 vaccinated pregnant women were included. However, the study uh investigators uh mentioned that there was insufficient power to really observe any risks or side effects. Luckily, uh we know that the major vaccine producers are starting to do trials in pregnant women. How about the recommendations about children? Are those any clearer with respect to the guidelines?

Yep, so for children, um the CDC is much more clear. So all the trials were either performed in those 16 years of age or older or 18 years of age or older Therefore, children cannot receive the vaccine at the moment. However, as we know, to achieve herd immunity, we will likely require pediatric vaccination. Therefore, Johnson and Johnson have launched a trial in children, infants, and neonates. If you're currently sick with COVID-19, should you be avoiding vaccination?

The current CDC recommendation is to avoid vaccinating those with active COVID-19 disease, but to vaccinate them immediately following recovery. If we look at prior studies in coronavirus infections, we know that natural immunity may be short-lived. However, we don't currently have any long-term data in COVID-19. And therefore it is still a good idea to get vaccinated despite having COVID-19. And what if you're immunocompromised?

How should you approach vaccination? So the Pfizer trial specifically excluded anyone who was taking any immunosuppressive therapy or with a prior diagnosis of an immune-compromising condition. The CDC uh recommends that immunocompromised individuals still receive the COVID-19 vaccine, but they should be counseled by their healthcare provider on the potentials for a reduced effectiveness or reduced immune response. In addition, there are currently no recommendations for revaccination once immune competence is regained And I think this might be a helpful question for our perioperative colleagues. Can you have surgery after immunization?

Yeah, so this is a very interesting one for us. So currently the CDC does not have any specific recommendations regarding surgery and COVID-19 vaccination. However, it recommends that patients speak to their healthcare providers on a case-by-case basis. The NHS in the UK states that recent or imminent surgery is not a contraindication to vaccination However, there is some rationale in separating surgery from vaccination. For example, the vaccine is known to cause some lymphadenopathy.

So certain oncologic surgeries where you're looking at lymph nodes or certain procedures such as mammograms maybe should not be performed immediately following surgery In addition, uh it's thought that anesthesia is a kind of immune modulator in itself, and volatile anesthetics are believed to induce a relative immune compromise state So theoretically these considerations may reduce the effectiveness of the vaccine, but we don't currently have any data or conclusive data or studies on the topic Is there any information that you're aware of in terms of data for the use of antipyretics or NSAIDs when you do get vaccinated? So there is very limited data um surrounding the use of antipyretics such as Tylenol or NSIS in any vaccine effectiveness.

So what's interesting is in both the Moderna and Pfizer trials, participants were freely allowed to use over-the-counter medications. And up to 45% of people ended up taking these medications following their second dose And what's the feasibility of delaying vaccine doses? Yep, so the Pfizer vaccine requires a 21-day um period between the booster and the Moderna vaccine requires a 28-day uh delay before the booster. The CDC currently allows a four-day grace period so you can get them up to four days earlier. However, if it's administered earlier than four days, it's actually a uh reportable administration error that should be reported to the VAR system.

With respect to actually delaying the dose, as you mentioned, uh the CDC right now allows the Pfizer Moderna vaccine dose to be delayed up to six weeks, but cautions that there's no data beyond this point. And when we look at the Oxford vaccine They found that delaying the dose up to 12 weeks still provided a persistent neutralizing antibody response post the first dose at 90 days. Another topic that I've heard being discussed with my colleagues in the hospital is booster vaccines. Is this something that's gonna be coming down the down the pipeline? Yeah, so the the data on the durability of the immune response is still fairly limited because the trials all started in the summer of 2020.

But as we know, um the neutralizing antibody response to the Moderna vaccine, for example, does last at least four months. But there was a little bit of waning at the four-month mark Currently there are no recommendations for boosters. However, all three vaccine makers are currently making vaccines to cover the new UK and South African variants. And it's possible that we're probably going to receive those as booster doses in the future. Awesome.

Dr. Flachik, that was really such a comprehensive and truly data-driven approach to the entire COVID-19 vaccine landscape. Thank you for taking the time to join me today. And I know our listeners will have greatly benefited from your insights. Thank you for having me on your podcast today, David. To our listeners, thank you for joining us on the show today.

We're really excited about this episode and we pushed it out much quicker than usual because a lot of this information is time sensitive. If you enjoy the content, please be sure to leave a rating and review to help other listeners find our material. And as always, stay hungry and keep asking questions.