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Time Stamps

  • 02:30 Epidemiology of RSV
  • 03:46 Development of RSV vaccine
  • 05:55 Vaccine trial design
  • 12:22 ARESVI and RENOIR Trials
  • 18:18 Who should we recommend the RSV vaccine to?
  • 19:50 What don’t we know?

Show Notes

What makes a vaccine trial special? 

  • Placebo Considerations
    • Many vaccines contain both the vaccine itself as well as adjuvant compounds
    • Adjuvants stimulate the immune system, which can protect against disease
      • Examples include: aluminum, AS04, MF59 
    • So an adjuvant will affect the 
        • 1) How efficacious the vaccine may look 
        • 2) Side effective profile
    • Option 1: Adjuvant-only placebo
      • Assesses the efficacy of the vaccine substrate itself 
        • Since adjuvant is both in the vaccine AND placebo
      • Vaccine may look less efficacious
      • Vaccine side effect profile will appear better tolerated
    • Option 2: Saline placebo
      • Assesses the efficacy of vaccine with its adjuvant compounds
      • Vaccine may look more efficacious (adjuvant itself stimulates an immune response)
      • “Vaccine” side effects may be more (due to adjuvant) compared to saline placebo
  • Vaccine Trial Endpoints Examples
    • Surrogate markers
      • Useful if antibody levels correlate with disease protection or asymptomatic transmission (e.g. influenza)
    • Confirmed vaccine-specific disease 
      • Number of disease-specific cases
        • Relevant to patients
      • Disease-specific hospitalizations, ICU admissions, or all-cause mortality
        • Relevant to patients
        • Requires large sample size to achieve adequate power
    • All symptomatic respiratory infections
      • Most relevant to patients
      • Will make a vaccine look less efficacious because this outcome captures other diseases
    • More general markers of disease (e.g. hospitalizations, all cause mortality, all URIs not just RSV)
  • Disease Transmission 
    • Requires a unique trial design
      • Not likely to get adequate data from an intervention trial
      • Two main trial designs that  disease transmission:
        • Cluster randomized trial
        • Regular RCT with assessment of community infections rather than individual  participant infections 

RSV (Respiratory Syncytial Virus)

  • Epidemiology
    • Per CDC, Compared to children, adults ≥65 years old experience:
      • Twice as many RSV hospitalizations 
      • 40x as much RSV mortality  
      • RSV hospitalizations among adults ≥60 years old were less frequent but were associated with more severe disease compared to hospitalizations for COVID-19 or influenza in Feb 2022-May 2023
  • History of vaccine development:
    • Formalin-inactivated RSV vaccines in 1960s induced severe disease in vaccinated children, leading to deaths of two RSV-naïve children
    • Pre-clinical trials
      • F glycoprotein is a RSV structural protein responsible for cell entry
        • Ideal vaccine target since the sequence is relatively conserved across strains
        • Previously, vaccines targeted its post-fusion shape, which were less effective at neutralizing RSV infection
        • Preclinical studies showed the pre-fusion shape was more effective at viral neutralization
  • Pivotal RSV Trials (RENOIR and AReSVi-006)
    • Similarities:
      • Double-blind, randomized, placebo-controlled trials
      • Inclusion criteria: adults ≥60 years old with stable chronic conditions
      • Exclusion criteria: 
        • Receipt of other vaccines in the 2 weeks before intervention
        • Immunocompromised status
      • Saline placebo
      • Confirmed RSV infection defined as:
        • At least 2 symptoms lasting ≥24 hours
        • Positive RSV RT-PCR test confirming infection
      • Ascertainment of safety:
        • Participants kept journals for the first week after vaccination
        • Side effects solicited up to 30 days after injection
    • RENOIR Trial
      • Sponsored by Pfizer
      • Enrolled ~34,000 participants
      • Vaccine contained RSV A and RSV B antigens, no adjuvant
      • Results: 
        • Vaccine Efficacy = 1 – Number of Infections in Vaccine Group/Number of Infections in Placebo Group
          • 67% against RSV lower respiratory tract infections (LRTI) with 2 or more symptoms
            • 67% [1- (11/33)] comes from 11 cases in vaccine group/33 cases cases in placebo group
          • 86% against RSV LRTI with 3 or more symptoms
            • 86% [1- (2/14)]comes from 2 cases in vaccine group/14 cases cases in placebo group
        • Safety:
          • Local reactions more common with vaccine within 7 days of injection
          • Systemic events similar between the two groups
          • 2 cases of GBS reported in vaccine recipient group
            • Both participants recovered
    • AReSVi-006
      • Sponsored by GSK
      • Enrolled ~24,000 participants
      • Single RSV antigen + adjuvant
      • Results:
        • Vaccine efficacy
          • 83% [1- (7/40)]against all RSV-related LRTI
            • 83% comes from 7 cases in vaccine group/40 cases cases in placebo group
          • 94% [1- (1/17)] against for severe infections
            • Severe infections defined as an infection that prevents normal, everyday activities
            • 94% comes from 1 cases in vaccine group/7 cases cases in placebo group
          • Subgroup analysis similar across age range and risk profiles
        • Adverse events
          • Higher rate of fever and systemic symptoms in vaccine group compared to placebo group
  • Takeaways
    • RSV is associated with significant morbidity/mortality in patients ≥60 years old
    • Abrysvo and Arexvy seem protective with reassuring side effect profiles
      • BUT true efficacy difficult to discern with small number of RSV cases in both trials
      • Both vaccines use an antigen delivery system, a method which has a long track record in other vaccinations, giving us more confidence that we understand safety signals
      • Will need to continue post market surveillance (Vaccine Safety Datalink) for more rare side effects
    • Whether we recommend the vaccine to patients depends on patient-level risk factors e.g. for those with more comorbidities (in whom RSV infection could lead to death), recommending the vaccine appears reasonable 
    • Remaining questions:
      • Durability – Will the vaccine last more than a single winter? Will boosters be necessary to provide durable protection?
      • Applicability – Will younger individuals or immunocompromised patients have a similar risk/benefit profile?
      • Disease transmission – Does vaccination affect disease transmission?

Transcript

Dr. Greg Katz: Welcome to the fourth installment of Beyond Journal Club, a collaboration between CORE IM and NEJM group. 

Dr. Clem Lee: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context, telling the story of how we got to where we are and what it means for how we take care of patients.

Dr. Ann Cheung: And today we’re discussing a topic that somehow become politically charged over the last couple of years. We’re talking vaccines and vaccination. I’m Dr. Ann Cheung an editorial fellow at the New England Journal of Medicine. And a pediatric hospitalist at Tufts Medical Center with a background in vaccine development.

Dr. Greg Katz: I’m Dr. Greg Katz, a cardiologist at NYU. 

Dr. Clem Lee: And I’m Dr. Clem Lee, a former fellow and current guest editor at the New England Journal of Medicine. 

Dr. Ann Cheung: Today, we’re going to talk about the RENOIR RSV trials, which were published in the February 22nd and April 5th issues of the New England Journal of Medicine in 2023.

Dr. Clem Lee: These trials were the ones that led to the FDA’s approval of GSK’s Arexvy and Pfizer’s Abrysvo vaccines for the 2023-2024 respiratory season. And just to make it clear, yes, you heard that right. One of the RSV trials is called ARESVI, spelled A R E S V I, and the virus is obviously also called RSV, spelled R S & V.

Dr. Greg Katz: So that’s a pretty convenient way to name the trial after the virus, but it’s not so convenient when you’re doing a podcast talking about both of them. So nomenclature aside. I’m getting tons of questions from my patients about these new RSV vaccines as they’re bombarded with direct to consumer advertising and tons of media coverage, and somehow a lot of my patients are a little bit vaccine hesitant, and so there’s plenty of questions about side effects and efficacy. 

Dr. Clem Lee: Yeah, I’ve noticed that too, Greg. Vaccines have become a bigger issue for all of our patients since the pandemic, and it’s not just the RSV vaccine. So interpreting trials like the ARESVI trial and the RENOIR trial bring up bigger questions about vaccine trials in general. Yeah. Questions like, how do we evaluate the efficacy? Or, how do we capture short and long term side effects? And how does the vaccination impact transmission? Or does it even do that? Or even something seemingly so straightforward, like what’s the right placebo to test against a vaccine? 

Dr. Ann Cheung: So, with all those questions in mind, we’re going to start first with a discussion on RSV and how hard it was to develop an RSV vaccine.

Dr. Greg Katz: Next, we’ll get a bit meta with a dive into how to think about the design and interpretation of vaccine trials.

Dr. Clem Lee: And finally, we’re going to do a deep dive into RENOIR and ARESVI trials to help busy doctors figure out if it’s worth spending 5 minutes of a 15 minute visit to talk with patients about getting the RSV vaccine. 

Dr. Ann Cheung: You know what, guys? As a pediatrician, I was surprised to hear that older adults need a RSV vaccine, since RSV is classically referred to as a pediatric disease. 

Dr. Clem Lee: Yeah, I had to do some digging and, at least according to the CDC, hospitalizations for adults over 65 years may be as much as double as that in kids. That really shocked me. And RSV kills around 40 times as many people over 65 as it does children. So we’re talking about 8, 000 older folks dying from RSV every year compared to around 200 kids. 

Dr. Greg Katz: Those numbers make sense. You know, there are way more elderly people in the U.S. than there are children under five. And if the past few years have taught me anything, it’s that older folks tend to be more susceptible to getting really ill from a respiratory viral infection.

Dr. Ann Cheung: Totally, Greg. And just like any other virus, when it comes to RSV, prior infection doesn’t always mean complete immunity. 

Dr. Clem Lee: Yeah. That reminds me of the fact that by the age of five, essentially a hundred percent of the population is seropositive for RSV. And those stats about the morbidity and mortality of RSV in older adults suggest that their immunity wanes and that they might benefit from vaccination.

Dr. Ann Cheung: Hmm. Really good point, Clem. That said, the march to developing an RSV vaccine has been slow and filled with setbacks. 

Dr. Clem Lee: Yeah. Let’s take a look at the ups and downs in the development of RSV vaccine. 

Dr. Ann Cheung: So, attempts to make an RSV vaccine started pretty soon after the two strains A and B were discovered back in the 1950s. So the RENOIR and ARESVI trials were actually more than 60 years in the making. 

Dr. Clem Lee: Wow, that’s a long time! RSV proved to be a pretty tough nut to crack. Even though we had successful and safe vaccines against other diseases like the flu, polio, measles, and mumps since the 1960s, the initial RSV vaccines weren’t as wonderful.

Dr. Greg Katz: Those initial RSV vaccines developed in the 60s induced an immune response that wasn’t really protective. And so when vaccinated children had their first natural RSV exposure. Some kids developed really severe illness. This tragically led to the deaths of two RSV naive toddlers, which was caused by antibody dependent enhancement from the vaccine.

Dr. Ann Cheung: And unfortunately, that held up further RSV vaccine development for years. 

Dr. Clem Lee: And for decades, the problem with the RSV vaccine came down to the F glycoprotein, which is a protein that allows the virus to enter into cells. This F glycoprotein fuses with human cells and then changes shape.

Dr. Greg Katz: So all of those original vaccines had been focused on the post fusion shape, but the circulating virus is in a pre fusion confirmation. And so those original vaccines didn’t neutralize it. Which means they couldn’t prevent it from causing infection.

Dr. Ann Cheung: So the key was to figure out the pre-fusion shape so the antibodies could neutralize RSV before the virus entered the cells. 

Dr. Greg Katz: Unlocking that pre-fusion shape of the F glycoprotein enabled development of a vaccine that would produce antibodies that neutralize the virus. So the secret here was to lock the F protein in the pre-fusion state, which prevented infection.

Dr. Ann Cheung: Definitely. And getting a better understanding of the biology allowed for rapid vaccine development with the first small clinical trial starting in 2017 and progressively through the different phases until 2023 brought us the RENOIR and ARESVI trials.

Dr. Greg Katz: Those initial phases brought a lot of optimism that these vaccines would be safer than the initial generation, but successful vaccine trials need to demonstrate real world efficacy and not just biologic plausibility if they’re going to lead to approval. 

Dr. Clem Lee: Yeah. So before we dive into the details of the ARESVI and RENOIR trials, let’s just set some basic groundwork about the factors that even make a vaccine trial good in the first place.

Dr. Clem Lee: You know, guys, I trained in both medicine and pediatrics, and until recently, I’ll be honest, understanding vaccine trial design always seemed much more in the purview of pediatrics than medicine.

Dr. Greg Katz: Yeah, I never really paid too much attention about vaccine trial design, because it just didn’t seem relevant to my practice as a cardiologist. Unfortunately, a worldwide pandemic came along and made it way more important for those of us trained only in adult medicine to understand more about vaccine trial design.

Dr. Ann Cheung: Okay. So as the person with a background in vaccine development, just to start, I think it’ll be helpful to think about what makes a vaccine trial different from other clinical trials we’re used to interpreting. 

Dr. Clem Lee: Yeah. I’m glad you’re here with us on this journey, Ann, to teach us.

Dr. Clem Lee: Vaccine trials don’t seem all that complicated, but let’s talk about what makes them special. 

Dr. Greg Katz: So we’re going to discuss, one, what’s the best way to pick a placebo to evaluate vaccine efficacy? Two, what are the best end points for a vaccine trial? Three, what can we learn, if anything, about community transmission? And lastly, number four, how do we evaluate vaccine side effects? 

Dr. Ann Cheung: Okay, so starting with placebo, we should know that the vaccine contains both the vaccine substrate itself as well as adjuvant compounds. These adjuvant compounds stimulate the immune response, which brings us to the question of what the best placebo is. 

Dr. Clem Lee: Yeah, so should the placebo just be saline, because then what you’re actually studying is the vaccine with its adjuvant compounds? Or should the placebo include the adjuvant, which means you’re studying the vaccine by itself? 

Dr. Ann Cheung: Great question. There are pros and cons to each option, since what you choose for a placebo can impact your results, both in terms of efficacy and in terms of side effects. Remember, adjuvants used in these vaccines can induce cytokine release, which can protect against disease.

Dr. Clem Lee: So, a placebo containing an adjuvant, that adjuvant in the placebo will produce cytokine response as well, and so the intervention arm may look less efficacious. But on the flip side, the vaccine side effect profile will look like it’s better tolerated because some of those side effects are caused by the adjuvant.

Dr. Ann Cheung: Totally, Clem. But on the other hand, if you leave the adjuvant out of the placebo, that makes your vaccine look more efficacious. 

Dr. Greg Katz: So to recap, a saline placebo makes a vaccine look more efficacious, but with more side effects. An adjuvant placebo might make a vaccine look less efficacious, but with a more favorable side effect profile. Either approach here is reasonable. But we need to be mindful of the placebo choice when we’re interpreting the results of the trial. 

Dr. Clem Lee: And just like choosing the right placebo can be complicated, measuring the results of a vaccine trial can also be challenging. So some vaccine trials look at confirmed cases of disease, while others look at a surrogate marker, like antibody levels.

Dr. Greg Katz: Whether or not antibody titers are a reasonable surrogate really depends on the virus in question. After all, I’m pretty sure none of my patients care what their antibody levels are. They only care if they’re protected against disease. And so antibodies are only going to be useful if we have real confidence that those titers are truly a reliable marker of protection against either symptomatic disease or asymptomatic disease transmission. 

Dr. Ann Cheung: For sure. Just putting it into perspective, when it comes to the flu, antibody titers seem to correlate with disease protection and serves as the basis for the annual updated flu vaccine approval process by the FDA.

Dr. Clem Lee: So for a new vaccine where we just don’t have that correlation data, the antibody levels just aren’t going to cut it. 

Dr. Ann Cheung: Right. So, swinging back to RSV, it’s not just antibody levels you can look at. There are other markers of a disease, like confirmed RSV infections, all symptomatic respiratory infections including RSV, different degrees of severity of RSV, even ICU admissions are all cause mortality.

Dr. Clem Lee: From a patient perspective, I guess you could argue that it would be better just to measure all respiratory infections, right? Because why would I as a patient care if my specific infection is from RSV or from a different virus? 

Dr. Greg Katz: Yeah, but if I’m a vaccine manufacturer, that is a way harder sell in trial design. An RSV specific outcome is going to make a vaccine look more effective, but you compare that to an outcome that focuses on severe infections like hospitalizations, mechanical ventilation, or death, that’s going to require a huge sample size to achieve adequate power if we’re going to capture a difference.

Dr. Greg Katz: So it ends up being kind of impractical or just way too expensive to study those really severe markers of disease. 

Dr. Clem Lee: Yeah, that makes sense. If we’re focused on a RSV specific outcome, that means we are going to need to be able to detect the disease. And is there any concern that vaccinated individuals might be able to get sick with a bug but are less likely to have a positive test?

Dr. Ann Cheung: That’s a good question, Clem. In theory, yes, that’s possible. But in general, more severe cases lead to more viral shedding. So there’s a lower chance of a false negative. So as long as we’re looking at severe cases, we should be able to catch an effect and not need to worry about the possible lower sensitivity of case detection in vaccinated individuals.

Dr. Greg Katz: That makes sense. And to continue our general look at vaccine trials, I think it’s time for us to confront one of the major controversies we saw with the COVID vaccines. How do you figure out if a vaccine reduces disease transmission? 

Dr. Ann Cheung: Another great question, Greg. Studying disease transmission is the type of thing that isn’t going to be captured well with trials that are just focused on individual participants.

Dr. Ann Cheung: To get high quality data on transmission, you’re going to need to measure overall cases in the community or do a cluster randomized trial where you randomize geographic cohorts rather than individuals. 

Dr. Clem Lee: So community case detection is particularly hard for RSV because the vast majority of adults aren’t going to get particularly sick from it.

Dr. Clem Lee: The most symptomatic people tend to be the youngest, like babies, and the oldest. So while the ones in the middle are going to be responsible for the largest number of cases, they are also least likely to come to medical attention and are hard to capture in a trial. 

Dr. Greg Katz: It seems to me like assessing a vaccine’s impact on transmission is going to be logistically quite challenging and also super expensive. And so while it’s definitely a nice to have on my wishlist for the ideal vaccine trial, we’ll still be able to interpret efficacy for an individual with the disease in question without knowing anything about disease transmission. 

Dr. Ann Cheung: Okay, that’s a pretty good run through on vaccine trial design. To recap on the things we want you to take away, a high quality vaccine trial can either use a saline or an adjuvant placebo. For a new vaccine, it’s better to measure a hard outcome like infections over a surrogate outcome, like antibody titers. Looking at RSV specific infections rather than general respiratory tract infections is going to be more practical. And we’re pretty unlikely to get anything useful from vaccine trials and transmission, where there’s a variable degree of severity of infection.

Dr. Clem Lee: Okay, so now that we’ve gone through how to evaluate a vaccine trial with Anne’s help, we’re equipped to discuss the ARESVI and RENOIR trials.

Dr. Ann Cheung: All right. So both the ARESVI and RENRAR trials had similar study designs. They were double blinded, randomized, and placebo controlled. 

Dr. Clem Lee: Yeah, and the inclusion criteria were pretty broad for both trials. They included adults over age 60 with stable chronic medical conditions. Neither trial permitted any other vaccines in the two weeks before the intervention. The ARESVI trial enrolled over 24, 000 participants and RENOIR over 34,000, and half of each group received the vaccine and the other half placebo. 

Dr. Greg Katz: The ARESVI group studied a vaccine containing a single RSV antigen plus an adjuvant, and that was compared to a saline placebo. 

Dr. Clem Lee: And the vaccine studied in the RENOIR trial contained antigens for both A and B strains of RSV, but no adjuvant. So the placebo in this trial was freeze dried so that it matched the vaccine and appearance. 

Dr. Greg Katz: So both trials use a saline placebo. And as we mentioned earlier, a saline placebo can make a vaccine look more efficacious compared to an adjuvant only placebo.

Dr. Ann Cheung: Right, Greg. And along that same line, the investigators in both groups measured efficacy with a similar outcome, confirmed RSV, lower respiratory tract infection. 

Dr. Clem Lee: Yeah, they were pretty strict about what qualified as an infection. Participants needed to have at least two symptoms lasting at least 24 hours, and then have a test for RSV to confirm that infection.

Dr. Clem Lee: The two trials had slightly different protocols for the specifics of nasal swabbing and symptom reporting, but the overall effect was the same. I think it was a robust way to look for respiratory infections and RSV, specifically. 

Dr. Greg Katz: And I was pleased to see the investigators chose real endpoints of confirmed disease rather than just antibody levels.

Dr. Greg Katz: And while I think we all would have preferred to look at all respiratory infections rather than just confirmed RSV specific infections, it’s reasonable for an RSV vaccine study to look only at confirmed RSV infections. 

Dr. Clem Lee: Yeah, and the measurement of safety was also rigorous. Participants in both trials kept journals for about the first week after vaccination and were questioned about side effects up to 30 days afterwards.

Dr. Ann Cheung: Totally. And overall, I feel pretty comfortable that they had an effective way of monitoring both efficacy and safety, especially since the history of vaccination against other viral infections tells us that the majority of vaccine adverse effects occur in the first 7 to 10 days after vaccine administration.

Dr. Clem Lee: And the moment we’ve all been waiting for, onto the results. So it looks like both vaccines look pretty good. 

Dr. Greg Katz: That’s a long kind of like drum roll for sort of like a generic response about what the trials look like. So the way that these results are reported in the trials is as a percent efficacy, which is basically just a ratio between infections in the vaccination arm versus infections in the placebo arm.

Dr. Greg Katz: So if there’s one infection in the vaccine group and three in the control group, then you get an efficacy of 66.7% since the vaccine prevented two out of three infections compared to the placebo.

Dr. Ann Cheung: Thanks for going over that, Greg. Just going to the RSV trial, the overall efficacy was about 83% for all RSV related lower respiratory tract infections and 94% for severe infections. Subgroup analysis looked pretty similar across the board, whether you looked at protection against either RSV strain, age range of the participants, and risk profile for the groups. It really doesn’t matter how you slice it, the RSV vaccine looked pretty efficacious. 

Dr. Clem Lee: Yeah, the RENOIR trial told a similar story. 67% efficacy against RSV related lower respiratory infection with two or more symptoms, and 86% efficacy if you look at people reporting three or more symptoms.

Dr. Greg Katz: So before we all get just way too excited about those impressive sounding efficacy numbers, we all should just zoom in and take a look at how small those total number of infections were. 17 patients in the ARESVI trial and 14 patients in the RENOIR trial had severe infections. So only about one patient out of a thousand in the placebo groups developed an RSV confirmed infection.

Dr. Greg Katz: So based on that, what’s my level of confidence that these vaccines prevent hospitalization or save lives with numbers this small. It’s really not all that high. 

Dr. Ann Cheung: Wow, that really puts the results into perspective, Greg. With that being said, what about safety? 

Dr. Clem Lee: Yeah, I think that’s a question that all of our patients are going to have.

Dr. Clem Lee: The safety signal for the big stuff looks pretty good. There’s no sign of increased rate of severe illness, fatal events, or anything super scary. 

Dr. Ann Cheung: Totally. And you’d expect local reactions to look worse than the vaccine groups, of course, which both studies found. Serious or systemic reactions weren’t that different in the RENOIR trial, but the ARESVI group had a signal towards higher events of fever and systemic symptoms. Overall, numbers were pretty reassuring with about a third of people reporting things like myalgias and fatigue. 

Dr. Greg Katz: So RENOIR studied about 17,000 patients and ARESVI trial closer to 12,000. So I wouldn’t necessarily feel like I understand all of the rare side effects, but the overall safety profile on both of these studies makes me look at the RSV vaccines very similarly to how I think about a flu shot, fair chance of mild side effects with a safety profile. That’s pretty reassuring overall. 

Dr. Ann Cheung: For sure! And the history of vaccine trials tells us that we’ll know the common side effects through a trial enrolling a few thousand people. But we won’t know the rare side effects until the vaccine is more widely distributed, probably until it’s been given to hundreds of thousands or even millions of people. I’ll be particularly interested to see the risk of Guillain Barré. Putting in perspective, two patients in the RENOIR trial did develop GBS but these numbers are way too small to draw any conclusions. 

Dr. Clem Lee: Yeah, I’d like to bring up another point, which is, if you look at the Kaplan Meier curves, it does seem that the protection wanes as the trials went on, and the curves separate, but then there’s a plateau in both groups 7 months after. So while that’s probably just a sign of the natural season of RSV, there is the possibility that there’s waning immunity over time, but I think it’s too soon to say too much about this.

Dr. Greg Katz: And so even with those caveats about the long term, I do think it’s safe to say that the top line results look pretty good so far. 

Dr. Ann Cheung: I definitely agree. So just to summarize, both the ARESVI and RENOIR trials showed pretty good vaccine efficacy, over 80% for severe disease in adults over the age of 60, with an overall pretty reassuring side effect profile. 

Dr. Greg Katz: So, what’s a busy primary care doctor supposed to take away from these trials? Are the RSV vaccines good enough to take time out to recommend during a busy clinic day? 

Dr. Clem Lee: Yeah, I think it sort of depends. I mean, on one hand, you can make an easy case for recommending the vaccine widely, right, like a lot of people die from RSV. These vaccines seem to protect older folks against severe illness with the reassuring side effect profile. But on the other hand, with the small numbers of cases that we saw in the trials, I don’t think any of us are super confident that these vaccines are particularly life saving. 

Dr. Greg Katz: I would also caveat that the safety profile is pretty well established in older adults, but we don’t know what that means for other demographic groups. This makes me think about the myocarditis in young men that we saw with widespread rollout of the mRNA COVID vaccines. When we’re considering making recommendations to our patients, we need to be thoughtful both about who the trials apply to, but also who they don’t apply to. 

Dr. Ann Cheung: That’s totally right, Greg. But, I’d at least take some comfort that this isn’t a novel vaccine delivery system. With COVID, the mRNA vaccines were completely new. Providing it an antigen like the ARESVI and RENOIR trials is a similar type of vaccine delivery system, just like hepatitis B, HPV, and tetanus diphtheria pertussis. So there’s a bit more comfort that we understand it’s safety. 

Dr. Greg Katz: That said the New England Journal of Medicine recently published a phase 2 to 3 trial testing vaccine efficacy and safety of an RSV mRNA vaccine, which was sponsored by Moderna that had similar efficacy as the vaccines from the ARESVI and RENOIR trials.

Dr. Greg Katz: Whenever I’m thinking about a new intervention, I’m always wondering about the unknown unknowns. What don’t we know that we don’t know? 

Dr. Clem Lee: In the case of the RSV vaccines, I think the biggest outstanding questions in my mind are durability and applicability. So does this vaccine last more than a single winter or will younger individuals like kids or the immunocompromised have a similar risk benefit profile? Um, and so questions like, will we be recommending boosters will be unanswered for a while. 

Dr. Greg Katz: And we also haven’t learned anything here about the impact of these vaccines on disease transmission. And so while that’s the inevitable limitation of a trial that doesn’t track community cases and isn’t organized in a cluster randomized design, I do think that the lack of information on transmission is an important gap in our understanding when it comes to counseling our patients or thinking about making more broad recommendations. 

Dr. Ann Cheung: For sure, Greg. And that said though, for our older patients who are at greater risk for serious problems from respiratory viruses, the RSV vaccines seem like a pretty easy win. 

Dr. Greg Katz: So I think that you’re right, but I’m always going to be a little bit of a pain here by pointing out that it would be great if we saw high quality data on the outcomes that my patients care most about. I’m talking about things like hospitalizations, intubations, ICU visits, all cause mortality. But, I agree with you that for older folks, this does seem like a pretty reasonable recommendation to make. 

Dr. Clem Lee: I think for me it does come down to who the patient in front of me is. If I were a 65 year old man with no health problems, I’m not sure I would go for the vaccine. I don’t have data that it reduces hospitalizations or death, and I would be a little wary of the signal for Guillain-Barre, which is potentially life threatening. But if I were a 65 year old smoker with COPD, lung cancer, frailty, and if I got the RSV it could kill me, I think the calculus changes and I would take the small risk of GBS.

Dr. Ann Cheung: And in the meantime, at least we can feel pretty comfortable that post-market surveillance for a vaccine is really robust. The CDC spends millions and millions annually on their vaccine safety data link. Which provides us with a much higher likelihood of seeing a signal for harm than we’d ever get from a drug after it goes into the market. 

Dr. Greg Katz: So we’ll get the common side effects from the initial trials, but the more rare side effects don’t show up until the vaccine is approved and out there in the real world. It sounds like a scary method until you realize that it’s actually a totally reasonable compromise. Get something out there to the vulnerable population. Once we have a good understanding of the efficacy and the major side effect profile, and then use robust post-market surveillance to capture a signal for any rare side effects.

Dr. Ann Cheung: Right. Now that we’re coming to a close, I feel good that we’ve talked about some of the general aspects of vaccine trial design and seen that both the ARESVI and RENOIR trials have a lot of strengths, so we can feel pretty confident about the results.

Dr. Clem Lee: Yeah, I also feel good about future vaccine trials in general, now that I’m equipped to look at them with a more analytic eye. I also encourage all pediatricians and internists, I’m looking at you Greg, to do the same so that we are prepared to have these nuanced discussions with our patients. 

Dr. Greg Katz: I’m certainly more ready to do that. And so there you have it. This is the fourth edition of Beyond Journal Club with NEJM Group. 

Dr. Clem Lee: And that is a wrap for today. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple Podcasts or whatever podcast app you use. It really does help people find us.

Dr. Ann Cheung: And if you have any feedback, please email us at hello at coreimpodcast. com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions. 

References


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