a16z Podcast - The Third Vaccine, and Vaccine Choice

Episode Date: March 18, 2021

https://a16z.com/2021/03/15/16-minutes-58-the-johnson-johnson-vaccine-and-covid-efficacy-rates/

Hi, everyone. I'm sharing our most recent 16 minutes episode here because it covers vaccines, a topic that we've covered here since January of last year in our early and ongoing pandemic coverage as part of our mission to continue bringing you everything you need to know about this crisis and how tech, and in this case, bio, changes our future. You can find our past coverage at A6NC.com slash coronavirus and A6NC.com slash vaccines, but in the discussion that follows, the team digs into vaccine efficacy. and frameworks given the third emergency use authorization approved vaccine. More details in the intro that follows. Welcome to this week's episode of our news analysis show 16 minutes. I'm Zoren, and our topic today is the ongoing buzz and the mixed news around the Johnson and Johnson vaccine, which was the third vaccine for COVID approved under emergency use authorization by the FDA just a few weeks ago, and which Johnson and Johnson reported in

its press release as the first single-shot vaccine, and as having 85% efficacy. in preventing severe disease across region studied. Meanwhile, stat headlines reported 66% efficacy overall and 72% in the U.S. in preventing moderate to severe disease, with their headlines saying it is, quote, a weapon, but not a knockout punch. And then we have various experts saying everything from, quote, disappointing to pointing out the dangers of comparing this vaccine to other vaccines, such as Pfizer's and Modernas, both of which we've talked about on this show.

You can find all our ongoing vaccines coverage at a16.com slash. vaccines. But in this episode, since 16 minutes is about teasing apart what's hype and what's real in the news and where we are in the long arc of innovation, we asked the A16Z bio team for their frameworks. General partner Jorge Condé joins us. He's been in all of our vaccine episodes, and he also previously led strategy and product for pharmaceuticals company, along with bio-editorial partner Lauren Richardson, who was previously an editor at PLOS Biology and hosts our sister show Journal Club on BioEats World. She also holds a PhD in Pharmacology. So this question is very much in the headlines. Let's tease apart what's hype and what's real about

J&J's lower efficacy rates. Do the clinical trial endpoints account for those, or is there something else we should be thinking about here about why the results are different? The J&J trials were being conducted when the virus was more widely spread, when arguably there were more variants circulating through the population. Some of the early evidence suggests that these vaccines have different rates of efficacy against different variants of the SARS-CoV-2 virus. When the vaccine, were designed, they were designed around one dominant variant, and that dominant variant was circulating much more widely earlier on in the pandemic, whereas new variants emerged, new variants become an increasingly larger percent of the virus population. So if any given vaccine

has differential efficacy against different variants, and the mix of those variants and the population changes over time, that could have an impact on the total efficacy that you see in terms of the vaccine's performance. Yeah, the variance and the distribution of variance is also linked to the populations that these vaccines were tested in. The Moderna vaccine was tested only in the United States. The Pfizer-BionTech was a worldwide study, 152 sites worldwide, but still dominantly tested in the United States. Whereas the Johnson and Johnson vaccine was tested. 40% in the United States, 40% in Latin America, and 15% in South Africa, and there is this critical variant that was first observed in South Africa. So the Johnson and Johnson vaccine was

being tested against these other variants. And you're also dealing with things like differences in host immune systems from these different populations. One thing that's really important to think about when you're comparing the Moderna and Pfizer vaccines to the Johnson-Johnson vaccine is that it is very difficult to directly compare their efficacy because the studies were set up to have a different endpoint. And when you're designing a clinical trial, the endpoint is how you decide what success is. Moderna and Pfizer were looking at could they prevent any symptomatic COVID infections after two doses? Johnson and Johnson is looking at whether it could prevent moderate to severe COVID after one dose.

So that difference, you can almost think about it as like they actually set themselves a higher bar. Let's talk some more about what these studies are targeting because that has a big effect on the stats, which I've received so much attention. What was the benchmark these drug companies were going for? And how does that target potentially affect how we should look at these numbers? When the U.S. government set out the benchmark for what they were looking for in an effective COVID vaccine, they were targeting two things. Number one, they were targeting preventing symptomatic illness. and the hurdle rate that they had set was a 50% reduction in the prevention of symptomatic illness. Now, we should take that phrase symptomatic illness and tease it apart because that is not the same

thing as severe illness. That's not the same thing as hospitalization and that, of course, is not the same thing as death. And the reason in part why symptomatic illness was set as the benchmark was really for speed. So one of the things that you can easily measure is, is someone symptomatic or not? And that is likely going to happen at a higher rate than someone getting hospitalized. And fortunately, at a higher rate than someone dying from the COVID disease. And so that became sort of the benchmark to hit is symptomatic illness. Now, you could make the argument that there's another benchmark that you could have set this at, which is infection, right?

You know, what number of people were infected? What percentage of cases is infection prevented in a vaccinated group versus an unvaccinated group? And the argument against doing that was that, of course, you'd have to be infected. to go out and test everyone and figure out who was infected and who wasn't, and that in and of itself could have been another limiting factor into getting, you know, data back quickly so we could make an assessment as to the quality of these vaccines. Okay, so given what you're both saying, this need for speed and that this is not an apples to apples comparison, how should we look at the

J&J numbers in the context of the other EUAs or emergency use authorizations? Like, help me tease it apart, since it's still kind of hard to evaluate, given all the mixed news and buzz out there. By that measure of 50% reduction in symptomatic illness, all of the vaccines that have received emergency use authorization thus far have far exceeded that benchmark. So J&J was in the low to mid-70s, Moderna and Vizer were much higher. They were in the mid-90s. So they all far exceeded the original sort of threshold benchmark that was set up for emergency use authorization. There's been a lot of talk about, well, we have this 100% protection against death and hospitalization. And all three of the vaccines are 100% against death and hospitalization.

Some of those statistics have been revised slightly downward as more data has come in. So what does all this mean and what can people take from this as they kind of think, well, hey, I want the 95% when that's 72%. It's natural for people to think that, right? So in any typical year of flu vaccine probably are anywhere between 40 to 60% effective. So the fact that we're in the 70s and 80s and 90s, we've already cleared a very high bar. And mind you, we did all of that within one year. So that in and of itself is a remarkable thing.

So I'd say a couple of things when it comes to that. I would take the first vaccine that's offered to me. If a point in time comes when all three vaccines are available and all three vaccines are an option and you can pick and choose between and among them, then the question becomes, well, what is it that you're optimizing for? If the main concern is trying to ensure that you don't suffer from severe disease or risk death, from the data we have today, all three vaccines, while not perfect, seem to be effective. If your concern is around preventing symptomatic disease, you're absolutely right,

that the data we have today suggests that the Pfizer and Moderna vaccines are more effective, even though we don't have an exact apples-to-apples comparison. They seem to be more effective based on the limited data we have at preventing symptomatic disease. That said, they also seem to have slightly more adverse events associated with them. When I say adverse events, it's fatigue or feeling crummy or pain, et cetera. And then convenience is an important factor as well. So, you know, getting one shot versus needing to schedule two shots and a follow-up and making sure you go back at the right time within the right window and that you're compliant in that regard is another important consideration. So when people have the choice to choose a specific vaccine,

there are going to be many factors that go into that decision, not just the headline number that we've been discussing right now. What else do we need to know here to make sense of these headlines about the efficacy of J&J or any vaccine's efficacy during an outbreak or a pandemic? Like, what are we not hearing enough about? It's important not to think of a clinical trial as the end. A clinical trial is really just the beginning, especially as COVID is continuing to mutate as it moves through populations and possibly becomes endemic. meaning that we have COVID-19 inversions of it constantly circulating in our populations. So this is the preliminary answers we have to how effective these vaccines are. They are not the final answer.

What's the significance of the J&J vaccine in terms of the way it's stored and the fact that it's one shot instead of two? The J&J vaccine is a DNA-based vaccine. The DNA is double-stranded. It is sort of much more robust than MRNA, which is single-stranded. And so you can store it in a much less restrictive environment in terms of temperature. The Moderna and Pfizer vaccines have to be stored at such extraordinarily low temperatures. At least that's what the initial data was. That means that only the most sort of advanced refrigerator technology can be used,

which means it's limited to certain centers, which means it becomes much less accessible. And so the fact that the J&J vaccine is a single dose means more people will be protected for a given supply. And the fact that it can be stored with standard cold storage techniques means it can mean, much more broadly distributed, which means it'll be more broadly accessible. And by the way, it's also much less expensive. J&J's providing this at cost and so on. The cost per dose is also lower. Yet despite all this, I think there's still a point of view out there that says, look, this sounds like hype to me. I keep hearing they're the same, but I'd sort of like the higher efficacy rate. Thank you very much. So why is this viewpoint persisting if indeed they're all really good vaccines? Let's separate

the hype from the real there. Unfortunately, in terms of the hype, folks have felt compelled because of the public health interest in making sure that everyone is vaccinated to just say that all three vaccines are the same. And they're not the same, but they are all effective, certainly by any standard that we set for ourselves when starting the process to find a COVID vaccine in the first place. And I think that both for individuals and certainly for society more broadly, I think that is what could have the most beneficial impact. You're saying good for society in this kind of general sense of getting folks vaccinated and reaching some sense of herd immunity.

That's right. If a virus is circulating broadly, the greatest risk you have is being infected by the virus. And so the best protection you can have for that is being broadly protected as opposed to trying to wait for the quote unquote best one. Okay, so let's get to the big picture here. What does this say for not just the next few weeks as vaccines continue to reach more Americans, but even for the future of how we think about vaccinations for COVID in the longer term?

The reality is SARS-CoV-2 is not going away. it's going to be with us, probably going to be endemic like influenza, like the flu. And we're already seeing efforts by the vaccine producers like Moderna that have announced that they are already developing an updated version of the vaccine for new emerging, dangerous variants. And so you will get boosters. There will be others that are made available over time. And that's why expediency in time are so important here, because this isn't the last vaccine you're going to take. It's really just the beginning of protecting yourself and the population. Okay, we've gone through the news and we've teased apart what's hype and what's real.

We've looked at the data. Now let's get to the bottom line. I think the takeaway for me is that in the midst of a raging global pandemic, scientists, governments, industry came together to produce these extraordinary vaccines at incredible unprecedented speed. We are just a just really beginning to understand how these vaccines work, how they work in the real world, how they work with diverse populations, and against different variants. Jorge, Lauren, thank you so much for being with us today. My pleasure. Thank you.