Kyle: Dr. Patrick, this next question is for you. It's about antibody-dependent enhancement. Can you explain what that is and if you think it's relevant or applies to COVID-19?

Dr. Patrick: Sure. So, antibody-dependent enhancement refers to when your immune system makes antibodies against a pathogen that is...it's non-functional. So the antibodies can bind to the pathogen, for example, in our interest here, a virus. They can bind to it, but they don't neutralize the virus. And, in fact, not only do they not neutralize it, they can activate other immune cells to become more aggressive and cause more damage. So, in the end, the immune system can end up being more damaging after being exposed to a virus than if it hadn't previously had those antibodies. And so when I say previously had those antibodies, most often I'm referring to vaccine-induced antibodies. I would say that in the United States, we really became aware of this phenomenon back in the 1960s. So this was when the respiratory syncytial virus vaccine...one of the vaccines was made, and it was being clinically tested in infants and toddlers. Half of the infants and toddlers in the treatment group were given the vaccine, and the other half were given the placebo. And then the infants were then, you know, going to be exposed to the RSV virus, which as all of us parents know like every child gets, and it's a respiratory virus. They end up having a cough that can oftentimes linger for quite a while.

So, what was terribly tragic about this vaccine story is that the infants and toddlers that had received the RSV vaccine, about 80% of them were hospitalized after being exposed to the RSV virus naturally versus the infants and toddlers that had placebo, only 5% of those infants and toddlers actually ended up in the hospital after being exposed to the RSV vaccine. So this was terrifying, and, of course, the vaccine never made it past this original clinical trial. But, you know, what was happening is antibody-dependent enhancement wasn't quite known at the time, but you know, much research has...you know, decades of research since then have been done, and it's now known that antibody-dependent enhancement occurred. So the antibodies that were generated from the RSV vaccine were binding to the virus. They were not neutralizing it, and, in fact, they were making the immune system worse. They're making the immune system act worse in response to the virus and become more damaging. And so what was figured out by many scientists, and including some of the work of Dr. Jason McLellan who I mentioned earlier, is that the antibodies that are generated that play a major role in antibody-dependent enhancement are called post-fusion antibodies. And you probably can guess it. We talked about how viral proteins go from a...they make a structural conformation change. They go from a pre-fusion conformation to a post-fusion conformation. Well, guess what. Your immune system is making antibodies to both of those different types of viral proteins. And so what the brilliant work of Jason McLellan showed is that you could basically lock a viral protein into the pre-fusion complex, and when you then, you know, use that pre-fusion viral protein in a vaccine, you don't make post-fusion antibodies because you don't...your body isn't exposed to that structure of the viral protein. That's what we have in all of our U.S. vaccines, the pre-fusion viral protein, the pre-fusion spike protein.

We are not making post-fusion antibodies against the spike protein, which is so reassuring that antibody-dependent enhancement is so...it's so unlikely to happen because we don't make those antibodies. And, of course, on top of that, what we would see in the hospitals as I mentioned with RSVs is that if you take an unvaccinated versus a vaccinated person and, you know, randomly choose them at any point, then the vaccinated person would always have the most severe disease. They would be the one that are most likely to be hospitalized compared to unvaccinated. They would be the most likely to die. And I'm not talking about, you know, if you have all of your population vaccinated. Well, of course, you're going to end up having some people in the hospital that have been vaccinated. I'm talking about comparing the unvaccinated to vaccinated. What you would see is that unvaccinated people would be less likely to have a severe disease, and that is not what we've seen at any point during this pandemic at all. So, that's also reassuring.

I think a lot of concern for antibody-dependent enhancement came out of both in vitro studies, again, those are studies done in cultured cells in like a petri dish as well as in vivo studies. These refer to animal studies, it can be, you know, a rodent or a hamster. Pick your animal. These studies were done with the original SARS virus back in 2003 or 2002, what we now call SARS-CoV-1. When vaccines were made for that virus and injected into some animals, they did cause antibody-dependent enhancement. That was not the case with all studies and all vaccines for the SARS-CoV-1. So it was sort of an inconsistent data. But that's really what started the initial concern. I myself was concerned. I was reading this data, and I thought, "Oh, geez, well, that's scary." So, at the time, I didn't know anything about the post-fusion antibodies that were involved in that and how, you know, Dr. Jason McLellan and his collaborators had figured out a way to bypass that, to lock that viral protein in the pre-fusion complex so we don't make those antibodies. So that is really...at the end of the day gives me a lot of peace of mind that antibody-dependent enhancement is not likely to ever happen with our current vaccines in the United States.

Kyle: Dr. Seheult, anything to add to that?

Dr. Seheult: Yeah. As Dr. Patrick was saying, if we look at Israel, which has been vaccinating with the Pfizer vaccine the longest out of any of the countries on the planet, and we look here at the Delta variant, which is what we're interested in, we really need to make sure that we're concentrating on the Delta variant because that's the current variant here in the United States, there was a study that was released. And you can see here on the graph we've got red as those who are unvaccinated in Israel, and green, those who are fully vaccinated in Israel. And you can see here that over the months of July and August, which were just pure Delta at the time, clearly, you can see that it was the unvaccinated that were having the most severe cases. And that would not be the case if we had antibody-dependent enhancement with the Delta variant. That's clearly not the case. If you break it down in the next graph even by age, you'll see that the same relationship occurs with age. But again, in each of these age categories, if you age stratify them, you will see that is the unvaccinated in these that are leading the severe cases. So this goes against the grain of what you may hear that Israel is telling us that the Pfizer vaccine is just breaking down, it's useless, it's not working. That's just totally not the case in terms of preventing severe cases, which is an important endpoint.