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Eric J. Topol, MD: Hello. This is Eric Topol for Medscape, with our Medicine and the Machine podcast that I have the privilege of cohosting with Abraham Verghese. Today we have a terrific guest, Florian Krammer, who is at Mount Sinai. He did his training in Austria and came to Mount Sinai as a postdoc, and continues on there as an endowed chair and professor in vaccinology. He is one of the leading virus experts in the world and has become an important source of trusted data and perspective during the pandemic. So, welcome, Florian.
Florian Krammer, PhD: Hi, Eric. Thanks for having me.
Where We’re Headed With Delta
Topol: We have many things to discuss today, but obviously what’s on the mind of many is the Delta variant. Can you give us a sense of what this has meant as compared to the prior variants and the original strain? How did we get here and where are we headed in the pandemic because of Delta?
Krammer: That’s a very interesting question. Delta seems to be different compared to other variants. Most of the variants that we started to see since late 2020 had an advantage in terms of spread, so they were probably more infectious — specifically, the Alpha variant that was clearly visible, but also the other variants that were picked up during surveillance because they expanded. The Delta variant is very good at that. The Alpha variant already had high infectivity, but Delta is much more infectious than Alpha. That’s one of the issues that we’re facing.
If you look at immune escape, which was always a question with these variants, Delta doesn’t stand out that much. It’s not comparable to something like the B.1.351 variant, which really had a huge increase in neutralizing antibody titers. Delta has an impact on that, but it’s not as big. So just from looking at neutralizing activity, you wouldn’t think that the virus causes issues in vaccinated individuals. But it seems that it’s more infectious and it replicates better in the upper respiratory tract. That causes an issue specifically with unvaccinated people.
We also see more breakthrough infections and even transmission in vaccinated individuals. That’s a problem. But it’s hard to see where we’re heading with that specifically because it’s so variable. If you look at different countries and regions worldwide and what it looks like right now in the United States, we might be at the peak of the Delta wave and cases might come down. In the UK, cases started to come down and then went back up. But in other countries, the Delta wave wasn’t actually that big and it was very short. I’m hoping that the case numbers will go down — and we are seeing the first signs of that — and hopefully they will stay down. But it’s really hard to predict what will happen after that.
Immune Response: Vaccines vs Natural Infection
Abraham Verghese, MD: You’ve done a lot of work on antibodies, and for most of us who are not in this world of antibodies, it’s a very confusing issue. What are we measuring? What does it tell us about immunity? Can you share some pearls with us about the nature of antibodies from vaccine and from natural infection?
Krammer: In general, there are still discussions about the role of different arms in the immune response and the protective effect that we see with vaccination and with natural infection. Of course, antibodies are easy to measure and neutralizing antibodies are interesting because, of course, they neutralize the virus and are a correlate of protection for many other viruses. In the past few weeks and months, we have actually seen a lot of data that suggest that neutralizing antibodies are an important correlate of protection for SARS-CoV-2. More data are coming out.
But there are other arms of the immune response that often co-correlate with antibody responses. For example, typically, if you have a good antibody response, you also have a good T-cell response. We actually know they can’t have a good antibody response without a good CD4 T-cell response, so it’s more complicated than antibodies alone. Different arms of the immune system do different things. My suspicion is that the neutralizing antibody response is really important for protecting you from infection and mild disease. But once you have a breakthrough infection, a T-cell response, more or less, prevents you from progressing to moderate to severe disease. There are different phases where these different arms of the immune system are important.
There are also, as you said, differences between immunity that is induced by natural infection and what is induced by vaccination. I wouldn’t say one is better than the other, but they are certainly different. If you get a natural infection, you also develop antibodies and those antibodies are very often also neutralizing, but the response is relatively variable. Some people have very high antibody responses and some people have low ones. In addition to that, you get these T-cell responses not just to the spike protein, but to the whole range of open reading frames that the virus has — there are a lot of proteins that are encoded by SARS-CoV-2 — and you get mucosal immunity because the virus replicates on mucosal surfaces and that stimulates things like secretory IgA production or tissue-resident memory T cells.
This is in contrast to vaccination, where we basically get a response only against the spike protein, with very high neutralizing antibody titers. In healthy adults, the responses are very homogeneous — everybody is high. But you’re lacking on the mucosal immune response to a certain degree, and your T-cell response is only focused on the spike protein because that’s what’s in the vaccine. So there are differences, and this might lead to different types of protection.
If you had an infection, I would still recommend that you get vaccinated because people who had an infection have variable titers. If you get vaccinated on top of natural infection, you bring these titers very high. Actually, people who were infected and then got vaccinated have a very broad and very high antibody response, even better than people who just got vaccinated.
The Truth About Antibody Tests
Topol: Getting a little bit more into the antibodies, is there a test that would show whether someone had prior COVID? Approximately 40 million Americans have had COVID infection, as confirmed by PCR or some other test, and probably another 90 million Americans were infected but didn’t have a confirmatory test at the time. Could you differentiate a natural immune response from a vaccine response by testing, let’s say, for a nuclear capsid protein antibody? Would that help? Also, could you respond to the idea that a lot of the antibody tests are for IgG and not for neutralizing antibodies per se, so they might not be a good correlate for protection?
Krammer: There are two targets for antibody tests out there. One is the nuclear protein, which you would only make antibodies against if you were infected with the virus or if you received one of those whole-inactivated virus vaccines that are used outside of the United States. But that vaccine is rare to find here; some people who travel might have gotten it, but basically a very small percentage. So if you have antibodies to a nuclear protein, that suggests that you had an infection. If you have antibodies to the spike protein, it could be from an infection or from vaccination. Of course, if you’ve been vaccinated, you know that you’ve been vaccinated. If you haven’t been vaccinated and you have spike antibodies, it’s probably because you were infected. But antibodies against the nuclear protein vs spike protein let you differentiate.
In terms of what we’re measuring, some antibody tests give you a yes-or-no response. That is okay to figure out if you had an infection or not, or if you made an immune response to the vaccine. But that’s all it can tell you. Then there are antibody tests that are semi-quantitative or quantitative, that tell you what level of antibody you have now. It’s correct that these antibody tests are not measuring neutralizing antibodies; they’re measuring binding antibodies. But what we have seen in general is that there’s a relatively good correlation between neutralizing and binding antibodies. In fact, studies coming out recently from Moderna and from David Goldblatt’s lab have begun to establish a number that is connected to protection. There isn’t really a single number above which you know you’re protected, and below it, you’re not. This looks very different; it’s usually a probability. Typically what is established with a correlation is a titer of antibody that reduces your chance of getting an infection or disease by 50%. Those values are starting to come out in scientific papers.
The problem right now is that these tests are reported in international units — or if it’s a binding assay, it’s BAUs — but a lot of tests available today in the US have not been standardized to international units. So if you get an antibody test back from the lab and you have a certain number and you want to compare that to a paper that gives you a correlation for protection, you might have a hard time because that lab might not report that type of unit and you cannot directly compare. It’s still very complicated. But on the other side, we see more and more that antibodies do correlate with protection and that determining a 50% protective titer is possible.
Verghese: I have to confess that — like many physicians listening to this, I suspect — I got the antibody test and it came back negative, and I realized I had no idea what they were testing. There was no way to do anything with the information. I sheepishly talked to a few colleagues only to find that many of them had done the same thing, and 50% or so had the same awkward realization that they had no protection. But we don’t know what we were measuring. We don’t know that it mattered. And ultimately, we all concluded that in the absence of standardization, we just needed to ignore this. The bottom line is we shouldn’t have done the test.
Krammer: Once the vaccine started to be rolled out, I got a lot of emails from people who had gotten tested and were negative after vaccination, and in 100% of cases, it turned out that they had done nuclear protein tests. So they were upset that they didn’t make a response. But then it turned out that they were just measuring the wrong antibody response.
Topol: And you have published how virtually everyone who gets vaccinated has at least some antibody response, even among people who are immunocompromised, although perhaps not as high a level.
Should Prior COVID Be Counted as a Vaccine Dose?
Topol: Prior COVID doesn’t get much respect. If you get a vaccine card, there’s no entry for prior COVID. Do you think that should count as one dose? In many other countries, perhaps in Austria, but in certain countries in Europe and Asia, confirmed prior COVID is counted as one dose of vaccine in terms of your vaccine status. What are your thoughts about that?
Krammer: Absolutely. There is a nice preprint out there in which they assessed vaccine effectiveness against Delta with AstraZeneca, Moderna, and Pfizer-BioNTech vaccines. But they also looked at prior infection, and prior infection is pretty much as good as what they see with the vaccines, in the range of 70%-80% protection against reinfection with the Delta variant. So just to assume that somebody who had an infection has no protection is wrong. Those people have substantial protection. They have variability in their response. Some might get reinfected and are less protected than others, but they certainly have a degree of protection. You might not want to consider them fully vaccinated; you can argue about that, but at least a one-dose equivalence from a scientific perspective is justified.
Topol: Any time cut-off on that within a year or 6 months, when you say “prior COVID”?
Krammer: The initial studies that came out that showed that previous infection is about 80%-90% protective against reinfection — we’re talking about infection, not disease; protection against disease was higher. Those studies were done mostly in December 2020 or January-February 2021.
There was a lot of talk about waning immunity in the beginning, and we hear that again now about the vaccines. But people don’t realize that those are normal responses. What we see is that the antibody response — I didn’t look at the T-cell response — but the antibody response after natural infection does stabilize over time. We have been following a cohort of people with Viviana Simon at Mount Sinai since the spring of 2020. Of course, we have fewer data points now because a lot of people got vaccinated. But for the people who got infected and did not get vaccinated, the antibody titers are now pretty stable. Even a longer time out, I think protection would still be there. It’s not 100%, but there is certainly a good amount of resistance to infection.
To Boost or Not to Boost
Verghese: Which leads us into the discussion of the booster doses. What are your thoughts on the timing of the booster, the particular booster to use, and so on?
Krammer: There are a lot of things that you have to consider when you think about booster doses, waning immunity, and Delta. First of all, we have to be very careful when we talk about waning immunity and reduced effectiveness. You see a lot of newspaper reports out there that compare the efficacy of the vaccine against disease, measured in clinical trials, with the effectiveness against infection, and those are apples and oranges. You cannot really compare them.
But even if you look at the efficacy data — Pfizer, for example, has data from 4-6 months, and they do see a drop. It makes sense because there is some waning of immunity initially. In addition to that, we have a variant circulating right now that seems to grow to higher titers. It’s more infectious. It might have a couple of tricks to evade immunity in general a little bit better, not just adaptive immunity. Now, the question is when vaccine efficacy or effectiveness falls to levels like 80% against disease (and I’m not talking about infection; I don’t care about infection that much at this point), is it time to give a booster shot or are we still good? And how do the levels against severe disease and hospitalization look?…
Créditos: Comité científico Covid