Clinical Conversations

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Governments’ directives about how and when to vaccinate people who’ve recovered from Covid-19 vary widely. But, according to this episode’s guest, Dr. Ronen Arbel, they all say they don’t have enough evidence to set firm policy. So, Arbel and his colleagues set out to collect evidence from some 150,000 patients’ records in Israel who’d recovered from the earliest waves of the pandemic.

About half the patients subsequently received at least one shot of the Pfizer-BioNTech vaccine, and all were followed over a period of some 9 months. Arbel’s group, using the patients’ health records, tracked how many became reinfected with Covid-19 — during that interval, the Delta variant was predominant. They found that reinfection was roughly fourfold higher among the unvaccinated; they also observed less benefit among patients aged 65 and older; in addition, the results from one or two shots were statistically the same.

Listen in to what this means for practicing clinicians.

[Running time: 15 minutes]

New England Journal of Medicine

TRANSCRIPT OF THE INTERVIEW 

Joe Elia: 

We have all heard people say that they have had COVID-19 and as a result are immune, but would vaccination boost that naturally acquired resistance?

You’re listening to Clinical Conversations from the NEJM Group. I’m Joe Elia, and I’m joined by my co-host Doctor Ali Raja who is in the department of emergency medicine at Mass. General Hospital and a professor of emergency medicine at Harvard Medical School.

We’re about to interview Doctor Ronen Arbel on Zoom from Israel. His paper on the effectiveness of the Pfizer BNT vaccine among the recovered has just been published in the New England Journal of Medicine. Doctor Arbel does health outcomes research at Clalit Health Services and lectures on health systems management at the Ben-Gurion University of the Negev. Welcome Doctor Arbel.

Dr. Ronen Arbel:

Thank you for having me. It’s a great honor.

Dr. Ali Raja:

Thank you, Doctor Arbel. First of all, could you please for our listeners describe briefly the problem that you and the team investigated?

Dr. Ronen Arbel:

Okay. So, if you look around the U.S. CDC, European CDC, or the UK, each one has a different policy regarding when and how should I vaccinate the recovered subjects or patients for COVID-19, and they all say we don’t have any evidence. If we start with the…I think the most extreme is the United States. CDC said “We don’t have any evidence, so let’s ignore. We are ignoring your infection-induced immunity and you’re going to get vaccinated.”

Like all the others, the EU and other countries than the U.S. have other policies. The UK has a different policy. Israel has a different policy, and they all said “We don’t have evidence.” The only evidence actually that we found when we looked at this was a 600-patient study from Kentucky, which is probably not enough for significant evidence for the world. So, we thought this was a very important clinical issue. We always look what is the clinical question.

I’m a physician. I have a patient who recovered. Should we vaccinate? What would be the benefits? Of course, are there any safety issues? And that was the question. We had no clue what is the answer.

Dr. Ali Raja:

That makes perfect sense. And you mentioned the smaller study from Kentucky. It looks like you did this by reviewing the medical records of some 150,000 people in Israel who’d recovered from COVID-19. Is that right?

Dr. Ronen Arbel:

Yeah. Actually, we looked at all the patients in our healthcare organization [Clalit met the eligibility criteria. So, that was the number. It was for nine months, not just for a couple of weeks — a couple of months was done in Kentucky.

Joe Elia:

And the Clalit organization — you used their medical records. They ensure — or care for — I should say, about half the population in Israel. Is that correct?

Dr. Ronen Arbel:

Yes. 54 percent. And about two thirds of the patients above 65.

Joe Elia:

So, briefly, what did you find? Your primary and secondary findings, what were they?

Dr. Ronen Arbel:

So, the primary finding, first of all, we saw an interaction with age, so that’s why we recorded by two age groups. Up to 65 years old, we saw about 80 percent reduction in reinfection rates and the other rate was about 60 percent reduction.

Joe Elia:

In the older group.

Dr. Ronen Arbel:

Yeah. In the older group. That’s our main findings. What is very interesting we think, it’s only secondary, but very interesting, with one shot is enough. We didn’t see any benefit, any additional protection from a second shot. It was our hypothesis by the way. It’s very interesting that you said “boost natural immunity.” That’s the way we look at it. I mean, you can see there are a lot of studies that show the infection-induced immunity is at least as good as vaccine-induced immunity.

Of course, if you survive COVID and all the problems (long COVID), then the question, if it’s similar to a primary vaccination then it’s really reasonable that one shot will act with some kind of booster, which was your first word, right? How do you boost natural infection-induced immunity?

So, this is the biology that we saw. It was a nice study and it’s very similar to our results on the second one. I think it’s important because I think Eric Topol said, “You know, why does the CDC ignore [natural immunity]?” It’s like you’re already reading over our paper.

You want your patients to get vaccinated, it has to make sense. You cannot say “Ignore it; we don’t care that you are recovered.” I mean, the science says it does matter, but still, importance of study, you have a protection from your infection-induced immunity, but you can boost it and you should boost it by a vaccination, but a single one is enough.

Joe Elia:

And this work was done mostly, maybe even exclusively, among those who recovered from the Delta variant. Is that right?

Dr. Ronen Arbel:

No. Exposure was to the Delta variant. Some of them recovered from the original, the wild type and some from alpha. Okay. After Delta, by the way, there were very little reinfections. What we see now, we saw in Delta many more reinfections and you see in Omicron really much, much more reinfections. But after Delta, the numbers were really, really small. So, I think it was a very important to see what happens with the Delta.

Dr Ali Raja:

So, given the fact this was an exposure of the Delta variant, any thoughts about what this might mean with Omicron?

Dr. Ronen Arbel:

I was sure that you’d ask. Of course, it’s a great question. We don’t have a study on that yet. It’s probably too soon, but if we look at what…if we can learn from the past (which I’m not sure in COVID, right?) you see that in beta you didn’t see any reinfections. In Delta, you saw many more reinfections. In Omicron, you see many, many more reinfections.

Hopefully, we did not check this, we need to research this. We can hypothesize, I’m not sure what the results will be, but we’ll have I don’t know if a similar effect, but an effect of the vaccine on your reinfection risk. But the basic reinfection risk, that’s very clear.

The basic reinfection risk is going higher and higher. It was higher in Delta, and it was much higher in Omicron. So, if we assume…we’re not sure. If we assume that we have a similar effect and since the basic reinfection rates are much higher, the absolute effect should be higher assuming the same hazard ratio, but again, we did not research this yet. So, it’s just an assumption.

But we need to act all the time, and Israel is doing it, you can see like the fourth vaccination and the uncertainty. I mean, we don’t have evidence. We can just look at what we understand until now. That’s why Israel decided on a second booster, right? — a fourth vaccination — because the first booster was a huge success. Is the second booster a huge success?

We actually have some results on this, and our results are not published, but the minister in Israel published. It’s too soon to really tell but the decision was made. You don’t have time. Do we have the luxury to wait to see if vaccination helps in Omicron? No. It’s spreading like crazy.

Dr. Ali Raja:

That’s a great point. So, much of what public policy has been based on has had to be the data that we have available now even though we’re doing studies, and there will be more data in just a few weeks or months. You mentioned, Doctor Arbel, that the lack of a difference between one shot and two wasn’t a huge surprise for you because it makes sense given the modeling, were there any results that you did find surprising?

Dr. Ronen Arbel:

We actually did not know what would be the effect. I think 80 percent was probably higher than what we thought. We did not expect that in the older age group [vaccination would] have less of an effect. This age group interaction was discovered in the analysis, and we didn’t know. We don’t know when we go into the study what the results will be. I must point out here, it’s very important to say this is not in any way funded by Pfizer or any other company. All of our researchers are totally unbiased really and I think it’s very important.

So, we report what we find and don’t look at what will Pfizer…you know, they may like the first part. They probably don’t like the second part because you don’t need a second vaccination or a third vaccination. So, we are very strict not to get industry funding for these studies to make sure to really…I think it’s important to ensure that there is not even…of course, we are unbiased, but to make sure there is not even a suspicion of bias. Okay.

So, we can freely report what we see and be focused and that’s the advantage of our team that has all the clinical physicians who are leading this effort in Israel. They always push for the clinical question: “Should I vaccinate? How many vaccinations should I do?” These are really important clinical questions. That’s what we’re trying to answer.

Dr. Ali Raja:

So, let me actually ask you Doctor Arbel, I’m an emergency physician. I see patients every day, many of whom have had COVID, and they’re recovered. Some of those…fewer here in Massachusetts, but many still here and around the country look at me and say I just had COVID, I don’t need to get vaccinated. What does this mean in terms of the conversations I have with them, or a primary care doctor, or a pediatrician, what does this mean for the physicians who are actually seeing patients who have had COVID? What can we use this data to say?

Dr. Ronen Arbel:

So, the easy answer is, “You recovered from COVID, you have some coverage, but you can improve it significantly, dramatically, by one more vaccine.” I think it’s very simple.

Joe Elia:

Okay. Well, we want to thank you Doctor Arbel for your time with us today.

Dr. Ronen Arbel:

Thank you. It’s a great honor.

Joe Elia:
The pleasure is ours, but what’s the next step? Are you going to be investigating Omicron and its effects?

Dr. Ronen Arbel:

So, right now, we are looking in I think some of the major clinical questions, a second booster. The real-world effect on this of oral medication. Especially Pfizer. Especially in the vaccinated because all these studies have been done in unvaccinated patients. Most of these patients are vaccinated. This is a big question. We don’t know from the RCTs [randomized trials], is it working on vaccinated patients? We should have the results soon.

Dr. Ali Raja:

Those are exciting. That is such an important question.

Joe Elia:

That was our 282^nd Clinical Conversation. We come to you from the NEJM Group and the writers and editors of NEJM Journal Watch. Kristin Kelley is our executive producer. I’m Joe Elia.

Dr. Ali Raja:

And I’m Ali Raja. Thanks for listening.