'The Impact of the Vaccine Has Been Tremendous'

; Abraham Verghese, MD; Eran Segal, PhD


February 17, 2021

This transcript has been edited for clarity.

Eric J. Topol, MD: This is Eric Topol, and with me is my co-host, Abraham Verghese. We're fortunate today to be talking about the pandemic with Eran Segal, from Israel. Welcome, Eran.

Eran Segal, PhD: Thanks for having me.

Topol: You've been a leading light during this pandemic, specifically in showing the way to handle it. Israel has gone through quite a bit with three lockdowns, the most aggressive vaccination program in the world, and all sorts of other things. Could you give us an overview of what your thinking has been throughout this year?

Segal: Obviously for us, as for the rest of the world, it's been an incredible year. So much has been going on. Overall, Israel did a few good things, which may have been by happenstance. I also believe that we did not do a good job of handling the pandemic. But in the end, we've had tremendous success in the vaccination rollout. I believe that this has been a great success story.

When the pandemic began, one thing Israel did well was to close down the borders. We view Israel as a kind of island. There is only one entrance to the country, so it's relatively easy to shut down the borders, unlike Europe, where you have many borders for many countries. Because of that, the first wave here was, in retrospect, fairly mild. We exited that wave with very few cases and that held up for a while. Then case numbers started rising and we saw where the outbreaks were, but for various political reasons we were not able to shut down and impose restrictions on those outbreak regions.

When case numbers started to rise, we defined a capacity threshold for the healthcare system. As with many things, when you define a threshold, you're bound to reach it, and that's what happened. Just when we were about to reach the threshold of 800 COVID beds in the ICU, we imposed our second lockdown. That took a longer time to have an effect because the cases and hospitalizations were already high.

We conducted research that showed that, even before reaching that capacity of 800 ICU beds, when we were at around 500 or 600 beds during this time of excess hospitalizations, we weren't giving patients the best care. We estimate that we had about 25% excess deaths in the ICU during these times. COVID mortalities could have been averted if these same people, given their age and health status at hospitalization, were to have come during periods of lower loads in the hospitals.

When we exited the lockdown, we opened things very quickly because there was a lot of pressure to open things up. Then came our third wave, but at the same time, the news about the vaccines' efficacy came out. When we put together our models, we thought that if the vaccines are made available, despite the rise in cases we had, we could defeat and crush our curves without imposing a third lockdown.

But now we're getting to mid-December. The B.1.1.7 variant, which we now understand infects at a 30%-50% higher rate, arrived in Israel. Again, this was a mistake in not monitoring our border closely enough. When we recalculated the models with a variant that's 50% more infectious, we immediately saw that no matter which parameters you use, all the sensitivity analyses showed that we wouldn't be able to beat this spread — even with the speed of the vaccine roll-out that we were able to accomplish, and even when you assume the high, optimistic 95% efficacy for the vaccines.

So, we recommended that Israel go into lockdown again; other experts recommended this as well. I believe that saved us from a huge surge. We still saw a rise in cases, so we can only imagine what would have happened if we hadn't gone into lockdown. The B.1.1.7 variant by now is pretty much the variant here; it probably causes 80% or 90% of all cases. I predict that this will happen all across the world as the variant spreads to and through other countries.

In parallel, we saw the number of COVID ICU beds rising even further. We were steady at about 1200, which is way over our capacity. We recalculated and found roughly a 30% excess death for quite some period of time. This is now a lot of lives that could have been saved at different times. The hospitals really are beyond capacity.

The optimistic news is that for the past several weeks we have been seeing the vaccines having a real effect on case numbers. I believe we're the first country to see it, because we're furthest ahead.

The vaccination rollout program in Israel went amazingly well. We started in late December. We thought it would go at a pace of about 50,000-60,000 people a day, which is a bit less than 1% of the population. But at the peak, we vaccinated a quarter of a million people every day. To translate that to the size of the US population, you have to multiply that number by 40, which would amount to vaccinating 10 million people every day in the United States.

About 3 or 4 weeks into the program, we began to see our numbers going down. We didn't report it, because initially you don't know — is it noise? Is it real? But in retrospect, when we analyzed the data from 3 weeks earlier, we could say that it was the vaccines having an effect. Every day the trend continues and further improves.

In Israel, people who are 60 years and older were prioritized to get the vaccine first. When we analyze that group, we see that since the peak in mid-January, there's now a 55% reduction in cases, 40% reduction in hospitalizations, 35% reduction in critically ill patients, and also now even a 35% reduction in mortality in that age group.

This is great news. In the group that's below the age of 60 years, who were vaccinated later, we don't see the same trends [as of February 10]. If anything, we're seeing an increase in hospitalizations. This is because of the most recent overall surge that we had and the limited success of the third lockdown here, given the battle against the B.1.1.7 variant. But I believe that we're now turning the corner. We're beginning to see the reduction in the next age group to be vaccinated, people in the 50- to 60-year-old group. So we have some optimism.

Extrapolating Success to Other Countries

Abraham Verghese, MD: These are remarkable data. The world is looking to your data to project what could happen elsewhere. Are these benefits in mortality a function of the completeness of the vaccination effort? In other words, here in America, given that our vaccination schedule is far from complete, will we start to see the benefits in the way that you are?

Segal: That's an excellent question. I believe that we expected results sooner, but in retrospect, we didn't take into account certain biases that we're beginning to see all over the world, including in the United States, which has to do with who the people are who go to get vaccinated. It's the people who are more cautious to begin with. So from the pandemic perspective, vaccinating them has less of an effect. That's number one.

Number two is we're seeing that, in general, in the regions where there are outbreaks, fewer people are seeking vaccination. The cities and regions with lower rates of infection are where people were vaccinated first. You would want the opposite from the pandemic perspective. Those may be key reasons for not seeing a quicker response to our vaccination efforts.

It's also possible, although we don't know, that this B.1.1.7 variant is not just spreading faster but also may be causing a more severe disease. I think the numbers are showing that it may cause more severe disease and a higher likelihood of being critically ill and hospitalized. That may be offsetting the effect of the vaccine.

Finally, and we don't know this yet, it's possible that the first dose has less of an impact compared with what you see in the Pfizer data, which suggest a 90% efficacy even after the first dose. I can't say we're not seeing that; I'm just saying that may also be a reason the effect was delayed. I believe you have to try to vaccinate as many from the high-risk groups as you can.

When we do the sensitivity analyses, we find that going that extra mile, managing to get not just to the 80% or 85% of the people above the age of 60 vaccinated, but reaching 95%, or even reaching close to 100%, could really have a major impact on the death toll and overall hospitalizations from COVID.

Progress Stalled

Topol: We're learning so much from you and the experience of Israel, Eran. The B.1.1.7 story is just beginning to unfold here. That is the primary strain in Israel now. At worst, we're approaching a 10% rate in Florida. We haven't had to reckon with it yet.

You also emphasized how modeling has helped you and predicted that vaccination could help, that you could almost vaccinate out of this mess. And finally, we knew from the beginning of the pandemic that it was vital to flatten the curve to avoid overwhelming our medical resources. You validated that, too. Israel has been kind of the leading edge of the pandemic in so many respects.

Even though you have much better buy-in to the vaccine in your country, you also have a lot of heterogeneity, such as with the Orthodox and the Palestinians. Can you tell us more about how you deal with these other important groups of people?

Segal: Despite all of the success we just talked about with the rollout of the vaccines, we still have 10% of people above the age of 60 who didn't go to be vaccinated. We haven't made a lot of progress on those approximately 150,000 people who are left. When we analyze the data, we ask, what would happen if we had an uncontrolled pandemic now? What would be the casualties? We still find that even today, two thirds of them would come from this group of 150,000. So it's critical to get to them.

We have an issue with the Israeli Arab population. Only about 60%-65% of those who are eligible to be vaccinated, because they are in the high-risk group, were vaccinated. It's a low number when you consider the fact that it saves lives and allows us to exit the pandemic.

In the ultra-Orthodox, the vaccination rate is around 70%-75%. By comparison, in the general population, the rate of those eligible who were vaccinated is 94%. I believe we should do better than 94%, but it's a fairly good number now.

The issue is that we have people who are still advocating against the vaccines. Nothing they are saying has any basis in fact, but we still have these voices here. That's one battle.

The government has now allocated funds for educating the public and reaching out to these groups. I hope this has an effect. The majority of cases and hospitalizations now are coming from those who have not been vaccinated, so the impact of the vaccine has been tremendous. We just have to go that extra mile. A lot of effort is going into that.

Until now, the health and medical organizations have rolled out the program amazingly well, but they put together vaccination centers and waited for people to come to these centers. This worked very well with the first people to come. But now we're saying that it's time for the health organizations to knock on the doors of those people who are left. We can do such an operation in a matter of a week or two. I believe the majority will agree to be vaccinated, if you come to them.

As is the case in the United States, in general, people of lower socioeconomic status are more likely to be infected. Those are the outbreak regions. These are people who also have a harder time getting vaccinated; they may have to lose a day of work to go to a vaccination site. They have to use public transportation. It's just more difficult for them to get to these centers. We have to go to the people now, because that can save lives and lower the pandemic numbers.

Serology and Side Effects

Verghese: You obviously have good data on who's getting vaccinated, who's not, and what happens to them in terms of hospitalization and mortality. What other data are you collecting? I imagine that this is a rich opportunity for all the rest of us to truly understand what's going on. Are you collecting antibody data? What else do you have that we might look forward to?

Segal: Our Ministry of Health has published a lot of data on side effects of the vaccines. They're doing serologies and have published some of those excellent results. In all, 97% of people who were vaccinated have antibodies detected after the first dose, and the levels go up after the second dose in the majority of people.

Our centralized healthcare system is one of the unique aspects of Israel and why the vaccination program was rolled out so quickly. It is made up of four organizations. By law, each citizen must be a member of one of these. Thus, the number of people in any of the organizations is relatively small, which makes the logistics easier to control. Plus, all of these organizations are linked electronically to health records. Soon we will also have links to those who were vaccinated and what happens to them in terms of hospitalizations, and whether it has anything to do with preexisting diseases and so on. This is a unique dataset and may be why a deal was struck between Pfizer and Israel, for Israel to be a signature country that can roll out the vaccination program quickly, and which could generate data to analyze and provide insights into what's going on.

Worse Variants to Come?

Topol: Do you have a sense about long COVID in Israel? Is it a significant disability in a proportion of people?

Segal: We don't have hard data on this yet. Long COVID exists in Israel and we hear anecdotal reports, but these haven't been collected in a systematic way. That is one concern.

In addition, we're vaccinating during a surge of the pandemic when we still have a lot of cases. This puts a pressure on the virus to escape the vaccine. We heard reports from the United Kingdom that, through several independent events, the B.1.1.7 variant can acquire a mutation that's present in the South African variant that renders the vaccine less effective. We are concerned that we still have such a big spread. We're still detecting new cases; every week there are newly verified cases of COVID-19 in over half a percent of the population. So it's still a big number and we're concerned about that.

Topol: You're emphasizing something that is a vital teaching point about how there's still a proliferation of cases, even though you've had such great success in the high-risk group that you've vaccinated. B.1.1.7 is a beast for sure. Could you speak about the B.1.351 variant first detected in South Africa? I think it's present in Israel. Will it be overrun by B.1.1.7? Because with the B.1.351 variant, the immune escape from the vaccine seems to be real and is a concern. If that one gets into high spread, we've got another version of trouble.

Segal: We have detected the B.1.351 variant, but it's still at low numbers. That's what we know right now. We hope we will have very few cases of people being hospitalized after being vaccinated and sufficient time passes after the second dose. But in those hopefully rare cases, we should sequence the virus to make sure it's not a variant that is either the B.1.351 variant, the B.1.1.7 variant, the B.1.1.7 that acquired a new mutation, or an altogether newly evolved strain, given the high vaccination rates that we have and the big spread of infection. That could be a smart way to monitor and catch in real time the situations where there's a variant that has escaped.

Topol: The Weizmann Institute, where you work, is one of the most extraordinary places in the world with its scientific contributions — not just during the pandemic, but the many things that you've done to help us unravel the mysteries of the gut microbiome. If something has to do with an -omic or if it's immunology, the Weizmann Institute is involved.

Tell us about the relationship between you, the Institute, your Ministry of Health, and the government. Do you have frequent cross-talk? Is there a Tony Fauci there? How does it all work?

Segal: The Ministry of Health is the medical authority and they report to the government. The Ministry of Health is the official body that manages, leads, directs, and decides on the pandemic. They hold all the data. By and large, the public follows the guidelines.

Several scientists, including me, have volunteered to collaborate with them. We're not officially affiliated with anything; I could stop working on this tomorrow. I don't have a commitment to do this. But as we became interested and engaged with the Ministry of Health, with cabinet members and the government, we had an opportunity to contribute from our work in data analyses and so on.

Obviously, it's not just us. Several scientists are doing this voluntarily, and we advise them. We appear frequently in the cabinet discussions, which are going nicely. The prime minister and the cabinet members listen to the reports and overviews by those they consider to be experts. Those experts give them advice. Many times we agree with each other; sometimes not entirely. But we have good debates — professional, scientific debates.

We have learned a lot of lessons in modesty throughout this pandemic. When we started making predictions, we wanted to take baby steps. So we said, let's predict what will happen in a week. And when we started that, people said, it's not interesting, everybody knows what's going to happen in a week. Four groups are making predictions about what will happen next week. Frequently one group will say that the pandemic is going to shrink next week, and others will say it's going to get worse.

There are so many unknowns, some having to do with parameters of the virus itself. If B.1.1.7 is 30% or 50% more infectious, it makes a ton of difference if the vaccine is 95% vs 91% effective. This has a huge impact on what will happen. Obviously, you can't know all the parameters.

With time, we learned to conduct these sensitivity analyses and also learned that it's even better to come to the government and say that we don't know. It could go one way or it could go the other. When it happens, we'll be able to analyze in retrospect and may be able to tell you why it went this way and not the other way. But right now, we don't know. So we want to reflect this uncertainty to you when you make a decision, so that you know how to take it into account when you consider all the risks.

1% Death Toll Among Some Groups

Verghese: You spent a considerable amount of time at Stanford as a postdoc and for your PhD. All through this pandemic, Eric and I have commented on the fact that the triumph of the science has contrasted with the disarray of our societal responses. Can you compare what you read about what's happening here in the United States vs in Israel in terms of how societal responses shape the pandemic?

Segal: It seems that a lot of places in the United States didn't fare that well. I would say that is also the case in Israel. The ultra-Orthodox population here has had a huge surge compared with the general population. And this also had consequences.

When we analyze the numbers now, we see that 1% of all people above the age of 60 from the ultra-Orthodox population here have died of COVID-19. That's 3.5 times more than in the general population in that same age group.

Israel now has 5300 deaths from COVID-19. If, in the general population, we had a spread of the disease similar to what occurred in the ultra-Orthodox, we would have had by now 7500 more deaths just in that age group in the general population.

When the pandemic began, some of the projections warned that if we don't control it, it'll be a catastrophe. But then it didn't happen because measures were put in place. Then people said, ah, you just scared us unnecessarily. But now we see that it's not the case. It actually happened. If people were not careful in the general population and they let it spread like they did in the ultra-Orthodox world, where they still held a lot of events — funerals, weddings, and so on — we would have had a much higher death toll.

It's not only that population. But we also have to acknowledge that the ultra-Orthodox have much more difficult objective conditions. They have bigger families, they live in higher-population-density areas in general, and obviously those are parameters that will affect the spread of disease. But also, when we look at the numbers now, I believe the behavior of that group was not as cautious as the other groups.

With good societal behavior and response, you can control this pandemic. We've seen it happen in several countries. I believe Israel should not be compared with European countries, but rather should be compared with New Zealand, Australia, countries with a similar political system, and island countries with a single border. When we compare ourselves with those countries, we're not even coming close to their successes.

In that sense, I believe there's a lot of justified criticism to how we handled the pandemic. We can point to specific things that we didn't do. When you see your government not doing what you know needs to be done, like not locking down certain outbreak regions and waiting for the virus to spread from those regions to the rest of the country, that damages public belief in the government. That also has an effect on how people behave.

Topol: Very important point. We really appreciate your taking the time with us in your evening, Eran. To our audience, if you don't follow Professor Segal on Twitter, you're missing out. All eyes are on Israel and he is a great window into what's going on there.

We'll want to get back to you again, because there's just so much that we can learn and hopefully adapt to rather than just watch, because there's a lot going on there.

Segal: Thank you very much for having me.

Eric J. Topol, MD, is one of the top 10 most cited researchers in medicine and frequently writes about technology in healthcare, including in his latest book, Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again.

Abraham Verghese, MD, is a critically acclaimed best-selling author and a physician with an international reputation for his focus on healing in an era when technology often overwhelms the human side of medicine.

Eran Segal, PhD, is a computational biologist at the Weizmann Institute of Science in Israel. His team recently demonstrated that individuals have widely varied glucose responses to the same food, which was unexpected. In his spare time, he's a marathon runner and reports that his best time is 2 hours and 56 minutes. You can follow him on Twitter @segal_eran.

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