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COVID-19 Boosters: Why Do We Need Them?

Authors: Sarah Jarvis, MA (Cantab), BM BCh (Oxon), DRCOG, FRCGP, MBE; Peter Openshaw, CBE FMedSciFaculty and Disclosures

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Activity Transcript

Sarah Jarvis, MA (Cantab), BM BCh (Oxon), DRCOG, FRCGP, MBE: Hello, a very good afternoon, good evening, or even good morning to you. My name is Dr Sarah Jarvis, and it is my privilege to be here to take part in our presentation on, "COVID-19 Boosters: Why Do We Need Them?" But don't worry, you have a proper doctor here to give you the real detail. My name is Dr Sarah Jarvis, and it is my pleasure to be joined by a man who is a true legend.

In this program, we're going to be discussing SARS-CoV-2 variants and vaccine effectiveness over time. It seems only a few moments since we were celebrating the development of the first vaccine in record time. Now, of course, suddenly we have to think seriously about waning of immunity and what that means for future programs. We've also, of course, not just had 1 variant. We've now got more than 1 vaccine, and we're going to be looking at the rationale for using bivalent vaccines. We're also going to be looking at how those strains, the booster vaccines would be selected. An absolute expert, Professor Peter Openshaw, professor of experimental immunology and ex-president of the Royal Society of Immunology... apologies that I said that wrong.

Peter Openshaw, CBE FMedSci: British Society.

Dr Jarvis: British Society, but it's royal too... is going to be here to take you through the detail. But perhaps, at the end, we'll touch very briefly on I think the thing that we all want to know about, which is where are we going, where vaccines are concerned?

So let's start at the beginning. And here, perhaps is a picture of our new world in a single-colored image, over on the left dark gray, perhaps very dull now, when we consider all the new variants is the original variant. Of course, it emerged in perhaps November, perhaps December 2019, and by March 2020, it had spread across the world.

No sooner had we had the first wave and thought that just maybe we were over the worst, then Alpha was with us. It started in the UK and it spread very rapidly because it was so much more transmissible. Just as spring came and we thought maybe things were going to get a little better, we were visited with the unwelcome specter of Delta, not only more infectious, but also more serious. And then, since then, not just Omicron, but all those variations on the theme. And of course, it was right at the outset of the pandemic with the original variant that the mad global search for a vaccine really took hold. And it's here that I hand over to my colleague to tell you about that search.

Dr Openshaw: Well, thank you so much, Sarah. I think it has been the most extraordinary journey that we've all been on together watching not only the evolution of those variants, but also the extraordinary progress that's been driven by science and particularly by the science that underpins the vaccines. And at the outset, I just wanted to make a very simple point about the 2 different areas that are important in terms of defense against mucosal infection. One is the mucosal immune system, which you can see on the right of this graphic. And on left, you can see systemic immunity, which is what's induced by the vaccine.

So when the vaccine gets injected into your deltoid muscle, the immune system doesn't know that it's important to mount any sort of response except in the deltoid muscle. So the site-specific information is not there. What the immune system generates is then a flood of antibody which circulates around in the blood and which is very, very good at preventing the more severe complications of infection, but not so good at protecting against the superficial infection of the mucosal surface.

So in order to induce mucosal immunity, what we need is either a challenge via the mucosal surface or something, maybe some instruction that could be incorporated in that injection which might direct the immune system to the mucosal surface. And this is important because I think we all know the vaccines are really good at preventing the very severe disease, but not so good at preventing the superficial because of infection. And that's really the important message from that slide.

So let's look at some of the real-world data in terms of waning vaccine effectiveness against the Omicron lineage. So we've got these new variants which arose, we know not how, but possibly in somebody who is in immunosuppressed, which have come from quite old variants, which were not around for about a year.

And if we look first at the vaccine effectiveness against dose 2, we can see on the left-hand side of this depiction, you can see that over time, as time passes, then the amount of protection against the BA.1, BA.2 Omicron does diminish down to about 40% at 7 to 8 months. If you look at the protection against the BA.4, BA.5 with 2 doses, you can see also that diminishes and you can see that there's longer on that time course because it's been around for longer.

If we now switch to the right-hand side, if we see the effect of an extra booster dose, dose 3, then we can see that you raise your protection right up against both the BA.1, BA.2, but also against the BA.4, BA.5. So it looks like these booster doses are really good at raising your protection back up to where it was before.

I think the important thing is to recognize that we don't always have that real-world data of actual vaccine effectiveness in the field. We have to have laboratory surrogates, correlates of protection that we can measure in the lab, where we can look at the immune response and see how likely it is that we're going to have protection when we go out into the field with these vaccines.

And one of the best things that we can look at is the amount of neutralizing antibody which is present. And that can be measured in a number of different ways in the lab. And this is an example of the amount of protection that you can infer from measuring in the lab, the amount of neutralizing antibody against the Wild type, the Delta, and the Omicron. And just looking at these graphs, you can see that generally the protection against the Omicron on the right-hand side of the depiction is rather low. But that if you give additional doses, then you can get a lot of incremental improvement in terms of protection. So I think these laboratory studies looking at the neutralizing antibody are very much in favor of these booster responses.

This is another study which looks at the waning protection against hospitalization. This is from very large studies done by the UK Health Security Agency (UKHSA) looking over time at the waning protection you get either with single vaccines or with mix-and-match-type vaccines. And you can see that actually you do get a really significant increase in protection with these boosters raising the amount of protection in the real world when you give these boosters.

Dr Jarvis: Now let's just translate that then into the real world as we see it today. And I think this is a really important slide for many reasons. The first one, if you look at the top, what you are seeing here is this is after a booster dose. And this is UK data constructed, prospective cohorts across all 4 nations, looking at no fewer than 30 million people. So you don't get a lot more robust than that.

What we are seeing at the top is that by the time you get to be 75 to 79, then you are about twice as likely to become seriously unwell, to end up hospitalized, or to die, even if you've had a booster than compared to say a 14- to 18- to 49-year-old. If you're over 80, you are 3.6 times more likely to die.

Now, if you were a glass half-empty person, you might say, "Well, that's dreadful because the booster clearly isn't protecting old people." But let's cast our minds back just 2 short years because 2 years ago, when the vaccine first struck, what we saw was data again coming out of the UK, very large figures, which showed that your likelihood of serious illness or hospitalization or death from COVID with every 6 to 7 years doubled the risk. So that meant that by the time you were over 80, you weren't 3.6 times more likely to die. You were about 128, or for the very elderly 256 times more likely to die than a healthy 18- to 24-year-old. And I think that really does put the protection that we've received from vaccination into perspective.

But the middle line, I think is also really interesting -- that middle set of data about comorbidities, because what we are seeing here is that, again, cast our minds back 2 and a half years, we thought COVID was a respiratory infection. We, therefore, thought the people at highest risk were going to be smokers, people with COPD. Well, some patients with COPD are at higher risk, but interestingly, if we look at the really big risk factors, they are comorbidities which are not necessarily respiratory and indeed often are not respiratory at all. So we're talking type 2 diabetes, obesity, cardiovascular disease, chronic kidney disease, and so on.

But again, let's put it into perspective without vaccination. This patient with 5 or more comorbidities who is currently 9.5 times more likely to die or be hospitalized from COVID than somebody with no comorbidities would've been in a much worse position before we had vaccination.

And what we are also looking at the bottom is the protection that you get from prior COVID infection. And this is a question I get repeatedly from patients now, and it is, "Why do I need a booster? I've already had COVID once," or twice or in some cases 3 times, "Why do I need a booster? It's much better to get my own immunity." Well, as we're going to see in the future slides coming up very shortly from Professor Openshaw, that is not the case. You get additional protection even though having an infection, certainly an Omicron infection, provides quite good protection against Omicron, but a pre-Omicron infection, not so much.

But let's just drill down then into those comorbidities and let's think about those patients who are at particularly high risk. And what we are seeing over there on the left are the ones that we really need to worry about, the solid organ and then slightly lower, but still high risk, the bone marrow transplant patients. Those patients who are taking immunosuppressive therapy is not as much of a risk, but it is still a significant risk. So all immunosuppression is equal, but some as George Orwell would say, is more equal than others.

If we then look, there are some surprise cases perhaps down at the bottom left-hand side. So for instance, patients with chronic kidney disease, severe chronic kidney disease, by the time you get to stage 5, you are over 3 times, in fact 3.7 times more likely to die than somebody who did not have that single comorbidity. And that's before we get to that cumulative effect that you have from multiple comorbidities. So what we're seeing here is the need for novel approaches to really highlight that high-risk set of patients so that we can provide better protection.

And this slide really just drills down a little bit more into those immunosuppressed patients. There was concern that they were not getting the same level of protection from a second booster. And what we saw here was the primary plus 2 boosters for immunocompetent patients certainly was better protection if you look at the top graph than no booster, but you weren't getting a lot of difference if you had 2 boosters almost at the same time. This is not booster 1 a year ago, booster 2 now. This was US data between June and December 2021. So it was actually people who are being given 2 boosters in short succession.

The immunocompromised people, we do see at the bottom there that you do get enhanced protection from giving that first booster. So let me ask you now, Professor, to take us through that data.

Dr Openshaw: Okay, so let's just look at the rationale for adapting the vaccines according to the ever-changing immunogenicity of these different viruses. So if we look back at the original Wuhan strain, we thought that the virus wasn't really going to change very much. We were being told by the coronavirus experts, the very few that there were up until recently, that actually these viruses are extremely stable genetically. They have ways of essentially stabilizing their genome, preventing the evolution that would otherwise occur.

What we've actually seen is a massive amount of evolution, as we said before, driven initially by transmissibility and then by immune escape. And the Omicron variant and the subvariants all came from what looks like something which was perhaps resident in somebody with a degree of immunosuppression, which then adapted within that individual and then spread out into the community.

And I think it's been remarkable that we've almost given up trying to rename the subvariants of Omicron. There's so many, but they are really capable of escaping from the original immune response. So the obvious question then is, how do we take that into account in the design of vaccines?

One of the great things about the RNA vaccines is that they are very adaptable. It's very easy to reprogram and update and incorporate new antigens. And so clearly, the incorporation of components of Omicron within the vaccine is something that can be done with relative ease using this new technology of RNA vaccination.

So if we look at how that works, so here, we've got ancestral RNA, that's the red strand. And then you've got the Omicron BA.1 RNA, that's the blue strand. So co-injection of both of those into the muscle generates the proteins which are both ancestral and also the updated spike proteins. And there's a possibility that they could be hybridizing as well into heterodimers. We're not sure what the significance of that would be. And this generates not only antibody against the ancestral and boost antibody against any response which you may have acquired through infection, but also generates a new response against the novel antigens present in Omicron.

So there's really good scientific rationale for doing this. And we know at molecular detail and atomic detail, where these variations are. It's quite extraordinary the amount of science that's gone into studying the pandemic and also informing the way in which we respond with vaccination. And we know that there are really just a few amino acid changes which are key in terms of changing the antigenicity. We know where those are, and we can incorporate that into the vaccines.

So what evidence do we have that these bivalent vaccines are going to be effective? If we look at the neutralizing antibody responses, and remember that's all we've really got to go on at the moment. We don't know how much actual protection in the real world there's going to be. But if we look at the Omicron variant vs the ancestral RNA in terms of the neutralizing antibody, which is expressed as this geometric mean titer, then you can see that on the right-hand side, the original type of vaccine does induce an improvement in immunity even if you've been infected, and that that's roughly equivalent if you look at the response to the updated vaccine.

If you look at the Omicron variant, then you can see probably a rather more significant improvement in terms of the laboratory-measured antigenicity. So that's really what we've got to go on at the moment in terms of, are these vaccines going to be an improvement?

So are they worse in terms of side effects? You might think that if you're incorporating 2 different types of RNA, you might get more side effects and we can break those side effects down into the local side effects and the systemic side effects. And on the depiction on the right, you can see 2 bars for each of those side effects is starting off with pain, erythema, swelling, and so on. And you can see that actually the severity of side effects and the frequency of side effects are really equivalent for the booster, which has got the bivalent component recognizing Omicron. So the side effects are no worse.

So what about the evidence that neutralization might be better? There's a lot of studies gone on to try and explore this particular issue. Just concentrate on the right-hand side of this particular graphic, and you can see that the improvement of neutralization of Omicron is about 1.5 fold, 1.6 fold. So it looks like the amount of antibody that's generated against Omicron is improved by moving to these bivalent vaccines. So no worse in terms of side effects, laboratory evidence that they induce more antibody, which we would hope would be highly effective.

This is another look at the amount of reactogenicity, both looking at the local and the systemic effects. And again, there's no evidence of enhanced reactogenicity with the updated bivalent vaccines. So in terms of the laboratory evidence and the clinical evidence we have so far, it looks as good or better, but we still need to wait for the real-world evidence of the vaccine effectiveness.

So just to recap the limitations of these studies so far, we are still waiting to see what will happen if we need to update and we need to add additional elements in. I think an interesting reflection is that actually it's perfectly possible to add new strands of RNA and to get additional immune responses. Does this mean we might be able to get multivalent vaccines against many different respiratory pathogens? Possibly.

So far, it really depends on neutralizing antibodies and we don't know whether that will translate into a big clinical benefit. And the data we've got so far is really limited to only the second booster. We don't know how long this is going to last and whether this is going to be a long-term benefit or whether we're going to keep needing to boost. My own feeling is that immunity is building up in the population. And eventually, I hope we'll be able to not have to boost so frequently.

Dr Jarvis: I'm very interested that you made that point about immunity building up in the population, because if we now move on and look at our next slide, now it's not peer reviewed, so we need to take this one just with a little bit of caution, but it came out very, very recently on the 25th of October. And what this is looking at is how likely it is you're going to get additional protection from having a variant booster dependent on what proportion of the population is protected.

And we go back to Professor Openshaw's point about population-level immunity building up. So what we are seeing here is that the bivalent response, as we saw there, increased the neutralizing antibodies by about 1.5 fold. What does that mean in real terms? Well, what it means is given that we had about 90% protection from the original vaccines against the original variant, if previous vaccination and/or infection combined at population level resulted in about 50% of the population being protected, then giving an original booster would increase that to about 86% protection against severe illness and you would then have an increase to 90% -- sorry, not severe illness... against symptomatic illness from having a new variant booster. But you would only get about a 1% protection, extra protection against severe disease. Having said that, that translates into about, according to this paper, 7 to 8 extra people protected against severe disease for 1000 people vaccinated with a new variant or a bivalent as opposed to the original vaccine. So we'll talk a little bit more about that just at the end with our expert here, what that means in real life.

This one is another way of saying the same thing, effectively about 8 fewer hospitalizations for every 1000 people. Now again, glass half-empty, glass half-full, 8 in 1000 maybe does seem so much, 1 in 120. But actually, if you think about how perilously balanced our health service has been in recent years -- certainly, ours in the UK and I know in many other countries across the world -- that could just make all the difference in terms of the health service being overwhelmed or not. And interestingly enough, in 2022, the FDA did suggest that companies should be looking at BA.4 and BA.5 vaccines rather than the BA.1, which has been trialed.

But really importantly, the other side of the coin is that there simply aren't enough bivalent vaccines for everybody to have them instead of the monovalent, which basically means I think we must still be giving out the message that you can tweak up your protection, as Professor Openshaw has said, by having a bivalent vs a monovalent. But the really important thing is getting a booster in the first place. And we've got a couple of slides which will just show what's happened with vaccination rates.

Now you can see that second boosters are very low there. They are increasing with time. But of course, let's not forget that the vast majority of people have only very recently had access to their second boosters. What's perhaps slightly more worrying is that we're stuck at about 54% of the population getting their first booster. And I think that is perhaps something of a concern because actually not everybody, not as many people have been offered the first booster. Children, for instance, in some countries have only been offered their first 2 doses. But nonetheless, we are gradually seeing that level of second booster going upwards.

What we're seeing here is the answer to that question, "I've had 1 infection. I've had 2 infections. Do I need a vaccine at all, or certainly do I need a booster?" So I think what we are seeing here is that immunity from natural infection, as we've heard at the outset from Professor Openshaw, is not necessarily predictable. And it can be very variable depending on the dose of disease that you get, if you like, and other demographic features. And we don't have a lot of research into the duration of that immunity.

But what we are seeing here is that if you've had previous infection, as you can see here on the left-hand side, 46% protection of having previous infection and a vaccine against any illness, if you just had previous infection, 46% protection, very little protection from 2 doses of vaccine alone. But the timing of this study meant that most people who'd had only 2 doses had had them more than 12 months before and we must bear that in mind. That doesn't mean they don't protect. It means protection wanes. What we then see is that if you've had 2 doses of vaccine and previous infection, then you get up to 55% protection, which was very similar to 3 doses of vaccine without being infected. But the best protection actually came from getting 3 doses of vaccine and previous infection.

On the right-hand side though, I think is the one we really need to worry about, and this is severe infection. And what we are seeing there is that while you get 73% protection from severe infection, just by having been infected previously, 3 doses of vaccine without getting any previous infection still provides 98.2% protection against severe infection, with if you add on previous infection on top, an increase to 100%. So that right-hand side, I think, really is what we need to think about because it's the severe infection, the one that ends up landing people in hospitals, the ones that overwhelm our health service, which we really need to think about.

So let's just touch very briefly then on the effectiveness of previous infection against Omicron, specifically looking at Omicron. And I think again, this is very important because many, many of our patients have had COVID, but they haven't necessarily had it since December last year when Omicron first became prevalent. And what we are seeing is that if you are looking at protection against symptomatic BA.4 or BA.5, then having Omicron before gives great protection, 84.5% protection, but actually a previous infection, if it wasn't Omicron, if it was original, Alpha, Beta, or Delta only provides 38% protection. And if you look down at the bottom, the likelihood of being infected, if you've been infected with Omicron, you are significantly less likely to get infected again, 80% protection. But again, if you've had a previous infection, but it was pre-Omicron, relatively very little protection, only 33% protection.

So these are the recommendations of the ECDC and the EMA. They all recommend that people who are at high risk should be given a second booster, the ECDC and the EMA recommending it for 60 to 79-year-olds and people with any medical conditions that put them at severe risk. But with the bivalents, they were prioritizing those people at especially high risk, the most vulnerable in our population, the over 60s, the immunocompromised, the people with severe underlying health conditions, and of course people in care homes.

So this one, this next slide is a variation of the previous theme that I showed, and it relates to this concept, that when we first started out, we had a population which was largely unprotected and we did not know anything really about vaccine efficacy. So we had huge numbers of people being protected, and we were able to do placebo controlled trials. I know I was in one, I got placebo, not that I'm bitter or anything. And we were able to compare the likelihood of severe illness and symptomatic illness between placebo and vaccine. Big differences. Big.

Issue we've got here is that now most people have been vaccinated or infected, most people vaccinated, as we saw, the incremental differences from boosters would be much smaller, wouldn't they? So it's just not feasible. It's just not feasible to do the studies and wait for the long-term data, is it?

Dr Openshaw: Yes, I think it's been remarkable how fast it's been to do these studies because there's been a vast number of infections. And we do absolutely see such amazing protection against severe disease. I think many of us, when we first saw those results, couldn't stop smiling for several days. Just amazing. But in order to get protection against symptomatic disease, which we can see on the left-hand side of this depiction, there, we need mucosal vaccines. And I think that's really the future in terms of vaccinology, how we can switch this response into mucosal protection and then stop transmission and stop the evolution of new variants.

Dr Jarvis: Now let's just go back to that slide that I showed building on your comment about population-level immunity because what we're seeing there on the left-hand side again is it very much depends what proportion of the population has protection. But if we look over on the right-hand side, we can see that although in absolute terms, the difference between those curves is not so great. You're not preventing that many people from becoming severely unwell. Actually, these are the people who end up in hospital. They're the people who block the beds. They're the people who are really sick, who overwhelm ITUs, who overwhelm our NHSs or our Health Services. And it doesn't take that many of them, does it, to really make a difference?

Dr Openshaw: Yes. And it's the people that you see in your practice who have that very severe disease that really, it's so important that we protect them effectively using very, very good vaccine regimes and perhaps other methods as well.

Dr Jarvis: Now, you touched earlier on what drives the development of new variants, but it's a question that I am asked so often by my patients, especially when they're thinking about the future. Just take us through because I believe you've experienced not just 1, but 2 pandemics.

Dr Openshaw: Yes, right. I think it's been absolutely fascinating to see the way in which what's driving the variation of the virus has changed. It was initially just transmission really, which was driving it. And then as immunity built up in the population as a result of infection and vaccination, so it was clear that what was driving the variation was immunological pressure. Pressure not only it seems through B cells, antibody, but also there's some evidence that it may be T cells as well, which are important in that protection, maybe mucosal T cells actually sitting in the mucosal surface.

I think chronic infection in immunocompromised patients may enable the genetic selection for immune escape. And that's another reason that we need to really concentrate on those vulnerable immunosuppressed people. And I think we absolutely have to keep prioritizing vaccination in vulnerable groups and learning more about how to identify those groups for enhanced protection.

Dr Jarvis: Well, one of the great joys for me of having the privilege of doing these sessions is that I get to hear it from the horse's mouth. We produced this slide and then Peter made these wonderful little subtle tweaks which just demonstrate the depth of his understanding. And that allows me, I think, to ask the ultimate question, do we need to keep chasing vaccines forever? Because as we've seen, we've lost count and we've had Alpha, we've had Delta, we've had Omicron. And now, I mean, we are on Q.1 and Q.11 or something.

Dr Openshaw: Yes. I mean, I think in terms of what the future holds, that's very difficult to predict as ever. And that's what we'd all like to know. I think it's inevitable that the vaccines are going to have to continue to be adapted to match whatever is circulating. And that's perfectly okay. That's what we've done for many, many years with influenza. And I think that's what we're likely to be doing here. The excitement is going to be, how do we make polyvalent vaccines against different response pathogens all built into 1 shot? And how do we direct the response into mucosal sites and stop transmission?

Dr Jarvis: Well interestingly, if you look at flu, we do have adjuvanted trivalent. We have quadrivalent vaccines. It is it not as simple as that.

Dr Openshaw: They're okay, but they're not great vaccines. Let's admit it. They're not great vaccines. They're good vaccines. They're not great vaccines. Let's aim for great vaccines in the future.

Dr Jarvis: Well, we have set the bar pretty high with what we've managed so far with COVID. Well, ladies and gentlemen, time for our questions in just a few short seconds, but just a couple of reminders for you to summarize that point. Boosters undoubtedly help to restore the effectiveness of primary vaccination and boosters work, even if you've been infected and particularly if your infection was pre-Omicron. Waning protection, decreased effectiveness against emerging variants in particular, means that it's highly likely that in the short to medium term, we're going to continue to need boosters.

Bivalent boosters do improve antibody response. We don't have clinical outcomes, as we've heard from Professor Openshaw very clearly, but about 56% higher level of neutralizing antibodies from the bivalent rather than the single, the monovalent ancestral version. And if we are looking at bivalent, we've seen clearly from governing bodies recommendations that we should be prioritizing those who are most likely to benefit most. And that means those who are most at risk, whether as a result of age, frailty, or immunocompromised status, along with, of course, multiple comorbidities.

Ladies and gentlemen, thank you very much indeed for joining us. We're hugely grateful to you for joining us. But of course, most importantly of all, let's say a big thank you to our expert.

Dr Openshaw: And thank you, Sarah. It's been a pleasure.

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