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To Boost or Not to Boost: The Debate Continues

Authors: Karine Lacombe, MD, PhD; Saul N. Faust, MBBS, PhD, FRCPCHFaculty and Disclosures


Activity Transcript

Karine Lacombe, MD, PhD: Hello everybody. I'm really happy to welcome you to this webinar from Medscape Education Global: "To Boost or Not to Boost? The Debate Continues." I am Karine Lacombe, infectious disease specialist from Paris, and I will co-chair this webinar with Saul Faust, who is a professor of pediatric immunology and infectious disease from Southampton.

Saul N. Faust, MBBS, PhD, FRCPCH: Thanks, Karine.

Dr Lacombe: Okay. So, what will we go through during this program? While this includes the following. The clinical data bivalent boosters, who needs a booster. We'll also go through the current recommendation to the EU and UK. And finally, talk a little bit about the expectations for winter 2022. So, first, to set up the scene, what is the rationale for booster doses in COVID-19? You all know that vaccine effectiveness wanes after primary vaccination, and a booster, either a third or subsequent doses, can increase neutralizing antibody titers, and also vaccine effectiveness. But of course, the effect of a third dose varies depending on patient characteristics, vaccine class, and vaccine sequence. We think that a subsequent booster can restore antibody and cellular response to levels achieved after the previous dose.

So, what are the currently available boosters right now in the EU? We have the original boosters either from Moderna, Pfizer, Novavax, Sanofi-Pasteur, GlaxoSmithKline, AstraZeneca, and Jansen. You've got the name on the left side of the slide. In the middle you see the new boosters called bivalent original Omicron BA1, either from Moderna or from Pfizer. And finally, the latest one released, the bivalent original Omicron BA4, and BA5 also from Moderna and Pfizer.

Dr Faust: So, here's a bit of the data from what we know now about the boosters we're using this winter. So, there was a phase 2/3 trial of a fourth dose of the Moderna bivalent BA1 vaccine and the slide's a bit complicated, but you can see that the neutralizing antibody response was a bit better with the bivalent booster compared to the original booster regardless of the previous infection status.

You can see on the left all participants. The taller bar, the light blue bars, are the original vaccine and the bivalent vaccine is in the dark blue bars. And you can see that previous infection didn't make any difference to that improved immunogenicity on antibody in the company's own study. And that's published in the New England Journal of Medicine at the beginning of October this year. Pfizer has also been looking at their bivalent vaccines. These are data that were presented to the American government as they were making their decisions. And on this slide, you can see the top line is the BA1 Omicron bivalent vaccine and the bottom line is the wild type vaccine. And again, you can see an improvement in the top line, the difference between 700 and about 450, an improvement in the bivalent against Omicron.

Although against the reference strain, very little difference at all between the vaccines. And that's the bottom line, the 2 numbers, that are around 6000 of the units that they've used for those assays. So if we then look at the immunogenicity, the antibody produced in this case of a fourth dose of the bivalent BA45 vaccine compared to the monovalent, you can see here that regardless of the strain that you are looking at, and the strains are on the x-axis, the blue bars and the red bars are virtually the same. And that, the blue, is the 4 shots of wild-type virus, 4 injections of wild type, and the "3" is 3 wild type followed by the BA45 bivalent. So very little difference at all between the bivalent and the wild type vaccine in the neutralizing antibody titers. And then another study preprint available for this one, small study of only 33 people who'd received 3 prior vaccine doses.

So, this is a third dose of a BA5 containing bivalent where 15 received the monovalent and 15 received the bivalent. And you can see there's a mixture of 2 doses of Pfizer and 2 doses of Moderna between each group. And you can see again this is with the original 2 doses mixed up, so either both monovalent Pfizer together with monovalent Moderna or the both bivalents on the right. So left is monovalent, right is bivalent, and again you can see against the different strains, and they're running along the X-axis, very little difference between the monovalent and bivalent. So, a similar increase in neutralizing antibodies with monovalent and bivalent boosters, and no difference in the activated T cell or memory B cell profiles. And in the same study, you can see very, very similar immunogenicity between bivalent Pfizer and Moderna. The dose of the mRNA is different between the 2 vaccines just like the first doses of vaccine we were giving people last year. The Moderna has slightly higher numbers, but clinically we don't think there's going to be a significant difference because as the antibody titers wane, things become more equivalent. So very similar antibody profiles with each type of bivalent booster. So, what about the safety and reactogenicity, the side effects of the bivalent vaccines? Can you tell us about those please, Karine?

Dr Lacombe: Yeah, sure. Exactly. So, what do we know about safety and tolerability? So, you've got here the safety of a fourth dose of original vaccine from UK randomized trials. You see from those little stars the adverse events within 7 days of the fourth dose, so you've got the moderate to severe events and the severe events. If we look at the prevalence of those events, you can see that we have reported some pain, mainly pain, otherwise all the other events were really mild and the frequency was very, very small. If you look at the severe grade 3 or 4 events, nothing really to note in any case under 5% of prevalence. So, both boosters were well tolerated and really the pain was the most common adverse events. Next slide.

Dr Faust: And very similar to the original, the third dose boosters as well, between the third and fourth dose.

Dr Lacombe: Exactly. So now if we look at the safety of the fourth dose of bivalent booster from Moderna, so you've got here the incidences of adverse events very similar with the 2 boosters. And here again, the most common adverse events were pain at ejection site, fatigue, headache, myalgia, arthralgia, and most of those events were grade 1 or 2. So very little local and even systemic side effects. So here this is the safety of the first dose of a bivalent booster from Pfizer in patients age more than 55 years old. Again, a similar local and systemic event profile. Among participants age more than 55 years old, no severe adverse events were related to the vaccine. So, you see from the graph the pain at injection site again around 50, 60% and swelling or redness, very, very low. And regarding the systemic effects, about 50% of patient reported some fatigue, but otherwise very, very mild adverse events.

Dr Faust: In summary, what should we use? Bivalent or monovalent? Countries are buying the bivalent vaccines because that's what the manufacturers have made available. But if you haven't got a bivalent vaccine in your area or your region, then to the people who need it, you can give a wild type vaccine and you'll get just as good response for the current circulating variants.

Bivalent vaccines add to our armamentarium if you like. They're an insurance policy. If the virus changes again in the direction further away from the wild type, then it might be that actually we are going to need the bivalent vaccine. And the European Union strategy and UK as well is to have a broad range of adapted vaccines available so that countries and vaccine committees have various options to meet the needs. The manufactured sponsored studies suggest that there's a modest increase in neutralizing antibodies with bivalent compared to the monovalent, but there are other studies now appearing suggesting that really that the bivalent or monovalent vaccines are equivalent. Definitely the safety and side effects, the safety and reactogenicity of the bivalent and monovalent vaccines appears to be equivalent and equivalent for third and fourth doses.

Again, if you look at modeling, based on some of the data at a population level, some of the modeling has shown benefit with bivalent vaccines. But actually, if you look at the commentaries around that paper, clinical experts around the world, both in the UK and in the United States, have said actually there's very little to choose between those vaccines. So how effective will the current boosters be against emerging and future variants? Well, against the current variants, they're doing fine, but we don't know at this point how long they're going to last. We know that antibody goes very high with RNA vaccines in the first 2 to 4 weeks and then it wanes over time. But we don't know how long exactly people will remain protected, which is why surveillance is very important and why we shouldn't be saying to people, oh, you've got to have this vaccine and it's going to be your last one. The fact is we just don't know when vaccine committees are going to need to recommend future doses.

So, who needs a fourth dose in autumn and winter 2022? Some patients remain at risk even after the third dose. And those people where the impact of the antibody waning is most strong are the elderly. And you can see in the top slide here that advanced age is associated with an increased risk of hospitalization and death after the third dose. And that's true also for the people with an increasing number of comorbidities. But previous infection doesn't seem to be so strong looking at those groups. So, the elderly and people with comorbidities or risk factors are the people we are most focused on boosting this autumn and winter. And if you look at the data from Israel, there's a couple of studies here we can show you, a fourth dose of vaccine may protect against Omicron in the older adults. This was a study done in the beginning of the year with a fourth dose of the wild type Pfizer in people over 60 in Israel.

And you can see that compared with 3 doses, a fourth dose was associated with lower risk of Omicron infection itself, albeit for a short period of time for the study. But the durability was the impact and the prevention of severe illness, ie. hospitalization and death. So, a definite benefit of that fourth dose. And in a separate study in Israel of healthcare workers, about 30,000, about 25,000 of whom had received no additional dose and 5,000 of whom had received a fourth dose and no infection immediately after that dose, studying breakthrough infection, fourth dose recipients had less breakthrough than the third dose recipients. So, 4 doses seemed to be useful in healthcare workers, obviously all ages, not just the elderly for that study. So, what are the recommendations this year, Karine? In the European Union.

Dr Lacombe: Yes, exactly. So, you see here on this slide the European Centre for Disease Prevention and Control-European Medicines Agency(ECDC-EMA) recommendation for the second booster, which will be the fourth dose. So, second booster should be considered in people aged more than 60 years old, and you'll see that is a little bit different from what recommended in the UK, and also in medically vulnerable people regardless of age. You have to remember that bivalent vaccines are presently approved for use in people age more than 12, and the priority of these vaccine should be given to people at risk of developing severe disease. And we have told you about the age but also about the comorbidities, immunosuppression, etc. So, the national authorities from each country might release guidelines which are bit different from a country to the other. So, I really recommend you to refer to your own country guidelines. But all the guidelines are based on factors related to hospitalization rates, vaccination coverage, etc. Saul, can you tell us how it is in the UK now.

Dr Faust: Yeah, so in the UK, we have a 50 year cutoff instead of the European Union for our recommendation for this winter. And a bit more specific, the Joint Committee for Vaccination Immunization, or JCVI, have recommended also having a booster for people living or working in a care home, carers aged over 16, anybody over the age of 5 years living with somebody who's immunocompromised, pregnant women, and or frontline healthcare workers. And I won't read them out, they're on the slide, but the JCVI have specified which are the high risk groups of people who should be receiving that fourth dose. And I will just highlight pregnant women who have been very slow to come forward. And I think everybody, we all as a medical community, need to do better explaining to pregnant women the impact of COVID on themselves and their newborn baby, because pregnant women are very much more at risk of severe COVID than other women of the same age.

Dr Lacombe: And I have to say that in France it's exactly the same recommendations as in the UK. So now, recommendation for age threshold for the first dose by country or region, we have put on this graph the countries and the age threshold. So, if you look for example for Canada and Germany, the age threshold is 70, and for the Netherlands it's recommended from the age of 12 and above. For example, in France it's 60, as I told you earlier, and in the UK it's 50. What is also very important is to look at the guidelines for a combination of flu and COVID-19 vaccination campaign. You look at the countries, for example in the Netherlands, Switzerland, UK, France, etc, we recommend to couple the campaign against flu with the campaign against COVID. But in Austria, Canada, Germany, Ireland, or the USA, there is no such recommendation so far.

Maybe, Saul, we can do a small wrap up regarding the needs of a first dose and deliver to your audience a few key takeaways message. So, what would you like them to keep from what you have said?

Dr Faust: Sure. That boosters are recommended for the elderly, for healthcare workers, for other at risk groups for this year. But for younger people, we're not needing to give them a fourth dose right at this stage. The other thing we've been explaining is that there's marginal differences between the booster vaccines available. If your country has a bivalent vaccine then great, you can use that. But if you only have a wild type vaccine, then that's okay to use as well. The key thing is to use a booster in the groups of people who actually need them.

Dr Lacombe: Exactly. And maybe if I can add a few things to that, you can be reassured about the adverse events, nothing very different from what we already know from the primary vaccination. And also, very important to think about coupling the vaccination campaign against COVID to the vaccination campaign against flu, because in most countries the targets are exactly the same.

Dr Faust: Yeah. Thank you. Now people are going to be asking, well, okay. You've told us that for the variants that are circulating now, any of the vaccines we've got are just fine. What do we expect to happen next, Karine?

Dr Lacombe: Oh, well, you know from those 2 past years that the epidemiological landscape of SARS-CoV2 is an ever changing one, and indeed, Omicron continues to evolve. We have talked a lot about this BA.275 strain which exhibits an increased infectivity and immune evasion. If you look at the infectivity side, increase ACE2 binding affinities when we compare the BA.275 to the BA4 or BA5. And there is also an increased use of the endosomal pathway for cell entry. On the immune evasion side, we have seen unfortunately an escape from therapeutic antibodies targeting BA5 epitopes, and also this strain BA275 evades antibody from convalescent plasma from patients with prior delta and BA5 and BA5 infection. And that's a big problem for us when dealing with immunosuppressed patients because sometimes convalescent plasma was the only option we had as a therapeutic tool. In the next slide, you see now a few data regarding the new variants, BQ1 and BQ11, which are rising very rapidly in the US and the EU right now, in France for example. It occurs for more than 50% of fall infections and it's already the case in the USA and we know that by the start of 2023 it will account for more than 80% of all the variants.

So, what a problem with those 2 subvariants? Well, they contain mutations that promote immune escape and reduce or completely abolish the efficacy of monoclonal antibody treatment for example, monoclonal antibodies recommended for prophylaxis and other monoclonal antibodies such as bebtelovimab completely lose activity against this variant. So those 2 subvariants are sublineages of Omicron BA5, but we think that the vaccines that are effective against Omicron should work against BAQ1 and BAQ11. So, it's very important to promote this fourth dose booster in patients and participants or people who are in need of them. Those bivalent vaccines, BA4 and BA5, have been recommended very recently for approval by the EMA.

Dr Faust: And I think you've just made a very good point there, Karine. It's that some of the treatments we've got in terms of the monoclonal antibodies for people who can't make antibody aren't going to work so well. But actually vaccines work in multiple different mechanisms, and so far, and fingers crossed it will stay the same, so far the protection against severe illness hospitalization and death is being maintained and we would expect it to be maintained with the variance that we've seen regardless of the theoretical immune evasion because the vaccines work in many different ways, not just by providing antibody.

So, should we boost or not boost? Well boost the doses can increase antibody levels and vaccine effectiveness and can boost the cellular response both T and B cells. Despite emerging variants, the protection against hospitalization and death remains very high. A fourth dose can be beneficial but we are prioritizing in developed countries at the moment, certainly in the UK and EU to the elderly and high risk groups. And booster and safety reactogenicity profiles are very similar for the bivalent, all wild type vaccines used as fourth doses as we saw for primary immunization or the third doses with those original vaccines.

I think now, Karine, we've got a Q and A session. So, I'm going to start off with the first question that's at the top of the list, what is the recommended duration between the third and fourth boosters? The fact is the trials that have been done have been done quite quickly with 6 months between the 2 doses because the trials have been trying to inform the policy decisions. But the fact is that you should have your next dose when your country has recommended it because some of the elderly people might need extra doses sooner than the say healthcare workers. So really people should be looking out for the time points that are being recommended country by country and not worrying about the exact time of the booster itself. So Karine, how many boosters do you think we're going to expect our patients to receive in the next year or two?

Dr Lacombe: Oh, well, that's a very difficult question to answer and I think that's impossible to answer with a definitive answer. At the beginning we thought that maybe we would need only the primary vaccination schedule and we saw that with a booster we enhanced the response and especially the durability. So we've got this first and second booster, so maybe in the future the fight against SARS-CoV-2 will be like the fight against the flu with common sub variants to take into account every year and maybe a booster every year for elderly and people with comorbidities in order not to stop transmission but to decrease the risk of hospitalization and severe evolution of the disease. And I guess that's the only thing we can say now. It's more prediction than reality right now.

Dr Faust: And I guess it could be that elderly people in particular may be recommended another interim dose but at this moment in time we just don't know because it depends on what happens with the pandemic.

Yeah, there's a couple of questions about children. So, the first one is, "do children need boosters after the primary schedule?" Well it has been very difficult for pediatricians because actually as we've progressed in the pandemic, although there are a few children who do get effects of long COVID, the numbers are very, very small compared to the numbers of adults and elderly and at risk people who are becoming ill. And so generally, certainly in the EU and in the UK, we are not recommending boosters in normal healthy children. And we know also that normal healthy children have got very high seroprevalence. So very high antibody levels in surveys and in the studies that have been doing. So, children have either met COVID or they've been given a vaccine and they seem to have a lot of immune protection relative to older people. So, the resources for vaccines are being targeted at the elderly and at risk population. That's different for the at risk children. Children with cancers, children with immune problems, with severe asthma or other respiratory disorders. There's a big long list that if you look back at the slides you'll see in the UK slide was listed out and in the EU children have been, I think, Karine, you might have to remind me of the EU recommendation of age. Certainly, in the UK, we are offering boosters to any at risk children over the age of 5 years.

Dr Lacombe: Yeah, the same. Yeah, the same for us. With bivalent boosters we've got an indication above 12 years, but with the monovalent vaccine, it's above 5 years.

Dr Faust: And this isn't because those people are necessarily getting really sick and coming into hospital, it's as much as, well, we've got the vaccines, we know they're at risk, we don't want to take the chance. So, we're going to offer boosters, we're going to encourage people who are at risk of any age above 5 years to have a booster in order to maximize their protection. And that will also of course protect them if the virus changes again and the pandemic changes again. Karine, just to go back, do we think the current vaccines will be useful against the really new variants that are popping up, not just the ones we've shown data on?

Dr Lacombe: Yes. Very probably because we have told you the vaccine developed with the ancestral strain has been proved to be efficient against Omicron strain sub variants, strains of Omicron. So, there is no reason why it should not be efficient against BQ1, BQ11, etc, and the other variants that will emerge in 2023. So definitely the importance is to get the booster when we need it because it has been shown to prevent severe disease and hospitalization.

Dr Faust: Thanks. And one more's popped up about whether naturally acquired immunity has been studied and compared to vaccinated people and boosted immunity trials or studies. I guess we did touch on that with the data from Israel, didn't we? Where you have the difference between people who've had 3 and 4 doses and there was a definite advantage to the fourth dose. So, I think there's good evidence that you can't just assume that natural infection is going to protect you from the most severe disease. And of course, I think we discussed this in our last webinar, didn't we, Karine, when you've got so many people being infected at the same time, boosters are really important to take the pressure off our healthcare systems. And all over Europe in the wintertime, the healthcare systems are under pressure from winter respiratory viruses, one of which is COVID. So really would encourage you to encourage your patients and in your education of your communities for people to have the booster vaccines as recommended by your country's immunization committees.

Great. Well I think we're just about at the end of our time with no more questions, so it's been great talking to you again. Thanks very much and thank you all for watching this webinar. Thank you very much.

Dr Lacombe: And thanks to you, Saul.

This transcript has not been copyedited.

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