Activity Transcript

Ulrich Heininger, MD: Hello, I'm Ulrich Heininger. I'm a professor of pediatrics and head of Division of Pediatric Infectious Diseases and Vaccinology at the University of Basel Children's Hospital in Basel, Switzerland. Welcome to this program, entitled "Five-in-One Meningococcal Vaccines: Just Over the Horizon." Joining me today are Tero Heikkinen, who is professor of pediatrics at the University of Turku in Finland, and Federico Martinón-Torres, who is head of pediatrics at Hospital Clínico Universitario de Santiago in Spain, and associate professor of pediatrics at the University of Santiago. Welcome to both of you.

In this program, we are going to discuss several things: where things stand globally with meningococcal serogroup distribution and epidemiology in the context of the ongoing COVID-19 pandemic; the vaccines currently available for meningococcal disease; the pentavalent meningococcal vaccines that are in development, including the potential benefits and latest clinical trial data; and, last but not least, how best to communicate with healthcare providers about pentavalent meningococcal vaccines.

So, I'll start with a brief overview of invasive meningococcal disease (IMD), its epidemiology, and the vaccines to prevent it. Now, IMD a disease with an acute onset of fever and reduced well-being. There is often rapid progression to meningitis and/or septic shock and disseminated intravascular coagulation. The outcome unfortunately is fatal in about 8% to 12% of patients, and those who survive often suffer from late sequelae, such as necrosis, leading to amputation of legs sometimes, deafness, and hydrocephalus, which needs specific treatment.

On this slide, you can see the mortality of IMD summarized for Germany over the years 2001 to 2015, by age groups and also by serogroups B versus C. As you can see on this slide quite nicely, on average, serogroup C fatality is higher than with serogroup B. And also you can see that fatality is highest in young adults, but overall it's about 8% for invasive MenB disease and about 12% for invasive MenC disease. The serogroup distribution varies quite substantially across the globe. In the Northern hemisphere, in most countries which have surveillance in place, serogroup B has been dominating the picture for as long as we have been assessing serogroup typing, whereas in the Southern hemisphere, we have a more diverse picture in some countries, especially in Africa, where we can see serogroup A or W or C predominating, and in Australia, it's also serogroup B which is most prevalent.

The COVID-19 pandemic, which started in March 2020, has had a tremendous effect on lots of other infectious diseases in addition to SARS-CoV-2. We can look at a country which also has a very good record of meningococcal invasive disease surveillance, and it is the United Kingdom. Here you can see, from left to right, starting in January 2018 and ending in November 2021, the absolute numbers of IMD, and the color-coding gives you the different serogroups. And as you can see, basically the same thing happened in the UK as internationally. As of March 2020, the cases came down quite substantially, remained at a very low level until the lockdown measures were relieved in late 2021, and then the cases started climbing again. So we see a reemergence of serogroup B cases, mainly, and they are almost approaching the prepandemic levels, especially in adolescents and young adults.

So what can we do against it? There are a number of different available meningococcal vaccines and, for example, we do have a stand-alone group C conjugate vaccine. Conjugate means that the polysaccharide of the capsule is conjugated to a carrier protein, which can either be diphtheria toxoid, tetanus toxoid, or cross-reacting material (CRM) from the diphtheria organism 197. And these are the different available vaccines against MenC. This has been further developed to a quadrivalent A, C, W, Y conjugate vaccine, and here the carrier proteins are also tetanus toxoid and CRM₁₉₇.

One of the latest developments has been 2 different meningococcal group B vaccines, where the capsule has not been used, but specific proteins from the membrane of the organism. Either 4 components or 2 different factor H binding proteins have been used as the pivotal antigens of that organism and composed into vaccines. Especially for the purpose of the situation in Africa, a meningococcal group A tetanus toxoid conjugate vaccine has been developed and implemented. And last but not least, there is 1 amorphous influenza type B conjugate vaccine combined to a MenC and Y tetanus toxoid conjugate vaccine.

Now let's talk about pentavalent, or 5-in-1, vaccines for prevention of meningococcal disease. Terho, can you tell us what is being developed and what the potential benefits of such a 5-in-1 vaccine might be?

Terho Heikkinen, MD, PhD: Sure, thanks. So in recent years, the main development in this field of meningococcal vaccines has been the 5-valent vaccines that combine the existing, separately available A, C, W, Y, and B vaccines into just 1 vaccine that includes all these 5 serotypes. This is a very welcome and important advancement in the field that has been awaited for a long time, because now we will have a new pentavalent vaccine that could cover practically all major serogroups that cause meningococcal disease in just 1 vaccine. There are actually a couple of different formulations of pentavalent vaccine candidates that are currently being tested in clinical trials in different age groups, so we are eagerly waiting for the efficacy results from those studies.

Regarding the potential benefits of these 5-in-1 vaccines, certainly the big benefit is the reduction in the number of injections required. This is something that we've seen during the past years with many childhood vaccines. It also simplifies the vaccination schedules in any country and, very importantly, as Ulrich described just before, the outbreaks in different countries in different seasons are pretty unpredictable. There's no one who can tell which serogroup might cause an outbreak next year, so this new formulation that includes all major serotypes helps overcome this unpredictability and takes away the guessing game.

A pentavalent vaccine has the promise of being able to reach larger target groups. We know that adolescents and young adults are usually basically healthy, they have less contact with health care compared with young children who go to the well-baby clinics regularly. And when you're young, you have many other interests than vaccinations. Vaccination is not on the top 5 list of any regular young adult. What also adds to the problem here is that when children grow older and become independent, they start making their decisions by themselves, so they don't need parental consent for vaccination anymore. So certainly, if you can deliver all important serogroups in just 1 vaccine, that sounds appealing.

It’s also important to notice that when we are talking about pentavalent vaccines, it's not only these A, B, C, W, Y vaccines that are being developed. There is also a pentavalent vaccine called A, C, W, Y, X that is being produced in India. And this, as you can see, does not include type B, but instead it includes the serotype X which is increasing in Africa. And this pentavalent vaccine is especially developed for the so-called African meningitis belt countries, where in the past, as we heard, group A disease was very common. Then after a successful MenA vaccination campaign, the incidence of A disease was virtually zero, but there is a new serogroup, X, that has increased in those countries. Therefore, I believe that this pentavalent vaccine will be very important for those countries. So these are the major developments that I see happening in the meningococcal vaccine field.

Dr Heininger: Thank you, Terho. This is really interesting. Federico, can you tell us about the clinical trial data for the pentavalent vaccines? What do we know already?

Federico Martinón-Torres, MD, PhD: Yes, sure, Ulrich. There are some interesting data that I'm about to share. First, following on from the pentavalent vaccine that Terho has just mentioned, the conjugated A, C, W, Y, and X vaccine. This fully conjugated technology-based vaccine is doing well in clinical development and, as a matter of fact, the data from the phase 2 trial have been recently published in The New England Journal of Medicine. In this particular paper, in this phase 2 trial, they compares 2 versions of this new pentavalent vaccine, 1 adjuvanted and the other nonadjuvanted, with the already-licensed tetravalent vaccine, the A, C, W, Y conjugated with diphtheria toxoid. And the results are good because they show that there are no issues with regards to safety. And if you look at the figures, so the immunogenicity results, we can see that for the common serogroups, so the A, C, W, X, and Y serogroups, the responses are comparable, if not better, for the new pentavalent vaccine as compared to the conjugated vaccine. So good news with regards to this conjugated vaccine that can be of particular interest, as Tero already mentioned, in developing countries where X serogroup is becoming a worrisome serogroup in these particular settings.

And then we have the A, B, C, W, Y vaccines, and we have 2 big pharma companies working on this development. In the first generation of these B serogroup vaccines, they just combined the existing licensed vaccines against the B serogroup and the A, C, W, Y serogroups. So these clinical developments of this first generation of A, B, C, W, Y vaccines actually are testing the immunogenicity and safety of the combination of preexisting licensed vaccines against the B serogroup group and then the A, C, W, and Y serogroups.

To start with one of them, we are here analyzing the clinical development of the combination of the recombinant LP2086 vaccine against the B serogroup with the tetanus toxoid conjugated ACWY vaccine. This vaccine is being studied in a 2-dose schedule. There are different ongoing trials, and most of the data of these trials are not yet publicly available or have not been published yet, or some of these studies are still on active recruitment, but we have the data from the Peterson study where they assessed the immune response of this vaccinecompared with the administration of both vaccines separately. As you can see in this figure, in the upper part, for the different serogroups, A, C, W, B, and Y, the responses are comparable when these vaccines are administered separately, or as part of the investigational product of the pentavalent ABCWY vaccine. And in the lower part of the graph, we can see the response for the B component and, again, using different tested strains, we can see that the response is comparable when administered concomitantly in separate products or in the investigational product, in a single vial.

So, as said, this vaccine clinical development is still ongoing, and as a matter of fact, one of the studies consists of the administration of this pentavalent vaccine to the infant age group, a phase 2b trial that is currently recruiting subjects. We still have to wait for the results of all these trials, but so far so good in terms of immunogenicity and safety.

And the other, let's say, first-generation vaccine of ABCWY, in this case developed by another pharma company using the combination of their already-licensed B vaccine, the 4CMenB vaccine together with their licensed conjugated ACWY vaccine -- in this case, the CRM-conjugated ACWY vaccine, is already ongoing in terms of clinical development.

But, as compared to the previous vaccine, I can share more data because more data is already publicly available or has been published. So let's get it started with the immunogenicity of a 2-dose schedule of the ACBWY vaccine compared to the separate administration of these vaccines. And in this particular study, already published by Timo Vesikari, we are seeing, in this particular graph, the response for the different antigens of the B component. And what they're assessing is the comparison of different intervals of the pentavalent vaccine as compared to the standalone 4CMenB vaccine. The results are that the immunogenicity is good, but the best immune response is obtained with a 6-month interval between the 2 doses of the investigational product, the ABCWY vaccine analyzed here.

Also, the immunogenicity of the vaccine with this 2-dose schedule has been assessed in terms of the response against the A C, W, B, and Y components. And, not unexpectedly,what we see is that the results are comparable when a single dose of MenABCWY is administered or a single dose of the already-licensed ACWY vaccine. And not unexpected either, when a second dose of Men ABCWY vaccine is administered, both the geometric mean titers (GMT) and the percentage of responders is greater than with just a single dose of either the ABCWY or the already-licensed tetravalent vaccine.

In this regard, we also already have available data on 4-year persistence of the immune response. In this graph, we can see on the left side the response for each of the 4 antigens of the B serogroup, and on the right hand, the percentage of subjects achieving the protection threshold of the human serum bactericidal antibody assay (HbSA) for the different 4 serogroups of the conjugated part of the vaccine. Not unexpectedly, there is a decrease in the percentage of patients who are protected as compared to baseline, but still the number of subjects that are protected is higher than those who are vaccine naive, or those that have received only 1 of the components - in this case, the middle bar, those that only received the MenACWY vaccine.

Also in this study, and this is important, they have assessed the response to a booster dose. So in this graph, we are checking the response for the B serogroup components for each of the 4 antigens and we are comparing the response in those who were previously vaccinated with 2 doses of MenABCWY and who received an additional dose of MenABCWY; those that only received a primary series with MenACWY and now received a booster dose with MenABCWY; and the third group of ours represents those who were naive and now received a single dose of the investigational product, MenABCWY.

And in brief, what we can see here is that the MenACWY vaccine elicits a very good and anamnestic response following prior exposure to the multivalent meningococcal vaccine and, as suspected, this response is better than those who have not received the B component previously. And it's better than those who are naive to any of the components included in the investigational product.

If we also have a look in this same study of Sáez-Llorensin terms of the persistence and immune response to the other part of the pentavalent vaccine, in this case to the A, C, W, B, and Y serogroups, again, the response is very good.

And finally, and also interestingly, we have another study that was published in The Pediatric Infectious Diseases Journal which assessed the capability of the MenABCWY vaccine to booster the immune response, irrespective of the vaccine that they received in the primary vaccination. In this particular slide, you are seeing the percentage of subjects who achieved the protective threshold in HbSA for the A, B, C, W, and Y serogroups. And, as you can see, for any of those who previously received a vaccine and now received the booster with the pentavalent vaccine, the percentage of responders is very good for all the serogroups. And we can see a lower response, as expected, is in those receiving placebo as a booster dose. So in summary, I think this is good news with regards to the development of a pentavalent vaccine, this first generation of pentavalent vaccines. And I have tried to summarize the results, particularly of the 4CMenB+CRM₁₉₇-ACWY pentavalent vaccine, which is the one that has more data available.

And finally, before giving back the floor to our chairman, Ulrich, there is also another pentavalent vaccine under development, the so-called second generation of pentavalent vaccines. In this case, in addition to the already-licensed quadrivalent vaccine, the CRM-conjugated MenACWY vaccine, additional antigens, additional subcapsular proteins are included in this vaccine with the aim to improve the potential coverage of this vaccine. The specific antigens that are included in this second-generation vaccine have not been disclosed yet, but the recruitment of the studies with this vaccine are ongoing, and we are looking forward to knowing the results. So in summary, I think we have pretty reassuring data so far for any of the pentavalent vaccines under development.

Dr Heininger: Thank you very much, Federico, for sharing this wealth of data with us, and I think this looks really promising. Let's talk a little bit about implementation and compliance with vaccinations. Obviously, vaccines only can work if we get them out of the refrigerator into the arms of the individuals so that they can develop an immune response. The question I have is, how do you see the role of pentavalent vaccines compared to the individual vaccines to improve compliance? Terho, what are your thoughts on this?

Dr Heikkinen: Well, as we've discussed before, the benefits of pentavalent vaccines are clear. If I'm trying to take the position of a young adult who's going to college or university and then reads or hears that, "Hey, meningococcal infections are more frequent in those environments than at home," and I was wondering whether to be vaccinated or not, then I would search the literature or read the leaflets and find out that about half of the meningococcal illnesses are caused by A, C, W and Y serogroups and about half by B, so that would mean two 2. In the end, I might decide, "Hey, that's a guessing game. No one can tell reliably which serogroup will cause the next outbreak, so let it be." But in if instead there's a vaccine that covers, in a single vaccination, all these 5 major serogroups, I think I might find it very appealing and a rational choice to get vaccinated with such a vaccine.

Dr Heininger: And Federico, you mentioned the 2-dose schedule required for the pentavalent vaccines with an interval of 6 months appearing to be ideal. Do you find it a challenge to get individuals who receive the first dose to also get their second dose, and how does that compare to the existing vaccines?

Dr Martinón-Torres: Well, indeed, we need to wait and see when the clinical development of these vaccines is completed,but we know that for the conjugated vaccines, from 1 year of age, 1 dose could be enough. But for the B component, we know that at least 2 doses are needed, irrespective of age. So that's the rationale for the use of at least 2 doses and then to find out which is the best interval. So, indeed, it may happen that for particular age groups, using the pentavalent vaccine could mean additional unnecessary doses for some of the components, or it might be that eventually, additional doses could have a mid- or long-term benefit. We don't know.

Dr Heininger: But when we do the math, even if it needs 2 injections, it's still less than with the separate vaccines, isn't it?

Dr Martinón-Torres: Yes, indeed. I buy all the statements that Terho pointed out, in terms of the importance of the pentavalent vaccines, but I'd also like to remind you that, at least for this first generation of pentavalent vaccines, I would not withhold the use or the decision in terms of public health to include meningococcal vaccination in the national immunization programs until pentavalent vaccines are available, because as we try to explain, this first generation is the combination of already-existing vaccines, so it's indeed, once the pentavalent vaccines are available, the compliance and . . . there are a lot of interesting positive factors, as Terho already mentioned . . . but if we want to prevent disease, and this is the main goal, we can already do that with the vaccines that are already licensed, and we need to keep this in mind.

Dr Heininger: This makes perfect sense, and still, we are looking forward to yet another multicomponent vaccine, namely, the pentavalent vaccines. I would like to spend the last few minutes discussing how we should communicate with our colleagues, the healthcare providers, about the potential benefits of the pentavalent vaccines, and also to whom they should offer them. So, Terho, what are your thoughts on this?

Dr Heikkinen: As Federico already alluded to, the situation is different if a vaccine is in the official vaccination program. Then, the healthcare providers have very little to say about that. But if we are talking about a vaccine that is offered on a more so-called voluntary basis, I believe that we should deal with the healthcare providers and also the target groups, like we've done always with all vaccines. Go back to the basics, educate and inform everyone about the burden of the illness, the seriousness of the illness, and the many serotypes that are causing the illness. Then, on the other side, there is an easy way to prevent those illnesses with a vaccine that covers all those major serotypes. I think that sounds like a deal that most sensible people would buy.

They ask questions about the safety of the vaccines, especially now after the COVID-19 pandemic, so there has to be reliable information and evidence on the safety of the vaccines to make people take them. But in the end, I think that with these pentavalent vaccines, the possibilities to convince people about the importance of this vaccination are higher than with separate meningococcal vaccines. [To whom] should we offer them? Well, basically to everyone belonging to an age group that has an indication. I think that's the case, because there's no way to predict who will get an invasive meningococcal infection and who will not.

Dr Heininger: Yes. I think we can all agree on that, Terho. And Federico, what's your point on this?

Dr Martinón-Torres: Well, my point is that IMD is a single disease caused by different serogroups, but a single disease. Up to now, we have different vaccines because of technical promise to develop a single vaccine containing all potential targets. That's the reality, but at the end of the day, we want to prevent the disease, not a specific serogroup. So we will need some sort of change in the mindset, because when these vaccines are available and they are licensed, and once we know they are safe and they have a complete label that allows us use in different situations, we should use the vaccine that has the broader coverage. So for me, it's an easy way of thinking, and if we think about other diseases, pneumococcal disease, we use the vaccines that have more valency, irrespective of whether some of the serotypes are not currently present in your country, but you use the vaccine that has the wider valency.

So here, it's the same and, as a matter of fact, we are already doing that. When we use the MenACWY vaccine against the W serogroup, and in Europe, for example, we hardly have A serogroup and nobody thinks about that. We are using that because we want the broader protection and we don't have another choice. So I think that it's some sort of natural step we need to take in the future, once these vaccines are available, and then you will need 1, 2, 3 doses or whatever, as Terho said, depending on which serogroup you target, which is the predominant epidemiology in your particular region, but we have to try to avoid every single case irrespective of what's the causing serogroup.

Dr Heininger: I can very much agree on that, Federico, being a practicing infectious disease specialist. I like your pragmatic approach and that makes perfect.

So I would like to conclude this activity by saying that, indeed, IMD is horrible, and it has detrimental sequelae, both somatic but also psychosocial for the affected individuals and also for their families. Most cases worldwide are caused by vaccine-preventable serogroups, namely A, B, C, W and Y, and to some extent also X, with globally and timely variable proportions. The COVID-19 pandemic-associated honeymoon period with low IMD incidence has now come to an end and, unfortunately, case numbers are rising again. A pentavalent meningococcal ABCWY vaccine, rather than a separate A, C, W, Y, and B vaccine, in our view, addresses the variable epidemiology of this disease best. And with this, I would like to conclude and thank Federico and Terho for a really great discussion and great presentations, and also thank you for participating in this activity. Now, please continue on and answer the questions that follow and complete the evaluation. Thank you very much indeed.

This is a verbatim transcript and has not been copyedited.