
==== Front
Hum Vaccin Immunother
Hum Vaccin Immunother
Human Vaccines & Immunotherapeutics
2164-5515
2164-554X
Taylor & Francis

39263919
10.1080/21645515.2024.2396220
2396220
Version of Record
Review Article
Meningococcal
Policies for the immunization against serogroup B meningococcus for adolescents immunized during the first two years of life: A mini review
C. PALMIERI ET AL.
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Palmieri Claudia
Moscara Lorenza
Tafuri Silvio
https://orcid.org/0000-0002-3279-0196
Stefanizzi Pasquale
Interdisciplinary Department of Medicine, Hygiene Unit, University of Bari Aldo Moro , Bari, Italy
CONTACT Pasquale Stefanizzi pasquale.stefanizzi@uniba.it Interdisciplinary Department of Medicine, Hygiene Unit, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, Bari (BA) 70124, Italy.
12 9 2024
2024
12 9 2024
20 1 2396220Integra31 8 2024
Integra31 8 2024
09 6 2024
02 8 2024
21 8 2024
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

Two vaccines are available to prevent serogroup B meningococcal disease, i.e. the four-component meningococcal serogroup B vaccine (4CMenB) and the bivalent-factor-H-binding-protein meningococcal serogroup B vaccine (MenB-fHbp). Currently, 4CMenB is offered as part of routine infant immunization schedules. Available immunogenicity data showed a progressive decline in protective serum bactericidal antibodies (SBA) titers, with a re-enhancement following a booster dose during infancy. Responses did not seem to be long-lasting and vaccinated individuals might be at risk of meningococcal diseases duriṇg adolescence. Only one study evaluated the possibility to administer a single booster dose to immunocompetent adolescents who received a primary series during infancy. Despite a high proportion of enrollees achieving protective SBA levels 28 days post-booster, titers tended to decrease 1 year after. Immunocompetent adolescents who received a primary series and a booster during the first two years of life might rather benefit from re-vaccination against MenB; current evidence does not support the possibility of a booster.

KEYWORDS

MenB vaccines
adolescents
long-term immunogenicity
booster
re-vaccination
The author(s) reported that there is no funding associated with the work featured in this article.
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pmcThe aim of this mini-review is to summarize current evidence about the use of serogroup B meningococcal (MenB) vaccines for immunization campaigns targeting immunocompetent adolescents already immunized during the first two years of life.

Serogroup B meningococcal vaccines

Two vaccines are widely available for the prevention of invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B, i.e., the four-component, protein-based serogroup B meningococcal vaccine (4CMenB, Bexsero®, GlaxoSmithKline Inc.) and the bivalent recombinant Factor H binding protein meningococcal serogroup B vaccine (MenB-fHbp, Trumenba®, Pfizer Inc.).

In detail, 4CMenB vaccine administration is intended to stimulate the production of serum bactericidal antibodies (SBA) against four protein antigens variably expressed by serogroup B meningococci, i.e., neisserial heparin-binding antigen (NHBA), neisserial adhesion A (NadA), factor-H binding protein (fHbp), and PorA P1.4 (the latter present in outer membrane vesicles, OMV).1,2 On the other hand, the MenB-fHbp vaccine aims at stimulating the production of SBA that recognizes two recombinant variants of fHbp (subfamily A and B), a lipoprotein expressed on >97% of MenB strains.3,4

Both vaccinal products are currently approved in over 50 countries worldwide,5 although licensing differences between countries exist.6

4CMenB vaccine received marketing authorization from the European Medicines Agency (EMA), Canada and Australia in 2013 and by the Food and Drug Administration (FDA) in 2015.6,7 In Europe, as well as in Australia, 4CMenB is indicated for active immunization of individuals from 2 months of age and older,1,8 while in Canada an upper age limit of 25 years is set.9 On the other hand, in the United States (US), the vaccine is currently approved for use in individuals aged 10 through 25 years.10 According to the age at first dose, 4CMenB is administered to infants up to 23 months of age as a two- or three-dose primary series plus a booster.1 In individuals 2 years of age and older, the two-dose vaccination cycle is not routinely followed by a booster dose.1,9,10 Nevertheless, based on official recommendations, a booster dose should be considered in individuals at continued risk of exposure to meningococcal disease.1 In this regard, the US Advisory Committee on Immunization Practices (ACIP) recommendations specifically state that individuals at increased risk (i.e., those belonging to selected health- or exposure-based risk groups) should receive booster doses at 1 year after the completion of primary vaccination and every 2–3 years thereafter.11 As in Europe, in the US, no routine booster doses are indicated for healthy individuals who are not at increased risk of IMD.1,11

MenB-fHbp vaccine was approved by the FDA in 201412 and by EMA, Canada and Australia in 2017.13 In Europe and Australia, MenB-FHbp is indicated for active immunization of individuals from 10 years of age and older,14,15 while in the US and Canada, the vaccine is approved for use in subjects 10 through 25 years of age.16,17 The vaccine can be administered following either a two- or three-dose primary series schedule. As with 4CMenB, no routine booster doses are recommended, unless the individual remains at increased risk of IMD.11,14,16

Serogroup B meningococcus epidemiology and national vaccination policies

Based on epidemiologic evidence and vaccine approval and availability, MenB vaccines have been progressively included in National Immunization Programmes (NIPs) worldwide.6

Indeed, in the 2010–2019 decade, MenB has been the predominant serogroup accounting for roughly half of IMD cases in Europe, Israel, Australia, New Zealand, Quebec as well as in some South American countries (Argentina, Chile).18,19 Based on the available data, in 2017–2019, serogroup B prevailed also in South Africa, Russia, the United States, and China.18–20

Many of the countries where MenB is the most common cause of IMD offer 4CMenB vaccination free of charge as part of routine infant immunization schedules. In particular, this is the case in many European countries (including, but not limited to, Italy,21 UK,22 Ireland,23 France, and Portugal).6,22–25 Outside Europe, South Australia also funded infant and children vaccination programs using 4CMenB.26 In other countries (e.g. Austria and Germany), instead, infant vaccination is routinely recommended nationwide, but not funded.22,23

However, it should be noted that no immunization policies against MenB are available in many countries where group B is the most prevalent meningococcal serogroup. For example, none of the MenB vaccines has been licensed in China27 or Russia23 so far. Moreover, due to 4CMenB approval in more restricted age groups, in the US, the vaccine is not used for infant immunization; actually, both MenB vaccines are recommended only for adolescents and young adults aged 16−23.28 Adolescent vaccination is also offered actively and free of charge in some Italian regions (with MenB-FHbp being preferentially used)29,30 and in South Australia,26 among others.

In addition to age-based recommendations, vaccination against serogroup B meningococcus using either vaccine is widely recommended and offered worldwide for individuals belonging to selected health (e.g., asplenia, immunodeficiencies, or complement deficiencies) and exposure-based (e.g., laboratory staff working with N. meningitidis, people living in overcrowded settings, military personnel) risk groups, even outside the licensed age indications11 and in countries where routine MenB immunization is not included in NIPs (e.g. Canada).31 However, there is no universal consensus on the definition of risk categories.23

Immunogenicity after primary immunization series plus booster doses

Due to the overall low incidence of IMD, effectiveness data of 4CMenB and MenB-fHbp were not available at the time of vaccine licensure.1,3 However, more recent real-world evidence from Quebec, South Australia, the UK, Italy, and Portugal, obtained after the inclusion of the vaccine in NIPs or its use in outbreak management, showed the estimated 4CMenB effectiveness in fully vaccinated cohorts to range from 59% to 100%.32

On the other hand, immunogenicity data were widely available and considered for both MenB vaccine approval.1,3 Since protection against extracellular bacterial infections is mainly mediated by specific antibody responses,33 a hSBA titer of ≥4 was considered an accepted protective threshold against serogroup B meningococci.34 Despite T cells being useful in promoting phagocytosis, potentiating antibody responses, and establishing immunological memory, T cell responses are more difficult to evaluate and have been thus poorly assessed.33

A systematic review and meta-analysis, published in 2018, summarized existing immunogenicity data following 4CMenB vaccination in both children and adolescents.35 Ten randomized trials and eight extension trials provided evidence of optimal seroconversion against four reference MenB strains 30 days after the primary immunization course (ranging from 91% to 100% in the per-protocol analysis and 84–92% in the intention-to-treat analysis, depending on the strains considered). Six months or more after the primary course, immunogenicity remained adequate-to-high in adolescents for all tested strains (≥77%), while it declined substantially in children for some strains (with values as low as 33% in the per-protocol analysis). However, as reported in seven datasets, administration of a booster dose at various time points (i.e., between 12 and 40 months of life)36–41 re-enhanced the proportion of patients who achieved seroconversion (≥93% for all strains). Nevertheless, the result was not long-lasting: 6 months after booster administration, the proportion of individuals who achieved protective SBA dropped to pre-booster levels for the same strains.35

The role of 4CMenB booster doses was also investigated in a phase IIIb study42 enrolling 276 adolescents and young adults aged 15–24, who completed a two-dose 4CMenB primary series 4 and 7.5 years before as part of a parent study. Compared to the 1-month post-primary vaccination titers, SBA levels were found to be lower for almost all vaccine antigens at 4- and 7.5-years post-vaccination. However, a booster dose 4 and 7.5 years after completing the primary vaccination series elicited significant immune responses in nearly all enrollees (93–100%) 30 days post-booster, regardless of the interval between the 4CMenB booster and the last received dose.

As regards MenB-fHbp, a phase III study addressed immuno-persistence for up to 4 years in 623 adolescents (11–18 years) who received a complete two- or three-dose primary series during previous phase II studies and, 30 days after the last primary dose, achieved seroconversion in 73.8% to 100.0% of cases (depending on the considered strain).43 A decline in serum bactericidal antibodies was recorded during the first 12 months post-primary series, with a plateau through 48 months after the last received dose. Overall, only 18% and 61.3% of participants maintained protective antibody titers at 48 months. At this point, nearly half of the enrolled patients received a MenB-fHbp booster dose and were followed up for an additional 26 months. The booster dose was well tolerated and, regardless of the primary dosing schedule received, it led to protective antibody titers against each test strain in 93.4–100.0% of subjects 1-month post-booster. For those who continued the follow-up, percentages of immune persistence at 12 and 26 months following booster dose decreased; still, they were higher than those recorded at similar time points following primary vaccination, potentially suggesting a role for booster doses.

Potential role of MenB vaccine boosters in adolescents who received infant schedules

These preliminary findings suggest that MenB vaccination-induced protective levels of SBA tend to decline over time. Low circulating antibody titers might not effectively prevent IMD, as in this instance the immunological memory response might be too slow to protect against the rapid evolution of meningococcal disease.44 As previously mentioned, it has not been clearly assessed so far whether memory T cell responses might persist and remain stable over a longer time span and thus protect against IMD.33 Nevertheless, the reasonable assumption that a downfall in humoral memory might increase the risk of IMD poses a Public Health challenge: indeed, due to the progressive introduction of MenB vaccines in NIPs, more and more adolescents will have already received a complete primary immunization series during infancy (and possibly a booster, depending on the age at first dose). However, despite previous vaccination, these subjects might not be protected against MenB due to waning antibody titers. For example, 4CMenB was introduced in Italian routine infant immunization programs as early as 2017; thus, in a few years, almost all adolescents will have been primed (and boosted) during infancy.20,45,46 Considering serogroup B meningococci prevalence in Europe and the relatively high risk of IMD in adolescents,18,47 it is imperative to evaluate the possibility of administering a MenB vaccine booster dose to adolescents who received a primary immunization cycle during infancy. It should also be considered that, due to the absence of effective vaccination policies in countries where MenB circulates, international travel might allow possible re-introduction of MenB even in countries with established vaccination programs;48 in such case, adolescents would be particularly at risk, especially if considering the decrease in protective SBA titers.

Moreover, it should also be investigated whether heterologous vaccination using a different MenB vaccinal product would be possible, as different manufacturers’ serogroup B-containing vaccines are not interchangeable, at least according to the latest indications.11

The first study to explore the usefulness of a 4CMenB booster dose administered to adolescents who received a primary MenB vaccination series during infancy was conducted in 2018–2020 in the UK.34 Researchers quantified the persisting SBA levels against three reference strains in 38 adolescents approximately 11 years after primary vaccination. In particular, among those who received an infant schedule without a pre-school booster (n = 15), only 0–26.7% had protective SBA titers, depending on strains; on the other hand, patients who received a booster dose at 40–42 months of age (n = 23) had a higher proportion of immuno-persistence (17.4–69.6%). An adolescent 4CMenB booster dose was then administered, and SBA titers were measured 28, 180, and 365 days following vaccination. Predictably, the highest proportion of protective SBA values was recorded 28 days after booster dose administration (ranging from 78.6 to 100% of cases, depending on the strain tested and primary dosing schedule received). Protective responses were found to decline over time. However, by the time of the 1-year post-booster follow-up, the proportion of individuals who maintained protective SBA titers was higher in vaccinated individuals belonging to the pre-school boosted cohort (45.5–100% vs 30.8–69.2% of those who did and did not receive the pre-school booster, respectively).34

Conclusion

Given the few available data, further investigation is warranted to explore the long-term immunogenicity of infant MenB immunization. Indeed, MenB vaccination schedules are safe and extremely beneficial during the first years of life, when the risk of IMD caused by MenB is high;49 nevertheless, despite the proven benefits during infancy and childhood,50 MenB vaccination in early life might not provide adequate immuno-protection during other high-risk periods later in life.47,51 Therefore, the possibility of administering additional MenB vaccine doses to adolescents with a primary immunization series given during infancy should be assessed. Moreover, the optimal timing for booster administration should be investigated, in order to maintain protective circulating antibody titers during adolescence and early adulthood, when the risk of meningococcal disease is high.47,51–53

However, currently available data do not seem to support the idea of administering a booster dose to immunocompetent adolescents already primed during infancy. Safety issue (occurrence of adverse events, systematic causal link evaluation) and organizational barriers needs to be further investigated.54–57 To our knowledge, the possibility has only been explored in one study so far, with results limited by the small sample size (n = 38).34 In addition, Regulatory Authorities do not seem to support this vaccination strategy to date. Hence, based on available evidence, serogroup B meningococci protection in immunocompetent adolescents who received complete primary immunization schedules during infancy might be more likely enhanced by “re-vaccination” strategies, rather than by administering a single booster dose.

Pasquale Stefanizzi qualified in Medicine at the University of Parma in 2014, and he achieved a post-degree in Hygiene and Preventive Medicine at the University of Bari in 2019. He is a consultant of the Apulian Observatory for Epidemiology in the field of immunization policies (focus on safety and effectiveness of vaccination programs), surveillance and management of infectious diseases, and health organizations. Since July 2020, he has been an Assistant Professor of Public Health at the School of Medicine in Bari. He works as a medical doctor at the Bari Policlinico General Hospital – Hygiene Unit, in which he is charged with the management of vaccination activities; since March 2020, he is a member of the COVID-19 Control Room Unit.

He is a member of the National Group of monitoring the safety of vaccines coordinated by the National Drug Agency.

He is the author or co-author of 120 indexes of scientific papers and over 10 teaching books in the fields of epidemiology and public health.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions statement

CP and PS conceived the study. CP and LM did the literature research and data collection. CP and ST co-drafted the first version of the article. All authors have revised and approved the submitted version of the manuscript.
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