Immunogenicity of a single 4CMenB vaccine booster in adolescents 11 years after childhood immunisation.

The clinical development of the meningococcal vaccine, 4CMenB, included 2 doses in vaccine-naïve adolescents, which was considered unlikely to be cost-effective for implementation. Theoretically, priming with 4CMenB in early childhood might drive strong immune responses after only a single booster dose in adolescents and reduce programmatic costs. To address this question, children over 11 years old who took part in previous trials involving the administration of 3-5 doses of 4CMenB at infant/preschool age from 2006 were recruited into a post licensure single-centre trial, and were divided into two groups: those who received their last dose at 12 months old (infant group) and those who received their last dose at 3 years old (infant + preschool group). Naïve age-matched controls were randomised to receive one (adolescent 1 group) or two doses at days 0 and 28 (adolescent 2 group) of 4CMenB. Serum bactericidal antibody (SBA) assays using human complement were performed against three reference strains prior to vaccination, and at 1, 6 and 12 months. Previous vaccination was associated with a higher response to a single booster dose at 11 years of age, one-month post-vaccination, when compared with a single dose in naïve age-matched controls. At day 180, the highest responses were observed in participants in the infant + preschool group against strain 5/99 (GMT 316.1 [CI 158.4 to 630.8]), as compared with naïve adolescents who received two doses (GMTs 84.5 [CI 57.7 to 123.6]). When the last dose was received at 12-months of age, responses to a single adolescent dose were not as robust (GMT 61.1 [CI 14.8 to 252.4] to strain 5/99). This descriptive study indicates that the highest SBA responses after a single dose in adolescence were observed in participants who received a preschool dose, suggesting that B cell memory responses are not sufficiently primed at less than 12 months of age. Trial registration EudraCT 2017-004732-11, ISRCTN16774163.

Implementation Experience With Meningococcal Serogroup B Vaccines in the United States: Impact of a Nonroutine Recommendation.

BACKGROUND: Meningococcal serogroup B (MenB) is the leading cause of invasive meningococcal disease among US adolescents and young adults, accounting for 62% of cases in 16-23-year-olds in 2018. Since 2015, the Advisory Committee on Immunization Practices (ACIP) has recommended vaccination of healthy adolescents against MenB based on shared clinical decision-making (previously called "Category B" or individual clinical decision-making). However, MenB vaccine coverage and series completion rates remain low. Herein we examine implementation experience of adolescent MenB vaccination in the United States under this nonroutine ACIP recommendation. METHODS: PubMed was searched for English-language articles published after 2015 examining MenB vaccination implementation in the United States. Studies reporting MenB vaccination awareness, coverage, knowledge of recommendations and implementation barriers or access disparities were included. RESULTS: Identified studies provided evidence that ACIP's MenB vaccination recommendation is poorly understood and prone to misinterpretation by US healthcare providers. Parental awareness of MenB vaccines is low, and racial and socioeconomic disparities exist regarding vaccine receipt. Parents rely on providers to learn about MenB disease risk and benefits of vaccination, with provider recommendations carrying substantial weight in vaccination decisions. CONCLUSIONS: Five years of evidence regarding the MenB vaccination implementation experience suggest that the nonstandard recommendation for MenB vaccines is partly responsible for low vaccine coverage. Further, inconsistent implementation of ACIP recommendations could be limiting access to MenB vaccines. Providers need additional support and guidance to implement the shared clinical decision-making recommendation, in turn ensuring equitable access for vaccine-eligible adolescents to enable comprehensive protection against meningococcal disease.

Use of Cost-Effectiveness Analyses for Decisions About Vaccination Programs for Meningococcal Disease in the United States, United Kingdom, The Netherlands, and Canada.

INTRODUCTION: Meningococcal vaccines to protect against invasive meningococcal disease (IMD) vary in terms of vaccine technology and serogroup coverage (Polysaccharide MnACWY, conjugated C and ACWY, outer membrane vesicle-based or protein-based B vaccines), and the national recommendations for each of them vary in terms of target population and number of doses. We sought to understand factors associated with the evolution of meningococcal vaccination program recommendations in four countries with formal evaluation processes: the UK, US, the Netherlands, and Canada. AREAS COVERED: A targeted review of published literature and internet sources for the four countries relating to meningococcal vaccination decision-making was conducted. The review focused on the impact of cost-effectiveness analyses on vaccine policy decisions and the extent to which variation in incidence of IMD and its potential catastrophic consequences influenced policy decisions.The evolution of meningococcal vaccine recommendations in the four countries was mainly driven by changes in vaccine availability and changes in serogroup incidence. Public pressure due to the catastrophic nature of IMD influenced recommendations. The role of cost-effectiveness analyses varied across the 4 countries. EXPERT OPINION: The value of implementing meningococcal vaccination programs should be assessed using factors beyond those included in traditional cost-effectiveness analyses.

Introduction of a second MenB vaccine into Europe - needs and opportunities for public health.

INTRODUCTION: Invasive meningococcal disease (IMD) can be devastating; it is associated with high case fatality rates and long-term sequelae among many survivors. Five serogroups (A, B, C, W, and Y) cause nearly all IMD cases worldwide, and serogroup B (MenB) is the most prevalent in Europe. The European Medicines Agency approved the use of MenB-fHbp (Trumenba®; Pfizer Ltd, Sandwich, UK) in individuals ≥10 years of age for the prevention of MenB IMD in May 2017. MenB-fHbp contains two lipidated recombinant fHbp variants from two different fHbp subfamilies that help provide broad coverage against circulating meningococcal strains and may also improve antibody response compared to a nonlipidated antigen. AREAS COVERED: This review summarizes the latest epidemiology evaluating the disease burden of MenB in Europe, introduces MenB-fHbp (the vaccine most recently approved in the European Union for the prevention of MenB IMD), and provides an overview of its development. EXPERT OPINION: MenB is by far the most prevalent meningococcal serogroup in Europe, and its epidemiology is not currently addressed by European immunization recommendations. New strategies to prevent MenB IMD in Europe will continue to develop with the growing use of vaccines to prevent MenB disease, with increasing support through national immunization programs.

[Efficacy, safety, and cost-effectiveness of meningococcal vaccines].

Meningococcal meningitis is an acute, severe respiratory infectious disease caused by Neisseria meningitidis. Immunization with meningococcal vaccine is the most effective measure to control and prevent transmission of meningococcal meningitis. Meningococcal vaccines in the Chinese market include meningococcal polysaccharide vaccine, meningococcal polysaccharide conjugate vaccine, and a combined vaccine containing meningococcal polysaccharide conjugate vaccine. This article reviews research progress on the efficacy, safety, and cost-effectiveness of meningococcal vaccines, particularly in the Chinese market, to support appropriate use of the various meningococcal vaccines for preventing meningococcal meningitis.

Lessons from the Meningitis Vaccine Project.

From 2001 to 2017 the Meningitis Vaccine Project (MVP), a Gates Foundation funded partnership between PATH and the World Health Organization (WHO), successfully developed, tested, licensed, and introduced an affordable new Group A meningococcal conjugate vaccine, MenAfriVac, in sub-Saharan Africa. The vaccine was well received, and from 2010 to 2016, over 260 million Africans have received a dose of the vaccine in campaigns largely directed at 1­29-year olds. The public health impact has been dramatic with the elimination of Group A meningococcal infections wherever the vaccine has been used at public health scale. Over its 16-year life span, MVP faced many challenges, and lessons were learned that may be of interest to other groups seeking to develop vaccine products for resource-poor countries. We have chosen to highlight six elements that were keys to the success of the project: (a) country and African regional engagement during all phases of the project; (b) the evolution of the WHO/PATH partnership; (c) funding the introduction of MenAfriVac in meningitis belt countries; (d) regulatory challenges; (e) clinical trials in Africa and India; and (f ) the realities of vaccine development partnerships.

Successful African introduction of a new Group A meningococcal conjugate vaccine: Future challenges and next steps.

The introduction of a new Group A meningococcal conjugate vaccine, MenAfriVacR, has been a important public health success. Group A meningococcal meningitis has disappeared in all countries where the new Men A conjugate vaccine has been used at public health scale. However, continued control of Group A disease in sub-Saharan Africa will require that community immunity against Group A meningococci be maintained. Modeling studies have shown that unless herd immunity is maintained Group A meningococcal disease will return. To ensure that African populations remain protected birth cohorts must be protected with an EPI formulation of MenAfriVacR (5 mcg) given at 9 months with Measles 1. In addition, populations born after the initial 1-29 year old campaigns and consequently not yet immunized with the new Men A conjugate vaccine, will have to be immunized in country-specific catch-up campaigns. Countries with poor EPI coverage (Measles 1 coverage < 60%) will likely need quinquennial vaccination campaigns aimed at covering 1-4 year olds. Implementing these strategies is the only sure way of ensuring that Group A meningococcal meningitis epidemics will not recur. A second problem that requires urgent attention is the challenge of dealing with Non-A meningococcal meningitis epidemics in sub-Saharan Africa. Groups C, W and X meningococci are well-established circulating strains in sub-Saharan Africa and are responsible for yearly focal meningitis epidemics that vary in severity and remain unpredictable as to size and geographic distribution. For this reason, polyvalent meningococcal conjugate vaccines that are affordable and appropriate for the African context must be developed and introduced. These new meningococcal vaccines when combined with more affordable pneumococcal conjugate vaccines offer the promise of a meningitis-free Sub-Saharan Africa.

Developmental strategy for a new Group A meningococcal conjugate vaccine (MenAfriVacR).

Until recently, periodic Group A meningococcal meningitis outbreaks were a major public health problem in the sub-Saharan Africa. In 2001, the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and PATH, a Seattle-based NGO, and the Serum Institute of India Pvt Ltd (SIIPL) initiated discussions aimed at establishing a collaboration to develop a Group A meningococcal conjugate vaccine for this unmet medical need. Over the next 8 years the partnership made countless strategic decisions about product characteristics, raw materials, potential target populations, geographic prioritization and affordability of the vaccine to name a few. These decisions evolved into detailed plans for preclinical development, extensive field trials in Africa and India and a focused regulatory strategy specific for the Men A conjugate vaccine. Important characteristics of the process included, flexibility, transparency andeffective partnerships that included public agencies as well as private companies in Africa, Europe, the United States and India.

Vaccine prevention of meningococcal disease in Africa: Major advances, remaining challenges.

Africa historically has had the highest incidence of meningococcal disease with high endemic rates and periodic epidemics. The meningitis belt, a region of sub-Saharan Africa extending from Senegal to Ethiopia, has experienced large, devastating epidemics. However, dramatic shifts in the epidemiology of meningococcal disease have occurred recently. For instance, meningococcal capsular group A (NmA) epidemics in the meningitis belt have essentially been eliminated by use of conjugate vaccine. However, NmW epidemics have emerged and spread across the continent since 2000; NmX epidemics have occurred sporadically, and NmC recently emerged in Nigeria and Niger. Outside the meningitis belt, NmB predominates in North Africa, while NmW followed by NmB predominate in South Africa. Improved surveillance is necessary to address the challenges of this changing epidemiologic picture. A low-cost, multivalent conjugate vaccine covering NmA and the emergent and prevalent meningococcal capsular groups C, W, and X in the meningitis belt is a pressing need.

The Impact of Nucleotide Sequence Analysis on Meningococcal Vaccine Development and Assessment.

Since it became available as a routine tool in biology, the determination and analysis of nucleotide sequences has been applied to the design of vaccines and the investigation of their effectiveness. As vaccination is primarily concerned with the interaction of biological molecules with the immune system, the utility of sequence data is not immediately obvious and, indeed, nucleotide sequence data are most effective when used to complement more conventional immunological approaches. Here, the impact of sequencing on the field of vaccinology will be illustrated with reference to the development and implementation of vaccines against Neisseria meningitidis (the meningococcus) over the 30-year period from the late-1980s to the late-2010s. Nucleotide sequence-based studies have been important in the fight against this aggressive pathogen largely because of its high genetic and antigenic diversity, properties that were only fully appreciated because of sequence-based studies. Five aspects will be considered, the use of sequence data to: (i) discover vaccine antigens; (ii) assess the diversity and distribution of vaccine antigens; (iii) determine the evolutionary and population biology of the organism and their implications for immunization; and (iv) develop molecular approaches to investigate pre- and post-vaccine pathogen populations to assess vaccine impact. One of the great advantages of nucleotide sequence data has been its scalability, which has meant that increasingly large data sets have been available, which has proved invaluable in the investigation of an organism as diverse and enigmatic as the meningococcus.

Cost-effectiveness of expanding childhood routine immunization against Neisseria meningitidis serogroups C, W and Y with a quadrivalent conjugate vaccine in the African meningitis belt.

BACKGROUND: Neisseria meningitidis constitutes a major public health problem among countries in the African meningitis belt. Following regional vaccination campaigns for serogroup A and subsequent increases in protection against this serogroup, non-A serogroups such as C and W now pose significant epidemic threats, particularly in young children. OBJECTIVE: To evaluate the cost-effectiveness of broadening coverage from conjugate serogroup A to quadrivalent ACWY vaccination. METHODS: We developed a 40-year Markov state transition model with annual cycles to simulate costs and clinical outcomes in children aged 1 to 10 in the 26 countries of the African meningitis belt. The incidence of CWY meningitis cases among an unvaccinated population was held constant at inter-epidemic rates of 50 per 100,000/year and 150 per 100,000/year. The country-specific cost and probability of access to meningitis care, vaccine efficacy, the mortality risk among treated and untreated meningitis cases, the risk of clinical sequelae and their respective disability weights were based on published sources. Vaccination cost was based on international prices lists, presented in 2014 US$. RESULTS: At an incidence rate of 50 per 100,000/year, routine conjugate vaccination is highly cost-effective in 14 out of 26 countries with a cost/DALY averted ranging from US$555-US$787. At the higher incidence rate of 150 per 100,000/year, quadrivalent vaccination is cost-effective in all 26 countries with a cost/DALY averted ranging from US$105-US$250. The annual incidence rate at which routine conjugate quadrivalent vaccination is expected to be economically justifiable ranges from 13 per 100,000/year in Nigeria to 142 per 100,000/year in Burundi. CONCLUSION: Routine quadrivalent conjugate vaccination against Neisseria meningitidis is cost-effective at incidence rates well below the epidemic threshold among children living in the African meningitis belt.

Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007-08 and 2014-15: a qualitative and quantitative assessment.

BACKGROUND: The UK introduced 4CMenB-a multicomponent vaccine against serogroup B meningococcal disease-into the national infant immunisation programme in September, 2015. The Meningococcal Antigen Typing System (MATS) was used to estimate coverage by 4CMenB of invasive meningococcal group B isolates obtained during 2007-08 in England and Wales (MATS coverage). We aimed to repeat the MATS survey for invasive meningococcal group B isolates obtained during 2014-15, before 4CMenB introduction; compare strain coverage between 2007-08 and 2014-15; and investigate associations between MATS coverage, age, region, and disease outcomes. METHODS: Invasive serogroup B meningococcal isolates from cases in England, Wales, and Northern Ireland during 2014-15 were assayed using MATS and compared with 2007-08 data. MATS coverage was assessed by geographical region and age group. Clinical characteristics, risk factors, and outcomes were assessed according to MATS coverage for 2014-15 English cases. FINDINGS: In 2014-15, 165 of 251 (66%; 95% CI 52-80) meningococcal group B isolates were estimated by MATS to be covered by 4CMenB, compared with 391 of 535 (73%; 95% CI 57-87) in 2007-08. The proportion of MATS-positive isolates with one vaccine antigen increased from 23% (122 of 535) in 2007-08 to 31% (78 of 251) in 2014-15, whereas the proportion with more than one antigen fell from 50% (269 of 535) to 35% (87 of 251). This effect reflected changes in circulating strains, particularly ST-269 clonal complex strains. MATS coverage increased with age, varied by geographical region, and was associated with more severe disease. INTERPRETATION: In 2014-15, two-thirds of meningococcal group B isolates were predicted to be covered by 4CMenB. Temporal changes in MATS coverage underscore the need for continued monitoring of antigen expression and diversity, particularly in countries with 4CMenB programmes. FUNDING: Public Health England, GlaxoSmithKline.

Does post-implementation vaccine effectiveness data support pre-implementation predictions of 4CMenB utility?

Meningococcal serogroup B vaccines have been licensed on the basis of safety and immunogenicity data without efficacy studies. Establishing the breadth of coverage of these new vaccines has proved difficult and relied on correlates of protection such as serum bactericidal antibody and a novel assays such as the meningococcal antigen typing system. The demonstration of the effectiveness of 4CMenB in a reduced infant dose schedule together with detailed phenotypic and genotypic information gained from isolates and sera from cases of invasive MenB disease in vaccine eligible infants will enable a re-evaluation of our knowledge of correlates of protection. This review includes how the utility of 4CMenB was estimated and key considerations that were taken.

High-dimensional assessment of B-cell responses to quadrivalent meningococcal conjugate and plain polysaccharide vaccine.

BACKGROUND: Neisseria meningitidis is a globally important cause of meningitis and septicaemia. Twelve capsular groups of meningococci are known, and quadrivalent vaccines against four of these (A, C, W and Y) are available as plain-polysaccharide and protein-polysaccharide conjugate vaccines. Here we apply contemporary methods to describe B-cell responses to meningococcal polysaccharide and conjugate vaccines. METHODS: Twenty adults were randomly assigned to receive either a meningococcal plain-polysaccharide or conjugate vaccine; one month later all received the conjugate vaccine. Blood samples were taken pre-vaccination and 7, 21 and 28 days after vaccination; B-cell responses were assessed by ELISpot, serum bactericidal assay, flow cytometry and gene expression microarray. RESULTS: Seven days after an initial dose of either vaccine, a gene expression signature characteristic of plasmablasts was detectable. The frequency of newly generated plasma cells (CXCR3+HLA-DR+) and the expression of transcripts derived from IGKC and IGHG2 correlated with immunogenicity. Notably, using an independent dataset, the expression of glucosamine (N-acetyl)-6-sulfatase was found to reproducibly correlate with the magnitude of immune response. Transcriptomic and flow cytometric data revealed depletion of switched memory B cells following plain-polysaccharide vaccine. CONCLUSIONS: These data describe distinct gene signatures associated with the production of high-avidity antibody and a plain-polysaccharide-specific signature, possibly linked to polysaccharide-induced hyporesponsiveness.

Prevention of Meningococcal Infection in the United States: Current Recommendations and Future Considerations.

Neisseria meningitidis is a common cause of bacterial meningitis and septicemia that can lead to permanent sequelae or death. N meningitidis is classified into serogroups based on the composition of the capsular polysaccharide, with serogroups A, B, C, W, X, and Y recognized as the major disease-causing organisms. The unpredictability of infection coupled with the poor prognosis for some patients suggests immunization as an effective preventive strategy. Importantly, four of the six disease-causing serogroups (A, C, Y, and W) may be prevented with available quadrivalent capsular polysaccharide-protein conjugate vaccines; these vaccines have been successfully implemented into immunization programs in the United States. Unfortunately, quadrivalent conjugate vaccines are not effective against serogroup B, now the most common cause of invasive meningococcal disease. Two recombinant protein vaccines recently were licensed for prevention of serogroup B disease. Recommendations for use of these serogroup B vaccines in the United States have been made by the Advisory Committee on Immunization Practices. This article will discuss all available meningococcal vaccines, current recommendations for use, lessons learned from previous experiences, and future considerations, with the hope of further understanding how use of these vaccines may help reduce incidence of meningococcal disease in the United States.

Can we control all-cause meningococcal disease in Europe?

Invasive disease caused by Neisseria meningitidis is potentially devastating, with a case fatality rate of 5-15% and high rates of significant sequelae among survivors after septicaemia or meningitis. Capsular group C (MenC) conjugate vaccines have been highly successful in achieving control of MenC disease across Europe, and some countries have also introduced quadrivalent MenACWY conjugate vaccines to reduce disease caused by groups A, W and Y in addition to C. These vaccines putatively elicit protective levels of bactericidal antibodies in all age groups, induce immunologic memory and reduce nasopharyngeal carriage, thereby leading to herd protection. Protein-based meningococcal vaccines based on subcapsular components, and designed primarily to target capsular group B (MenB) disease, have recently been licensed. These vaccines are highly immunogenic in infants and adolescents, inducing bactericidal antibodies against strains expressing high levels of vaccine antigens which are identical to the variants present in the vaccines. Effectiveness of these vaccines at a population level will be determined by whether vaccine-induced antibodies provide cross-protection against variants of the vaccine antigens present on the surface of the diverse collection of circulating invasive strains. The level of serum bactericidal activity induced against strains also seems to depend on the level of expression of the vaccine antigens. The duration of protection and the impact on carriage of meningococci will have a major bearing on the overall effectiveness of the programme. In September 2015 the UK became the first country to introduce the multicomponent meningococcal serogroup B vaccine (4CMenB) into a national routine immunization schedule, and data on the effectiveness of this programme are anticipated in the next few years.

Comparative Assessment of a Single Dose and a 2-dose Vaccination Series of a Quadrivalent Meningococcal CRM-conjugate Vaccine (MenACWY-CRM) in Children 2-10 Years of Age.

BACKGROUND: We compared the immunogenicity, safety and 1-year antibody persistence of a single-dose and a 2-dose series of a licensed meningococcal ACWY-CRM conjugate vaccine (MenACWY-CRM) in 2- to 10-year-old children. METHODS: In this phase III, multicenter, observer-blind study, children aged 2-5 years (n = 359) and 6-10 years (n = 356) were randomized 1:1 to receive 2 doses of MenACWY-CRM (ACWY2) or 1 dose of placebo followed by 1 dose of MenACWY-CRM (ACWY1), 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement (hSBA). Primary outcomes were to assess the immunologic noninferiority and superiority of ACWY2 versus ACWY1. RESULTS: One-month after the second dose, the hSBA seroresponse in ACWY2 was noninferior to ACWY1 for all 4 serogroups, in both age cohorts, and was superior for serogroups C and Y in the 2- to 5-year-old age cohort and for serogroup Y in the 6- to 10-year-old age cohort. Overall, 90%-99% of subjects in ACWY2 and 65%-96% in ACWY1 had hSBA titers ≥ 8; geometric mean titers were 1.8- to 6.4-fold higher in ACWY2 than ACWY1 across serogroups. At 1 year postvaccination, geometric mean titers declined, and the differences between ACWY2 and ACWY1 remained significant for serogroups A and C in the 2- to 5-year-old age cohort and for serogroups C and Y in the 6- to 10-year-old age cohort. The safety profile of MenACWY-CRM was similar in both groups. CONCLUSIONS: The single dose and 2-dose MenACWY-CRM series were immunogenic and well tolerated. Although antibody responses were greater after 2 doses, especially in the 2- to 5-year-old age cohort, this difference was less pronounced at 1 year postvaccination.

The multicomponent meningococcal serogroup B vaccine (4CMenB): origin, composition, health impact and unknown aspects.

Neisseria meningitidis serogroup B is the main cause for meningococcal invasive disease in many parts of the world. Since 2013, a new multicomponent vaccine against meningococcal serogroup B (4CMenB) has been licensed in Europe, Australia, Canada, Chile, Uruguay, USA and Brazil with different immunization schedules. Clinical trials involving adults, adolescents, children and infants showed 4CMenB has a good immunogenicity and safety profile. Strain coverage estimates are similar to or better than other recently approved vaccines, ranging from 66% in Canada to 91% in Unites States. Some points still remain to be clarified such as the best immunization strategy, the effect of 4CMenB on carriage, the long-term persistence of protective bactericidal antibodies titers, long-term safety outcomes, the possible emergence of N. meningitidis escape mutants and the vaccine cost-effectiveness. In this review, we focus on the vaccine composition, clinical trials and suggested schedules, safety data, potential strain coverage and future challenges.