The Diverse Spectrum of Invasive Meningococcal Disease in Pediatric and Adolescent Patients: Narrative Review of Cases and Case Series.

INTRODUCTION: Invasive meningococcal disease (IMD) is a potentially life-threatening disease caused by Neisseria meningitidis infection. We reviewed case reports of IMD from newborns, infants, children, and adolescents, and described the real-life clinical presentations, diagnoses, treatment paradigms, and clinical outcomes. METHODS: PubMed and Embase were searched for IMD case reports on patients aged ≤ 19 years published from January 2011 to March 2023 (search terms "Neisseria meningitidis" or "invasive meningococcal disease", and "infant", "children", "paediatric", pediatric", or "adolescent"). RESULTS: We identified 97 publications reporting 184 cases of IMD, including 25 cases with a fatal outcome. Most cases were in adolescents aged 13-19 years (34.2%), followed by children aged 1-5 years (27.6%), children aged 6-12 years (17.1%), infants aged 1-12 months (17.1%), and neonates (3.9%). The most common disease-causing serogroups were W (40.2%), B (31.7%), and C (10.4%). Serogroup W was the most common serogroup in adolescents (17.2%), and serogroup B was the most common in the other age groups, including children aged 1-5 years (11.5%). The most common clinical presentations were meningitis (46.6%) and sepsis (36.8%). CONCLUSIONS: IMD continues to pose a threat to the health of children and adolescents. While this review was limited to case reports and is not reflective of global epidemiology, adolescents represented the largest group with IMD. Additionally, nearly half of the patients who died were adolescents, emphasizing the importance of monitoring and vaccination in this age group. Different infecting serogroups were predominant in different age groups, highlighting the usefulness of multivalent vaccines to provide the broadest possible protection against IMD. Overall, this review provides useful insights into real-life clinical presentations, treatment paradigms, diagnoses, and clinical outcomes to help clinicians diagnose, treat, and, ultimately, protect patients from this devastating disease.

Meningococcal B Immunisation in Adults and Potential Broader Immunisation Strategies: A Narrative Review.

Recombinant vaccines against invasive meningococcal disease due to Neisseria meningitidis serogroup B (MenB) have shown substantial impact in reducing MenB disease in targeted populations. 4CMenB targets four key N. meningitidis protein antigens; human factor H binding protein (fHbp), Neisserial heparin binding antigen (NHBA), Neisseria adhesin A (NadA) and the porin A protein (PorA P1.4), with one or more of these expressed by most pathogenic MenB strains, while MenB-FHbp targets two distinct fHbp variants. While many countries recommend MenB immunisation in adults considered at high risk due to underlying medical conditions or immunosuppression, there are no recommendations for routine use in the general adult population. We reviewed the burden of MenB in adults, where, while incidence rates remain low (and far lower than in young children < 5 years of age at greatest risk), a substantial proportion of MenB cases (20% or more) is now observed in the adult population; evident in Europe, Australia, and in the United States. We also reviewed immunogenicity data in adults from clinical studies conducted during MenB vaccine development and subsequent post-licensure studies. A 2-dose schedule of 4CMenB generates hSBA titres ≥ 1:4 towards all four key vaccine target antigens in up to 98-100% of subjects. For MenB-FHbp, a ≥ fourfold rise in hSBA titres against the four primary representative test strains was observed in 70-95% of recipients following a 3-dose schedule. While this suggests potential benefits for MenB immunisation if used in adult populations, data are limited (especially for adults > 50 years) and key aspects relating to duration of protection remain unclear. Although a broader adult MenB immunisation policy could provide greater protection of the adult population, additional data are required to support policy decision-making.

A comprehensive review of clinical and real-world safety data for the four-component serogroup B meningococcal vaccine (4CMenB).

INTRODUCTION: Neisseria meningitidis causes invasive meningococcal disease and, globally, significant morbidity, with serogroup B (MenB) being the most common cause of endemic disease and outbreaks in several regions. Extensive use of the four-component serogroup B meningococcal vaccine (4CMenB; Bexsero, GSK) and its inclusion in immunization programs in several countries have generated substantial safety data during the 9 years since its first authorization in 2013. AREAS COVERED: 4CMenB safety data from clinical trials and post-marketing surveillance studies (2011 to 2022), and spontaneously reported adverse events of medical interest from the GSK global safety database. We discuss these safety findings in relation to the benefit of 4CMenB vaccination and implications for further enhancing vaccine confidence. EXPERT OPINION: 4CMenB has been consistently well tolerated across clinical trials and post-licensure surveillance studies, despite a higher incidence of fever reported in infants than with other pediatric vaccines. Surveillance data have not identified any significant safety issues, consistent with an acceptable safety profile of 4CMenB. These findings highlight the need to balance the risk of relatively common, transient, post-immunization fever with the benefit of affording protection that reduces the risk of uncommon but potentially fatal meningococcal infection.

The four-component serogroup B meningococcal vaccine 4CMenB (Bexsero®, GSK) was licensed in 2013 and has acquired substantial safety evidence through clinical trial and real-world data. Availability of real-world and clinical 4CMenB safety evidence is important to help address vaccination hesitancy. This comprehensive review of safety data, from 9 years of 4CMenB use including recent data from the real world, shows no significant safety issues in a variety of age groups. Data show that transient fever may occur after vaccination. Invasive meningococcal disease, although rare, can be life-threatening. Abundant safety data from this review can help reassure individuals and healthcare providers on the use of 4CMenB.

Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels.

Immune responses to vaccination are tested in clinical trials. This process usually requires years especially when immune memory and persistence are analyzed. Markers able to quickly predict the immune response would be very useful, particularly when dealing with emerging diseases that require a rapid response, such as avian influenza. To address this question we vaccinated healthy adults at days 1, 22, and 202 with plain or MF59-adjuvanted H5N1 subunit vaccines and tested both cell-mediated and antibody responses up to day 382. Only the MF59-H5N1 vaccine induced high titers of neutralizing antibodies, a large pool of memory H5N1-specific B lymphocytes, and H5-CD4(+) T cells broadly reactive with drifted H5. The CD4(+) response was dominated by IL-2(+) IFN-gamma(-) IL-13(-) T cells. Remarkably, a 3-fold increase in the frequency of virus-specific total CD4(+) T cells, measurable after 1 dose, accurately predicted the rise of neutralizing antibodies after booster immunization and their maintenance 6 months later. We suggest that CD4(+) T cell priming might be used as an early predictor of the immunogenicity of prepandemic vaccines.

Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine.

Proactive priming before the next pandemic could induce immune memory responses to novel influenza antigens. In an open-label study, we analyzed B cell memory and antibody responses of 54 adults who received 2 7.5-microg doses of MF59-adjuvanted A/Vietnam/1194/2004 clade 1 (H5N1) vaccine. Twenty-four subjects had been previously primed with MF59-adjuvanted or plain clade 0-like A/duck/Singapore/1997 (H5N3) vaccine during 1999-2001. The prevaccination frequency of circulating memory B cells reactive to A/Vietnam/1194/2004 was low in both primed and unprimed individuals. However, at day 21 after boosting, MF59-adjuvanted primed subjects displayed a higher frequency of H5N1-specific memory B cells than plain-primed or unprimed subjects. The immune memory was rapidly mobilized by a single vaccine administration and resulted in high titers of neutralizing antibodies to antigenically diverse clade 0, 1, and 2 H5N1 viruses already at day 7. In general, postvaccination antibody titers were significantly higher in primed subjects than in unprimed subjects. Subjects primed with MF59-adjuvanted vaccine responded significantly better than those primed with plain vaccine, most notably in early induction and duration of cross-reacting antibody responses. After 6 months, high titers of cross-reactive antibody remained detectable among MF59-primed subjects. We conclude that distant priming with clade 0-like H5N3 induces a pool of cross-reactive memory B cells that can be boosted rapidly years afterward by a mismatched MF59-adjuvanted vaccine to generate high titers of cross-reactive neutralizing antibodies rapidly. These results suggest that pre-pandemic vaccination strategies should be considered.

Combined, concurrent, and sequential administration of seasonal influenza and MF59-adjuvanted A/H5N1 vaccines: a phase II randomized, controlled trial of immunogenicity and safety in healthy adults.

OBJECTIVE: We performed a phase II randomized, controlled, open-label, single-center study (Centros de Estudios de Infectología Pediátrica, Colombia) to examine the feasibility of combined administration of seasonal and MF59-adjuvanted A/H5N1 influenza vaccines using extemporaneous mixing or simultaneous administration. METHODS: The primary objective of the study was to assess the immunogenicity of seasonal influenza and A/H5N1 vaccines using European licensure criteria (Committee for Medicinal Products for Human Use [CHMP]); the secondary objective was to assess vaccine reactogenicity and safety. RESULTS: In 401 healthy 18-40-year-old subjects, both vaccines were immunogenic in all settings; the vaccine for seasonal influenza met all CHMP criteria, unaffected by coadministration of A/H5N1 vaccine in separate or mixed injections. Likewise, the immunogenicity of A/H5N1 vaccine was unaffected by seasonal influenza vaccination, with hemagglutination inhibition seroprotection rates of 28%-40% after 1 dose and 67%-80% after 2 doses, sufficient to meet CHMP criteria. Solicited local and systemic adverse events were mainly mild to moderate. No vaccine-related serious adverse events were reported during the study period. CONCLUSIONS: These data demonstrate that seasonal and MF59-adjuvanted A/H5N1 influenza vaccines can be given as a mixed injection or by simultaneous separate injections without affecting immunogenicity or safety, supporting the feasibility of incorporating prepandemic MF59-adjuvanted A/H5N1 vaccines into seasonal influenza vaccination programs and the development of tetravalent influenza vaccines, including pandemic strains. Clinical Trials Registration. NCT00481065.

Passive surveillance of adverse events of an MF59-adjuvanted H1N1v vaccine during the pandemic mass vaccinations.

INTRODUCTION: Systemic safety surveillance is an essential component of vaccination programmes to elucidate the full safety profile of a vaccine and to detect previously unrecognized adverse reactions that might be related to new vaccines. This article summarizes the spontaneous adverse drug reactions (ADR) from approximately 12 million administered doses of the pandemic MF59-adjuvanted H1N1v vaccine (Focetria®, Novartis Vaccines and Diagnostics) from the mass vaccination programmes in Europe. METHODS: All ADR reports from October 2009 to March 2010 were included in the analyses and classified according to Medical Dictionary for Regulatory Activities. Adverse events of special interest were compared with pooled spontaneous case reports for seasonal influenza vaccines, and signal detection analyses were performed. RESULTS: In the reporting period we received a total of 5315 pandemic vaccine ADR reports, of which 19.9% were serious. The reporting rate was higher after H1N1 pandemic vaccines, i.e. 44.3 cases/100.000 doses, than for seasonal influenza vaccines covering the same time period, i.e. 1.7 cases/100.000 doses. The majority of reports included expected local and systemic postvaccination reactions. Rates for adverse events of special interest, for example, Guillain-Barré syndrome, anaphylaxis, and convulsions showed no signs of disproportionality between the pandemic and the seasonal vaccines. There were 36 deaths reported after use of the pandemic vaccine; however, no evidence for a causal relationship with the vaccine was found. CONCLUSION: The analyses of the spontaneously reported adverse events support the good safety profile of the MF59-adjuvanted H1N1v pandemic influenza vaccine.

Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination.

OBJECTIVES: 4CMenB is a broadly protective vaccine against invasive meningococcal capsular group B disease (MenB IMD). Licensed worldwide based on immunogenicity and safety data, effectiveness and impact data are now available. We comprehensively reviewed all available real-world evidence gathered from use of 4CMenB since licensure. RESULTS: Data from 7 countries provide evidence of effectiveness and impact across different healthcare settings and age-groups, including national/regional immunization programs, observational studies and outbreak control. At least 2 4CMenB doses reduced MenB IMD by 50%-100% in 2-month to 20-year-olds depending on length of follow-up. Estimates of vaccine effectiveness in fully vaccinated cohorts ranged from 59%-100%. The safety profile of 4CMenB administered in real-world settings was consistent with pre-licensure clinical trial data. CONCLUSION: MenB IMD is an uncommon but life-threatening disease with unpredictable epidemiology. The substantial body of data demonstrating 4CMenB effectiveness and impact supports its use in IMD prevention. The results reinforce the importance of direct protection of the highest risk groups; infants/young children and adolescents. Direct protection via routine infant immunization with catch-up in young children and routine adolescent vaccination could be the preferred option for MenB disease control. A Video Abstract linked to this article is available on Figshare: https://doi.org/10.6084/m9.figshare.14546790.

Methods to evaluate serogroup B meningococcal vaccines: From predictions to real-world evidence.

Serogroup B meningococci (MenB) remain a prominent cause of invasive meningococcal disease (IMD). The protein-based multicomponent 4CMenB and the bivalent MenB-FHbp are the only currently available vaccines against MenB-caused IMD. Efficacy studies are not possible, due to the low incidence of IMD. Therefore, the vaccines' immunogenicity has been evaluated against several target strains chosen to quantify complement-mediated killing induced by each vaccine component in the serum bactericidal antibody assay. However, due to the wide genetic diversity and different expression levels of vaccine antigens across MenB strains, vaccine performance may differ from one strain to another. Here, we review the methods used to predict MenB strain coverage for 4CMenB and MenB-FHbp. Phenotypic assays such as the meningococcal antigen typing system (MATS, 4CMenB-specific) and the flow cytometric meningococcal antigen surface expression assay (MEASURE; MenB-FHbp-specific) were developed. Genomic approaches are also available, such as genetic MATS (gMATS) and the Bexsero antigen sequence type (BAST) scheme, both 4CMenB-specific. All methods allow tentative predictions of coverage across MenB strains, including that afforded by each vaccine antigen, and are rapid and reproducible. Real-world data on vaccine effectiveness are needed to confirm predictions obtained by these methods.

Persistence of the immune response after 4CMenB vaccination, and the response to an additional booster dose in infants, children, adolescents, and young adults.

The multicomponent meningococcal serogroup B vaccine, 4CMenB, has demonstrated effectiveness in preventing invasive MenB disease in infants and in controlling MenB outbreaks. The need for/timing of additional booster doses is not yet established. We reviewed eight studies that evaluated antibody persistence and booster following primary 4CMenB vaccination of infants, children, adolescents, and young adults. Putative seroprotective hSBA titers for ≥1 vaccine antigen were maintained by 76-100% of children 24-36 months after priming during infancy and in 84-100% after priming in the second year of life. hSBA levels were higher in vaccinees at 4 and 7.5 years following priming during adolescence than in vaccine-naïve individuals of a similar age. Antibodies persisted at higher levels to NHBA and NadA than to PorA or fHbp. Booster vaccination induced robust anamnestic responses, demonstrating effective priming by 4CMenB across age-groups. These data can inform decision-making to optimize vaccination strategies.

Optimizing the timing of 4CMenB vaccination in adolescents and young adults based on immune persistence and booster response data.

INTRODUCTION: Meningococcal disease has an incidence peak spread over several years during adolescence and young adulthood in the United States. Meningococcal serogroup B (MenB) vaccines have been introduced relatively recently and may help protect individuals in these age groups. Currently there is insufficient long-term experience to determine the duration of disease protection after any MenB vaccine. Understanding antibody persistence after primary vaccination and responses to booster can help inform MenB vaccination strategies and optimize disease prevention. Areas covered: Four studies in adolescents/young adults vaccinated with meningococcal B vaccine 4CMenB were reviewed with the aim to compare findings across studies and draw key learnings. The studies varied by geographic location, population characteristics, and timing of antibody measurement relative to primary vaccination. Expert opinion: Antibody persistence data for 4CMenB are substantial, extending 7.5 years post-primary vaccination. Vaccination at age 16-18 years may help protect adolescents throughout their highest age-based risk period. Similar robust responses to a single booster dose were observed 4 and 7.5 years after primary vaccination. In outbreak settings it is beneficial to have received prior vaccination; residual circulating antibodies may provide protection, and a single dose induces booster responses within 7 days, which is quicker than administration of a 2-dose series to vaccine-naïve individuals.

Protection against tick-borne encephalitis (TBE) for people living in and travelling to TBE-endemic areas.

Once considered a local health issue confined to certain regions in Russia and Central and Eastern Europe, tick-borne encephalitis (TBE) is now considered an international health concern, and the most important and widespread viral disease transmitted by ticks in Europe. The number of reported TBE cases continues to increase in many endemic regions, and new foci have been identified. Increases in travel, access to high-risk areas, and the pursuit of leisure activities within TBE-endemic areas are placing more people at risk of TBE. Travellers from non-endemic regions are often unaware of the risk of acquiring TBE and therefore many travellers are not protected against TBE. Active immunization is the most effective way to avoid TBE and its potentially life-threatening sequelae. After a tick bite, no post-exposure treatment including active/passive vaccination is available or recommended in the immunologically naive patient. Available vaccines have undergone a series of modifications and improvement in both composition (with special formulations for children) and schedules to further enhance the safety of immunization and to meet the needs of vaccinees. Efforts to develop internationally recognized recommendations for TBE vaccination for travellers are underway.

Pre-exposure rabies vaccination using purified chick embryo cell rabies vaccine intradermally is immunogenic and safe.

OBJECTIVE: To demonstrate the safety and immunogenicity of intradermal rabies pre-exposure prophylaxis with purified chick embryo cell vaccine (PCECV) in schoolchildren age 5 to 8 years in Thailand. STUDY DESIGN: In a randomized, open-label, phase II clinical trial, 2 or 3 intradermal doses of 0.1 mL PCECV (Rabipur) were administered to 703 schoolchildren on days 0 and 28 or on days 0, 7, and 28. In 206 children, 2 simulated post-exposure booster doses were given 1 year after the primary vaccination series. Rabies virus- neutralizing antibody (RVNA) titers were determined by the rapid fluorescent focus inhibition test. RESULTS: In school-age children in Thailand, a pre-exposure immunization regimen of 3 intradermal doses of PCECV produced adequate immune responses. After primary vaccination, all subjects developed RVNA titers > or =0.5 IU/mL and demonstrated a rapid increase in RVNA titer after 2 simulated post-exposure booster immunizations 1 year after the primary vaccination series. No serious adverse drug reactions occurred. CONCLUSIONS: Rabies pre-exposure immunization with PCECV is safe and immunogenic, and its implementation could save the lives of many children in rabies-endemic areas.

Multicomponent meningococcal B vaccination (4CMenB) of adolescents and college students in the United States.

Meningococcal disease is rare, easily misdiagnosed, and potentially deadly. Diagnosis in the early stages is difficult and the disease often progresses extremely rapidly. In North America, the incidence of invasive meningococcal disease (IMD) is highest in infants and young children, with a secondary peak in adolescents, a population predominantly responsible for the carriage of disease. Neisseria meningitidis serogroup B (MenB) accounts for a large proportion of meningococcal disease in North America, with documented outbreaks in three universities in the United States (US) during 2008-2013. Vaccination is the most effective way to protect against this aggressive disease that has a narrow timeframe for diagnosis and treatment. 4CMenB is a multi-component vaccine against MenB which contains four antigenic components. We describe in detail the immunogenicity and safety profile of 4CMenB based on results from four clinical trials; the use of 4CMenB to control MenB outbreaks involving vaccination at two US colleges during outbreaks in 2013-2014; and the use of 4CMenB in a Canadian mass vaccination campaign to control the spread of MenB disease. We discuss the reasons why adolescents should be vaccinated against MenB, by examining both the peak in disease incidence and carriage. We consider whether herd protection may be attained for MenB, by discussing published models and comparing with meningitis C (MenC) vaccines. In conclusion, MenB vaccines are now available in the US for people aged 10-25 years, representing an important opportunity to reduce the incidence of IMD in the country across the whole population, and more locally to combat MenB outbreaks.

Comparison of the immunogenicity and safety of the purified chick embryo cell rabies vaccine manufactured in India and Germany: A randomized, single blind, multicentre, phase IV clinical study.

This phase IV, single blind study assessed the immunogenicity and safety of India-manufactured purified chick embryo cell rabies vaccine (PCECV), compared with a German-manufactured batch obtained by the same production process. A total of 340 participants enrolled at 2 study sites in India were randomized (1:1:1:1) in 4 groups to receive a 5-dose Essen regimen with either 1 of the 3 Indian batches (PCECV-I) or the German batch (PCECV-G), administered on Days (D) 0, 3, 7, 14 and 30. The lot-to-lot consistency of PCECV-I batches in terms of induced immune response at D14 was demonstrated. The immune response elicited by PCECV-I was shown to be non-inferior to that induced by PCECV-G, as the lower limit of the 95% confidence interval for the ratio (PCECV-I/PCECV-G) of rabies virus neutralising antibody (RVNA) geometric mean concentrations was higher than 0.5 at D14. At least 96% of participants developed adequate RVNA concentrations (≥ 0.5 IU/mL) by D14 and all achieved RVNA concentrations ≥ 0.5 IU/mL by D90. RVNA levels were comparable across all groups throughout the entire study. Solicited local and general symptoms had a similar incidence in all groups. Unsolicited adverse events (AEs) were reported by 11% of participants. Only 1 serious AE (leg fracture) was reported and was not related to vaccination. No deaths and no rabies cases were recorded during the 90 days of observation. The study showed that the 3 PCECV-I and the PCECV-G batches induced a similar immune response and had a comparable safety profile when administered according to a 5-dose schedule.

Protection against tick-borne encephalitis with a new vaccine formulation free of protein-derived stabilizers.

BACKGROUND: Vaccination against tick-borne encephalitis (TBE) has been successfully employed for many years in TBE-endemic countries. Post-marketing experience gained from widespread use, however, prompted the development of improved TBE vaccines, the most modern versions of which do not contain the commonly used protein-derived stabilizers (human albumin or polygeline) of former vaccines. METHOD: This article summarizes both the medical need for and clinical experience with a new TBE vaccine formulation (pediatric and adult versions). To this end, data from clinical trials and post-marketing experience are presented. The clinical database comprises immunogenicity and/or safety data of approximately 7,500 subjects ages 1 to 77 years who participated in eight clinical trials. The clinical trials were conducted at 69 centers in five European countries. Post-marketing experience includes safety data from passive pharmacovigilance systems in 18 countries where these vaccines have been licensed since 2001. RESULTS: All subjects analyzed for immunogenicity achieved postimmunization levels of TBE antibodies that meet the definition of seroconversion or represent a fourfold increase. The pooled data of clinical trials revealed the expected rate of solicited local and systemic reactions. The majority of these transient postimmunization reactions were mild. Pharmacovigilance data confirm the high level of safety of these new TBE vaccines: only a common range of the side effects already noted for licensed TBE vaccines was reported. After the distribution of more than five million vaccine doses, no potential safety risk was noted. CONCLUSION: Post-marketing experience supports results from clinical trials showing that these new TBE vaccines may safely be used for the vaccination of children, adolescents, and adults.

Combined administration of MF59-adjuvanted A/H5N1 prepandemic and seasonal influenza vaccines: long-term antibody persistence and robust booster responses 1 year after a one-dose priming schedule.

Having previously demonstrated the feasibility of administering A/H5N1 and seasonal influenza vaccine antigens in an MF59-adjuvanted tetravalent formulation, we now report on long-term antibody persistence and responses to a booster dose of a combined seasonal-pandemic, tetravalent influenza vaccine in adults. The primary objective was the evaluation of responses to a booster dose of tetravalent influenza vaccine containing seasonal (A/H1N1, A/H3N2, and B) and avian (A/H5N1, clade 2) influenza virus strains administered to 265 healthy 18- to 40-year-old volunteers 1 year after priming with one or two clade 1 A/H5N1 doses. Secondary objectives were assessment of reactogenicity, safety, and antibody persistence 1 year after priming with a combined seasonal-pandemic, tetravalent vaccine. Responses to seasonal strains met all European licensure criteria; seroprotection rates were 94 to 100%, 100%, and 61 to 90% for A/H1N1, A/H3N2, and B strains, respectively. Anamnestic responses were observed against homologous and heterologous A/H5N1 strains whether priming with one or two A/H5N1 doses, with a monovalent A/H5N1 vaccine, or with a tetravalent vaccine. A single dose of MF59-adjuvanted A/H5N1 vaccine given alone or as part of a fixed combination with a seasonal influenza vaccine was sufficient to prime adult subjects, resulting in robust antigen-specific and cross-reactive antibody responses to heterologous booster immunization 1 year later. These data support the feasibility of incorporating prepandemic priming into seasonal influenza vaccination programs. (This study has been registered at clinicaltrials.gov under registration no. NCT00481065.).