World Experience in the Use Serogroup B Meningococcal Vaccines (literature review)

Relevance. The success of vaccine prophylaxis of meningococcal infection depends on the composition and properties of vaccine preparations and the strict implementation of recommendations on vaccine prophylaxis tactics by the territorial epidemiological characteristics of meningococcal infection. Despite the high burden of B-meningococcal infection, especially among young children, the design of B-meningococcal vaccines has faced serious difficulties. Aim. The literature review presents the history of the development of B-meningococcal vaccines and provides characteristics of two immunologically effective and safe new generation B-meningococcal vaccine preparations. Conclusion. The licensing of the two new B-meningococcal vaccines presented in the review (Bexsero and Trumenba) was based on immunogenicity and safety. The inclusion of vaccines in national vaccination programs requires careful analysis, including analysis of the antigenic characteristics of circulating strains.

Detection of Neisseria meningitidis in saliva and oropharyngeal samples from college students

Carriage of Neisseria meningitidis is an accepted endpoint in monitoring meningococcal vaccines effects. We have assessed N. meningitidis and vaccine-type genogroup carriage prevalence in college students at the time of MenACWY vaccine introduction in the Netherlands, and evaluated the feasibility of saliva sampling for the surveillance of carriage. For this, paired saliva and oropharyngeal samples collected from 299 students were cultured for meningococcus. The DNA extracted from all bacterial growth was subjected to qPCRs quantifying meningococcal and genogroup-specific genes presence. Samples negative by culture yet positive for qPCR were cultured again for meningococcus. Altogether 74 (25%) of students were identified as meningococcal carrier by any method. Sixty-one students (20%) were identified as carriers with qPCR. The difference between number of qPCR-positive oropharyngeal (n = 59) and saliva (n = 52) samples was not significant (McNemar’s test, p = 0.07). Meningococci were cultured from 72 students (24%), with a significantly higher (p < 0.001) number of oropharyngeal (n = 70) compared with saliva (n = 54) samples. The prevalence of genogroups A, B, C, W, and Y was none, 9%, 1%, 1% and 6%, respectively, and 8% of students carried MenACWY vaccine-type genogroup meningococci. Saliva is easy to collect and when combined with qPCR detection can be considered for meningococcal carriage studies.

27. Immunologic Hyporesponsiveness with Subsequent Dosing of Meningococcal Vaccines: Re-Evaluating the Current Paradigm

Background Immunologic hyporesponsiveness (HyR) is considered as an inability to mount immune responses to vaccination of at least the same degree as earlier doses. For meningococcal vaccines, HyR has classically been associated with unconjugated but not conjugated polysaccharide (PS) vaccine dosing, but the clinical relevance is unclear. Methods To characterize meningococcal vaccine HyR, a PubMed search was conducted without date limits as follows: (hyporespons*) AND (meningococcal) AND (vaccine OR mechanism OR MOA OR causes). Papers from the authors’ files, including HyR insights with other vaccines, were included. Results Classic HyR with repeat unconjugated PS vaccine (MPV) dosing is thought to be associated with memory B-cell (BC) depletion, causing reduced responses on redosing with the same PS. This lack of immunologic memory and interference is seen years after MPV dosing across age groups. As data is added, other examples seem to fit the HyR definition but differ from the classical mechanism and its implications. First, passively transferred maternal antibodies (Abs) may interfere with neonatal adaptive immune response and ultimately those of childhood vaccination by binding to vaccine antigen (Ag) and inhibiting Ab production. Second, multiple dose schedules of meningococcal conjugate vaccines can show reduced responses to later doses in the series but memory is still established and amnestic booster response later achieved. Finally, carrier-induced epitopic suppression, occurring when PS Ag epitopes presented on a protein carrier are inhibited by prior/concurrent dosing with the same carrier, has also been reported. These 3 examples of alternative HyR mechanisms are not associated with memory BC depletion but are likely due to high circulatory Ab levels reducing responses, which is transient, reduces with Ab waning, immunologic memory remains intact, and is not clinically significant. Conclusion This literature review identified HyR mechanisms other than the classic mechanism associated with memory BC depletion that may account for decreased immune response to subsequent vaccination. Understanding the type of HyR observed with meningococcal vaccines is crucial, as these mechanisms vary in terms of potential clinical significance and the duration of their impact. Disclosures Jamie Findlow, PhD, Pfizer (Employee, Shareholder) Paul Balmer, PhD, Pfizer (Employee, Shareholder)

Clinical and Laboratory Findings of 12 Children with Invasive Meningococcal Disease in Pediatric Intensive Care Unit

Introduction. Invasive meningococcal disease (IMD) is a serious infectious disease requiring stay in a pediatric intensive care unit (PICU) that continues to be associated with high morbidity and mortality rates. Prompt recognition, early antibiotic therapy, and aggressive supportive therapies can reduce mortality. We aimed to assess the clinical and laboratory characteristics of children with IMD. Patients and Methods. We retrospectively evaluated the medical records of 12 children with IMD requiring PICU stay between January 2018 and July 2019. Results. We followed up 12 patients (five girls and seven boys, 5–168 months of age, and four below one year of age) with IMD (nine patients have meningococcemia with meningitis, and three patients have meningococcemia) in PICU. All children were previously healthy and have not received meningococcal vaccines. Their pediatric risk of mortality (PRISM) scores varies between 5 and 37, four of the patients required mechanical ventilation, and the predicted mortality was 39% at admission. Seven patients had catecholamine refractory septic shock and disseminated intravascular coagulation (DIC). Three of the patients required extracorporeal treatment. The predominant serogroup is Men B (5/12). The mortality rate was 16.6% with early use of antibiotics, fluids, and other interventions. Conclusion. Mortality related to IMD is higher among children with severe meningococcemia despite early interventions in PICU. Routine use of meningococcal vaccines during childhood would be a better strategy for controlling IMD in both developing and developed countries.

Meningococcal Vaccines of New Generations – the First 20 Years of Use

Relevance. Meningococcal vaccine refers to any of the vaccines used to prevent infection by Neisseria meningitidis. Therefore, there is a great scientific and practical interest in the existing and developed menicococcal vaccines.Aims the review is to provide an analysis: literature data on the effectiveness of meningococcal vaccines of new generations - conjugated polysaccharide serogroups A, C, W and Y and protein serogroup B.Conclusions. With regard to conjugated vaccines, there are a large number of reliable observations confirming the high immunological and epidemiological effectiveness of these vaccine preparations, including the prevention of bacterial carriage and the development of herd immunity. These vaccines are weakly reactogenic, and in many countries, they are introduced into national immunization programs and in some countries are used as mandatory (UK) or in connection with the existing epidemic indications. The protein «vesicle» vaccine based on serogroup B meningococcal outer membrane proteins, showed high efficacy only in those cases when the protein composition of the strain that caused the morbidity corresponded to the composition (mainly in terms of the PorA subtype antigen) of the vaccine. Genetic-engineered vaccines containing only a few serogroup B meningococcal protein antigens with or without the addition of «vesicle» proteins are difficult to evaluate due to the small number of observations associated with low serogroup В prevalence, but in Great Britain, such vaccine was also introduced as mandatory in the national immunization schedule for babies. At the same time, new vaccines of serogroup B induce immune protection against some strains of meningococcus of other serogroups C, W, and Y, and even against other species of Neisseria, in particular - gonococcus. This circumstance gives rise to hope for the development of protein meningococcal vaccines with a wider spectrum of specificity than the group, and even than the species.

Exploring the Ability of Meningococcal Vaccines to Elicit Mucosal Immunity: Insights from Humans and Mice

Neisseria meningitidis causes a devastating invasive disease but is also a normal colonizer of the human nasopharynx. Due to the rapid progression of disease, the best tool to protect individuals against meningococcal infections is immunization. Clinical experience with polysaccharide conjugate vaccines has revealed that an ideal meningococcal vaccine must prevent both invasive disease and nasal colonization, which confers herd immunity. However, not all meningococcal vaccines are equal in their ability to prevent nasal colonization, for unknown reasons. Herein, we describe recent efforts to utilize humanized mouse models to understand the impact of different meningococcal vaccines on nasal colonization. These mice are susceptible to nasal colonization, and they become immune following live nasal infection or immunization with matched capsule-conjugate or protein-based vaccines, replicating findings from human work. We bring together insights regarding meningococcal colonization and immunity from clinical work with findings using humanized mouse models, providing new perspective into the different determinants of mucosal versus systemic immunity. Then, we use this as a framework to help focus future studies toward understanding key mechanistic aspects left unresolved, including the bacterial factors required for colonization and immune evasion, determinants of nasal mucosal protection, and characteristics of an ideal meningococcal vaccine.

Carbohydrate based meningococcal vaccines: past and present overview

Neisseria meningitidis is a major cause of bacterial meningitidis worldwide. Children less than five years and adolescents are particularly affected. Nearly all invasive strains are surrounded by a polysaccharide capsule, based on which, 12 N. meningitidis serogroups are differentiated. Six of them, A, B, C, W, X, and Y, cause the vast majority of infections in humans. Mono- and multi-valent carbohydrate-based vaccines against meningococcal infections have been licensed or are currently in clinical development. In this mini-review, an overview of the past and present approaches for producing meningococcal glycoconjugate vaccines is provided.

PRECLINICAL STUDIES AND CLINICAL TRIALS IN DETERMINATION OF SAFETY AND EFFICACY OF MENINGOCOCCAL VACCINES: PRESENT SCENARIO

Meningitis, a serious communicable inflammatory disease continues to be a worldwide threat especially in sub-Saharan Africa affecting millions of people with high death rates every year. Strains from six serogroups of the principal causative organism Neisseria meningitidis are found to be responsible for the majority of infections. Incidences of antibiotic resistance and efforts to provide mass protection have necessitated the development of meningococcal vaccines since the latter half of the 20th century. Aiming to ostracize meningitis by 2030, the World Health Organization focuses on vaccination as an important strategy to reach the goal. Due to limited efficacy and stability issues of earlier polysaccharide and protein conjugate vaccines respectively, outer membrane vesicle (OMV) vaccines were developed. Gene manipulations have also led to the development of more efficacious tailor-made OMV vaccines due to over-expression of antigenic outer membrane proteins along with lesser pyrogenicity. Available data from preclinical studies in animal models and clinical trials, on meningococcal vaccine candidates report the strength of immune response measured by serological tests such as enzyme-linked immunosorbent assay and serum bactericidal assay. Post-immunization adverse reactions have been also monitored as a part of safety assessment. The novelty of the present review lies in summarizing the outcomes of the preclinical animal studies and clinical trials conducted on various types of meningococcal vaccines till date and thereby highlighting the paucities in the existing information which can facilitate understanding the present scenario, challenges, and future scope in the field of meningococcal vaccine development.

A Narrative Review of the W, X, Y, E, and NG of Meningococcal Disease: Emerging Capsular Groups, Pathotypes, and Global Control

Neisseria meningitidis, carried in the human nasopharynx asymptomatically by ~10% of the population, remains a leading cause of meningitis and rapidly fatal sepsis, usually in otherwise healthy individuals. The epidemiology of invasive meningococcal disease (IMD) varies substantially by geography and over time and is now influenced by meningococcal vaccines and in 2020–2021 by COVID-19 pandemic containment measures. While 12 capsular groups, defined by capsular polysaccharide structures, can be expressed by N. meningitidis, groups A, B, and C historically caused most IMD. However, the use of mono-, bi-, and quadrivalent-polysaccharide-conjugate vaccines, the introduction of protein-based vaccines for group B, natural disease fluctuations, new drugs (e.g., eculizumab) that increase meningococcal susceptibility, changing transmission dynamics and meningococcal evolution are impacting the incidence of the capsular groups causing IMD. While the ability to spread and cause illness vary considerably, capsular groups W, X, and Y now cause significant IMD. In addition, group E and nongroupable meningococci have appeared as a cause of invasive disease, and a nongroupable N. meningitidis pathotype of the hypervirulent clonal complex 11 is causing sexually transmitted urethritis cases and outbreaks. Carriage and IMD of the previously “minor” N. meningitidis are reviewed and the need for polyvalent meningococcal vaccines emphasized.