Clinical trial and postmarketing safety experience with MenACWY-TT, a meningococcal group A, C, W, and Y tetanus conjugate vaccine.

BACKGROUND: The meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix®; Pfizer Ltd, Sandwich, Kent, UK) is licensed in more than 80 countries worldwide for the prevention of meningococcal disease caused by serogroups A, C, W, and Y in individuals throughout their lifespans. This report summarizes safety data from the MenACWY-TT clinical development program and postmarketing experience. METHODS: Within the clinical study program, reactogenicity data were based on 3 primary studies, including a large pooled analysis across multiple age groups, and long-term safety data were derived from 3 studies evaluating long-term antibody persistence. Postmarketing safety data through April 19, 2021, were collected and analyzed in connection with the MenACWY-TT Periodic Safety Update Report. RESULTS: Approximately 32 million doses of MenACWY-TT have been administered worldwide, with more than 21,530 additional individuals receiving MenACWY-TT as part of clinical trials. The safety profile of MenACWY-TT was consistent between the clinical study program and the postmarketing experience, as well as with other licensed meningococcal vaccines. The most commonly observed adverse events (AEs) were pyrexia/fever, headache, injection site pain/reactions, nausea/vomiting, and fatigue; serious AEs were rare relative to the number of doses administered. Several cases of serogroup replacement/lack of efficacy were observed in the 1-year postmarketing period but did not appear to be related to MenACWY-TT use. CONCLUSION: Extensive data derived from clinical trials and postmarketing experience indicate a consistently favorable safety profile for MenACWY-TT across a wide range of age groups.

Preventing invasive meningococcal disease in early infancy.

This review considers the pathogenesis, diagnosis, and epidemiology of invasive meningococcal disease in infants, to examine and critique meningococcal disease prevention in this population through vaccination. High rates of meningococcal disease and poor outcomes, particularly for very young infants, highlight the importance of meningococcal vaccination in early infancy. Although effective and safe meningococcal vaccines are available for use from 6 weeks of age, they are not recommended globally. Emerging real-world data from the increased incorporation of these vaccines within immunization programs inform recommendations regarding effectiveness, appropriate vaccination schedule, possible long-term safety effects, and persistence of antibody responses. Importantly, to protect infants from IMD, national vaccination recommendations should be consistent with available data regarding vaccine safety, effectiveness, and disease risk.

Translating meningococcal serogroup B vaccines for healthcare professionals.

INTRODUCTION: Vaccination is an effective strategy to combat invasive meningococcal disease (IMD). Vaccines against the major disease-causing meningococcal serogroups are available; however, development of vaccines against serogroup B faced particular challenges, including the inability to target traditional meningococcal antigens (i.e. polysaccharide capsule) and limited alternative antigens due to serogroup B strain diversity. Two different recombinant, protein-based, serogroup B (MenB) vaccines that may address these challenges are currently available. These vaccines have been extensively evaluated in pre-licensure safety and immunogenicity trials, and recently in real-world studies on effectiveness, safety, and impact on disease burden. AREAS COVERED: This review provides healthcare professionals, particularly pediatricians, an overview of currently available MenB vaccines, including development strategies and evaluation of coverage. EXPERT OPINION: Overall, recombinant MenB vaccines are valuable tools for healthcare professionals to protect patients against IMD. Their development required innovative design approaches that overcame challenging hurdles and identified novel protein antigen targets; however, important distinctions in the approaches used in their development, evaluation, and administration exist and many unanswered questions remain. Healthcare providers frequently prescribing MenB vaccines are challenged to keep abreast of these differences to ensure patient protection against this serious disease.

Review of clinical studies comparing meningococcal serogroup C immune responses induced by MenACWY-TT and monovalent serogroup C vaccines.

Many countries are replacing meningococcal serogroup C (MenC) conjugate vaccines (MCCV) with quadrivalent conjugate (MenACWY) vaccines, such as MenACWY-TT (Nimenrix®). This review examined eight studies comparing MenC immune responses induced by MenACWY-TT and MCCV to determine if these data support these changes. MenC serum bactericidal antibody levels using human (hSBA) or rabbit complement (rSBA) were evaluated at ~1 month postvaccination. Overall, ≥98.4% of infants administered 2 + 1 MenACWY-TT or MCCV schedules had rSBA titers ≥1:8 postprimary and postbooster vaccination; hSBA titers ≥1:8 were similar. In toddlers administered single MenACWY-TT or MCCV doses, ≥97.3% had rSBA titers ≥1:8 postvaccination; percentages with hSBA titers ≥1:8 were higher post-MenACWY-TT. Of children and adolescents receiving primary and booster MenACWY-TT and MCCV, ≥98.6% had rSBA titers ≥1:8; all children receiving MenACWY-TT or MCCV booster had hSBA titers ≥1:8 postdosing. MenC immune responses induced by MenACWY-TT are robust and generally comparable/superior to MCCV, supporting changes to recommendations.

A Review of the Epidemiology of Invasive Meningococcal Disease and Vaccination Strategies in North Africa.

OBJECTIVE: This narrative review considers the epidemiology of invasive meningococcal disease (IMD) in North Africa and the adequacy of current preventive measures to provide guidance for future vaccination strategies. METHODS: Literature searches were conducted using PubMed for articles published from 1998 onwards to identify publications on IMD in North Africa. Additional relevant articles not included within the search results and data sources were identified from the reference lists of identified publications, authors' personal files, and publicly available government or regional surveillance data. RESULTS: Although IMD is an endemic and notifiable disease in several North African countries, inadequacies exist regarding each country's surveillance, vaccination strategies, and disease understanding. Studies showed bacterial meningitis in North Africa caused by Neisseria meningitidis mostly affects young children (aged <5 years), with meningococcal serogroup B (MenB) being the most frequently identified serotype. Importantly, MenB isolates were genetically heterogeneous. Serogroup A incidence and meningococcal outbreaks decreased over time in Morocco and Egypt, possibly because of their nationwide or school-based vaccination programs. Within the region, meningococcal vaccines are only included in the national immunization program of Egypt. CONCLUSIONS: Improving IMD diagnosis and surveillance would provide a reliable estimate of IMD burden, leading to better vaccination strategies.

Systematic literature review of the impact and effectiveness of monovalent meningococcal C conjugated vaccines when used in routine immunization programs.

BACKGROUND: Monovalent meningococcal C conjugate vaccine (MCCV) was introduced into the routine immunization program in many countries in Europe and worldwide following the emergence of meningococcal serogroup C (MenC) in the late 1990s. This systematic literature review summarizes the immediate and long-term impact and effectiveness of the different MCCV vaccination schedules and strategies employed. METHODS: We conducted a systematic literature search for peer-reviewed, scientific publications in the databases of MEDLINE (via PubMed), LILACS, and SCIELO. We included studies from countries where MCCV have been introduced in routine vaccination programs and studies providing the impact and effectiveness of MCCV published between 1st January 2001 and 31st October 2017. RESULTS: Forty studies were included in the review; 30 studies reporting impact and 17 reporting effectiveness covering 9 countries (UK, Spain, Italy, Canada, Brazil, Australia, Belgium, Germany and the Netherlands). Following MCCV introduction, significant and immediate reduction of MenC incidence was consistently observed in vaccine eligible ages in all countries with high vaccine uptake. The reduction in non-vaccine eligible ages (especially population > 65 years) through herd protection was generally observed 3-4 years following introduction. Vaccine effectiveness (VE) was mostly assessed through screening methods and ranged from 38 to 100%. The VE was generally highest during the first year after vaccination and waned over time. The VE was better maintained in countries employing catch-up campaigns in older children and adolescents, compared to routine infant only schedules. CONCLUSIONS: MCCV were highly effective, showing a substantial and sustained decrease in MenC invasive meningococcal disease. The epidemiology of meningococcal disease is in constant transition, and some vaccination programs now include adolescents and higher valent vaccines due to the recent increase in cases caused by serogroups not covered by MCCV. Continuous monitoring of meningococcal disease is essential to understand disease evolution in the setting of different vaccination programs.

Persistence of bactericidal antibodies following primary and booster MenACWY-TT vaccination of toddlers: A review of clinical studies.

The long-term persistence of antibody responses following primary vaccination with quadrivalent conjugate vaccines targeting meningococcal serogroups A, C, W, and Y (MenACWY) and the duration of protection following a booster dose have not been fully elucidated, particularly in children who received primary dosing as toddlers. This review summarizes the findings of one phase 3 and three phase 2 open-label, randomized clinical studies that assessed the long-term antibody persistence of MenACWY conjugated to tetanus toxoid as a carrier protein (MenACWY-TT) in toddlers. Following primary vaccination, antibody responses persisted for approximately 2-3 years and then decreased up to 5 years after vaccination. Geometric mean titers remained elevated for all serogroups up to 5 years after primary vaccination. In children who received a booster dose of MenACWY-TT at 4-5 years after primary dosing as toddlers, antibody responses were documented in >99% of subjects across all serogroups, with minimal decreases in antibody persistence from 2-6 years after booster vaccination. The persistence of meningococcal serogroup C (MenC) antibody responses was similar between MenACWY-TT and MenC vaccine recipients after primary and booster dosing. Together, these findings indicate that antibody responses to primary MenACWY-TT vaccination persist for 2-3 years. Additionally, these findings indicate that in subjects who receive primary MenACWY-TT vaccination as toddlers, the antibody response to booster MenACWY-TT vaccination lasts for up to 6 years and suggest that immune memory is afforded at least into early adolescence, which is an age group at increased risk of invasive meningococcal disease.

Carriage of Neisseria Meningitidis in Low and Middle Income Countries of the Americas and Asia: A Review of the Literature.

INTRODUCTION: Meningococcal colonization, or carriage, can progress to invasive meningococcal disease, a serious public health concern, with rapid progression of disease and severe consequences if left untreated. Information on meningococcal carriage and epidemiology in low/middle income American and Asian countries remains sparse. These data are crucial to ensure that appropriate preventive strategies such as vaccination can be implemented in these regions. The goal of this study was to summarize the Neisseria meningitidis carriage literature in low and middle income countries of the Americas and Asia. METHODS: Target countries were categorized as low and middle income according to the International Monetary Fund classification of low income/developing economies and middle income/emerging market economies, respectively. A PubMed search identified English-language publications that examined carriage in these countries. Studies reporting the epidemiology of N. meningitidis carriage or assessing risk factors for carriage were included. RESULTS: Fourteen studies from the Americas [Brazil (n = 7), Chile (n = 3), and Colombia, Cuba, Mexico, and Paraguay (n = 1 each)] and nine from Asia [China (n = 2), India (n = 3), and Malaysia, Nepal, Philippines, and Thailand (n = 1 each)] were identified; an additional Cuban study from the authors' files was also included. Studies were not identified in many target countries, and substantial diversity was observed among study methodologies, populations, and time periods, thereby limiting comparison between studies. The carriage rate in the Americas ranged from 1.6% to 9.9% and from 1.4% to 14.2% in Asia. Consistent risk factors for carriage were not identified. CONCLUSIONS: There is a lack of comprehensive and contemporary information on meningococcal carriage in low and medium income countries of the Americas and Asia. Future carriage studies should incorporate larger representative populations, a wider age range, and additional countries to improve our understanding of meningococcal epidemiology and disease control.

Protecting the most vulnerable age group: a review of MenACWY-TT immunogenicity and safety in infants.

INTRODUCTION: Neisseria meningitidis causes invasive meningococcal disease (IMD), with the highest incidence observed in infants and young children. Meningococcal serogroups A, B, C, W, X, and Y account for almost all IMD cases worldwide. Available meningococcal vaccines targeting serogroups A, C, W, and Y (MenACWY) include those conjugated to diphtheria toxoid (MenACWY-D), diphtheria protein cross-reactive material 197 (MenACWY-CRM197), and tetanus toxoid (MenACWY-TT). MenACWY-TT is indicated for use starting at 6 weeks of age. AREAS COVERED: This review discusses data from the four primary studies assessing MenACWY-TT safety and immunogenicity in infants, which evaluated a variety of dosing schedules, short-term and long-term outcomes, and impact of coadministration on the immunogenicity of routine childhood vaccines. Remaining gaps in the field are addressed. EXPERT OPINION: Robust data support the use of MenACWY-TT in infants starting as early as 6 weeks of age. MenACWY-TT was safe and well tolerated in infants, was immunogenic after priming and booster, and demonstrated persistent immunogenicity. Lower persistence for serogroup A relative to other serogroups based on serum bactericidal assays (SBAs) using human complement appears to be a class effect of MenACWY conjugate vaccines. Correlates of protection other than SBA are being explored, including immunologic responses associated with different carrier proteins.

Mediating effect of social support on the relationship between resilience and burden in caregivers of people with dementia.

OBJECTIVE: This study examined different predictive factors of burden in a sample of family caregivers of patients with dementia (PWD). In particular, the influence of social support and resilience on burden was tested, considering potential mediation effects. METHODS: A total of 283 primary and family caregivers in Spain were evaluated using a standardized protocol to assess sociodemographic characteristics, clinical state of PWD and specific variables of caregiving and care providers. RESULTS: The role of caregiver of PWD was more common in women, reporting significantly higher levels of burden than men. Resilience and social support accounted for most of the variance in burden. Furthermore, social support partially mediated the relationship between resilience and burden in caregivers. CONCLUSIONS: Caregivers' resilience and social support are protective factors against burden in caregivers of PWD. Both factors should be considered for tailored interventions aimed at reducing the health costs of burden in this population.

Incidence and Prevention of Invasive Meningococcal Disease in Global Mass Gathering Events.

INTRODUCTION: Mass gathering events involve close contact among large numbers of people in a specific location at the same time, an environment conducive to transmission of respiratory tract illnesses including invasive meningococcal disease (IMD). This report describes IMD incidence at mass gatherings over the past 10 years and discusses strategies to prevent IMD at such events. METHODS: A PubMed search was conducted in December 2018 using a search string intended to identify articles describing IMD at mass gatherings, including religious pilgrimages, sports events, jamborees, and refugee camps. The search was limited to articles in English published from 2008 to 2018. Articles were included if they described IMD incidence at a mass gathering event. RESULTS: A total of 127 articles were retrieved, of which 7 reported on IMD incidence at mass gatherings in the past 10 years. Specifically, in Saudi Arabia between 2002 and 2011, IMD occurred in 16 Hajj pilgrims and 1 Umrah pilgrim; serotypes involved were not reported. At a youth sports festival in Spain in 2008, 1 case of serogroup B IMD was reported among 1500 attendees. At the 2015 World Scout Jamboree in Japan, an outbreak of serogroup W IMD was identified in five scouts and one parent. At a refugee camp in Turkey, one case of serogroup B IMD was reported in a Syrian girl; four cases of serogroup X IMD occurred in an Italian refugee camp among refugees from Africa and Bangladesh. In 2017, a funeral in Liberia resulted in 13 identified cases of serogroup C IMD. Requiring meningococcal vaccination for mass gathering attendees and vaccinating refugees might have prevented these IMD cases. CONCLUSIONS: Mass gathering events increase IMD risk among attendees and their close contacts. Vaccines preventing IMD caused by serogroups ACWY and B are available and should be recommended for mass gathering attendees. FUNDING: Pfizer.

Epidemiologic Trends, Global Shifts in Meningococcal Vaccination Guidelines, and Data Supporting the Use of MenACWY-TT Vaccine: A Review.

Neisseria meningitidis is a major cause of meningitis and septicemia with cases, outbreaks, and epidemics reported globally in industrialized and non-industrialized countries. N. meningitidis is categorized into 12 serogroups; however, only 5 serogroups (A, B, C, W, Y) are responsible for the majority of disease. Invasive meningococcal disease (IMD) occurs unpredictably; protection is therefore best achieved by initiating proactive vaccination strategies. Vaccines are currently available for the five main disease-causing serogroups. With the evolution of meningococcal vaccines and changes in IMD epidemiology, different vaccination strategies have been used. Recently, the rapid clonal expansion of meningococcal serogroup W (MenW) has been associated with a change in the national and regional vaccination recommendations from monovalent meningococcal serogroup C vaccines to meningococcal serogroup A, C, W, Y (MenACWY) vaccines in several countries. This review highlights these and other changes in IMD epidemiology and meningococcal vaccination recommendations, summarizes information available for currently available conjugate MenACWY vaccines, and focuses on clinical study data for the most recently approved MenACWY conjugate vaccine, MenACWY vaccine conjugated to tetanus toxoid (MenACWY-TT). MenACWY-TT studies spanned multiple age groups and generally demonstrated safety and immunogenicity in comparison with other meningococcal vaccines and under concomitant administration of other routine vaccines. Continuous updates to meningococcal vaccine recommendations in response to changing epidemiology, as have been undertaken for MenW, are necessary to ensure optimal population protection. FUNDING: Pfizer, Inc.

Meningococcal disease in adolescents and young adults: a review of the rationale for prevention through vaccination.

Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is characterized by high mortality and morbidity. While IMD incidence peaks in both infants and adolescents/young adults, carriage rates are often highest in the latter age groups, increasing IMD risk and the likelihood of transmission. Effective vaccines are available for 5 of 6 disease-causing serogroups. Because adolescents/young adults represent a significant proportion of cases, often have the highest carriage rate, and have characteristically low vaccination adherence, efforts should be focused on educating this population regarding long-term consequences of infection and the importance of meningococcal vaccination in prevention. This review describes the role of adolescents/young adults in meningococcal transmission and the clinical consequences and characteristics of IMD in this population. With a focus on countries with advanced economies that have specific meningococcal vaccination recommendations, the epidemiology of meningococcal disease and vaccination recommendations in adolescents/young adults will also be discussed.

Meningococcal Group A, C, W, and Y Tetanus Toxoid Conjugate Vaccine: A Review of Clinical Data in Adolescents.

MenACWY-TT (Nimenrix) is a quadrivalent meningococcal vaccine containing polysaccharides from serogroups A, C, W, and Y conjugated to a tetanus toxoid carrier protein. MenACWY-TT is licensed in some countries as a three-dose primary series in individuals as young as 6 weeks of age and as a single dose in individuals ≥12 months of age. MenACWY-TT use is supported by long-term immunogenicity and safety across age groups, including data from several phase 2, 3, and 4 clinical studies in adolescents and young adults. Adolescents are an important population in the epidemiology, transmission, and prevention of invasive meningococcal disease, with this age-based population having the highest risk for carriage and transmission as well as one of the highest risks of disease. This age group is emerging as a target population in meningococcal vaccination programs globally, as vaccinating adolescents and young adults could potentially not only decrease disease rates directly for those vaccinated but also indirectly for unvaccinated individuals by decreasing carriage and eliciting herd protection. This review will consider available data for MenACWY-TT in adolescents, including safety and immunogenicity, booster and memory responses, persistence, and coadministration with other vaccines, with an emphasis on the rationale for use of MenACWY-TT and other quadrivalent meningococcal vaccines in adolescents to address the changing epidemiology of meningococcal disease.

Resilience and social support as protective factors against abuse of patients with dementia: A study on family caregivers.

OBJECTIVE: Scientific literature has identified different vulnerability factors associated to abuse in people with dementia (PWD), but little is known about the psychosocial protective variables against abuse. The main objective of this study is to investigate a set of caregiver and patient factors linked to abuse-related behavior of PWD. METHODS: A total of 326 primary and family caregivers, residents of the Castilla and León community (Spain), were evaluated. All participants filled out a standardized protocol, which assessed the sociodemographic characteristics, patient and care-related variables, as well as the perceived burden, resilience, and social support. Abuse-related behavior was evaluated using the Caregiver Abuse Screen. RESULTS: Results show that the severity of cognitive impairment and behavior disorders of PWD, a greater number of caregiving hours, a worse previous relationship with the caregiver, and perceived burden are positively related with abuse. However, resilience and social support showed a negative relationship with Caregiver Abuse Screen scores, suggesting a protective effect on abuse, even after controlling the effect of a number of covariates. Indeed, resilience was the only variable that remained significant after including the effect of burden. CONCLUSIONS: This paper states the role of burden in abuse of PWD, while resilience and social support are abuse protective factors. These variables should be considered in future guidelines for the prevention of abuse against PWD.

A Review of Meningococcal Disease and Vaccination Recommendations for Travelers.

International travel has been steadily increasing since the middle of the twentieth century, including travel to regions with high levels of endemic meningococcal disease and areas with sporadic or sustained meningococcal outbreaks. Although invasive meningococcal disease (IMD) is relatively rare in travelers since the advent of quadrivalent meningococcal vaccines, it remains a serious concern because of its rapid progression, poor prognosis and outcomes, associated treatment delays, and the potential to precipitate outbreaks. Moreover, fatality occurs in up to 22% of those infected. This review will focus on IMD in travelers, with an emphasis on IMD epidemiology and the geographic regions of potential concern for international travelers. As vaccination is the best approach for preventing IMD among travelers, currently available meningococcal vaccines and corresponding country-specific national meningococcal vaccination recommendations, where available, will be summarized by age and type of vaccine recommended. The use of the quadrivalent meningococcal vaccines, specifically the tetanus toxoid conjugate vaccine (including MenACWY-TT; Nimenrix®), as a protective measure against IMD in travelers will be emphasized. FUNDING: Pfizer Inc.

Impact of meningococcal vaccination on carriage and disease transmission: A review of the literature.

Colonization of the human nasopharyngeal tract by the bacterium Neisseria meningitidis is usually asymptomatic, but life-threatening meningococcal disease with a clinical presentation of meningitis, septicemia, or more rarely, gastrointestinal symptoms, can develop. Invasive meningococcal disease (IMD) can be fatal within 24 hours, but IMD is vaccine-preventable. Vaccines used to protect against IMD caused by 5 of the 6 most common serogroups (A, B, C, W, and Y) may also influence carriage prevalence in vaccinated individuals. Lower carriage among vaccinated people may reduce transmission to nonvaccinated individuals to provide herd protection against IMD. This article reviews observational and clinical studies examining effects of vaccination on N. meningitidis carriage prevalence in the context of mass vaccination campaigns and routine immunization programs. Challenges associated with carriage studies are presented alongside considerations for design of future studies to assess the impact of vaccination on carriage.

Intravenous antimicrobial therapy in the hospital-at-home setting: data from the Spanish Outpatient Parenteral Antimicrobial Therapy Registry.

AIM: To evaluate outpatient parenteral antimicrobial therapy (OPAT) in the hospital-at-home (HaH) model, using data from a Spanish registry. PATIENTS & METHODS: We describe episodes/characteristics of patients receiving OPAT. RESULTS: Four thousand and five patients were included (mean age 66.2 years), generating 4416 HaH episodes, 4474 infections and 5088 antibiotic treatments. Most patients were from the hospital admission ward and emergency department. Respiratory, urinary and intra-abdominal infections predominated (72%). Forty-six different antimicrobials were used, including combinations of ≥ 2 drugs (20.7%). Most HaH episodes had a successful outcome (91%). CONCLUSION: Our findings are similar to those obtained previously although our study case profiles differ, suggesting that disease processes of greater severity and complexity can be treated using this healthcare model, without compromising patient safety.

The Scc2-Scc4 complex acts in sister chromatid cohesion and transcriptional regulation by maintaining nucleosome-free regions.

The cohesin complex is at the heart of many chromosomal activities, including sister chromatid cohesion and transcriptional regulation. Cohesin loading onto chromosomes depends on the Scc2-Scc4 cohesin loader complex, but the chromatin features that form cohesin loading sites remain poorly understood. Here we show that the RSC chromatin remodeling complex recruits budding yeast Scc2-Scc4 to broad nucleosome-free regions, which the cohesin loader helps to maintain. Consequently, inactivation of either the cohesin loader or the RSC complex has similar effects on nucleosome positioning, gene expression and sister chromatid cohesion. These results show an intimate link between local chromatin structure and higher-order chromosome architecture. Our findings pertain to the similarities between two severe human disorders, Cornelia de Lange syndrome, which is caused by alterations in the human cohesin loader, and Coffin-Siris syndrome, which results from alterations in human RSC complex components. Both syndromes can arise from gene misregulation due to related changes in the nucleosome landscape.