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Background: Real-world studies on vaccine effects are diverse in terms of objectives, study setting and design, data type and scope, and analysis methods. In this review, we describe and discuss four-component meningococcal serogroup B vaccine (4CMenB vaccine, Bexsero) real-world studies with the aim of synthesizing their findings with application of standard methods., Methods: We performed a systematic literature review of all real-world studies on 4CMenB vaccine effects on meningococcal serogroup B disease, with no restriction for population age, vaccination schedule and/or type of vaccine effect evaluated (vaccine effectiveness [VE] and vaccine impact [VI] outcomes) published since its licensure in 2013 (from January 2014 until July 2021) in PubMed, Cochrane and the grey literature. We then aimed to synthesize the findings of the identified studies through application of standard synthesis methods., Results: According to reported criteria we retrieved five studies presenting estimates on 4CMenB vaccine effectiveness and impact. These studies showed great diversity in population, vaccination schedule and analysis methods mainly due to diversity in vaccine strategies and recommendations in the study settings. Directed by this diversity, no quantitative pooling methods to synthesize findings could be applied; instead we descriptively assessed study methods. We report VE estimates ranging from 59% to 94% and VI estimates ranging from 31% to 75%, representing diverse age groups, vaccination schedules and analysis methods., Conclusion: Both vaccine outcomes showed real-life effectiveness of 4CMenB vaccine despite differences in study methodologies and vaccination strategies. Based on appraisal of study methods, we highlighted the need for an adapted tool which facilitates synthesis of heterogenic real-world vaccine studies when quantitative pooling methods are not applicable., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elisa Cinconze, Kumaran Vadivelu, Rafik Bekkat-Berkani and Victoria Abbing-Karahagopian are employed by GSK. Dominique Rosillon, Kumaran Vadivelu and Rafik Bekkat-Berkani hold shares in GSK. Dominique Rosillon and Rino Rappuoli were employed by GSK at the time of the study. All authors declare no other financial or non-financial relationships and activities., (Copyright © 2023 GSK. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Invasive meningococcal disease (IMD) is a life-threatening disease that can rapidly progress to death or leave survivors with severe, life-long sequelae. Five meningococcal serogroups (A, B, C, W and Y) account for nearly all IMD. Meningococcal serogroup distribution fluctuates over time across the world and age groups. Here, we consider the potential public health impact of a pentavalent MenABCWY vaccine developed to help further control meningococcal disease and improve immunisation rates., Results: The GSK MenABCWY vaccine combines the antigenic components of MenACWY-CRM (Menveo®) and 4CMenB (Bexsero®), building on a wide body of clinical experience and real-world evidence. Both approved vaccines have acceptable safety profiles, demonstrate immunogenicity, and are broadly used, including in national immunisation programmes in several countries. Since the advent of quadrivalent vaccines, public health in relation to IMD has improved, with a decline in the overall incidence of IMD and an increase in vaccine coverage., Conclusion: A pentavalent MenABCWY has the potential to provide further public health benefits through practical, broad IMD protection programmes encompassing serogroups A, B, C, W and Y, and is currently in late-stage development., Competing Interests: Declaration of Competing Interest All authors are employees of the GSK group of companies and hold shares as part of their employee remuneration. GlaxoSmithKline Biologicals SA funded all costs associated with the development and the publishing of the present manuscript., (Copyright © 2022. Published by Elsevier Ltd.)

Predictions of vaccine efficacy against Neisseria meningitidis serogroup B (NmB) disease are hindered by antigenic variability, limiting the representativeness of individual NmB isolates. A qualitative human serum bactericidal assay using endogenous complements of individual subjects (enc-hSBA) enables large panels of NmB isolates to be tested. A 110-isolate panel was randomly selected from 442 invasive NmB isolates from United States cases reported to the Centers for Disease Control (CDC) from 2000 to 2008. Typing analyses confirmed the 110-isolate panel is representative of the 442 isolates. The genetic features of the 110-isolate panel were compared against over 4,200 invasive NmB isolates collected from 2000 to 2018 in the United States, Australia, Canada, and nine European countries. Clonal complexes in the 110-isolate panel are also present in each geographical region; cumulative percentages show that these account for around 81% of the clonal complexes found in NmB isolates in other panels. For the antigens (fHbp, NHBA, PorA1.4, NadA) included in the currently licensed meningococcal serogroup B (MenB) vaccines, specifically considering the presence of at least one antigen with a matched genotype, the 110-isolate panel represents approximately 89% of the NmB isolates circulating worldwide, ranging from 87% for the European isolates to 95% and 97% for NmB isolates in the United States and Australia, respectively. The 110-isolate panel includes the most prevalent clonal complexes and genetic variants of MenB vaccine antigens found in a multinational collection of invasive NmB isolates. This panel is useful for assessing the efficacy of MenB vaccines in clinical trials worldwide. IMPORTANCE Neisseria meningitidis serogroup B (NmB) is a major cause of invasive meningococcal disease (IMD). Predicting the effectiveness of vaccines against NmB is difficult because NmB is an uncommon disease and because antigens targeted by meningococcal serogroup B (MenB) vaccines have highly variable genetic features and expression levels. Therefore, a large number of NmB isolates from different regions would need to be tested to comprehensively assess vaccine effectiveness. We examined a panel of 110 isolates obtained from NmB IMD cases in the United States and compared the genetic features of this panel with those of panels from different countries around the world. We found the 110-isolate panel included the most common clonal complexes and genetic variants of MenB vaccine antigens that exist in the global collections of invasive NmB isolates. This confirms the value of the NmB 110-isolate panel in understanding the effectiveness of MenB vaccines in clinical trials worldwide.

Background: Recombinant protein-based vaccines targeting serogroup B meningococci protect against invasive disease but impacts on carriage are uncertain. This study assessed carriage prevalence of disease-associated meningococci in 2018-2020 as the proportion of vaccinated adolescents increased following introduction of a school-based 4CMenB immunization program., Methods: Eligible participants who completed high school (aged 17-25) in South Australia in the previous year had an oropharyngeal swab taken and completed a risk factor questionnaire. Disease-associated meningococci (genogroups A, B, C, W, X, Y) were detected by meningococcal and genogroup-specific polymerase chain reaction., Results: The analysis included 4104 participants in 2018, 2690 in 2019, and 1338 in 2020. The proportion vaccinated with 4CMenB increased from 43% in 2018, to 78% in 2019, and 76% in 2020. Carriage prevalence of disease-associated meningococci in 2018 was 225/4104 (5.5%). There was little difference between carriage prevalence in 2019 (134/2690, 5.0%; adjusted odds ratio [aOR], 0.82; 95% confidence interval [CI], .64-1.05) and 2020 (68/1338, 5.1%; aOR, 0.82; 95% CI, .57-1.17) compared to 2018., Conclusions: Increased 4CMenB uptake in adolescents was not associated with decline in carriage of disease-associated meningococci. 4CMenB immunization programs should focus on direct (individual) protection for groups at greatest risk of disease., Clinical Trials Registration: NCT03419533., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The four-component serogroup B meningococcal 4CMenB vaccine (Bexsero, GSK) has been routinely given to all infants in the United Kingdom at 2, 4 and 12 months of age since September 2015. After 3 years, Public Health England (PHE) reported a 75% [95% confidence interval 64%; 81%] reduction in the incidence of serogroup B invasive meningococcal disease (IMD) in age groups eligible to be fully vaccinated. In contrast, vaccine effectiveness (VE) evaluated in the same immunization program applying the screening method was not statistically significant. We re-analyzed the data using an incidence model., Methods: Aggregate data-stratified by age, year and doses received-were provided by PHE: serogroup B IMD case counts for the entire population of England (years 2011-2018) and 4CMenB vaccine uptake in infants. We combined uptake with national population estimates to obtain counts of vaccinated and unvaccinated person-time by age and time. We re-estimated VE comparing incidence rates in vaccinated and non-vaccinated subjects using a Bayesian Poisson model for case counts with person-time data as an offset. The model was adjusted for age, time and number of doses received., Results: The incidence model showed that cases decreased until 2013-2014, followed by an increasing trend that continued in the non-vaccinated population during the immunization program. VE in fully vaccinated subjects (three doses) was 80.1% [95% Bayesian credible interval (BCI): 70.3%; 86.7%]. After a single dose, VE was 33.5% [12.4%; 49.7%] 95%BCI and after two doses, 78.7% [71.5%; 84.5%] 95%BCI . We estimated that vaccination averted 312 cases [252; 368] 95%BCI between 2015 and 2018. VE was in line with the previously reported incidence reduction., Conclusions: Our estimates of VE had higher precision than previous estimates based on the screening method, which were statistically not significant, and in line with the 75% incidence reduction previously reported by PHE. When disease incidence is low and vaccine uptake is high, the screening method applied to cases exclusively from the population eligible for vaccination may not be precise enough and may produce misleading point-estimates. Precise and accurate VE estimates are fundamental to inform public health decision making. VE assessment can be enhanced using models that leverage data on subjects not eligible for vaccination., (© 2021. GlaxoSmithKline Biologicals S.A.)

Invasive meningococcal disease (IMD), an uncommon but severe disease, affects mainly infants, young children and adolescents. Meningococcal B (4CMenB) and ACWY (MenACWY) vaccines targeting IMD-causing serogroups B and A, C, W and Y, respectively are available for these mostly-affected age-groups. The objective was to assess the impact of 4CMenB and/or MenACWY vaccination strategies on IMD in England, considering MenACWY carriage protection and potential cross-protection of 4CMenB against non-B serogroups. A novel dynamic transmission model was developed, accounting for vaccine characteristics, with separate variables for meningococcal carriage and IMD for three groups: B; ACWY; and 'Other' mostly non-pathogenic serogroups. A dynamic force of infection is assumed for each group. The model analysis uses data from England before 2015 (when 4CMenB and MenACWY were introduced), and accounts for existing MenC vaccination impact. Compared with no vaccination, the smallest decrease in IMD cases is observed for MenACWY strategies (toddler and/or adolescent). 4CMenB (infant or infant/adolescent), alone or with MenACWY, always results in the most rapid and steep decline in IMD cases. Combined strategies with adolescent 4CMenB result in the largest decrease in IMD cases, whereas adding MenACWY for toddlers has a minor impact. With potential 4CMenB cross-protection, 4CMenB infant strategy has a notable impact on reduction of MenW and MenY IMD cases in strategies where MenACWY toddler and/or adolescent vaccination is absent. This novel model allows for analysis of combined 4CMenB and MenACWY strategies including potential 4CMenB cross-protection. In settings comparable to England, a comprehensive meningococcal vaccination programme should include infant 4CMenB as essential building block. Decisions to include MenACWY toddler programmes should consider herd effects of MenACWY adolescent programmes and 4CMenB potential cross-protection effects. Extending 4CMenB infant and MenACWY adolescent programmes with a 4CMenB adolescent programme allows for the largest overall reduction in IMD cases., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ekkehard Beck, Veronique Abitbol, Jane Whelan, Lorenzo Argante, Cosmina Hogea, Rafik Bekkat-Berkani, Kumaran Vadivelu and Kinga Meszaros are employees of the GSK group of companies and hold shares in it. Victoria Abbing-Karahagopian is an employee of the GSK group of companies. Mohamed Neine is a freelance consultant for the GSK group of companies and therefore receives consulting fees. Stephanie Garcia was a consultant for the GSK group of companies at the time of the study conduct and manuscript development and her previous employer, Business & Decision Life Sciences, therefore received consulting fees. Stephanie Garcia is now an employee of the GSK group of companies. Johan Klint (previously ICON plc, now Parexel International) and Orjan Akerborg (ICON plc) are consultants for the GSK group of companies and their employers receive(d) consulting fees., (Copyright © 2020 GlaxoSmithKlineBiologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Background: The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain., Methods: We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing Neisseria meningitidis (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for PorA (encoding porin protein A) and N. meningitidis genogroups. Secondary outcomes included carriage prevalence and acquisition of all N. meningitidis and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline., Results: A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing N. meningitidis between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing N. meningitidis included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified., Conclusions: Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.)., (Copyright © 2020 Massachusetts Medical Society.)

Introduction: Invasive meningococcal disease is uncommon but associated with a high-case fatality rate. Carriage prevalence of the causative bacteria, Neisseria meningitidis , is high in adolescents. A large (n=34 500) cluster randomised controlled trial (RCT) to assess the impact of a meningococcal B (MenB) vaccine on meningococcal carriage was implemented in the state of South Australia (SA) for year 10, 11 and 12 senior school students in 2017-2018. This study will assess the impact of MenB vaccine (4CMenB) on carriage prevalence in school leavers in SA, 1 and 2 years after implementation of the cluster RCT in adolescents. Measuring the impact of population programmes on carriage can assist in informing future meningococcal immunisation programmes such as targeted age groups and use of catch-up campaigns., Methods and Analysis: This repeat cross-sectional study will assess carriage prevalence in 2018 and 2019. All school leavers who attended year 12 in any school in SA in 2018 or 2019 will be invited to participate in this study. An oropharyngeal swab will be taken from each participating student and a risk factor questionnaire completed by the student following informed consent. Students will attend clinics at SA universities, technical colleges, and metropolitan, rural and remote government council clinics. Confirmed vaccination history will allow a comparison in carriage prevalence between vaccinated and unvaccinated school leavers. A sample size of 4096 students per year will provide 80% power to detect a 20% difference in carriage prevalence of disease-causing meningococci (defined as genogroup A, B, C, W, X or Y) between years., Ethics and Dissemination: The study was approved by the Women's and Children's Health Network Human Research Ethics Committee. Results will be published in international peer review journals and presented at national and international conferences., Trial Registration Number: NCT03419533; Pre-results., Competing Interests: Competing interests: HSM is supported by an NHMRC CDF APP1084951 and is a member of the Australian Technical Advisory Group on Immunisation, Australian Government. HSM is an investigator on vaccine trials sponsored by Industry (GSK, Novavax, Pfizer). HSM’s and MMcM’s institution receives funding for investigator-led studies from Industry (Pfizer, GSK). HSM and MMcM receive no personal payments from Industry. CT has received a consulting payment from GSK and an honorarium from Sanofi Pasteur. RB performs contract research on behalf of Public Health England for GSK, Pfizer and Sanofi Pasteur. PR is an investigator on vaccine trials sponsored by Industry (GSK, Novavax, Pfizer). PR’s institution receives funding for investigator-led studies from Industry (Pfizer, GSK, CSL). PR has been a member of scientific vaccine advisory boards for Industry (Pfizer, GSK, Sanofi) but has not received any personal payments from Industry. AF’s institution is in receipt of research funding from GlaxoSmithKline, Pfizer and consultancy fees from Alios BioPharma/Johnson & Johnson, BioNet-Asia and VBI Vaccines. AF is a member of the UK Department of Health’s Joint Committee on Vaccination, chair of the WHO European Technical Advisory Group of Experts and president of the European Society for Paediatric Infectious Diseases, which receives sponsorship for its annual meeting from vaccine manufacturers. KV and JW are employees of the GSK group of companies and hold shares in the GSK group of companies as part of their employee remuneration., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Meningococcal Antigen Typing System (MATS) was developed to identify meningococcus group B strains with a high likelihood of being covered by the 4CMenB vaccine, but is limited by the requirement for viable isolates from culture-confirmed cases. We examined if antigen genotyping could complement MATS in predicting strain coverage by the 4CMenB vaccine., Methods: From a panel of 3912 MATS-typed invasive meningococcal disease isolates collected in England and Wales in 2007-2008, 2014-2015 and 2015-2016, and in 16 other countries in 2000-2015, 3481 isolates were also characterized by antigen genotyping. Individual associations between antigen genotypes and MATS coverage for each 4CMenB component were used to define a genetic MATS (gMATS). gMATS estimates were compared with England and Wales human complement serum bactericidal assay (hSBA) data and vaccine effectiveness (VE) data from England., Results: Overall, 81% of the strain panel had genetically predictable MATS coverage, with 92% accuracy and highly concordant results across national panels (Lin's accuracy coefficient, 0.98; root-mean-square deviation, 6%). England and Wales strain coverage estimates were 72-73% by genotyping (66-73% by MATS), underestimating hSBA values after four vaccine doses (88%) and VE after two doses (83%). The gMATS predicted strain coverage in other countries was 58-88%., Conclusions: gMATS can replace MATS in predicting 4CMenB strain coverage in four out of five cases, without requiring a cultivable isolate, and is open to further improvement. Both methods underestimated VE in England. Strain coverage predictions in other countries matched or exceeded England and Wales estimates., (Copyright © 2019 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Neisseria meningitidis serogroup B (MenB) is the most common cause of bacterial meningitis in many industrialized countries and occurs at any age. The highest incidence is in infants aged <1 year, followed by children and adolescents. Four-component MenB vaccine (4CMenB, Bexsero) is the only MenB vaccine authorized for use in all age-groups. Experience with 4CMenB is growing as it is implemented in different countries/age-groups encompassing university students, children, adolescents, and infant mass vaccination programs., Areas Covered: An update of recently available data describing the mechanism of immunogenicity of 4CMenB and real-world evidence of vaccine effectiveness and disease impact. We discuss the appropriate age for vaccination to maximize population impacts., Expert Commentary: Invasive meningococcal disease is uncommon and sufficiently powered efficacy studies were not feasible during 4CMenB development. Additionally, several thousand genetically diverse invasive MenB strains circulate globally, varying widely in surface protein expression. This posed significant challenges in predicting clinical protection with MenB vaccines. Five years of 4CMenB use post-licensure confirm the clinical benefit of vaccination as predicted during development. Preliminary evidence suggests an extended impact on other meningococcal serogroups and Neisseria gonorrhoeae.

Introduction: Menveo, quadrivalent meningococcal ACWY-CRM conjugate vaccine, was first licensed in 2010 in the United States and has a long track record of immunogenicity and safety in all age groups, including infants from 2 months of age., Areas Covered: This review presents clinical and post-marketing experience with MenACWY-CRM from 32 studies conducted in 20 countries that included individuals aged from 2 months to 75 years., Expert Commentary: This decade has seen an increased number of countries reporting serogroup W ST-11 clonal complex outbreaks of invasive meningococcal disease. As infant vaccination programs targeting the meningococcus are reevaluated, the role of quadrivalent meningococcal vaccines including MenACWY-CRM will be expanded. MenACWY-CRM was immunogenic in all populations and age groups studied, regardless of country of origin. MenACWY-CRM can be coadministered with many routinely used infant, toddler and adolescent vaccines, and traveler vaccines in adults, allowing for flexible use within national immunization programs and recommendations. Antibody persistence has been demonstrated up to 5 years post vaccination in all age groups. Booster doses induced robust increases in antibody titers for all four serogroups, indicative of effective priming and induction of immunological memory. The acceptable safety profile of MenACWY-CRM has been confirmed in large post-marketing safety studies.

Introduction: South Australia (SA) has the highest notification rate of invasive meningococcal disease in Australia with the majority of cases due to serogroup B. Neisseria meningitidis is carried in the pharynx, with adolescents having the highest rates of carriage. A vaccine designed to offer protection against serogroup B (4CMenB) is licensed in Australia. The SA MenB vaccine carriage study aims to assess the impact of 4CMenB on carriage of N. meningitidis in adolescents., Methods and Analysis: This is a parallel cluster randomised controlled trial enrolling year 10, 11 and 12 school students (approximately 16-18 years of age) throughout SA, in metropolitan and rural/remote areas. Schools are randomised to intervention (4CMenB vaccination at baseline) or control (4CMenB vaccination at study completion) with randomisation stratified by school size and socioeconomic status, as measured by the Index of Community Socio-Educational Advantage (Australian Curriculum). Oropharyngeal swabs will be taken from all students at visit 1, and 12 months later from year 11 and 12 students. Students unvaccinated in 2017 will receive vaccine at the 12-month follow-up. Carriage prevalence of N. meningitidis will be determined by PCR at baseline and 12 months following 4CMenB vaccination and compared with carriage prevalence at 12 months in unvaccinated students. A questionnaire will be completed at baseline and 12 months to assess risk factors associated with carriage. The primary outcome of carriage prevalence of disease causing N. meningitidis at 12 months will be compared between groups using logistic regression, with generalised estimating equations used to account for clustering at the school level. The difference in carriage prevalence between groups will be expressed as an OR with 95% CI., Ethics and Dissemination: The study was approved by the Women's and Children's Health Network Human Research Ethics Committee (WCHN HREC). The protocol, informed consent forms, recruitment materials, social media and all participant materials have been reviewed and approved by the WCHN HREC and updated on ClinicalTrials.gov. Results will be published in international peer-reviewed journals and presented at national and international conferences. The study findings will be provided in public forums and to study participants and participating schools., Trial Registration Number: ACTRN12617000079347. NCT03089086; Pre-results., Competing Interests: Competing interests: HSM is supported by a NHMRC CDF APP1084951 and is a member of the Australian Technical Advisory Group on Immunisation, Australian Government. HSM is an investigator on vaccine trials sponsored by Industry (GSK, Novavax, Pfizer). HSM’s and MMcM’s institution receives funding for investigator-led studies from Industry (Pfizer, GSK). HSM and MMcM receive no personal payments from Industry. CT has received a consulting payment from GSK and an honorarium from Sanofi Pasteur. RB performs contract research on behalf of Public Health England for GSK, Pfizer and Sanofi Pasteur. PR is an investigator on vaccine trials sponsored by Industry (GSK, Novavax, Pfizer). PR’s institution receives funding for investigator-led studies from Industry (Pfizer, GSK, CSL). PR has been a member of scientific vaccine advisory boards for Industry (Pfizer, GSK, Sanofi) but has not received any personal payments from Industry. AF’s institution is in receipt of research funding from GlaxoSmithKline, Pfizer and consultancy fees from Alios BioPharma/Johnson & Johnson, BioNet-Asia and VBI Vaccines. AF is a member of the UK Department of Health’s Joint Committee on Vaccination, Chair of the WHO European Technical Advisory Group of Experts and President of the European Society for Paediatric Infectious Diseases, which receives sponsorship for its annual meeting from vaccine manufacturers. KV and JW are employees of the GSK group of companies and hold shares in the GSK group of companies as part of their employee remuneration., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)