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BACKGROUND: To date, there is no commercially available vaccine to prevent infectious mononucleosis, a disease frequently induced by Epstein-Barr virus (EBV) infection in adolescents or adults devoid of preexisting immunity to the virus. METHODS: A total of 181 EBV-seronegative, healthy, young adult volunteers were randomized in a double-blind fashion to receive either placebo or a recombinant EBV subunit glycoprotein 350 (gp350)/aluminum hydroxide and 3-O-desacyl-4'-monophosphoryl lipid A (AS04) candidate vaccine in a 3-dose regimen. RESULTS: The vaccine had demonstrable efficacy (mean efficacy rate, 78.0% [95% confidence interval {CI}, 1.0%-96.0%]) in preventing the development of infectious mononucleosis induced by EBV infection, but it had no efficacy in preventing asymptomatic EBV infection. One month after receipt of the final dose of gp350 vaccine, 98.7% of subjects showed seroconversion to anti-gp350 antibodies (95% CI, 85.5%-97.9%), and they remained anti-gp350 antibody positive for >18 months. Furthermore, there were no concerns regarding the safety or reactogenicity of the gp350/AS04 vaccine. CONCLUSION: These data support the clinical feasibility of using an EBV vaccine to prevent infectious mononucleosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00430534. [ABSTRACT FROM AUTHOR]

Background: This study attempted to (1) determine the prevalence of alcohol problems in college freshmen, (2) assess the performance of both the CAGE and the Alcohol Use Disorders Identification Test (AUDIT) questionnaires in this population, and (3) assess the possibility of improving the CAGE and/or AUDIT. Methods: A sample of 3564 consecutive college freshmen, with a mean age of 18 years, at the Catholic University of Leuven, (Belgium) completed, during a cross-sectional study, a questionnaire assessing drinking behavior and identifying students at risk as defined by DSM-IV criteria. The questionnaire also included the CAGE questionnaire and the AUDIT. Calculations of sensitivity, specificity, negative predictive value, positive predictive value, likelihood ratios, and receiver operating characteristic curves for different scores of the CAGE and the AUDIT were performed, using DSM-IV criteria as the reference standard. Results: The area under the receiver operating characteristic curve of the CAGE and the AUDIT was 0.76 and 0.85, respectively. The cutoff score of 1 for the CAGE was associated with a sensitivity of 42%, a specificity of 87%, a positive predictive value of 36%, and a negative predictive value of 90%. A score of 6 or more for the AUDIT gave a sensitivity of 80%, a specificity of 78%, a positive predictive value of 37%, and a negative predictive value of 77%. These results were related with a prevalence of 14.1% of alcohol problems. Replacing one question of the CAGE by 'often driving under the influence' resulted in the CUGE (acronym for 'cut down, under influence, guilty feelings, and eye opener'), with an area under the curve of 0.96, a positive likelihood ratio of 8.7, and a negative likelihood ratio of 0.04. Conclusions: Prevalence of alcohol problems in college students is confirmed to be high. When screening for alcohol problems in a college freshmen population, one question seems extremely important. The newly constructed CUGE questionnaire may improve screening efforts in students, compared with existing questionnaires. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of this study was to measure the coverage and influencing determinants of hepatitis B virus, measles-mumps-rubella, and Meningococcus serogroup C vaccination in 14-year-old adolescents in Flanders, Belgium, in 2005. METHODS: A total of 1500 adolescents who were born in 1991 and were living in Flanders were selected with a 2-stage cluster sampling technique. Home visits to copy vaccination documents and complete a questionnaire on sociodemographic and other related factors were conducted by trained interviewers. Only documented vaccination dates were accepted. Missing data were, when possible, retrieved through medical charts of the School Health System. RESULTS: For 1344 (89.6%) adolescents, a home visit was performed. Vaccination coverage was 75.7% for the third dose of hepatitis B virus, 80.6% for the first dose and 83.6% for the second dose of measles-mumps-rubella, and 79.8% for Meningococcus serogroup C. Only 74.6% of the adolescents had proof of 2 measles-mumps-rubella vaccines. Although 1006 (74.8%) adolescents had vaccination data available at home at the time of the interview, only 427 (31.8%) were able to show written proof of all studied vaccines. The probably underestimated coverage rates are well below World Health Organization recommendations, but timeliness of vaccinations was respected. Univariate logistic regression showed that unemployment of the father as proxy measure of socioeconomic status was detrimental for vaccination status, in contrast to partial employment of the mother, which was a favorable factor. Previously unreported determinants of lower coverage rates inferred from this study are single divorced parents, larger families (> or = 4 children), lower adolescent educational level, enrollment in special education, and repeating a grade. CONCLUSIONS: Insufficient documentation is a major barrier in this vaccination coverage study. More attention should go to those with the lowest coverage rates, such as adolescents from large families, with separated parents, and with a lower socioeconomic background. [ABSTRACT FROM AUTHOR]

Abstract: Background: The MMRV combination vaccine, Priorix-Tetra™, is currently licensed in several European countries using a two-dose schedule in infants aged ≥9 months, with a preferred 6-week to 3-month interval between doses. This study was undertaken to generate safety and immunogenicity data for two doses of MMRV vaccine administered according to dose schedules using the shortest permitted interval of 4 weeks versus a longer interval of 12 months, which would allow flexible adaptation to local immunization calendars. Methods: Healthy children aged 11–13 months were randomized (1:1:1) to receive 2 doses of either: MMRV vaccine with a 4-week interval between doses (MMRV-4W group, N =188), MMRV vaccine with a 12-month interval between doses (MMRV-12M group, N =184), or MMR vaccine with a 4-week interval between doses (MMR group, N =187). Blood samples were taken prior to, and 4–6 weeks after each vaccination. Results: Post-Dose 2, both MMRV groups exhibited an adequate immunogenic response for all components; however the MMRV-12M group showed significantly greater geometric mean titers for mumps, rubella and varicella. Two varicella breakthrough cases occurred within the 12-month interval between doses in the MMRV-12M group. Local and general reactogenicity results were similar for all groups except for the MMRV-4W group, which had a greater incidence of fever during Days 0–14 post-Dose 1. Conclusions: Two doses of MMRV vaccine administered in the second year of life elicited adequate immunogenicity and were well-tolerated whether administered with a dose interval of 4 weeks or 12 months. [Copyright &y& Elsevier]

Background: The adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) is approved in adults aged ≥60 years. We evaluated RSVPreF3 OA immunogenicity and safety in adults aged 50-59 years without or with increased risk for RSV disease due to specific chronic medical conditions., Methods: This observer-blind, phase 3, noninferiority trial included adults aged 50-59 years, stratified into 2 subcohorts: those with and those without predefined, stable, chronic medical conditions leading to an increased risk for RSV disease. Participants in both subcohorts were randomized 2:1 to receive RSVPreF3 OA or placebo. A control group of adults aged ≥60 years received RSVPreF3 OA. Primary outcomes were RSV-A and RSV-B neutralization titers (geometric mean titer ratios and sero-response rate differences) 1 month post-vaccination in 50-59-year-olds versus ≥60-year-olds. Cell-mediated immunity and safety were also assessed., Results: The exposed population included 1152 participants aged 50-59 years and 381 participants aged ≥60 years. RSVPreF3 OA was immunologically noninferior in 50-59-year-olds versus ≥60-year-olds; noninferiority criteria were met for RSV-A and RSV-B neutralization titers in those with and those without increased risk for RSV disease. Frequencies of RSVPreF3-specific polyfunctional CD4+ T cells increased substantially from pre- to 1 month post-vaccination. Most solicited adverse events had mild-to-moderate intensity and were transient. Unsolicited and serious adverse event rates were similar in all groups., Conclusions: RSVPreF3 OA was immunologically noninferior in 50-59-year-olds compared to ≥60-year-olds, in whom efficacy was previously demonstrated. The safety profile in 50-59-year-olds was consistent with that in ≥60-year-olds., Clinical Trial Registration: ClinicalTrials.gov: NCT05590403., Competing Interests: Potential conflicts of interest . H. A. H., M. d. H., B. S., S. D., M.-P. D., D. D., J. H., C. V., and V. H. are/were GSK employees at the time when the study was designed and/or conducted. H. A. H., M. d. H., B. S., S. D., M.-P. D., D. D., J. H., and V. H. hold shares in GSK as part of their employee remuneration. M.-P. D. is a co-applicant on a pending patent filed by GSK. M. F. received study-related payments for training and study conduct from GSK. T. F. S. received honoraria for lectures from AstraZeneca, Bavarian Nordic, Biogen, CSL-Seqirus, GSK, Janssen-Cilag, Merck-Serono, Moderna, Novavax, MSD, Pfizer, Roche, Sanofi-Aventis, and Takeda; he participated on advisory boards for Bavarian Nordic, CSL-Seqirus, BioNTech, GSK, Moderna, Novavax, and Takeda. S. A. N. declares study-related payments to his institution from GSK and support from GSK to attend investigators meetings. J. R.-G. declares study-related payments from GSK and honoraria and support for attending meetings and/or travel from GSK, Pfizer, and Sanofi-MSD; he also participated on data and safety monitoring boards or advisory boards from GSK and Pfizer. C. Z. received grants from GSK for the conduct of this study and support from GSK for attending meetings. J. G. declares study-related payments from GSK; grants from Novartis, Pharmalog, New Amsterdam Pharma, Syneos, Winecker Pharma, and Lilly; and consulting fees, honoraria, payment for expert testimony, and support for attending meetings and/or travel from GSK. C. V.-P. is a former employee of QPS Netherlands B.V. The other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: In the previous (parent) study, 2 doses of different formulations of an investigational vaccine against respiratory syncytial virus (RSVPreF3 OA) were well tolerated and immunogenic in older adults. This multicenter phase 2b extension study assessed safety and immunogenicity of a revaccination (third) dose of the 120 μg RSVPreF3-AS01E formulation., Methods: In total, 122 older adults (60-80 years), previously vaccinated with 2 doses of RSVPreF3-AS01E formulations (containing 30, 60, or 120 μg RSVPreF3 antigen), received an additional 120 μg RSVPreF3-AS01E dose 18 months after dose 2. Vaccine safety was evaluated in all participants up to 6 months and immunogenicity in participants who received 120 μg RSVPreF3-AS01E doses until 1 month after dose 3., Results: Similar to the parent study, mostly mild-to-moderate solicited adverse events and no vaccine-related serious adverse events or potential immune-mediated disorders were reported. Neutralizing titers and cell-mediated immune responses persisted for 18 months after 2-dose vaccination. Dose 3 increased RSV-specific neutralizing titers against RSV-A and RSV-B and median CD4+ T-cell frequencies. After dose 3, RSV-specific neutralizing titers but not CD4+ T-cell frequencies were below levels detected 1 month after dose 1., Conclusions: Revaccination with 120 μg RSVPreF3-AS01E 18 months after dose 2 is well tolerated and immunogenic in older adults., Clinical Trials Registration: NCT04657198; EudraCT, 2020-000692-21., Competing Interests: Potential conflicts of interest. I. L. R. reports funding from Icosavax and Virometix to her institution for the conduct of RSV vaccine trials, and from GSK to her institution for conduct of this clinical trial. M. V. R. reports GSK funding to the Leuven University Vaccinology Center for the conduct of the clinical trial. C. Vm. reports GSK funding to her institution for the conduct of the clinical trial as at the time of the execution of the clinical trial she was an investigator; C. Vm. joined GSK after the close of the study at her institution and is currently an employee of GSK; however, she does not hold any shares. C. V. A., N. D. S., B. S., C. V., M. P. D., S. K., and V. H. were employees of GSK at the time of the study conduct. N. D. S., B. S., M. P. D., C. V., S. K., and V. H. hold shares from GSK as part of their past/current employee remuneration. All current/previous employees of GSK declare financial and nonfinancial relationships and activities. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The aim of this study was to investigate safety and immunogenicity of vaccine formulations against respiratory syncytial virus (RSV) containing the stabilized prefusion conformation of RSV fusion protein (RSVPreF3)., Methods: This phase 1/2, randomized controlled, observer-blind study enrolled 48 young adults (YAs; aged 18-40 years) and 1005 older adults (OAs; aged 60-80 years) between January and August 2019. Participants were randomized into equally sized groups to receive 2 doses of unadjuvanted (YAs and OAs) or AS01-adjuvanted (OAs) vaccine or placebo 2 months apart. Vaccine safety and immunogenicity were assessed until 1 month (YAs) or 12 months (OAs) after second vaccination., Results: The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific immunoglobulin G [IgG] and RSV-A neutralizing antibody) responses, which increased in an antigen concentration-dependent manner and were highest after dose 1. Compared to prevaccination, the geometric mean frequencies of polyfunctional CD4+ T cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Postvaccination immune responses persisted until end of follow-up. Solicited adverse events were mostly mild to moderate and transient. Despite a higher observed reactogenicity of AS01-containing vaccines, no safety concerns were identified for any assessed formulation., Conclusions: Based on safety and immunogenicity profiles, the AS01E-adjuvanted vaccine containing 120 μg of RSVPreF3 was selected for further clinical development., Clinical Trials Registration: NCT03814590., Competing Interests: Potential conflicts of interest. D. C., M.-P. D., M. d. H., N. D. S., N. D., L. F., V. H., J. K., N. M., B. S., F. S., J. T., C. V. A., and C. Ve. are/were employees of the GSK group of companies at the time of the study conduct. C. Va. is currently an employee of the GSK group of companies. D. C., M.-P. D., M. d. H., N. D. S., N. D., B. S., F. S., and C. Ve. hold shares from the GSK group of companies as part of their past/current employee remuneration. F. S. is currently an employee of Janssen Pharmaceutical Companies of Johnson & Johnson and holds restricted shares from Johnson & Johnson as part of his employee remuneration. All current/previous employees of the GSK groups of companies declare financial and nonfinancial relationships and activities. C. P. A., E. K., I. L.-R., K. S., and C. Va. report grant/research support from the GSK group of companies to their institution for study conduct and, except for C. Va., they have no nonfinancial relationships and activities to declare. E. K. has served as consultant, in advisory boards, in speaker’s bureaus, or received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Forest, Cipla, Chiesi, GSK, Mylan, Novartis, Sunovion, Teva, Pearl Pharmaceuticals, and Theravance. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Data on respiratory syncytial virus (RSV) disease burden in adults remain scarce. We assessed the burden of confirmed RSV-acute respiratory infections (cRSV-ARIs) in community-dwelling (CD) adults and those in long-term care facilities (LTCFs)., Methods: In this prospective cohort study covering 2 RSV seasons (October 2019-March 2020 and October 2020-June 2021), RSV-ARIs were identified through active surveillance, in medically stable CD-adults ≥50 years (Europe) or adults ≥65 years in LTCFs (Europe and the United States). RSV infection was confirmed by polymerase chain reaction from combined nasal and throat swabs., Results: Of 1981 adults enrolled, 1251 adults in CD and 664 LTCFs (season 1) and 1223 adults in CD and 494 LTCFs (season 2) were included in the analyses. During season 1, overall incidence rates ([IRs] cases/1000 person-years) and attack rates (ARs) for cRSV-ARIs were 37.25 (95% confidence interval [CI], 22.62-61.35) and 1.84% in adults in CD and 47.85 (CI, 22.58-101.4) and 2.26% in adults in LTCFs. Complications occurred for 17.4% (CD) and 13.3% (LTCFs) of cRSV-ARIs. One cRSV-ARI occurred in season 2 (IR = 2.91 [CI, 0.40-20.97]; AR = 0.20%), without complications. No cRSV-ARIs led to hospitalization or death. Viral pathogens were codetected in ≤17.4% of cRSV-ARIs., Conclusions: RSV is an important cause of disease burden in adults in CD and LTCFs. Despite the observed low severity of cRSV-ARI, our results support the need for RSV prevention strategies among adults ≥50 years old., Competing Interests: Potential conflicts of interest. RD, SD, J-YP, and DL are employees of the GSK group of companies. SD, J-YP, and DL hold shares in the GSK group of companies as part of their employee remuneration. JMRT declares lectures for Pfizer and attending meetings for GSK and Pfizer. IL-R declares funding from GSK, ICOSAVAX, and Virometix to her institution for conducting RSV clinical trials and participation on Janssen advisory boards for RSV vaccines. CV reports grant/research support from GSK to her institution for the conduct of the current study and is currently an employee of the GSK group of companies. KS, JSTB, and LLH declares research funding received by their institution from GSK. RGF declares lectures for GSK. SM works as a freelance consultant on behalf of the GSK group of companies. All other authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Objectives: Currently existing pneumococcal vaccines have contributed to a major reduction in pneumococcal disease. However, there remains an unmet need for vaccine coverage of serotypes not included in PCV13 to further reduce the burden of disease. The objective of this review is to assess the potential impact of implementation of the investigational 20-valent pneumococcal conjugate vaccine (PCV20) in the childhood and adult immunization programme in Belgium and Europe., Methods: A literature search was conducted to identify publications and surveillance reports concerning the effectiveness and safety of pneumococcal vaccines, epidemiological data on pneumococcal disease or serotype distribution dynamics after introduction of systematic vaccination., Results: Serotypes included in PCV20 currently account for the majority of pneumococcal disease in Belgium and Europe. In Belgium, PCV20-serotypes accounted for 71.4% of invasive pneumococcal disease (IPD) cases across all age groups in 2019, of which 39.2% were caused by PCV20-non-PCV13-serotypes. In Europe, these seven serotypes accounted for 37,6% of IPD cases in 2018.  PCV20 has proven to be well tolerated in vaccine-naïve adults and elicits a substantial immune response against all serotypes included., Conclusion: Due to serotype replacement following the introduction of PCV7 and PCV13, a considerable proportion of pneumococcal disease is currently caused by PCV20-serotypes. PCV20 has the potential of preventing more pneumococcal disease in children and the adult population at risk than the existing conjugate vaccines. The available evidence on safety and immunogenicity of PCV20 is promising, but further research is needed to provide data about vaccine effectiveness, immune response duration and replacement phenomenon after introduction of PCV20.

Background: The development of technological applications in clinical research, such as electronic informed consent (eIC), is on the rise. The involvement of end users throughout the design process of eIC is of utmost importance to improve the current informed consent process., Methods: Using a provocative design, we conducted interviews with 30 clinical research participants. Provotypes were used as a starting base to discuss various aspects relevant to eIC. By providing a medium to encourage divergent thinking, participants' views and concerns were solicited. Thematic analysis was undertaken using NVivo., Results: The majority of participants placed trust in the principal investigator or the hospital to perform the role of eIC hosting party. Differing opinions were reported on the amount of information required related to stakeholders' access to an eIC system, and thus, to participants' personal data, to enable trust in an eIC system. Nevertheless, this study indicates a general willingness of participants to share personal data with physicians and pharmaceutical companies on an international level, and to receive requests for new research studies via an eIC system. Participants suggested to tailor an eIC system based upon their preferences, for example, regarding whom they want to share their personal data with. Moreover, they expressed a desire to choose how they can contact the research team, and to indicate which study-related information they would like to receive electronically. In addition, positive opinions were voiced on the integration of a test to assess participants' understanding before providing their eIC., Conclusions: Following a research through design approach, insights have been generated which inform the design of eIC. Provotypes were designed to help participants think beyond what is familiar to them. Study findings revealed that not all situations were perceived as provocative, because of participants' motivation to advance scientific research and the trust they place in the research team. Nevertheless, the use of provocative design resulted in additional insights, generated by clinical research participants, which could be considered in the further design of eIC., (© 2022. The Author(s).)

Governments regularly have to decide whether new vaccines should be adopted in their national immunization program. These choices imply complex trade-offs of epidemiological, medical and socio-economic criteria. We investigated how the population in Flanders (Belgium) wants their government to set vaccine-funding priorities. In December 2019, we executed a discrete choice experiment in a sample of the Flemish population (N = 1636). In total, we analysed 16 360 choices between vaccines competing for funding, described in terms of eight characteristics. Using a panel mixed logit model, we quantified the relative importance of each characteristic and investigated differences in preferences across respondent groups. The observed vaccine priorities were different from those that would be identified through cost-effectiveness analysis. People valued the health impact from infectious diseases differently than their weight expressed in QALYs would suggest. Mortality and frequently occurring mild illness were valued higher, whereas lasting morbidity received lower weight. Contribution of the vaccine to disease eradication and uncertainty in vaccine effectiveness were both highly influential factors. Health equity impact was also important whereas the economic impact of the disease did not matter at all. Our results can be used to incorporate public values into vaccine decision-making., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In the framework of new legislation on School Health Services (SHS) in Flanders (Belgium), nurses lead a preventive consultation with every three-year-old child and its parent(s), with the aim of assessing risks in child development and potential parenting problems. This study assesses the feasibility of the "Structured Problem Analysis of Raising kids aged 36 months" (SPARK36), a broad-scope structured interview to facilitate such consultations., Design and Methods: A feasibility study was conducted with SHS nurses across Flanders, to determine need for this instrument, acceptability and practical feasibility of SPARK36 with both parents and professionals. Nurses were trained to use the instrument. Mixed methods (i.e., questionnaires for both parents and nurses, and a focus group interview with nurses) were used to evaluate the feasibility of using SPARK36., Results: Parents were satisfied (97.0%) with what was discussed during the consultation and with the consultation's structure (98.8%). After the training, all 20 nurses felt strengthened in performing the consultation and in making a risk assessment. The interview was feasible in 20-30 min. During 561 interviews nurses gave parenting support in 88.2% of cases., Conclusions: SPARK36 is acceptable, practically feasible for parents and nurses, and it meets needs of both parties. The instrument supports nurses during their consultation. More research is needed to evaluate the instrument and to prepare its implementation in daily practice., Practice Implications: SPARK36 is a promising instrument for nurse-led consultations in the SHS setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Despite the increasing importance of teamwork in healthcare, medical education still puts great emphasis on individual achievements. The purpose of this study is to examine medical students' team role preferences, including the association with gender and specialty; and to provide implications for policy makers and medical educators., Methods: We used an exploratory methodology, following a cross-sectional design. Data was collected from first year master students in medicine (n = 2293) during five consecutive years (2016-2020). The Belbin Team Role Self Perception Inventory (BTRSPI) was used to measure medical students' self-perceptions of their team role., Results: The Team Worker was the most preferred team role among medical students (35.8%), regardless of gender or specialty. Female and male students had similar team role patterns, although female students scored higher on Team Worker (40.4% vs. 29.1%, P < .001) and Completer-Finisher (14.0% vs. 8.0%, P < .001). With regard to specialties, the Team Worker role was more often chosen by general practitioners than by person-centered and technique-oriented specialties (47.1% vs. 41.8% vs. 29.1%, P < .001)., Conclusions: Our findings contribute to an increased scientific understanding of how medical students perceive their own team role, and how this is related to gender and specialty. This is valuable due to the increased importance of interdisciplinary teamwork in healthcare. Medical schools should prioritize stimulating teamwork skills through the implementation of different interventions at all stages (i.e. from the admission process to curricula to residency) and all levels (i.e. explicit and implicit curricula)., (© 2022. The Author(s).)

It is not yet clear to what extent SARS-CoV-2 infection rates in children reflect community transmission, nor whether infection rates differ between primary schoolchildren and young teenagers. A cross-sectional serosurvey compared the SARS-CoV2 attack-rate in a sample of 362 children recruited from September 21 to October 6, 2020, in primary (ages 6-12) or lower secondary school (ages 12-15) in a municipality with low community transmission (Pelt) to a municipality with high community transmission (Alken) in Belgium. Children were equally distributed over grades and regions. Blood samples were tested for the presence of antibodies to SARS-CoV-2 with an enzyme-linked immunosorbent assay. We found anti-SARS-CoV-2 antibodies in 4.4% of children in the low transmission region and in 14.4% of children in the high transmission region. None of the primary schoolchildren were seropositive in the low transmission region, whereas the seroprevalence among primary and secondary schoolchildren did not differ significantly in the high transmission region. None of the seropositive children suffered from severe disease. Children who were in contact with a confirmed case (RR 2.9; 95%CI 1.6-4.5), who participated in extracurricular activities (RR 5.6; 95%CI 1.2-25.3), or whose caregiver is a healthcare worker who had contact with COVID-19 patients (RR 2.2; 95%CI 1.0-4.6) were at higher risk of seropositivity. If SARS-CoV2 circulation in the community is high, this will be reflected in the pediatric population with similar infection rates in children aged 6-12 years and 12-15 years. What is Known: •Children are generally less affected by COVID-19 than adults but SARS-CoV2 infection rates among children are not well known. •There were large regional differences in infection rates during the first wave of the SARS-CoV2 pandemic. What is New: •None of the primary schoolchildren (6-12 years) were seropositive for SARS-CoV2 in an area with a low community transmission, but infection rates were higher in adolescents (12-15 years). •In an area with high community transmission, seroprevalence rates in younger children were more comparable to those in adolescents., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: CG, KP, SD, TK, TN, CVR, LWH report a grant from Fonds Wetenschappelijk Onderzoek (FWO- Research Foundation – Flanders), to conduct social listening of vaccine concerns in Belgium. CS reports a grant from Johnson & Johnson and a grant from GSK on Research on Vaccine hesitance in different European countries. HL reports a grant from Merck on Research on Vaccine hesitancy among health care providers; from GSK on Research on Vaccine acceptance during pregnancy and honoraria for a training session; a grant from Astra Zeneca to run webinars with health care professionals on covid vaccination. CV; NV; TGV; AV have nothing to disclose.

A multicomponent vaccine has been developed to reduce the frequency of acute exacerbations of COPD associated with non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) infections, containing NTHi (PD and PE-PilA) and Mcat (UspA2) surface proteins. In a randomised, observer-blind, placebo-controlled study with two steps (NCT02547974), the investigational vaccine had good immunogenicity and no safety concerns were identified. In step 2, 90 adults aged 50-71 years with smoking history received two doses 60 days apart of one of two AS01 E -adjuvanted formulations containing 10 µg of each antigen (10-10-AS01) or 10 µg NTHi antigens and 3.3 µg UspA2 (10-3-AS01), or placebo. Long-term persistence of antigen-specific humoral antibodies was assessed in 81 participants during 3 years of follow-up after the initial 14-month study (NCT03201211). Antigen-specific antibody concentrations were measured in blood samples taken every 6 months. Safety monitoring evaluated serious adverse events (SAEs) and potential immune-mediated disease (pIMD). Immune responses against NTHi antigens persisted up to 4 years post-vaccination. For PD, PE and PilA, at each follow-up time point, adjusted antibody geometric mean concentrations (GMCs) were higher (non-overlapping 95% confidence intervals [CIs]) in the vaccine groups versus placebo and versus pre-vaccination. Antibody GMC point estimates were higher with 10-3-AS01 than with 10-10-AS01. For UspA2, 95% CIs included 1 for GMC ratios of 10-10-AS01 or 10-3-AS01 to placebo at each time point. During follow-up, SAEs were reported in nine (11.1%) participants, one of which was fatal (lung cancer, 607 days after second 10-10-AS01 dose). One non-serious pIMD, trigeminal neuralgia, was reported 771 days after second 10-3-AS01 dose. The SAEs and pIMD were considered not related to vaccination. Immune responses against NTHi antigens persisted for 4 years after two-dose vaccination with the investigational NTHi-Mcat vaccine. There was no persistent response against the Mcat antigen. No safety concerns were identified during the long-term follow-up., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PDS declares no financial or non-financial relationships and activities and no conflicts of interest. GL-R reports a grant paid by the GSK group of companies for the conduct of this study and consulting fees paid by the GSK group of companies in the context of clinical trials conducted in general. CV reports a grant paid to her employer by the GSK group of companies during the conduct of this study, and grants paid to her employer by MSD and Pfizer outside the submitted work. AT, GDM, MD, DC, MA, DR and AKA are employees of the GSK group of companies. MD holds shares in the GSK group of companies and is married to an employee of the GSK group of companies who holds shares in it. GL-R, CV, AT, GDM, MD, DC, MA, DR and AKA declare no other financial or non-financial relationships and activities., (© 2021 GlaxoSmithKline Biologicals S.A.)

Objective: To investigate vaccine hesitancy leading to underimmunization and a measles outbreak in Rwanda and to develop a conceptual, community-level model of behavioural factors., Methods: Local immunization systems in two Rwandan communities (one recently experienced a measles outbreak) were explored using systems thinking, human-centred design and behavioural frameworks. Data were collected between 2018 and 2020 from: discussions with 11 vaccination service providers (i.e. hospital and health centre staff); interviews with 161 children's caregivers at health centres; and nine validation interviews with health centre staff. Factors influencing vaccine hesitancy were categorized using the 3Cs framework: confidence, complacency and convenience. A conceptual model of vaccine hesitancy mechanisms with feedback loops was developed., Findings: A comparison of service providers' and caregivers' perspectives in both rural and peri-urban settings showed that similar factors strengthened vaccine uptake: (i) high trust in vaccines and service providers based on personal relationships with health centre staff; (ii) the connecting role of community health workers; and (iii) a strong sense of community. Factors identified as increasing vaccine hesitancy (e.g. service accessibility and inadequate follow-up) differed between service providers and caregivers and between settings. The conceptual model could be used to explain drivers of the recent measles outbreak and to guide interventions designed to increase vaccine uptake., Conclusion: The application of behavioural frameworks and systems thinking revealed vaccine hesitancy mechanisms in Rwandan communities that demonstrate the interrelationship between immunization services and caregivers' vaccination behaviour. Confidence-building social structures and context-dependent challenges that affect vaccine uptake were also identified., ((c) 2021 The authors; licensee World Health Organization.)

Background: The currently licensed quadrivalent MenACWY-CRM conjugate vaccine presentation consists of two vials (lyophilised MenA and liquid MenCWY) to be reconstituted before injection. A new fully liquid formulation in a single vial has been developed to further improve the vaccine presentation. Since the MenA structure is subject to hydrolytic degradation, this study was conducted to compare the immunogenicity and safety of the investigational MenACWY-CRM liquid vaccine with the licensed vaccine., Methods: In this multicentre, randomised, controlled, observer-blind, phase 2b study, 979 healthy adults were administered a single dose of MenACWY-CRM liquid presentation or the currently licensed MenACWY-CRM vaccine. MenA free saccharide generation was accelerated to approximately 30% in the liquid presentation and MenA polysaccharide O-acetylation was reduced to approximately 40%, according to a controlled procedure. Immunological non-inferiority of the MenACWY-CRM liquid to the licensed vaccine, as measured by human serum bactericidal assay (hSBA) geometric mean titres (GMTs) against MenA 1 month post-vaccination, was the primary study objective. Safety assessment was among the secondary objectives., Results: Immune responses against each serogroup were similar between the two vaccine groups and was non-inferior for MenA. Adjusted hSBA GMTs for MenA were 185.16 and 211.33 for the MenACWY-CRM liquid presentation and currently licensed vaccine presentation, respectively. The between-group ratio of hSBA GMTs for MenA was 0.88, with a two-sided 95% confidence interval lower limit of 0.64, greater than the prespecified non-inferiority margin of 0.5, thus meeting the primary study objective. Both vaccines were well tolerated. No serious adverse events were considered related to vaccination., Conclusions: The levels of MenA free saccharide and polysaccharide O-acetylation did not affect the immunogenicity of the fully liquid presentation, which was demonstrated to be non-inferior to the immunogenicity of the currently licensed MenACWY-CRM vaccine against MenA. The immunogenicity, reactogenicity and safety profiles of the two vaccine presentations were similar., Competing Interests: Declaration of Competing Interest TA, SVH, MA, BK, BdW, GFDD, MC, PVS, EF, ML and MP are employed by the GSK group of companies. TA, MA, BdW, PVS, EF, ML and MP hold shares in the GSK group of companies. CV reports her institution received payments from the GSK group of companies, MSD and Pfizer, outside the submitted work. ILR reports her institution received payments from the GSK group of companies for the conduct of the study. TN reports payments from the GSK group of companies, Merck, Sanofi Pasteur and Seqirus, outside the submitted work. TA, SVH, MA, BK, BdW, GFDD, MC, PVS, EF, ML, MP, CV, ILR and TN declare no other financial and non-financial relationships and activities. JV, TS, GG, MF, GI, TFS, AMN and SC declare no financial and non-financial relationships and activities and no conflicts of interest., (Copyright © 2021 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome., Competing Interests: The authors have declared that no competing interests exist.

Background: Influenza vaccination is the most commonly recommended immune prevention strategy. However, data on influenza vaccination in patients with congenital heart disease (CHD) are scarce. In this study, our goals were to: (1) measure vaccination coverage rates (VCRs) for influenza in a large cohort of children, adolescents, and adults with CHD; (2) identify patient characteristics as predictors for vaccination; and (3) investigate the effect of influenza vaccination on hospitalization., Methods: A nationwide cohort study in Belgium included 16,778 patients, representing 134,782 vaccination years, from the Belgian Congenital Heart Disease Database Combining Administrative and Clinical Data (BELCODAC). Data over 9 vaccination years (2006-2015) were used, and patients were stratified into 5 age cohorts: 6 months to 4 years; 5-17 years; 18-49 years; 50-64 years; and 65 years and older., Results: In the respective age cohorts, the VCR was estimated to be 6.6%, 8.0%, 23.9%, 46.6%, and 72.8%. There was a steep increase in VCRs as of the age of 40 years. Multivariable logistic regression showed that higher anatomical complexity of CHD, older age, presence of genetic syndromes, and previous cardiac interventions were associated with significantly higher VCRs. Among adults, men had lower and pregnant women had higher VCRs. The association between influenza vaccination and all-cause hospitalization was not significant in this study., Conclusions: The influenza VCR in people with CHD is low, especially in children and adolescents. Older patients, particularly those with complex CHD, are well covered. Our findings should inform vaccination promotion strategies in populations with CHD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The burden of human papillomavirus (HPV) in human immunodeficiency virus (HIV)-infected persons and solid organ transplant (SOT) recipients is high. Clinical trials on HPV vaccines in persons living with HIV and particularly in SOT recipients have been sparse to date, included low numbers of participants, and none of them assessed the 9-valent HPV (9vHPV) vaccine. We investigated the immunogenicity with respect to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and the safety of the 9vHPV vaccine in persons living with HIV and recipients of a kidney, lung, or heart transplant., Methods: This is a phase III investigator-initiated study in 100 persons living with HIV (age 18-45 years) and 171 SOT recipients (age 18-55 years). The 9vHPV vaccine was administered at day 1, month 2, and month 6. Primary outcome was seroconversion rates to the 9vHPV types at month 7. Secondary outcomes were geometric mean titers (GMTs) and frequency of adverse events (AEs)., Results: All HIV-infected participants seroconverted for all HPV types, but seroconversion ranged from 46% for HPV45 to 72% for HPV58 in SOT recipients. GMTs ranged from 180 to 2985 mMU/mL in HIV-positive participants and from 17 to 170 mMU/mL in SOT recipients, depending on the HPV type. Injection-site AEs occurred in 62% of participants but were mostly mild or moderate in intensity. None of the reported serious adverse events were deemed vaccine related. No patients died during the study., Conclusions: Immunogenicity of the 9vHPV vaccine is high in persons living with HIV but suboptimal in SOT recipients. The vaccine is safe and well tolerated in both groups., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age., Methods: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study., Results: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study., Conclusions: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Elmar Joura reports grants from Merck during the conduct of the study, and personal fees from Merck Sharpe & Dohme outside the submitted work. Angels Ulied reports personal fees through her institution from GSK, NUTRICIA, and MERK, outside the submitted work. Corinne Vandermeulen reports that her university received grants from GSK, Pfizer, and Merck for clinical studies for which she was principal investigator, and no personal grants. Milagrosa Rua Figueroa reports no conflicts of interest. Ilkka Seppä reports no conflicts of interest. Juan José Hernandez Aguado reports no conflicts of interest. Anitta Ahonen reports no conflicts of interest. Olaf Reich reports no conflicts of interest. Miia Virta reports no conflicts of interest. Antonino Perino reports grant and travel support from Merck Sharp & Dohme. Merce Peris Tuser reports no conflicts of interest. Klaus Peters reports no conflicts of interest. Massimo Origoni reports no conflicts of interest. Francesco Raspagliesi reports grants from GSK, Merck Sharpe & Dohme, Roche, and Tesaro, outside the submitted work. Wiebren AA Tjalma reports no conflicts of interest. Philippe Tummers reports no conflicts of interest. Linn Woelber reports grants from Merck Sharpe & Dohme during the conduct of the study, grants and personal fees from Medac Oncology, personal fees from GSK, Jenapharm, Pfizer, Roche, Tesaro, and TEVA, and grants from Roche Diagnostics, outside the submitted work. Pekka Nieminen reports no conflicts of interest. Pierre van Damme reports his university received grants from Merck Sharpe & Dohme for the conduct of this study, grants from GSK Biologicals, Pfizer, Sanofi, Merck Sharpe & Dohme, Takeda, Baxter, CanSino China, Themis, Osivax, J&J, and Abbott, and grants from The Bill & Melinda Gates Foundation, PATH, Flemish Government, and European Union, outside the submitted work. Jalid Sehouli reports no conflicts of interest. Gabriel Fiol Ruiz reports no conflicts of interest. Sara Brucker reports no conflicts of interest. Tanja Fehm reports personal fees from Daichi Sankyo, Lilly, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, and TEVA. Kyeongmi Cheon, Sonali Rawat, Alain Luxembourg, and Frederick Wittke are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Kenilworth, NJ, USA.]., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Seasonal influenza is an annually recurring threat to residents of long-term care facilities (LTCFs) since high age and chronic disease diminish immune response following vaccination. Although immunization of healthcare workers (HCWs) has proven to be an added value, coverage rates remain low. A ready-to-use instruction manual was designed to facilitate the implementation of interventions known to increase vaccination coverage in healthcare institutions. It includes easy-access vaccination, role model involvement, personalized promotional material, education and extensive communication. We evaluated this manual during the 2017-vaccination campaign in 11 LTCFs in Belgium. Vaccination coverage before and after the campaign was recorded by the LTCFs and the usefulness of the manual was assessed by interviewing the organizers of the local campaigns. Attitudes toward vaccination and reasons for vaccination were evaluated with a quantitative survey in HCWs before and after the campaign. The mean vaccination coverage reported by the LTCFs was 54% (range: 35-72%) in 2016 and 68% (range: 45-81%) in 2017. After the campaign, HCWs were less likely to expect side effects after influenza vaccination (OR (95%CI): 0.4 (0.2-0.9)) or to oppose vaccination (OR (95%CI): 0.3 (0.1-0.9)). The majority (>60%) indicated to be well informed about the risks of influenza and the efficacy of the vaccine. The main reason for vaccination in those who previously refused it was resident protection. The manual was found useful by the organizers of the campaigns. We conclude that the use of an intervention manual may support vaccination uptake and decrease perceived barriers toward influenza vaccination in countries without mandatory vaccination in HCWs.

The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response 1 . Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and-concomitantly-protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model 2 and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.

Patients with chronic diseases are at increased risk of complications following infection. It remains, however, unknown to what extend they are protected against vaccine-preventable diseases. We assessed seroprevalence of antibodies against diphtheria, tetanus and pertussis to evaluate whether current vaccination programs in Belgium are adequate. Antibody titers were assessed with a bead-based multiplex assay in serum of 1052 adults with chronic diseases. We included patients with diabetes mellitus type 1 (DM1) ( n = 172), DM2 ( n = 77), chronic kidney disease ( n = 130), chronic obstructive pulmonary disease (COPD) ( n = 170), heart failure ( n = 77), HIV ( n = 196) and solid organ transplant (SOT) recipients ( n = 230). Factors associated with seroprevalence were analysed with multiple logistic regression. We found seroprotective titers in 29% for diphtheria (≥0.1 IU/mL), in 83% for tetanus (≥0.1 IU/mL) and 22% had antibodies against pertussis (≥5 IU/mL). Seroprotection rates were higher ( p < 0.001) when vaccinated within the last ten years. Furthermore, diphtheria seroprotection decreased with age ( p < 0.001). Tetanus seroprotection was less reached in women ( p < 0.001) and older age groups ( p < 0.001). For pertussis, women had more often a titer suggestive of a recent infection or vaccination (≥100 IU/mL, p < 0.01). We conclude that except for tetanus, the vast majority of at-risk patients remains susceptible to vaccine-preventable diseases such as diphtheria and pertussis.

Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that infects approximately 10-20 million people worldwide and causes an aggressive neoplasia (adult T-cell leukemia/lymphoma - ATL). Therapeutic approaches for the treatment of ATL have variable effectiveness and poor prognosis, thus requiring strategies to identify novel compounds with activity on infected cells. In this sense, we initially screened a small series of 25 1,2,3-triazole derivatives to discover cell proliferation inhibitors and apoptosis inducers in HTLV-1-infected T-cell line (MT-2) for further assessment of their effect on viral tax activity through inducible-tax reporter cell line (Jurkat LTR-GFP). Eight promising compounds (02, 05, 06, 13, 15, 21, 22 and 25) with activity ≥70% were initially selected, based on a suitable cell-based assay using resazurin reduction method, and evaluated towards cell cycle, apoptosis and Tax/GFP expression analyses through flow cytometry. Compound 02 induced S phase cell cycle arrest and compounds 05, 06, 22 and 25 promoted apoptosis. Remarkably, compounds 22 and 25 also reduced GFP expression in an inducible-tax reporter cell, which suggests an effect on Tax viral protein. More importantly, compounds 02, 22 and 25 were not cytotoxic in human hepatoma cell line (Huh-7). Therefore, the discovery of 3 active and non-cytotoxic compounds against HTLV-1-infected cells can potentially contribute, as an initial promising strategy, to the development process of new drugs against ATL., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Automated methodologies allowing for rapid detection of Factor V Leiden and Factor II G20210A variants are desirable, due to a high number of tested patients. Here, we report a preliminary validation of a CE-marked in vitro diagnostic (IVD) certified method for simultaneous detection of Factor V Leiden and Factor II G20210A variants on whole blood samples. The novel method is based on Loop-mediated isothermal AMPlification (LAMP) applied for a duplex detection of Factor V Leiden and Factor II G20210A variants without requiring prior DNA extraction, whereas the routine one is a TaqMan SNP genotyping targeting genomic DNA. We tested routine patients for both variants using novel and current methods and estimated concordance rate. Patients were tested under similar laboratory procedures. One hundred and eight patients referred for the thrombophilia testing in the period between 9th December 2019 to 27th February 2020 represented the study population. We routinely identified for the Factor V Leiden variant 163 wild-type, 17 heterozygotes and no homozygote. Concerning the Factor II G20210A variant, we identified 170 wild-type, nine heterozygotes and one homozygous carrier. Two heterozygotes carried both variants (double heterozygotes). The LAMP method showed a 100% concordance rate, detecting rightly all genotypes. The LAMP for a duplex detection of common thrombophilia variants shows analytic performances as good as those of the standard method.

In addition to more narrow criteria such as safety, effectiveness and cost-effectiveness, vaccines can also be evaluated based on broader criteria such as their economic impact, contribution to disease eradication objectives, caregiver aspects, financial protection offered, equity or social acceptability. We summarize a survey executed in a sample of the population ( n = 1000) in Flanders, Belgium, in which we investigated support for using these broader criteria to evaluate vaccines for funding decisions. By means of both favourable and unfavourable framings of a hypothetical vaccine across 40 value dimensions, we find support for the view that people indeed consider a broad range of medical and socio-economic criteria relevant. Several of these are not incorporated in standard evaluation frameworks for vaccines. The different results we find for different framings highlight the importance of developing a consistent a priori value framework for vaccine evaluation, rather than evaluating vaccines on an ad hoc basis.

Upon exposure to vaccine-preventable diseases, certain individuals are at increased risk for complications due to preexisting diseases, age or immunosuppressive treatment. Vaccination against influenza, pneumococcal disease and hepatitis B (for some groups) is advised in addition to standard vaccination against diphtheria, tetanus and pertussis. We estimated the vaccination coverage and determinants of recommended vaccinations in patients with diabetes mellitus type 1 (n = 173) and type 2 (n = 177), chronic kidney disease (CKD) (n = 138), heart failure (n = 200), chronic obstructive pulmonary disease (COPD) (n = 187), HIV (n = 201) or solid organ transplantation (SOT) (n = 201) in a monocentric study. Vaccination data were retrieved from documents provided by patients and general practitioners, and from the Flemish vaccination register. Less than 10% had received all recommended vaccines. Overall, 29% of subjects were vaccinated against diphtheria-tetanus, 10% against pertussis, 44% against influenza, 32% against pneumococcal disease and 24% of HIV patients and 31% of CKD patients against hepatitis B. Age was positively associated with vaccination against influenza (OR:2.0, p < .01) and pneumococcal disease (OR:2.6, p < .001). Patients with COPD, HIV and SOT were more likely to be vaccinated against influenza (OR:2.8, p < .001, OR:1.8, p < .05; OR:2.0, p < .001, respectively) and pneumococcal disease (OR:2.9, p < .001, OR:25.0, p < .001; OR:2.6, p < .001, respectively) than patients with heart failure. Reason for non-vaccination were concerns about effectiveness, necessity and side effects of influenza vaccines, and not being aware of the recommendation for pneumococcal disease. Initiatives to monitor the vaccination status of vulnerable patients are needed, which is why we advocate systematic vaccination registration and frequent communication about vaccination.

Background: We evaluated the safety and immunogenicity of liquid and lyophilized formulations of an investigational trivalent group B streptococcus (GBS) vaccine in non-pregnant women and assessed the formulations' equivalence in terms of serotype-specific immune response., Methods: This phase II, randomized, comparative, observer-blind trial enrolled healthy non-pregnant women 18-40 years of age. Women received a single dose of fully liquid (n = 529) or lyophilized (n = 521) trivalent GBS vaccine on day 1. Safety assessments were performed up to day 181 (study termination). Serotype Ia/Ib/III-specific immunoglobulin G (IgG) antibodies were measured in sera from women on day 1 (pre-vaccination) and day 31. Equivalence between the two formulations was demonstrated if the two-sided 95% confidence interval (CI) for the ratio (liquid/lyophilized) of the geometric mean concentrations (GMCs) on day 31 was contained in a (0.5, 2.0) interval for each serotype., Results: Solicited and unsolicited adverse events were reported at similar rates for both formulations. Serious adverse events were reported for six (1.1%) liquid GBS and nine (1.7%) lyophilized GBS vaccinated women, none of which were considered related to vaccination or fatal. On day 31, serotype-specific IgG concentrations were 8-16-fold higher than on day 1 in both groups. Equivalence of the liquid to the lyophilized formulation 30 days post-vaccination was demonstrated as the 95% CIs of the GMC ratios were within the pre-specified interval for the three serotypes: GMC ratios were 1.02 (95% CI: 0.79, 1.32) for serotype Ia, 0.93 (0.71, 1.21) for serotype Ib and 0.99 (0.76, 1.30) for serotype III., Conclusions: Both formulations of the investigational trivalent GBS vaccine had favorable safety profiles and induced similar GBS serotype-specific antibody concentrations. This study demonstrated that the fully liquid formulation was equivalent to the lyophilized formulation in healthy non-pregnant women in terms of immunogenicity for all three serotypes., Clinical Trials Registration: NCT02270944., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ZB, ML, OH, BC, AK, AD and CS are employees of the GSK group of companies. ML, OH, BC and AK hold shares in the GSK group of companies. For the work under consideration, GLR, PVD, CV and MAI declare that their institutions have been compensated by the GSK group of companies for the costs involved in the conduct of the study, JdH declares funding from Novartis Vaccine for industry sponsored clinical trial and JP declares personal fees from the GSK group of companies for service as principal investigator. Outside the submitted work, GLR declares personal fees from the GSK group of companies, Osivax, Virometix and Ablynx for consulting activities, PVD declares that his institution has received grants from the GSK group of companies, Pfizer, Sanofi, Merck, Takeda, Baxter, CanSino China, Osivax, Themis, Johnson & Johnson, Abbott, the Bill & Melinda Gates foundation, the Flemish government and the European Union; SB declares that she is consultant statistician for the GSK group of companies. JB and CJ have nothing to disclose., (Copyright © 2020 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Recombinant technology has revolutionised the way novel vaccines are developed and manufactured. The possibility to genetically modify micro-organisms to bring immunogenic material (antigens/epitopes) to the human (or animal) immune system to provoke an immune response, provides new hope to producing prophylactic vaccines against HIV, malaria and tuberculosis and emerging diseases. Regulatory requirements associated with the development of genetically-modified organism (GMO)-containing vaccines in Europe add an additional burden to the clinical trial application procedure and to the preparation and initiation of a clinical trial of such vaccines. Moreover, the GMO regulatory framework is complex and only partially harmonised across Europe, which may hamper multi-country clinical trials with GMO-containing vaccines. This paper provides an overview of clinical trial applications with GMO-containing vaccines in Europe and reviews the regulatory framework in countries where GMO-containing vaccine clinical trial authorisation (CTA) applications were submitted between 2004 and 2017., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) are frequent pathogens in acute exacerbations of COPD. We assessed the safety, reactogenicity and immunogenicity of different investigational vaccine formulations containing surface proteins of NTHi (PD and PE-PilA) and Mcat (UspA2) in adults with smoking history ≥10 pack-years, to immunologically represent the COPD population. Participants received two doses 60 days apart in a randomised, observer-blind, placebo-controlled study (NCT02547974). In step 1, 30 healthy adults aged 18-40 years were randomised (1:1) to receive a non-adjuvanted formulation (10-10-PLAIN) or placebo. In step 2, 90 smokers/ex-smokers aged 50-70 years randomly (1:1:1) received an AS01-adjuvanted formulation containing either 10 µg of each antigen (10-10-AS01) or 10 µg of each NTHi antigen and 3.3 µg of Mcat antigen (10-3-AS01), or placebo. Incidences of solicited local adverse events (AEs) tended to be highest in the AS01-adjuvanted vaccine groups. Most solicited AEs had mild/moderate intensity. No vaccine-related serious AEs were reported. The 10-3-AS01 formulation induced the best humoral immune response against the NTHi antigens. Responses against the Mcat antigen were similar across groups, with waning immunogenicity after 30 days post-dose 2. The investigational NTHi-Mcat vaccine had an acceptable safety and reactogenicity profile and good immunogenicity in older adults with a smoking history., (Copyright © 2019 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

The P2X7 receptor (P2X7R) is an adenosine triphosphate-gated ion channel that is predominantly expressed on microglial cells in the central nervous system. We report the clinical qualification of P2X7-specific PET ligand 18 F-JNJ-64413739 in healthy volunteers, including dosimetry, kinetic modeling, test-retest variability, and blocking by the P2X7 antagonist JNJ-54175446. Methods: Whole-body dosimetry was performed in 3 healthy male subjects by consecutive whole-body PET/CT scanning, estimation of the normalized cumulated activity, and calculation of the effective dose using OLINDA (v1.1). Next, 5 healthy male subjects underwent a 120-min dynamic 18 F-JNJ-64413739 PET/MRI scan with arterial blood sampling to determine the appropriate kinetic model. For this purpose, 1- and 2-tissue compartment models and Logan graphic analysis (LGA) were evaluated for estimating regional volumes of distribution (V T ). PET/MRI scanning was repeated in 4 of these subjects to evaluate medium-term test-retest variability (interscan interval, 26-97 d). For the single-dose occupancy study, 8 healthy male subjects underwent baseline and postdose 18 F-JNJ-64413739 PET/MRI scans 4-6 h after the administration of a single oral dose of JNJ-54175446 (dose range, 5-300 mg). P2X7 occupancies were estimated using a Lassen plot and regional baseline and postdose V T Results: The average (mean ± SD) effective dose was 22.0 ± 1.0 μSv/MBq. The 2-tissue compartment model was the most appropriate kinetic model, with LGA showing very similar results. Regional 2-tissue compartment model V T values were about 3 and were rather homogeneous across all brain regions, with slightly higher estimates for the thalamus, striatum, and brain stem. Between-subject V T variability was relatively high, with cortical V T showing an approximate 3-fold range across subjects. As for time stability, the acquisition time could be reduced to 90 min. The average regional test-retest variability values were 10.7% ± 2.2% for 2-tissue compartment model V T and 11.9% ± 2.2% for LGA V T P2X7 occupancy approached saturation for single doses of JNJ-54175446 higher than 50 mg, and no reference region could be identified. Conclusion: 18 F-JNJ-64413739 is a suitable PET ligand for the quantification of P2X7R expression in the human brain. It can be used to provide insight into P2X7R expression in health and disease, to evaluate target engagement by P2X7 antagonists, and to guide dose selection., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir ( n  = 10) and the potential two-way pharmacokinetic interactions of elbasvir ( n  = 30) or grazoprevir ( n  = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC 0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC 0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir., (Copyright © 2019 American Society for Microbiology.)

Objectives: The aim of this study was to assess the effects of concomitant administration of erenumab and sumatriptan on resting blood pressure, pharmacokinetics, safety, and tolerability in healthy subjects., Methods: In this phase 1, parallel-group, one-way crossover, double-blind, placebo-controlled study, healthy adult subjects were randomized (1:2) to receive either intravenous placebo and subcutaneous sumatriptan 12 mg (i.e. two 6-mg injections separated by 1 hour) or intravenous erenumab 140 mg and subcutaneous sumatriptan 12 mg. Blood pressure was measured pre-dose and at prespecified times post-dose. The primary endpoint was individual time-weighted averages of mean arterial pressure, measured from 0 hours to 2.5 hours after the first dose of sumatriptan. Pharmacokinetic parameters for sumatriptan were evaluated by calculating geometric mean ratios (erenumab and sumatriptan/placebo and sumatriptan). Adverse events and anti-erenumab antibodies were also evaluated., Results: A total of 34 subjects were randomized and included in the analysis. Least squares mean (standard error) time-weighted averages of mean arterial pressure were 87.4 (1.0) mmHg for the placebo and sumatriptan group and 87.4 (1.2) mmHg for the erenumab and sumatriptan group. Mean difference in mean arterial pressure between groups was -0.04 mmHg (90% confidence interval: -2.2, 2.1). Geometric mean ratio estimates for maximum plasma concentration of sumatriptan was 0.95 (90% confidence interval: 0.82, 1.09), area under the plasma concentration-time curve (AUC) from time 0 to 6 hours was 0.98 (90% confidence interval: 0.93, 1.03), and AUC from time 0 to infinity was 1.00 (90% confidence interval: 0.96, 1.05). No clinically relevant safety findings for co-administration of sumatriptan and erenumab were identified., Conclusion: Co-administration of erenumab and sumatriptan had no additional effect on resting blood pressure or on pharmacokinetics of sumatriptan. Trial registration: ClinicalTrials.gov, NCT02741310.

Background: Seasonal influenza threatens hospitalised patients and residents of nursing homes annually. Due to age and chronic disease their protection following immunisation is diminished. Additional immunisation of direct contacts and in particular healthcare workers (HCWs) has proven added value. As vaccination coverage in HCWs remains low, we aimed to gain insight in the factors behind the demotivation for influenza vaccination., Methods: Attitudes and believes towards influenza vaccination and socio-demographic and professional determinants were surveyed in 5141 Belgian HCWs from 13 hospitals and 14 nursing homes. Additionally, influenza campaign coordinators of the participating healthcare institutions were interviewed about the factors of success/failure in their campaigns., Results: The mean vaccination coverage registered by the participating healthcare institutions was 40.4% in the hospitals and 45.3% in the nursing homes. Overall, up to 90% of HCWs found it important not to infect their patients. However, only 20% of non-vaccinated HCWs considered influenza vaccination a duty to not harm their patients. Up to 40% of unvaccinated staff believed they could get influenza after vaccination and that vaccination weakens their immune system. Also, only about 20% of unvaccinated staff thought to have a high chance of getting influenza. Reasons for unvaccinated staff to get vaccinated in the future are self-protection and protection of family members. Factors that positively influenced vaccination coverage are encouragement by supervisors (OR, hospitals: 7.1, p < 0.001; nursing homes: 7.5, p < 0.001) and well-organized vaccination campaigns with on-site vaccination. Factors that negatively affected vaccination coverage are misconceptions about influenza and its vaccine (OR, range 0.1-0.7, p < 0.001 for most misconceptions) and underestimation of the risk of contracting influenza by patients or HCWs (OR of perceived susceptibility, range 2.1-5.1, p < 0.001 for most factors)., Conclusion: There is a need for guidance for the organization of seasonal influenza campaigns, in which education, communication and easy accessible vaccination are promoted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In Flanders, Belgium, pertussis vaccination is recommended since 2013 and available free-of-charge in every pregnancy between 24 and 32 weeks of gestation. Influenza vaccination is recommended for more than 10 years with a co-payment system in the second or third trimester of pregnancy, when pregnancy coincides with the influenza season. This study aims to estimate the coverage of pertussis and influenza vaccination during pregnancy in 2016 and to determine predictors for missing vaccination., Methods: Postpartum women were visited at home for a vaccination coverage survey using an Expanded Program on Immunization (EPI)-based two-stage cluster sampling design. Predictors for missed vaccination were identified using a multiple logistic regression model., Results: Among 481 participating women, 69.3% were vaccinated against pertussis and 47.2% were vaccinated against influenza. Moreover, 65.3% of pertussis vaccine recipients and 96.9% of influenza vaccine recipients were vaccinated within the recommended gestational window. Surprisingly, among women who were completely informed (i.e. on disease-associated risks, maternal vaccination costs and recommendations), still 12.4% were unvaccinated against pertussis and 23.9% against influenza. In the final models, the only common predictor of missing maternal pertussis and influenza vaccination was multiparity. Significant predictors of maternal pertussis vaccination were family income (less likely if unknown or low (< €3000) than if moderate (€3001-€4000)) and hospital of delivery (less likely if >800 annual deliveries than <800). Significant predictors of maternal influenza vaccination, though with less straight-forward associations, were maternal ethnicity and educational level, involvement of a gynaecologist in pregnancy follow-up, and characteristics of the hospital of delivery., Conclusion: In Flanders, more than two-third of pregnant women receives pertussis vaccination but less than half of them receives the influenza vaccine. Further improvement for both maternal vaccination programs can be achieved by targeting the underserved populations and diminishing vaccination hurdles., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin-induced dermal blood flow, with no apparent dose-dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Here, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014-2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18-60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains.

Recruitment of volunteers is one of the main challenges in clinical trial management, and there is little information about recruitment barriers for preventative vaccine trials. We investigated both the recruitment barriers and recruitment strategies for preventive vaccine trials in Belgium. A 10 min survey was used as well as interviews of staff at all clinical trial sites in Belgium that regularly perform vaccine trials. We observed that there are successful recruitment strategies and few recruitment issues for trials involving healthy adults and those over 65 years old. However, challenges face the recruitment of paediatric populations, pregnant women, patients and the very elderly (over 85 years old). From these results, we identified three priority areas to increase recruitment for prophylactic vaccine trials in Belgium. These are: the lack of public knowledge about infectious diseases; the lack of resources of healthcare professionals to take part in clinical trials; and the burden to potential volunteers to take part in a trial. These were discussed with stakeholders and solutions were proposed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Calcitonin gene-related peptide (CGRP) is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742) binds to CGRP and may be effective in migraine prophylaxis. Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement. Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596) with single escalating and multiple subcutaneous (SC) doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab ( n = 7/dose) or placebo ( n = 2/dose) were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4) 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF). Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1-600 mg SC) and consecutive doses (150 mg SC). There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.