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Background: To overcome supply issues of COVID-19 vaccines, this partially single blind, multi-centric, vaccine trial aimed to evaluate humoral immunogenicity using lower vaccine doses, intradermal vaccination, and heterologous vaccine schedules. Also, the immunity after a booster vaccination was assessed., Methodology: 566 COVID-19-naïve healthy adults were randomized to 1 of 8 treatment arms consisting of combinations of BNT162b2, mRNA-1273, and ChAdOx1-S. Anti-Receptor-Binding Domain immunoglobulin G (RBD IgG) titers, neutralizing antibody titres, and avidity of the anti-RBD IgGs was assessed up to 1 year after study start., Results: Prolonging the interval between vaccinations from 28 to 84 days and the use of a heterologous BNT162b2 + mRNA-1273 vaccination schedule led to a non-inferior immune response, compared to the reference schedule. A low dose of mRNA-1273 was sufficient to induce non-inferior immunity. Non-inferiority could not be demonstrated for intradermal vaccination. For all adapted vaccination schedules, anti-RBD IgG titres measured after a first booster vaccination were non-inferior to their reference schedule., Conclusion: This study suggests that reference vaccine schedules can be adapted without jeopardizing the development of an adequate immune response. Immunity after a booster vaccination did not depend on the dose or brand of the booster vaccine, which is relevant for future booster campaigns. The trial is registered in the European Union Clinical Trials Register (number 2021-001993-52) and on clinicaltrials.gov (NCT06189040)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Pierre Van Damme reports financial support was provided by Belgian Health Care Knowledge Centre. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Our study aims to investigate the dynamics of conventional memory T cells (Tconv) and regulatory memory T cells (Treg) following activation, and to explore potential differences between these two cell types. To achieve this, we developed advanced statistical mixed models based on mathematical models of ordinary differential equations (ODE), which allowed us to transform post-vaccination immunological processes into mathematical formulas. These models were applied to in-house data from a de novo Hepatitis B vaccination trial. By accounting for inter- and intra-individual variability, our models provided good fits for both antigen-specific Tconv and Treg cells, overcoming the challenge of studying these complex processes. Our modeling approach provided a deeper understanding of the immunological processes underlying T cell development after vaccination. Specifically, our analysis revealed several important findings regarding the dynamics of Tconv and Treg cells, as well as their relationship to seropositivity for Herpes Simplex Virus Type 1 (HSV-1) and Epstein-Barr Virus (EBV), and the dynamics of antibody response to vaccination. Firstly, our modeling indicated that Tconv dynamics suggest the existence of two T cell types, in contrast to Treg dynamics where only one T cell type is predicted. Secondly, we found that individuals who converted to a positive antibody response to the vaccine earlier had lower decay rates for both Tregs and Tconv cells, which may have important implications for the development of more effective vaccination strategies. Additionally, our modeling showed that HSV-1 seropositivity negatively influenced Tconv cell expansion after the second vaccination, while EBV seropositivity was associated with higher Treg expansion rates after vaccination. Overall, this study provides a critical foundation for understanding the dynamic processes underlying T cell development after vaccination., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Benson Ogunjimi reports financial support was provided by European Research Council. Benson Ogunjimi reports financial support was provided by Research Foundation Flanders. Philippe Beutels reports financial support was provided by University of Antwerp. Pierre Van Damme reports financial support was provided by University of Antwerp. CONFLICT OF INTEREST STATEMENT: BO declares that the University Hospital Antwerpen and the University of Antwerp have received investigator-initiated grants from Abbvie, Pfizer and Roche. BO is a shareholder and member of the board of ImmuneWatch BV. NH declares that the Universities of Antwerp and Hasselt have received funding for advisory boards and research projects of MSD, GSK, JnJ, Pfizer and the European Commission’s IMI programme outside the proposed work. NH has not received any personal remuneration. PB declares the University of Antwerp received compensation for unrelated consultancy for Pfizer in 2019, research grants from MSD and Pfizer, and the European Commission’s IMI programme. PB has not received any personal remuneration. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. KL is a shareholder and member of the board of ImmuneWatch BV. PM is a shareholder, employee and member of the board of ImmuneWatch BV. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The immune system acts as an intricate apparatus that is dedicated to mounting a defense and ensures host survival from microbial threats. To engage this faceted immune response and provide protection against infectious diseases, vaccinations are a critical tool to be developed. However, vaccine responses are governed by levels that, when interrogated, separately only explain a fraction of the immune reaction. To address this knowledge gap, we conducted a feasibility study to determine if multi-view modeling could aid in gaining actionable insights on response markers shared across populations, capture the immune system's diversity, and disentangle confounders. We thus sought to assess this multi-view modeling capacity on the responsiveness to the Hepatitis B virus (HBV) vaccination. Seroconversion to vaccine-induced antibodies against the HBV surface antigen (anti-HBs) in early converters ( n = 21; <2 months) and late converters ( n = 9; <6 months) and was defined based on the anti-HBs titers (>10IU/L). The multi-view data encompassed bulk RNA-seq, CD4+ T-cell parameters (including T-cell receptor data), flow cytometry data, and clinical metadata (including age and gender). The modeling included testing single-view and multi-view joint dimensionality reductions. Multi-view joint dimensionality reduction outperformed single-view methods in terms of the area under the curve and balanced accuracy, confirming the increase in predictive power to be gained. The interpretation of these findings showed that age, gender, inflammation-related gene sets, and pre-existing vaccine-specific T-cells could be associated with vaccination responsiveness. This multi-view dimensionality reduction approach complements clinical seroconversion and all single modalities. Importantly, this modeling could identify what features could predict HBV vaccine response. This methodology could be extended to other vaccination trials to identify the key features regulating responsiveness.

Prior studies have identified genetic, infectious, and biological associations with immune competence and disease severity; however, there have been few integrative analyses of these factors and study populations are often limited in demographic diversity. Utilizing samples from 1,705 individuals in 5 countries, we examined putative determinants of immunity, including: single nucleotide polymorphisms, ancestry informative markers, herpesvirus status, age, and sex. In healthy subjects, we found significant differences in cytokine levels, leukocyte phenotypes, and gene expression. Transcriptional responses also varied by cohort, and the most significant determinant was ancestry. In influenza infected subjects, we found two disease severity immunophenotypes, largely driven by age. Additionally, cytokine regression models show each determinant differentially contributes to acute immune variation, with unique and interactive, location-specific herpesvirus effects. These results provide novel insight into the scope of immune heterogeneity across diverse populations, the integrative effects of factors which drive it, and the consequences for illness outcomes.

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability., (© 2022. The Author(s).)

Immunization during pregnancy has been recommended in an increasing number of countries. The aim of this strategy is to protect pregnant women and infants from severe infectious disease, morbidity and mortality and is currently limited to tetanus, inactivated influenza, and pertussis-containing vaccines. There have been recent advancements in the development of vaccines designed primarily for use in pregnant women (respiratory syncytial virus and group B Streptococcus vaccines). Although there is increasing evidence to support vaccination in pregnancy, important gaps in knowledge still exist and need to be addressed by future studies. This collaborative consensus paper provides a review of the current literature on immunization during pregnancy and highlights the gaps in knowledge and a consensus of priorities for future research initiatives, in order to optimize protection for both the mother and the infant., (Copyright © 2020 Abu-Raya, Maertens, Edwards, Omer, Englund, Flanagan, Snape, Amirthalingam, Leuridan, Damme, Papaevangelou, Launay, Dagan, Campins, Cavaliere, Frusca, Guidi, O'Ryan, Heininger, Tan, Alsuwaidi, Safadi, Vilca, Wanlapakorn, Madhi, Giles, Prymula, Ladhani, Martinón-Torres, Tan, Michelin, Scambia, Principi and Esposito.)

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72., Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried., Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death., Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates., Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS., (© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Background: Early effects of HPV (human papillomavirus) vaccination are reflected by changes observable in young women attending cervical cancer screening., Subject and Methods: The SEHIB study included HPV geno-typing of ∼6000 continuous and 650 pathological cervical cell specimen as well as biopsies, collected from women in Belgium in 2010-2014. Data were linked to vaccination status., Results: HPV vaccination offered protection among women aged <30years against infection with HPV16 (vaccine effectiveness [VE]=67%, 95% CI: 48-79%), HPV18 (VE=93%, 95% CI: 52-99%), and high-risk HPV (VE=16%, 95% CI: 2-29%). Vaccination protected also against cytological lesions. Vaccination protected against histologically confirmed lesions: significantly lower absolute risks of CIN1+ (risk difference [RD]=-1.6%, 95% CI: -2.6% to -0.7%) and CIN3+ associated with HPV16/18 (RD=-0.3%, 95% CI -0.6% to -0.1%). Vaccine effectiveness decreased with age. Protection against HPV16 and 18 infection was significant in all age groups, however no protection was observed against cytological lesions associated with these types in age-group 25-29., Conclusion: The SEHIB study demonstrates the effectiveness of HPV vaccination in Belgian young women in particular in age group 18-19. Declining effectiveness with increasing age may be explained by higher tendency of women already exposed to infection to get the vaccine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Purpose: Mutations in fused in sarcoma (FUS) were recently identified as a cause of familial amyotrophic lateral sclerosis (ALS). The frequency of occurrence of mutations in FUS in sets of patients with familial ALS remains to be established., Methods: We sequenced the FUS gene in a cohort of patients with familial ALS seen at the neuromuscular clinic in Leuven. A total of 28 patients with SOD1-negative ALS from 22 families were analyzed., Results: We identified a R521H mutation in 4 patients, belonging to a kindred of dominantly inherited classical ALS. The mutation segregated with disease. Mutations in FUS were observed in 2.9% of ALS pedigrees in our cohort., Conclusions: These results show that mutations in FUS are also a significant cause of familial ALS in Belgium.

The WAIFW matrix (Who Acquires Infection From Whom) is a central parameter in modelling the spread of infectious diseases. The calculation of the basic reproductive number (R0) depends on the assumptions made about the transmission within and between age groups through the structure of the WAIFW matrix and different structures might lead to different estimates for R0 and hence different estimates for the minimal immunization coverage needed for the elimination of the infection in the population. In this paper, we estimate R0 for varicella in Belgium. The force of infection is estimated from seroprevalence data using fractional polynomials and we show how the estimate of R0 is heavily influenced by the structure of the WAIFW matrix.

The long-term efficacy of hepatitis B vaccine, long-term effectiveness of hepatitis B immunisation programmes, immune memory induced by hepatitis B vaccine, current booster policies, and impact of hepatitis B virus mutants on immunisation programmes were reviewed at the Viral Hepatitis Prevention Board (VHPB) meeting in Sevilla, Spain, March 2004. The main focus was on universal vaccination programmes with data being presented from Italy, Saudi Arabia, Singapore, Spain, Taiwan, Thailand, The Gambia, and USA (Alaska).

Objective: To define the differences in emergency room usage patterns between patients with and without medical insurance coverage., Methods: A retrospective analysis of the database of 34 642 consecutive patient visits to an urban hospital emergency room over a period of 509 days. Arrival times and admission rates were compared for insured and uninsured patients., Results: A total of 46.8% of insured patients arrived at night or during the weekend versus 51.7% of the uninsured. Slightly more insured patients were admitted (18.6 versus 15.4%), both after their visit during the daytime (20.6 versus 17.1%) and outside daytime hours (16.3 versus 13.8%). The uninsured population was younger., Conclusion: Uninsured patients arrived more frequently during weekends and at night than insured patients. They were on average less likely to be admitted to the hospital. Demographic differences between both groups seemed to play an important role in the admission rate. Despite differences in emergency room usage patterns, it cannot be concluded that either group used the emergency room in excess of the other.

Unlabelled: The age-specific seroprevalence of varicella-zoster virus (VZV) antibodies was assessed in a sample of the Flemish (Belgian) population. ELISA tests were used to analyse 1673 sera from subjects aged 1 to 44 years (October 1999-April 2000). Chickenpox infections in Flanders appear to affect children at a younger age than in other European countries since 47.37% (95% CI: 37.33-57.41) is already immune at 2 years of age. For older age-groups, the prevalence is similar to that of most European countries: 80.19% (95% CI: 72.60-87.78) at 5 years, 92.52% (95% CI: 87.54-97.51) at 9 years and 100%> or =40 years. The accuracy of non-positive recollections of varicella histories among Flemish 10 to 17-year olds was examined on the basis of a second (residual) serum bank. In this group, VZV seroprevalence was almost always 100% (or nearly 100%), irrespective of age, degree of reliability (negative or uncertain answers) or level of ascertainment (child personally or parents). The limited size of this second data set did not allow for an accurate assessment of the negative predictive value of such recollections., Conclusion: since varicella-zoster virus predominantly affects very small children and is generally perceived as benign, the required high coverage rate of a universal childhood varicella vaccination programme may be hard to attain. Adolescent strategies can minimise the population risks involved but the accuracy of non positive antecedents of chickenpox needs to be documented to assess the efficiency of such strategies.

An emerging topic in plant biology is whether plant cells display similar elements of programmed cell death (PCD) as animal cells do. We have studied cell death in maize roots exposed to cold stress by using fluorescence microscopy, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL), DNA gel electrophoresis, single cell gel electrophoresis (SCGE), cell electrophoresis, and annexin binding techniques. The results showed that cell death in maize root cells triggered by cold stress was accompanied by a subset of features characteristic of animal PCD such as nuclear condensation and fragmentation, and oligonucleosomal DNA fragmentation. In addition to DNA laddering and TUNEL positivity, a "comet" pattern indicative of DNA breakage appeared as short as after one day of treatment. The maize root cell PCD process was also accompanied by an increase in negative surface charge of the dying cells due to exposure of phosphatiolylserine (PS) from inner to outer membrane. After annexin binding, however, the enhanced electrophoretic mobility (EPM) of the dying cells decreased nearly to normal values. This result suggests that the combination between cell electrophoresis and annexin binding provides a quantitative method for monitoring PS exposure during plant PCD.