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Madeleine Touma,1 Line D Rasmussen,2 Raquel Martin-Iguacel,2 Frederik Neess Engsig,3 Nina Breinholt Stærke,4 Mette Stærkind,5 Niels Obel,1 Magnus Glindvad Ahlström1 1Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2Department of Infectious Diseases, Odense University Hospital, Odense, 3Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, 4Department of Infectious Diseases, Aarhus University Hospital, Aarhus, 5Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark Background: Human immunodeficiency virus (HIV) infection with advanced immunosuppression predisposes to cryptococcal meningitis (CM). We describe the incidence, clinical presentation, and outcome of CM in HIV-infected individuals during the highly active antiretroviral therapy (HAART) era.Methods: A nationwide, population-based cohort of HIV-infected individuals was used to estimate incidence and mortality of CM including risk factors. A description of neurological symptoms of CM at presentation and follow-up in the study period 1995–2014 was included in this study.Results: Among 6,351 HIV-infected individuals, 40 were diagnosed with CM. The incidence rates were 3.7, 1.8, and 0.3 per 1000 person-years at risk in 1995–1996, 1997–1999, and 2000–2014, respectively. Initiation of HAART was associated with decreased risk of acquiring CM [incidence rate ratio (IRR), 0.1 (95% CI, 0.05–0.22)]. African origin was associated with increased risk of CM [IRR, 2.05 (95% CI, 1.00–4.20)]. The main signs and symptoms at presentation were headache, cognitive deficits, fever, neck stiffness, nausea, and vomiting. All individuals diagnosed with CM had a CD4+ cell count

Objectives: This study aimed to compare antibody trajectories among individuals with SARS-CoV-2 hybrid and vaccine-induced immunity., Methods: Danish adults receiving three doses of BTN162b2 or mRNA-1237 were included prior to first vaccination (Day 0). SARS-CoV-2 anti-spike IgG levels were assessed before each vaccine dose, at Day 90, Day 180, 28 days after 3rd vaccination (Day 251), Day 365, and prior to 4th vaccination (Day 535). SARS-CoV-2 PCR results were extracted from the national microbiology database. Mixed-effect multivariable linear regression investigated the impact of hybrid-immunity (stratified into 4 groups: no hybrid immunity, PCR+ prior to 3rd dose, PCR+ after 3rd dose and before Day 365, PCR+ after Day 365) on anti-spike IgG trajectories., Results: A total of 4,936 individuals were included, 47% developed hybrid-immunity. Anti-spike IgG increases were observed in all groups at Day 251, with the highest levels in those PCR+ prior to 3rd dose (Geometric Mean; 535,647AU/mL vs. 374,665AU/mL with no hybrid-immunity, P<0.0001). Further increases were observed in participants who developed hybrid immunity after their 3rd dose. Anti-spike IgG levels declined from Day 251-535 in individuals without hybrid-immunity and in those who developed hybrid-immunity prior to their 3rd dose, with lower rate of decline in those with hybrid-immunity., Conclusion: Hybrid-immunity results in higher and more durable antibody trajectories in vaccinated individuals., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outpaces monovalent vaccine cross-protection to new viral variants. Consequently, bivalent coronavirus disease 2019 (COVID-19) vaccines including Omicron antigens were developed. The contrasting immunogenicity of the bivalent vaccines and the impact of prior antigenic exposure on new immune imprinting remains to be clarified., Methods: In the large prospective ENFORCE cohort, we quantified spike-specific antibodies to 5 Omicron variants (BA.1 to BA.5) before and after BA.1 or BA.4/5 bivalent booster vaccination to compare Omicron variant-specific antibody inductions. We evaluated the impact of previous infection and characterized the dominant antibody responses., Results: Prior to the bivalent fourth vaccine, all participants (N = 1697) had high levels of Omicron-specific antibodies. Antibody levels were significantly higher in individuals with a previous polymerase chain reaction positive (PCR+) infection, particularly for BA.2-specific antibodies (geometric mean ratio [GMR] 6.79, 95% confidence interval [CI] 6.05-7.62). Antibody levels were further significantly boosted in all individuals by receiving either of the bivalent vaccines, but greater fold inductions to all Omicron variants were observed in individuals with no prior infection. The BA.1 bivalent vaccine generated a dominant response toward BA.1 (adjusted GMR 1.31, 95% CI 1.09-1.57) and BA.3 (1.32, 1.09-1.59) antigens in individuals with no prior infection, whereas the BA.4/5 bivalent vaccine generated a dominant response toward BA.2 (0.87, 0.76-0.98), BA.4 (0.85, 0.75-0.97), and BA.5 (0.87, 0.76-0.99) antigens in individuals with a prior infection., Conclusions: Vaccination and previous infection leave a clear serological imprint that is focused on the variant-specific antigen. Importantly, both bivalent vaccines induce high levels of Omicron variant-specific antibodies, suggesting broad cross-protection of Omicron variants., Competing Interests: Potential conflicts of interest. N. B. S. declares to have served as an investigator in clinical trials sponsored by Pfizer, Gilead, and Bavarian Nordic, and AstraZeneca. H. N. declares to have been on advisory boards for GSK and MSD and reports grants or contracts from Novo Nordisk Foundation (payment to institution, RCT of brain abscess treatment strategy). T. B. declares receipt of unrestricted grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen's Charitable Fund, GSK, Pfizer, Gilead Sciences, and MSD; and being advisory board member for GSK, Pfizer, Gilead Sciences, MSD, Janssen, and Astra Zeneca; and being principal investigator on clinical trials conducted by Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Roche, Novartis, Kancera AB, Bavarian Nordic, and Janssen; and being board member on Pentabase; and receiving consulting fees from GSK and Pfizer; and receiving honorarium for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, Abbvie, Astra Zeneca, and Bavarian Nordic; and receiving donation of trial medication (baricitinib) from Eli Lilly. M. T. declares to be on a Data Safety Monitoring Board for ImmunoCore. 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) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

SARS-CoV-2 Omicron quickly spread globally, also in regions with high vaccination coverage, emphasizing the importance of exploring the immunological requirements for protection against Omicron breakthrough infection. The test-negative matched case-control study (N = 964) characterized Omicron breakthrough infections in triple-vaccinated individuals from the ENFORCE cohort. Within 60 days before a PCR test spike-specific IgG levels were significantly lower in cases compared to controls (GMR [95% CI] for BA.2: 0.83 [0.73-0.95], p = 0.006). Multivariable logistic regression showed significant associations between high antibody levels and lower odds of infection (aOR [95% CI] for BA.2 spike-specific IgG: 0.65 [0.48-0.88], p = 0.006 and BA.2 ACE2-blocking antibodies: 0.46 [0.30-0.69], p = 0.0002). A sex-stratified analysis showed more pronounced associations for females than males. High levels of vaccine-induced antibodies provide partial protection against Omicron breakthrough infections. This is important knowledge to further characterize a threshold for protection against new variants and to estimate the necessity and timing of booster vaccination., Competing Interests: N.B.S. declares to have served as an investigator in clinical trials sponsored by Pfizer, Gilead, and Bavarian Nordic. H.N. declares to have been on advisory boards for GSK and MSD. T.B. declares receipt of unrestricted grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen’s Charitable Fund, GSK, Pfizer, Gilead Sciences, and MSD; and being advisory board member for GSK, Pfizer, Gilead Sciences, MSD, Janssen, and Astra Zeneca; and being principal investigator on clinical trials conducted by Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Roche, Novartis, Kancera AB, Bavarian Nordic, and Janssen; and being board member on Pentabase; and receiving consulting fees from GSK and Pfizer; and receiving honorarium for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie, Astra Zeneca, and Bavarian Nordic; and receiving donation of trial medication (baricitinib) from Eli Lilly. MT declares to be on a Data Safety Monitoring Board for Immunocore. The remaining authors declare no competing interests., (© 2023 The Author(s).)

Background: Older age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood., Methods: In a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51-72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections., Results: We show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified., Conclusions: SARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization., (© 2023. The Author(s).)

Background: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain., Methods: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 μg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points., Results: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively)., Conclusions: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: The ENFORCE cohort is a national Danish prospective cohort of adults who received a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as part of the Danish National SARS-CoV-2 vaccination programme. It was designed to investigate the long-term effectiveness, safety and durability of SARS-CoV-2 vaccines used in Denmark., Participants: A total of 6943 adults scheduled to receive a SARS-CoV-2 vaccine in the Danish COVID-19 vaccination programme were enrolled in the study prior to their first vaccination. Participants will be followed for a total of 2 years with five predetermined follow-up visits and additional visits in relation to any booster vaccination. Serology measurements are performed after each study visit. T-cell immunity is evaluated at each study visit for a subgroup of 699 participants. Safety information is collected from participants at visits following each vaccination. Data on hospital admissions, diagnoses, deaths and SARS-CoV-2 PCR results are collected from national registries throughout the study period. The median age of participants was 64 years (IQR 53-75), 56.6% were women and 23% were individuals with an increased risk of a serious course of COVID-19. A total of 340 (4.9%) participants tested positive for SARS-CoV-2 spike IgG at baseline., Findings to Date: Results have been published on risk factors for humoral hyporesponsiveness and non-durable response to SARS-CoV-2 vaccination, the risk of breakthrough infections at different levels of SARS-CoV-2 spike IgG by viral variant and on the antibody neutralising capacity against different SARS-CoV-2 variants following primary and booster vaccinations., Future Plans: The ENFORCE cohort will continuously generate studies investigating immunological response, effectiveness, safety and durability of the SARS-CoV-2 vaccines., Trial Registration Number: NCT04760132., Competing Interests: Competing interests: NBS declares to have served as investigator on studies sponsored by Pfizer, Gilead, Bavarian and Sanofi Pasteur. HN declares receiving a grant from Novo Nordisk Foundation and to have been on advisory boards for MSD and GSK. TB declares receipt of unrestricted research or travel grants from GSK, Pfizer, Gilead Sciences, MSD; and being principal investigator on trials conducted by Boehringer Ingelheim, Roche, Novartis, Kancera, Pfizer, MSD and Gilead; Board member on Pentabase, and advisory board member for MSD, Gilead, Pfizer, GSK, Janssen and AstraZeneca; consulting fees from GSK and Pfizer; receiving donation of study drug from Eli Lilly; and receiving honorarium for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie and AstraZeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tuberculosis (TB) prevalence is high among socially marginalized citizens in Denmark, and management of latent TB infection (LTBI) may be part of preventing new cases. Patients with LTBI are offered either preventive treatment (TPT) or follow-up chest x-rays, but knowledge about the long-term outcome in terms of active TB is sparse., Methods: We performed a retrospective cohort study investigating the long-term outcomes for socially marginalized citizens who were diagnosed with LTBI or who had a positive interferon-gamma release assay (IGRA) but were lost to follow-up. Information on TB examinations, diagnostics, and treatment along with data on death were gathered from medical records from the date of positive IGRA to February 1, 2021., Results: We identified 119 patients with LTBI, 18 of which (15.1%) were diagnosed with TB during the follow-up period (mean, 4.5 years). TPT was completed by 36.1% and the TB incidence rate ratio of those completing TPT to those who did not was 0.78 (confidence interval, 0.25-2.17; P =.6). Of the patients with TB, 16 of 18 achieved treatment success., Conclusion: High rates of TB development are found among socially marginalized citizens with LTBI. Overall incidence of TB was not significantly reduced by administration of TPT, although TB did not develop in the first 2 years following TPT., Competing Interests: Conflict of interest statement The authors have no conflict of interest with regard to this work., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The SARS-CoV-2 pandemic has, as of July 2022, infected more than 550 million people and caused over 6 million deaths across the world. COVID-19 vaccines were quickly developed to protect against severe disease, hospitalization and death. In the present study, we performed a direct comparative analysis of four COVID-19 vaccines: BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford/AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen), following primary and booster vaccination. We focused on the vaccine-induced antibody-mediated immune response against multiple SARS-CoV-2 variants: wildtype, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta) and B.1.1.529 (Omicron). The analysis included the quantification of total IgG levels against SARS-CoV-2 Spike, as well as the quantification of antibody neutralization titers. Furthermore, the study assessed the high-throughput ACE2 competition assay as a surrogate for the traditional pseudovirus neutralization assay. The results demonstrated marked differences in antibody-mediated immune responses. The lowest Spike-specific IgG levels and antibody neutralization titers were induced by one dose of the Ad26.COV2.S vaccine, intermediate levels by two doses of the BNT162b2 vaccine, and the highest levels by two doses of the mRNA-1273 vaccine or heterologous vaccination of one dose of the ChAdOx1 vaccine and a subsequent mRNA vaccine. The study also demonstrated that accumulation of SARS-CoV-2 Spike protein mutations was accompanied by a marked decline in antibody neutralization capacity, especially for B.1.1.529. Administration of a booster dose was shown to significantly increase Spike-specific IgG levels and antibody neutralization titers, erasing the differences between the vaccine-induced antibody-mediated immune response between the four vaccines. The findings of this study highlight the importance of booster vaccines and the potential inclusion of future heterologous vaccination strategies for broad protection against current and emerging SARS-CoV-2 variants., Competing Interests: The 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. The handling editor declared a shared parent affiliation with several of the authors AH, EB, OS, NS, MS, SA, AJ, LD, and SRA at the time of the review., (Copyright © 2022 Hvidt, Baerends, Søgaard, Stærke, Raben, Reekie, Nielsen, Johansen, Wiese, Benfield, Iversen, Mustafa, Juhl, Petersen, Ostrowski, Lindvig, Rasmussen, Schleimann, Andersen, Juhl, Dietz, Andreasen, Lundgren, Østergaard, Tolstrup and the ENFORCE Study Group.)

Passive immunotherapy with convalescent plasma may be the only available agent during the early phases of a pandemic. Here, we report safety and efficacy of high-titer convalescent plasma for COVID-19 pneumonia. Double-blinded randomized multicenter placebo-controlled trial of adult patients hospitalized with COVID-19 pneumonia. The intervention was COVID-19 convalescent plasma and placebo was saline allocated 2:1. The primary outcome was clinical status 14 days after the intervention evaluated on a clinical ordinal scale. The trial was registered at ClinicalTrials.Gov, NCT04345289, 14/04/2020. The CCAP-2 trial was terminated prematurely due to futility. Of 147 patients randomized, we included 144 patients in the modified intention-to-treat population. The ordinal clinical status 14 days post-intervention was comparable between treatment groups (odds ratio (OR) 1.41, 95% confidence interval (CI) 0.72-2.09). Results were consistent when evaluating clinical progression on an individual level 14 days after intervention (OR 1.09; 95% CI 0.46-1.73). No significant differences in length of hospital stay, admission to ICU, frequency of severe adverse events or all-cause mortality during follow-up were found between the intervention and the placebo group. Infusion of convalescent plasma did not influence clinical progression, survival or length of hospitalization in patients with COVID-19 pneumonia., (© 2022. The Author(s).)

Background: Screening for tuberculosis (TB) disease and infection is often a part of health screening programs offered to refugees, but the yield of screening varies and losses along the steps from screening to treatment completion was reported., Methods: A retrospective cohort study was performed investigating a newly arrived refugee population offered a systematic refugee health assessment in Aarhus, Denmark. Data was collected on screening, referral, diagnosis and treatment for TB disease and infection., Results: Among both adults and children IGRA positivity was associated with origin in a high TB incidence country and increasing age. The number needed to screen (NNS) to find one case of TB infection was 7 among adult refugees and 19 among children, while NNS for TB disease was 266 and 164 respectively. The proportion of the eligible population with a valid result was 78.1% for adults and 71.3% for children, while 43.1% and 50% of adults and children with presumed TB infection completed preventive treatment., Discussion: Screening for TB disease and infection among refugees in Aarhus had a high yield in terms of diagnosis, however significant losses were seen during screening, follow-up and preventive treatment completion., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To identify individual characteristics associated with serological COVID-19 vaccine responsiveness and the durability of vaccine-induced antibodies., Methods: Adults without history of SARS-CoV-2 infection from the Danish population scheduled for SARS-CoV-2 vaccination were enrolled in this parallel group, phase 4 study. SARS-CoV-2 Spike IgG and Spike-ACE2-receptor-blocking antibodies were measured at days 0, 21, 90, and 180. Vaccine responsiveness was categorized according to Spike IgG and Spike-ACE2-receptor-blocking levels at day 90 after first vaccination. Nondurable vaccine response was defined as day-90 responders who no longer had significant responses by day 180., Results: Of 6544 participants completing two vaccine doses (median age 64 years; interquartile range: 54-75), 3654 (55.8%) received BTN162b2, 2472 (37.8%) mRNA-1273, and 418 (6.4%) ChAdOx1 followed by an mRNA vaccine. Levels of both types of antibodies increased from baseline to day 90 and then decreased to day 180. The decrease was more pronounced for levels of Spike-ACE2-receptor-blocking antibodies than for Spike IgG. Proportions with vaccine hyporesponsiveness and lack of durable response were 5.0% and 12.1% for Spike IgG and 12.7% and 39.6% for Spike-ACE2-receptor-blocking antibody levels, respectively. Male sex, vaccine type, and number of comorbidities were associated with all four outcomes. Additionally, age ≥75 years was associated with hyporesponsiveness for Spike-ACE2-receptor-blocking antibodies (adjusted odds ratio: 1.59; 95% confidence interval: 1.25-2.01) but not for Spike IgG., Discussion: Comorbidity, male sex, and vaccine type were risk factors for hyporesponsiveness and nondurable response to COVID-19 vaccination. The functional activity of vaccine-induced antibodies declined with increasing age and had waned to pre-second-vaccination levels for most individuals after 6 months., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21-28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15-0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron., (© 2022. The Author(s).)

Background: Older adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years., Methods: Adults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50-64 years, 65-74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively., Results: Of 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5-2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F)., Conclusions: V114 is well tolerated with a consistent safety profile and immune response across manufacturing lots., Clinical Trials Registration: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gretchen Tamms reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Tulin Shekar reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Tina Sterling reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Alison Pedley reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Patricia Jumes reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Luwy Musey reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Jakub K. Simon reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Ulrike K. Buchwald reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Ron Dagan reports a relationship with Pfizer that includes: consulting or advisory, funding grants, and speaking and lecture fees. Ron Dagan reports a relationship with Merck Sharp & Dohme that includes: consulting or advisory and funding grants. Ron Dagan reports a relationship with Medimmune that includes: funding grants. Ron Dagan reports a relationship with MeMed that includes: consulting or advisory. Ron Dagan reports a relationship with Biondvax that includes: consulting or advisory., (Copyright © 2022 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction of vaccines against COVID-19 has provided the most promising chance to control the world-wide COVID-19 pandemic. However, the adenovirus-vector based Oxford/AstraZeneca [ChAdOx1] (AZ) and Johnson & Johnson [Ad26.CoV2.S] COVID-19 vaccines have been linked with serious thromboembolic events combined with thrombocytopenia, denominated Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). The pathogenesis of COVID-19 VITT remain incompletely understood; especially the initial events that trigger platelet activation, platelet factor (PF)4 release, complex formation and PF4 antibody production are puzzling. This is a prospective study investigating the impact of different COVID-19 vaccines on inflammation (CRP, TNF-α, IL-1β, IL-6, IL-8, IL-10), vascular endothelial activation (syndecan-1, thrombomodulin, E-selectin, ICAM-1, ICAM-3, VCAM-1), platelet activation (P-selectin, TGF-β, sCD40L) and aggregation (Multiplate ® impedance aggregometry), whole blood coagulation (ROTEM ® ), thrombin generation and PF4 antibodies to reveal potential differences between AZ and mRNA vaccines in individuals without VITT. The study included 80 (55 AZ and 55 mRNA) vaccinated individuals and 55 non-vaccinated age- and gender matched healthy controls. The main findings where that both vaccines enhanced inflammation and platelet activation, though AZ vaccination induced a more pronounced increase in several inflammatory and platelet activation markers compared to mRNA vaccination and that post-vaccination thrombin generation was higher following AZ vaccination compared to mRNA vaccination. No difference in neither the PF4 antibody level nor the proportion of individuals with positive PF4 antibodies were observed between the vaccine groups. This is the first study to report enhanced inflammation, platelet activation and thrombin generation following AZ vaccination compared to mRNA vaccination in a head-to-head comparison. We speculate that specific components of the AZ adenovirus vector may serve as initial trigger(s) of (hyper)inflammation, platelet activation and thrombin generation, potentially lowering the threshold for a cascade of events that both trigger complications related to excessive inflammation, platelet and coagulation activation as observed in epidemiological studies and promote development of VITT when combined with high-titer functionally active PF4 antibodies., Competing Interests: The 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., (Copyright © 2021 Ostrowski, Søgaard, Tolstrup, Stærke, Lundgren, Østergaard and Hvas.)

Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials., Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load., Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group ( P  = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P  = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log 10 copies/mL ( p  <0·05) and -0·82 log 10 in the placebo group ( P  <0·05)., Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42., Competing Interests: Dr. Mortensen reports a Gilead Travel Grant, outside the submitted work. Dr Østergaard reports personal fees from GlaxoSmithKlinePharma A/S, Gilead Science Denmark A/S, Pfizer A/S, MSD Denmark A/S, and Sanofi Pasteur Europe, outside the submitted work. Dr. Kjolby reports grants from The Lundbeck Foundation, during the conduct of the study; and has or has had stocks in Genmab, Novo Nordisk, Novartis, Amgen, and Regeneron. All other authors have nothing to disclose., (© 2021 The Authors.)

The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion, SARS-CoV-2 utilizes the human transmembrane surface protease, TMPRSS2, to cleave and activate the spike protein. Camostat mesylate, an orally available well-known serine protease inhibitor, is a potent inhibitor of TMPRSS2 and has been hypothesized as a potential antiviral drug against COVID-19. In vitro human cell and animal studies have shown that camostat mesylate inhibits virus-cell membrane fusion and hence viral replication. In mice, camostat mesylate treatment during acute infection with influenza, also dependent on TMPRSS2, leads to a reduced viral load. The decreased viral load may be associated with an improved patient outcome. Because camostat mesylate is administered as an oral drug, it may be used in outpatients as well as inpatients at all disease stages of SARS-CoV-2 infection if it is shown to be an effective antiviral agent. Clinical trials are currently ongoing to test whether this well-known drug could be repurposed and utilized to combat the current pandemic. In the following, we will review current knowledge on camostat mesylate mode of action, potential benefits as an antiviral agent and ongoing clinical trials., (© 2020 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Screening for TB (tuberculosis) among socially marginalized citizens has been implemented in many urban areas in countries with a low incidence of TB, including Denmark. This study aims to describe the findings of the screening programs for TB and latent tuberculosis (LTBI) used in the western part of Denmark in the period 2014-2019., Methods: Data was collected retrospectively on test results from interferon-gamma release assays (IGRA), spot sputum tests and chest X-rays performed as part of TB and LTBI screening among 1024 socially marginalized citizens in urban areas of western Denmark in 2014-2019., Results: The overall TB incidence was 2148/100.000 and number needed to screen to find one TB case was 39. The incidence of LTBI in the group screened using IGRA was 17.500/100.000. TB incidence when using spot sputum test was 2.5, while TB incidence when using IGRA as the primary screening test was 2.7. In total, 38.9% of TB diagnoses were obtained after the second or third round of screening., Conclusion: We demonstrated a high incidence of TB and LTBI among socially marginalized citizens in Denmark. Screening with spot sputum testing and IGRA generated comparable results in diagnosing TB in this setting., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: MenB-FHbp is a licensed meningococcal B vaccine targeting factor H-binding protein. Two phase 3 studies assessed the safety of the vaccine and its immunogenicity against diverse strains of group B meningococcus., Methods: We randomly assigned 3596 adolescents (10 to 18 years of age) to receive MenB-FHbp or hepatitis A virus vaccine and saline and assigned 3304 young adults (18 to 25 years of age) to receive MenB-FHbp or saline at baseline, 2 months, and 6 months. Immunogenicity was assessed in serum bactericidal assays that included human complement (hSBAs). We used 14 meningococcal B test strains that expressed vaccine-heterologous factor H-binding proteins representative of meningococcal B epidemiologic diversity; an hSBA titer of at least 1:4 is the accepted correlate of protection. The five primary end points were the proportion of participants who had an increase in their hSBA titer for each of 4 primary strains by a factor of 4 or more and the proportion of those who had an hSBA titer at least as high as the lower limit of quantitation (1:8 or 1:16) for all 4 strains combined after dose 3. We also assessed the hSBA responses to the primary strains after dose 2; hSBA responses to the 10 additional strains after doses 2 and 3 were assessed in a subgroup of participants only. Safety was assessed in participants who received at least one dose., Results: In the modified intention-to-treat population, the percentage of adolescents who had an increase in the hSBA titer by a factor of 4 or more against each primary strain ranged from 56.0 to 85.3% after dose 2 and from 78.8 to 90.2% after dose 3; the percentages of young adults ranged from 54.6 to 85.6% and 78.9 to 89.7%, after doses 2 and 3, respectively. Composite responses after doses 2 and 3 in adolescents were 53.7% and 82.7%, respectively, and those in young adults were 63.3% and 84.5%, respectively. Responses to the 4 primary strains were predictive of responses to the 10 additional strains. Most of those who received MenB-FHbp reported mild or moderate pain at the vaccination site., Conclusions: MenB-FHbp elicited bactericidal responses against diverse meningococcal B strains after doses 2 and 3 and was associated with more reactions at the injection site than the hepatitis A virus vaccine and saline. (Funded by Pfizer; ClinicalTrials.gov numbers, NCT01830855 and NCT01352845 ).

Background: HIV-associated incidence and prognosis of cerebral toxoplasmosis (CTX) is not well established during later years., Methods: From the Danish HIV Cohort Study, we identified 6325 HIV-infected individuals. We assessed incidence, mortality, predictive and prognostic factors of CTX during the pre-combination antiretroviral therapy (pre-cART; 1995-1996) and cART-era (1997-2014). Adjusted incidence rate ratios (aIRR), mortality rate ratios (aMRR) and 95% confidence intervals (CI) were assessed using Poisson regression analysis., Results: CTX IR was 1.17/1000 PYR (95% CI 0.93-1.47). We observed no change in CTX-risk in the first year after HIV-diagnosis, but a substantial reduction in mortality in the first 3 months after CTX diagnosis when comparing the cART-era to the pre-cART-era; {(aIRR: 0.79; 95% CI: 0.37-1.72) (aMRR: 0.15; 95% CI: 0.06-0.38)}. For individuals surviving the first year after HIV-diagnosis or the first 3 months after CTX-diagnosis, IRR and MRR had declined to minimal levels {(aIRR: 0.06; 95% CI: 0.03-0.10); (aMRR: 0.02; 95% CI: 0.01-0.05)}. Three years after CTX-diagnosis 30% of the patients still had neurological deficits., Conclusion: Although, CTX remains an important cause of morbidity and mortality in the cART-era, with high prevalence of neurological sequelae, incidence and mortality has largely declined, especially among those surviving the first year after diagnosis., (Copyright © 2017. Published by Elsevier Ltd.)

Introduction: Even in low-incidence countries, tuberculosis (TB) is common among socially marginalised people. Latent tuberculosis infection (LTBI) comprises a reservoir for future disease, and screening for LTBI and TB in these groups aids in the prevention and early detection of TB., Methods: We performed a screening for LTBI with interferon gamma release assay (IGRA) testing, and TB screening with sputum smear examination at four shelters and four additional locations in a Danish urban area. Additionally, shelter volunteers were offered examination., Results: A total of 145 subjects were tested; 124 with sputum smear and 100 with IGRA. Overall, 13 (13%) had LTBI, and one (0.8%) had smear-negative, culture-positive, non-cavitating TB. Among 107 socially marginalised citizens, persons of Greenlandic origin had significantly more LTBI (40.0%) than Danish subjects (9.1%) (odds ratio (OR) = 6.67 (range: 1.55-28.63)), and other ethnicities had an intermediate prevalence of LTBI (18.2%) (OR versus Danish subjects = 2.22 (range: 0.35-14.06)). A total of 38 shelter volunteers were also included; IGRA was performed in 30 of those and one (3.33%) had LTBI., Conclusions: Our results confirm that a screening approach may reveal early cases of active TB. LTBI is common among the socially marginalised people, but varies substantially with ethnic origin., Funding: T-spot.TB kits were provided by Oxford Immunotec., Trial Registration: not relevant.