Search

SummaryBackgroundA SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and welltolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration.MethodsThe HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine —either heterologous (PHH-1V group) or homologous (BNT162b2 group)— in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered withClinicalTrials.gov,NCT05142553.FindingsFrom 15 November 2021, 782 adults were randomly assigned to PHH-1V (n=522) or BNT162b2 (n=260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1·68 (p+and CD8+T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89·3%) in the PHH-1V and 238 (94·4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79·7% and 89·3%), fatigue (27·5% and 42·1%) and headache (31·2 and 40·1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10·14%) for the PHH-1V group and 30 (11·90%) for the BNT162b2 group (p=0·45), and none of the subjects developed severe COVID-19.InterpretationOur interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe.FundingHIPRA SCIENTIFIC, S.L.U.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., Andre Franke and David Ellinghaus were supported by a grant from the German Federal Ministry of Education and Research (01KI20197), Andre Franke, David Ellinghaus and Frauke Degenhardt were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). David Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". This project was supported by a Covid-19 grant from the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197). Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by a MIUR grant to the Department of Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program / Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa")., Beatriz Cortes is supported by national grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”). Additional data included in this study was obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià and Sara Marsal were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). Antonio Julià was also supported the by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán and Douglas Maya Miles are supported by the “Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health (CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from Research Council of Norway grant no 312780 during the conduct of the study. Dr. Solligård: reports grants from Research Council of Norway grant no 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF)., Oliver A. Cornely is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping was performed by the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. Kerstin U. Ludwig is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf are supported by the German Center for Infection Research (DZIF). Thorsen Brenner, Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).

Background To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). Methods We did a phase 2, open-label, randomised, controlled trial on adults aged 18–60 years, vaccinated with a single dose of ChAdOx1-S 8–12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. Findings Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84–85·33) at baseline to 7756·68 BAU/mL (7371·53–8161·96) at day 14 (p

Background: There are no immunological data on SARS-CoV-2 heterologous vaccinations schedules in humans. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, Astra Zeneca). Methods: We did a phase 2, open-label, adaptive, randomised, controlled clinical trial on adults under 60 years old, vaccinated with a single dose of ChAdOx1-S between 8 and 12 weeks before screening, and no history of SARS-CoV-2 infection (EudraCT No. 2021-001978-37 and NCT04860739). Participants were randomly assigned (2:1) to receive BNT162b2 (0.3 mL, single intramuscular injection) or observation. The primary outcomes were 7-day reactogenicity and 14-day anti-spike IgG response, measured by immunoassays covering SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibodies functionality and cellular immune response were assessed using a pseudovirus neutralization assay and IFN-gamma immunoassay, respectively. Findings: Between April 24 and April 30, 2021, 676 individuals were randomized (n=450 intervention group, n=226 control group) at 5 sites in Spain, and 663 (441 and 222, respectively) completed the study up to day 14 (mean age 44 [SD 9], 56·5% female). In the intervention group, geometric mean titres (GMT) of IgG-RBD increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 (7371·53; 8161·96) at day 14 (p < 0·0001). IgG against trimeric spike-protein increased from 98·4 [85.69–112.99] to 3684·87 [3429·87–3958·83]). 100% participants exhibited neutralizing antibodies 14 days after BNT162b2 administration, in comparison to 34.1% at enrolment. A 4-fold increase in cellular immune response was also observed. Reactions were predominantly mild (68·3%) or moderate (29·9%), and consisted more frequently on injection site pain (88·2%), induration (35·5%), headache (44·4%) and myalgia (43·3%). No serious adverse events were reported. Interpretation: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response with an acceptable and manageable reactogenicity profile. Clinical Trial Registration Details: EudraCT No. 2021-001978-37 and NCT04860739. Funding Information: Funded by Instituto de Salud Carlos III (ISCIII). Declaration of Interests: CB is the Deputy General Manager of the ISCIII. JRA has received fees from Janssen, outside of the submitted work. AMB is principal investigator of clinical trials sponsored by GSK, Daiichi-Sankyo, Janssen and Farmalider, outside of the submitted work. The other authors declare no competing interests. Ethics Approval Statement: All the participants provided written informed consent before enrolment. The trial complies with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved by the Spanish Agency of Medicines and Healthcare Products (AEMPS) and by the Ethics Committee at University Hospital La Paz.

SUMMARYCOVID-19 manifests with a wide diversity of clinical phenotypes characterized by dysfunctional and exaggerated host immune responses. Many results have been described on the status of the immune system of patients infected with SARS-CoV-2, but there are still aspects that have not been fully characterized. In this study, we have analyzed a cohort of patients with mild, moderate and severe disease. We performed flow cytometric studies and correlated the data with the clinical features and clinical laboratory values of patients. Both conventional and unsupervised data analyses concluded that patients with severe disease are characterized, among others, by a higher state of activation in all T cell subsets, higher expression of perforin and granzyme B in cytotoxic cells, expansion of adaptive NK cells and the accumulation of activated and immature dysfunctional monocytes which are identified by a low expression of HLA-DR and an intriguing abrupt change in the expression pattern of CD300 receptors. More importantly, correlation analysis showed a strong association between the alterations in the immune cells and the clinical signs of severity. These results indicate that patients with severe COVID-19 have a broad perturbation of their immune system, and they will help to understand the immunopathogenesis of severe COVID-19 as well as could be of special value for physicians to decide which specific therapeutic options are most effective for their patients.

The steady increase in colorectal cancer (CRC) could be reversed through timely secondary prevention (screening) as a main strategy. The aims of this study were to determine the main features of CRC, survival rate and related factors for different types of identified CRCs in a population-based screening programme using the faecal immunochemical test (FIT).The CRCs in the susceptible population to be screened between 2009 and 2014 were identified and classified into four groups: (a) nonscreening-detected CRC (diagnosed before first screening invitation and nonparticipants), (b) screening-detected CRC, (c) interval cancer (IC) FIT (diagnosed between screening rounds after a negative FIT) and (d) IC colonoscopy (diagnosed before the colonoscopy surveillance, which is recommended after the screening colonoscopy). Patient demographics and epidemiological characteristics, tumour characteristics and survival were compared between the four groups.5909 individuals were diagnosed with a CRC. The median follow-up of survival was 4.6 years (range: 0-9 years). The study highlights a significant difference (P0.0001) in the 5-year survival in the screening-detected CRC group compared with those who had nonscreening-detected CRCs (90.1 vs. 66.7%). Although ICs are not desirable events, the 5-year survival rate is significantly higher with respect to nonparticipants (P0.0001) (76.3 vs. 60.5%), this being the group with the lowest survival rate.The significantly higher 5-year survival rate of 23.4% of the participants in the screening programme suggests that incidence and mortality rates of CRC will decrease in the near future for participants in screening programmes. A high participation rate is essential to achieve health benefits, irrespective of the type of participation.

Screening by means of biennial fecal occult blood test has provided a reduction in overall colorectal cancer mortality. Notwithstanding, we should not underestimate the harms that it can produce.The aim of this article is to identify the independent risk factors of complications after a screening colonoscopy.A six-year, nested case-control study was conducted. Mortality/complications within 30 days after colonoscopy were registered and its predictors identified through logistic regression.After 39,254 colonoscopies, the complication rate was 1.0%. Independent predictors were sex (OR 1.68 for men; CI 95% 1.18-2.39), ASA physical status classification system (OR 1.73 for ASA II-III; CI 95% 1.53-3.69), history of abdominal surgery (OR 2.37; CI 95% 1.72-4.08), diverticulosis (OR 2.89; CI 95% 1.94-4.30), inadequate cleansing (OR 29.35; CI 95% 6.52-132.17), detection of advanced neoplasia (AN) (OR 4.92; CI 95% 3.29-7.36), detection of stage I adenocarcinoma (OR 9.44; CI 95% 4.46-20.0), polyps in right colon OR 2.27 CI 95% 1.38-3.74) and complex polypectomy (OR 2.00; CI 95% 1.25-3.20). The logistic model explained 82% of the complications (CI 95% 0.798-0.854,Colonoscopy, with or without removal of a lesion, is an invasive procedure with a non-deniable risk of major complications. Factors like inadequate cleansing or detection of AN are determinants. Therefore, it is vital to know which aspects predict their appearance to implement countermeasures.

Background The Basque Colorectal Cancer Screening Programme has both high participation rate and high compliance rate of colonoscopy after a positive faecal occult blood test (FIT). Although, colorectal cancer (CRC) screening with biannual (FIT) has shown to reduce CRC mortality, the ultimate effectiveness of the screening programmes depends on the accuracy of FIT and post-FIT colonoscopy, and thus, harms related to false results might not be underestimated. Current CRC screening programmes use a single faecal haemoglobin concentration (f-Hb) cut-off for colonoscopy referral for both sexes and all ages. We aimed to determine optimum f-Hb cut-offs by sex and age without compromising neoplasia detection and interval cancer proportion. Methods Prospective cohort study using a single-sample faecal immunochemical test (FIT) on 444,582 invited average-risk subjects aged 50–69 years. A result was considered positive at ≥20 μg Hb/g faeces. Outcome measures were analysed by sex and age for a wide range of f-Hb cut-offs. Results We analysed 17,387 positive participants in the programme who underwent colonoscopy. Participation rate was 66.5%. Men had a positivity rate for f-Hb of 8.3% and women 4.8% (p

Background: Stroke is a leading cause of severe and long-term disability in developed countries. Around 15 million people suffer a stroke each year, being most of them ischemic due to modifiable risk factors. Adequate self-management abilities may help to manage the consequences of stroke, but it is unknown which specific intervention could be effective to booster these self-management abilities. Objective: To evaluate the improvement of self-management in chronic stroke survivors using decision support and self-management system (STARR). Methods: A randomized, prospective, parallel group, open, and the unicentric pilot trial will be performed. Stroke survivors and their caregivers will be randomly allocated to STARR management or standard of care. Main inclusion criteria are mild to moderate disabled first stroke adult survivor, living at home, able to cope and follow the guidelines and devices, without socio-familial exclusion. All will get a conventional treatment in the acute and subacute phase; however, in the chronic period, cases will use the developed STARR App and Decision Support System. Measurements will be performed at baseline, at 3 months, and at 6 months. Outcome measures are patient-report outcome measure of self-management competency, physical function, risk factor reduction, healthcare resource utilization, knowledge of the condition, mood, and social isolation. Discussion: If effective, the results of this study will enable stroke patients and their caregivers to deal better with the everyday life obstacles of stroke, improve the adherence of the treatment, improve the control of cardiovascular risk, and, in consequence, reduce the recurrence of secondary strokes, the number of complications, the number of consultations, and readmissions; to ultimately reduce the health systems costs. Taking into consideration that the number of stroke survivors is increasing around the world, a large number of individuals could profit from this intervention.

IntroductionStroke is a leading cause of severe and long-term disability in developed countries. Around 15 million people suffer a stroke each year, most due to modifiable risk factors. Several reviews have shown that interventions mediating eHealth technologies can reduce the risk of suffering a stroke episode, improving the control of risk factors; nevertheless, all of them conclude that new and well-designed studies are needed.MethodsWe performed a prospective, randomized, parallel group and open, pilot trial. The study was carried out based on an initial sample of forty-three patients between 18 and 80 years old who have had an ischemic stroke. The control group got conventional treatment and the intervention group got conventional treatment and the assistance of STARR (the Decision SupporT and self-mAnagement system for stRoke survivoRs), as well as commercial wearables. The principal variable of the study was to evaluate the usability of the decision support system.ResultsAt month nine, the average score on the System Usability Scale in the intervention group was 64.7 and in month 12, 67.4, exceeding in both cases the margin of acceptability (50) and in the limit of “good” (68). When we analyzed clinical factors (systolic/diastolic blood pressure) as well as the analytical parameters related to prevention of reinfarction, we observed that the intervention group had good control of blood pressure and better analytical parameters, compared to the control group.ConclusionsTechnological support allowed participants to feel comfortable using the devices as well as resolving technical incidences by themselves after a training period. The self-management platform can be efficient in stroke survivors’ management of their disease condition, improving analytical and clinical parameters, which eventually can influence a decrease in associated comorbidities and, therefore, improvement of the disease. However, it should be noted that this type of platform is not useful for every patient profile, and studies in this regard should be expanded.