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The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group evaluates the safety and other key features of new platform technology vaccines, including nucleic acid (RNA and DNA) vaccines. This manuscript uses the BRAVATO template to report the key considerations for a benefit-risk assessment of the coronavirus disease 2019 (COVID-19) mRNA-based vaccine BNT162b2 (Comirnaty®, or Pfizer-BioNTech COVID-19 vaccine) including the subsequent Original/Omicron BA.1, Original/Omicron BA.4-5 and Omicron XBB.1.5 variant-adapted vaccines developed by BioNTech and Pfizer to protect against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initial Emergency Use Authorizations or conditional Marketing Authorizations for the original BNT162b2 vaccine were granted based upon a favorable benefit-risk assessment taking into account clinical safety, immunogenicity, and efficacy data, which was subsequently reconfirmed for younger age groups, and by real world evidence data. In addition, the favorable benefit-risk assessment was maintained for the bivalent vaccines, developed against newly arising SARS-CoV-2 variants, with accumulating clinical trial data., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Brighton Collaboration BRAVATO authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. BioNTech authors are current employees of BioNTech, a for-profit organization, who may own stock or hold stock options. AM is an inventor on patents and/or patent applications related to RNA technology and COVID-19 vaccines., (Published by Elsevier Ltd.)

The German Innovation Fund has funded various studies on patient safety. Their thematic spectrum, methodological quality, results and recommendations of the Innovation committee were to be systematically investigated in order to derive proposals for optimizing transfer success. As part of a scoping review, all Innovation Fund projects funded in the period 2016-02/2023 with a focus on patient safety were analyzed. Each included study document was critically reviewed by two independent persons. The 16 included projects addressed a wide range of populations, indications and interventions. The study quality was mostly good. The results ranged from feasible indicator sets and the prevention of adverse drug reactions to the optimization of error management. For seven projects, the Innovation Committee recommended forwarding the results to healthcare institutions with the request that they take note and/or examine the feasibility of implementation in standard care. Implementation, however, has not yet taken place. In order to facilitate implementation, the joint development of an implementation strategy by the recipients of the Innovation Committee's recommendations is necessary., Competing Interests: Lorenz Harst: Unabhängig von diesem Projekt hat LH von der Volkswagen Stiftung finanzielle Unterstützung für die Teilnahme an einem Scoping-Workshop zu Organisationsbezogener Versorgungsforschung erhalten. Lilly Rüthrich: Unabhängig von diesem Projekt führt LR die Aktualisierung des QISA-Bandes C6 Depression für das aQua-Institut für angewandte Qualitätsförderung und Forschung im Gesundheitswesen GmbH durch. Felix Walther: FW hat keine Interessenkonflikte. Laura Keßler: LK hat keine Interessenkonflikte. Christina Lindemann: CL: ist Mitglied im Deutschen Netzwerk Versorgungsforschung und hat von diesem und der DKG Reisekosten finanziert bekommen. Martin Härter: Unabhängig von diesem Projekt hat MH institutionelle Fördermittel von DFG, BMBF, BMG, Innovationsfonds, DAK Gesundheit u. a. sowie Beratungshonorare vom IQTIG und der TK erhalten. MH ist Vorsitzender des Beirats und wissenschaftlicher Leiter beim Ärztlichen Zentrum für Qualität in der Medizin (ÄZQ) in Berlin. Erik Farin-Glattacker: Unabhängig von diesem Projekt erhielt EFG institutionelle Fördermittel für wissenschaftlich-initiierte Forschung vom BMBF, BMAS, Gemeinsamer Bundesausschuss (Innovationsfonds), Deutsche Rentenversicherung, GKV; EFG ist Mitglied des wissenschaftlichen Beirats des IQTIG. Max Geraedts: MG war Teil der Leitung des Projekts IMPRESS Unabhängig von diesem Projekt erhielt MG institutionelle Fördermittel für wissenschaftlich-initiierte Forschung vom GB-A, BMBF, HMWK, Gesundheitsamt Marburg; zudem Gutachten- bzw. Vortrags- oder Beraterhonorare des IQTIG, APS, der Universitäten Hamburg, Dresden, Witten/Herdecke; KCQ-BW, LAG-QS-NS, LAG-QS-Bayern; MG ist Mitglied des wissenschaftlichen Beirats des IQTIG. Jochen Schmitt: JS war Teil der Leitung des Projekts IMPRESS. Unabhängig von diesem Projekt erhielt JS institutionelle Fördermittel für wissenschaftlich-initiierte Forschung vom GB-A, dem BMG, BMBF, Freistaat Sachsen, Novartis, Sanofi, ALK und Pfizer. Er nahm als Berater an Advisory Board Meetings der Firmen Sanofi, Lilly und ALK teil und erhielt hierfür ein persönliches Honorar. JS ist Mitglied des Sachverständigenrat Gesundheit und Pflege am Bundesministerium für Gesundheit und Mitglied der Regierungskommission für eine moderne und bedarfsgerechte Krankenhausversorgung der Ampelkoalition., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Increasing ocean temperature will speed up physiological rates of ectotherms. In fish, this is suggested to cause earlier spawning due to faster oocyte growth rates. Over time, this could cause spawning time to become decoupled from the timing of offspring food resources, a phenomenon referred to as trophic asynchrony. We used biological data, including body length, age, and gonad developmental stages collected from >125,000 individual Northeast Arctic cod (Gadus morhua) sampled between 59 and 73° N in 1980-2019. Combined with experimental data on oocyte growth rates, our analyses show that cod spawned progressively earlier by about a week per decade, partly due to ocean warming. It also appears that spawning time varied by more than 40 days, depending on year and spawning location. The significant plasticity in spawning time seems to be fine-tuned to the local phytoplankton spring bloom phenology. This ability to partly overcome thermal drivers and thus modulate spawning time could allow individuals to maximize fitness by closely tracking local environmental conditions important for offspring survival. Our finding highlights a new dimension for trophic match-mismatch and should be an important consideration in models used to predict phenology dynamics in a warmer climate., (© 2024 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Introduction: Since 2015, the Federal Joint Committee (G-BA)'s Innovation Fund has been supporting projects in health services research and new health service models ("Neue Versorgungsformen", NVF). By the end of 2022, 211 projects in the NVF category had been funded. A key objective is the transfer of successful projects into standard care. This article analyzes previous projects regarding their incorporation into routine care based on transfer recommendations of the Innovation Fund Committee ("Innovationsausschuss" IA)., Method: Descriptive analysis of all projects completed by August 1, 2023 with transfer recommendations in the "NVF" funding stream. Presentation by topic, project duration, time until IA transfer decision, categorization, and number of institutions and organizations (recipients) addressed per project, their feedback published on the G-BA website, response rates per recipient group, and a content classification and interpretation of exemplary feedback. Recommendations based on the results and their discussion in an expert workshop., Results: Out of 57 NVF projects, 17 had a transfer recommendation. A total of 57 feedback responses were received from a total of 431 recipients addressed by the IA across these projects. Response rates varied significantly. One-third of inquiries to the G-BA and its member organizations received a response (31%), while only every fifth inquiry to federal states (18%) and professional societies (18%) got a response. Less than one in ten inquiries to the Federal Ministry of Health (8%), administrative bodies (6%), and the German Medical Association (0%) received a response. Project-specific feedback within a recipient group was often contradictory or limited to regional scope., Discussion and Conclusion: The transfer process reveals significant structural and procedural obstacles regarding the incorporation of projects evaluated as successful into routine health care. To ensure that funding from the innovation fund is most effectively used, there needs to be a realistic chance of successful transfer of positive project outcomes into routine care. The DNVF recommends stronger involvement of rule-competent institutions, mandatory publication of responses, structured moderation of the transfer process, expanding types of selective contracts, financing of implementation phases and of studies drawing on results across successful NVF projects., Competing Interests: CL, MS geben ihre Mitgliedschaft im DNVF an, CL hat Reisekosten von der DKG und DNVF erhalten. MH, JS, WH sind im Vorstand des DNVF und verweisen auf die Darlegung ihrer Interessen (https://www.dnvf.de/über-uns/vorstand.html). TB, LK geben ihre Beschäftigung in der DNVF Geschäftsstelle an. ME, EF-G, MH, HCV, JS und WH geben an, Fördergelder des Innofonds erhalten zu haben. ME gibt eine Kooperation mit der DAK-Gesundheit an. AM ist Mitarbeiter der Techniker Krankenkasse. OS hat Honorare von Novartis erhalten. MG, HH, NvdB, MvK geben keine Interessenskonflikte an., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Although many individuals with alcohol dependence (AD) are recognized in the German healthcare system, only a few utilize addiction-specific treatment services. Those who enter treatment are not well characterized regarding their prospective pathways through the highly fragmented German healthcare system. This paper aims to (1) identify typical care pathways of patients with AD and their adherence to treatment guidelines and (2) explore the characteristics of these patients using routine data from different healthcare sectors., Methods: We linked routinely collected register data of individuals with a documented alcohol-related diagnosis in the federal state of Bremen, Germany, in 2016/2017 and their addiction-specific health care: two statutory health insurance funds (outpatient pharmacotherapy for relapse prevention and inpatient episodes due to AD with and without qualified withdrawal treatment (QWT)), the German Pension Insurance (rehabilitation treatment) and a group of communal hospitals (outpatient addiction care). Individual care pathways of five different daily states of utilized addiction-specific treatment following an index inpatient admission due to AD were analyzed using state sequence analysis and cluster analysis. The follow-up time was 307 days (10 months). Individuals of the clustered pathways were compared concerning current treatment recommendations (1: QWT followed by postacute treatment; 2: time between QWT and rehabilitation). Patients' characteristics not considered during the cluster analysis (sex, age, nationality, comorbidity, and outpatient addiction care) were then compared using a multinomial logistic regression., Results: The analysis of 518 individual sequences resulted in the identification of four pathway clusters differing in their utilization of acute and postacute treatment. Most did not utilize subsequent addiction-specific treatment after their index inpatient episode (n = 276) or had several inpatient episodes or QWT without postacute treatment (n = 205). Two small clusters contained pathways either starting rehabilitation (n = 26) or pharmacotherapy after the index episode (n = 11). Overall, only 9.3% utilized postacute treatment as recommended., Conclusions: A concern besides the generally low utilization of addiction-specific treatment is the implementation of postacute treatments for individuals after QWT., (© 2024. The Author(s).)

We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell-specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).

At high latitudes, the suitable window for timing reproductive events is particularly narrow, promoting tight synchrony between trophic levels. Climate change may disrupt this synchrony due to diverging responses to temperature between, for example, the early life stages of higher trophic levels and their food resources. Evidence for this is equivocal, and the role of compensatory mechanisms is poorly understood. Here, we show how a combination of ocean warming and coastal water darkening drive long-term changes in phytoplankton spring bloom timing in Lofoten Norway, and how spawning time of Northeast Arctic cod responds in synchrony. Spring bloom timing was derived from hydrographical observations dating back to 1936, while cod spawning time was estimated from weekly fisheries catch and roe landing data since 1877. Our results suggest that land use change and freshwater run-off causing coastal water darkening has gradually delayed the spring bloom up to the late 1980s after which ocean warming has caused it to advance. The cod appear to track phytoplankton dynamics by timing gonadal development and spawning to maximize overlap between offspring hatch date and predicted resource availability. This finding emphasises the importance of land-ocean coupling for coastal ecosystem functioning, and the potential for fish to adapt through phenotypic plasticity., (© 2024 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

In response to the 2022 outbreak of mpox driven by unprecedented human-to-human monkeypox virus (MPXV) transmission, we designed BNT166, aiming to create a highly immunogenic, safe, accessible, and scalable next-generation vaccine against MPXV and related orthopoxviruses. To address the multiple viral forms and increase the breadth of immune response, two candidate multivalent mRNA vaccines were evaluated pre-clinically: a quadrivalent vaccine (BNT166a; encoding the MPXV antigens A35, B6, M1, H3) and a trivalent vaccine (BNT166c; without H3). Both candidates induced robust T cell responses and IgG antibodies in mice, including neutralizing antibodies to both MPXV and vaccinia virus. In challenge studies, BNT166a and BNT166c provided complete protection from vaccinia, clade I, and clade IIb MPXV. Furthermore, immunization with BNT166a was 100% effective at preventing death and at suppressing lesions in a lethal clade I MPXV challenge in cynomolgus macaques. These findings support the clinical evaluation of BNT166, now underway (NCT05988203)., Competing Interests: Declaration of interests U.S. and O.T. are management board members and employees at BioNTech SE. R.B.G. serves on the Board of Directors for Alkermes PLC, Infinity Pharmaceuticals, and Zai Laboratory; serves on the Scientific Advisory Board for Leap Therapeutics; is a consultant for Third Rock Ventures; and is a stockholder and employee of BioNTech US. B.C. and S.K. are employees of Bioqual, Inc. S.S. is an employee of Southern Research. A.Z., C.L.D., N.D.S., M.M., Y.J.L., G.M.P., A.D., R.S.V., K.S., A.G., C.L., D.A.R., H.D., A.C.W., T.A.A., F.M., A.B.V., L.M.S., R.v.d.M., J.R.S., and A.P. are current/past employees of BioNTech SE/BioNTech US, are stockholders, and/or are inventors on patents and patent applications related to RNA vaccines., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)