The Paul Ehrlich Institute (German: Paul-Ehrlich-Institut – Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel, PEI) is a German federal agency, medical regulatory body and research institution for vaccines and biomedicines. It was founded in 1896 and is subordinate to the Federal Ministry of Health. The institute is a WHO Collaborating Centre for quality assurance of blood products and in vitro diagnostic devices. It is located in Langen, Hesse, near Frankfurt, and was located in Frankfurt for most of the 20th century. It is named for its founding director, the immunologist and Nobel Prize laureate Paul Ehrlich..
Abstract Despite the clinical success of CD19-directed CAR T-cell therapies, less than 50% of patients achieve long-term remission. Emerging evidence indicates that loss or reduced expression of CD19—due to mutations, deletions, alternative splicing—is a significant, underrecognized mechanism of treatment failure. Notably, CD19-negative subpopulations can be detected even prior to therapy, and patients with low CD19 expression consistently show poorer outcomes. Although current clinical guidelines do not mandate routine CD19 testing before treatment, this situation reflects both scientific and technical challenges. Importantly, patients with partial/ low CD19 expression may still benefit from therapy, complicating the definition of “target positivity.” From a regulatory perspective, targeted therapies should ideally be used only when target expression is confirmed. This principle is difficult to implement, considering the scarcity of data and the difficulties of current diagnostic tools, risking both undertreatment and overtreatment. EU regulators have addressed the issue by introducing harmonized warnings in product information, but more is needed. We highlight this regulatory-clinical gap and advocate for improved diagnostic standards, better data integration, and dialogue among clinicians, developers, and regulators.
In a process termed trained immunity activated dendritic cells (DCs) and macrophages undergo distinct metabolic changes that contribute to their effector function: While certain activated DC subsets and M1 macrophages undergo a switch towards higher rates of glycolysis and a “disrupted Krebs cycle” to produce important immune effector molecules, alternatively activated (M2) macrophages, plasmacytoid DCs (pDCs), and conventional DCs type 1 (cDC1s) can rely on oxidative phosphorylation for their effector function. DCs and macrophages are also important cells in allergic reactions. While the induction of trained immune responses by microbial stimuli and vaccines is meanwhile well characterized, the contribution of trained immunity to either the establishment, elicitation, or treatment of allergic responses is largely unknown. In this context, recent results suggest distinct trained immunity responses to be established in allergic children. Here it seems that infections early in life predispose to the latter development of allergies, and trained immunity to also contribute to the immune modulation occurring in allergic patients during allergen-specific immunotherapy. Therefore, better understanding of trained immunity in these antigen-presenting cell (APC) subsets may allow to establish new biomarkers and enable a more targeted and efficient treatment of allergic diseases. This article summarizes the specific immune metabolic alterations observed in activated DCs and macrophages explaining their connection to DC and macrophage effector function. It then discusses our current knowledge on the contribution of trained immune responses in the establishment and treatment of allergic diseases.
Regulation (EU) 2024/1938 on quality and safety standards for substances of human origin intended for human application (Substances of Human Origin, SoHO Regulation) represents a paradigm shift in the legal classification of human milk. This review article presents the innovations compared to previous regulations of human milk, describes current European harmonization efforts as well as the state of national implementation,and summarizes the possible impacts of the regulation on the clinical handling of human milk. Overall, new requirements arise for the handling of human milk, particularly with regard to an obligation for registration of entities that carry out a SoHO activity and for authorization as a SoHO establishment.It should be noted that Regulation (EU) 2024/1938 applies not only to the handling of donor human milk but also to the handling of processed mother's own milk.A transition phase until August 2028 enables gradual implementation while taking into account European harmonization efforts and national challenges
In vivo antibiotic pharmacokinetic-pharmacodynamic (PKPD) properties are typically studied in neutropenic infection models, limiting the understanding of interactions between immune cells and antibiotics. This study aimed to characterize the impact of immune status on meropenem PKPD and dose-response in a mouse lung infection model, and to quantify the relative contribution of immune response and meropenem to bacterial killing. Meropenem PK was analyzed in plasma and epithelial lung fluid, and bacterial counts were monitored over 24 h following 40 or 300 mg/kg meropenem doses every 4 h in a mouse lung infection model with varying immunosuppression levels (neutropenic, intermediate, or immunocompetent). A PKPD model was developed to quantify bacterial killing by the immune response and meropenem over time. Dose-fractionation studies were simulated to investigate meropenem dose-response in different immune states. Observed differences in meropenem concentration-time profiles were explained by a higher volume of distribution in immunocompetent mice. The immune response was described by phagocytosis and digestion processes. The meropenem effect was best quantified based on plasma concentrations, with a maximal killing rate of 0.934 h-1 and EC50 = 1.62 mg/L. The lower contribution of meropenem to bacterial killing in intermediate and immunocompetent conditions was explained as a lower fraction of bacteria being affected by meropenem. In simulations, the immune status impacted PKPD target derivation. The developed model characterized differences in meropenem PK between neutropenic and immunocompetent in vivo infection models and quantified the contributions of immune response and meropenem to bacterial killing, with a reduced effect of meropenem in immunocompetent systems.
The growing threat of antimicrobial resistance highlights the urgent need for new treatment strategies. Reliable animal data are essential to accelerate antibiotic development, and standardized murine infection models, like the neutropenic mouse pneumonia model, can improve the reproducibility and comparability of efficacy data across laboratories—key for clinical translation. This study aims to develop a standardized murine pneumonia model to enhance the clinical relevance of preclinical findings. Using a consensus lung infection protocol, we tested 32 Klebsiella pneumoniae and Pseudomonas aeruginosa isolates. Fifteen met predefined virulence criteria—showing at least a 1 log₁₀ increase in bacterial load from baseline to endpoint, while maintaining mouse survival for at least 12 h post-inoculation. These isolates are available through the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ). Follow-up studies at independent sites confirmed the virulence of eight isolates with minimal variability in bacterial growth. These were added to the Collaboration for Prevention and Treatment of MDR Bacterial Infection (COMBINE Preclinical Bacterial Strain Repository at DSMZ. Based on this work, we propose a standardized experimental framework using this isolate panel to support robust preclinical testing of new antibacterial therapies. This model offers a reproducible, well-characterized platform for evaluating anti-infective candidates. We believe the COMBINE protocol can enhance the reliability and consistency of preclinical efficacy assessments and help reduce the number of animals required, aligning with the 3R principles—reduce, refine, replace—in animal research.IMPORTANCEThe rise of antibiotic-resistant bacteria has made it increasingly difficult to treat common infections, such as pneumonia. To develop new antibiotics, scientists rely on animal infection models to test how well potential drugs work before human trials. However, inconsistent methods between laboratories make it hard to compare results and slow the progress of new treatments. This study established and validated a standardized mouse pneumonia model for Klebsiella pneumoniae and Pseudomonas aeruginosa—two major pneumonia pathogens—across three international research centers. By identifying and sharing a set of well-characterized bacterial strains and a common experimental protocol, we provide a reliable foundation for comparing drug efficacy data. This model will help improve the quality and reproducibility of preclinical antibiotic research, reduce unnecessary animal use, and accelerate the discovery of new treatments against life-threatening bacterial infections.
