Janssen (Netherlands)

Most human invasive infections caused by extraintestinal pathogenic Escherichia coli (ExPEC) are associated with a limited number of O-serotypes and O-serogroups, including O101/O162. Here, we examined E. coli O101/O162 O-serogroup epidemiology among bacteremia isolates and performed genetic, biochemical and structural analyses. We demonstrate that the O101/O162 O-serogroup is globally widespread and highly associated with multidrug resistance (MDR). Dominant lineages belonged to clonal complex 10, including the high-risk clone ST167. Most O101/O162 ExPEC isolates contained an unusual O101 rfb locus previously identified as Onovel32, of which 30% harbored disruptions in the methyltransferase (MT) encoding gene. These disruptions resulted in alteration of the polysaccharide composition, and we identified two major O101 variants. Additionally, we found that an intact MT is a prerequisite for O-methylation of the polysaccharide, indicating terminal capping. Our data supports a model of a co-polymeric O101 O-antigen structure, which is unique for E. coli. Finally, we established that the two clinically relevant O101 O-antigen variant structures are highly immunogenic as polysaccharide-protein conjugates but differ in their ability to elicit opsonophagocytic antibodies. Altogether, our data provides important insights into O-serotype epidemiology and O-polysaccharide variation within E. coli O101/O162 isolates associated with bacteremia.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-026-45688-7.

Sample analysis: we analysed various samples including meteorites from Moon, Mars, asteroids, and analogue field samples from campaigns (Vulcano, Etna, Hawaii HI-SEAS) using spectrometry, hyperspectral imaging and Raman .LUNEX also participates in collaboration with TU Delft in the study of ice, minerals and organics mixture relevant for Moon, Mars and icy Moons.Payload development: we have developed a test bench for sample analysis using reflectance and transmission spectroscopy, Raman spectroscopy and microscopy. We also adapted an Hyperspectral camera for sample analysis and for telescopic observations of the Moon and other celestial objects. Space Photonics Lab : this is being developed with in collaboration with Fotonika Latvia, with cubesat synergy .Shoebox instruments for laboratory tests and analogue were developed for future Moon and Mars missions. We are conceiving a concept of a shoebox module for extracting organics from icy moons of Jupiter and Saturn, with special prototype for Enceladus plumes or surface. LUNEX ExoGeoLab lander is currently adapted with shoebox instruments for supporting future missions to Moon, Mars and icy moons.Cubesats for education, EarthMoonMars exploration: LUNEX EMMESI has initiated the development of university education cubesats with the support of Leiden University (Observatory, LIACS computer science, Physics and Optics), Leiden Instrument Schools LiS, Deft TU, InHolland Delft, ESA BIC. The development starts with a table top bench & a prototype 3U system, with spacecraft and payload functions. First applications include an Earth and Moon remote sensing cubesat, a 3U adapted on a lunar rover platform, and a 3U shoe-box instrument deployed from surface lander.Field work and testing of instruments and protocols. Extreme environments on Earth provide similar terrain conditions to sites on the Moon and Mars, in order to rehearse mission operations in the field and through simulations. EuroMoonMars field campaigns were organised in specific locations of technical, scientific and exploration interest. In 2023-24, EuroMoonMars co-sponsored Vulcano 2024 Geo-Astrobiology field school, and a specific EuroMoonMars field tests at Etna, building on the experience of campaigns conducted earlier with DLR and ESA for ROBEX 2019, and ARCHES 2022 campaigns (Wedler et al 2017 & 2022)EuroMoonMars Analogue astronauts simulations. Lunex EuroMoonMars, has been organizing since 2009 in collaboration with ESA, NASA, European and US universities a programme of data analysis, instrumentation tests, field work and analog missions for students and researchers in different locations worldwide, including Utah MDRS, IMA Hawaii HI-SEAs, Iceland, Etna/ Vulcano Italy, Atacama, AATC Poland, ESTEC Netherlands, Eifel Germany, etc… Analogue missions provide a practical ground in which researchers can test in a realistic simulation context. During these missions, students have access to special Space instrumentation, laboratories, Facilities, Science Operations, Human Robotic partnerships. In 2023-24, EuroMoonMars co-sponsored EMMPOL Moonbase isolation simulation campaigns in Poland (Hutchison, Laforet, Tataj, Della Guardia) , and at IMA International Moonbase Alliance HI-SEAs (EMMIHS) .ExoSpaceHab Xpress (ESH-X) is an innovative portable lunar base simulator designed for education, analog missions and public outreach. This habitat has been funded by European consortium EuroSpaceHub and its partner LUNEX EuroMoonMars. After inauguration at Padova Botanical Garden in Italy, ExoSpaceHab-X was shown 20/9-13/10 2023 at the Science week fair of ENS Paris Saclay, and then used at SBIC Space Business Innovation Center Noordwijk in Oct-Dec, then in Leiden with University Jan-April 2024 and 3Aug-18 Sept, Pleaux Auvergne 8 May-1 Aug, Padova Science Festival with 2000 visitors, Grenoble University Space Center in October. t. It is also planned for other locations in Europe in 2025. ESH-X lab-hab module is used to test experiments and investigations for Artemis programme.Acknowledgments: We thank collaborators and partner institutions from EMMESI academy, EuroSpaceHub/GreenSpaceHub Consortia, ESA ESTEC, NASA, EuroMoonMars programme, Space Renaissance International, Qosmosys & Moon Village Association. ILEWG/EMM

Abstract Background Invasive E. coli disease (IED) poses a substantial public health concern globally. Anti-microbial resistance (AMR) displayed by some E. coli strains further limits the treatment options. We sought to identify and synthesize evidence on prevalence of AMR among adult IED patients in the United States. Figure 1. PRISMA flowchart Methods A systematic literature review was conducted in EMBASE, MEDLINE, and MEDLINE In-Process databases to identify studies of prevalence of AMR E. coli among adult IED patients, published January. 2010–September. 2023. Figure 2. Antimicrobial resistance of E. coli isolates to antibiotics across patient groups Results Seventeen publications met eligibility criteria and were included (Fig. 1). The review reports study-specific prevalence from these included studies. Variation in AMR was observed across study designs (retrospective: 12; cross-sectional: 1; prospective: 4) with varying population characteristics, and 19-year time period (2002–2020) (Fig. 2). Four studies had high prevalence (≥50%) of ampicillin-resistant E. coli. Extended-spectrum cephalosporin resistance (ESC-R) increased over time in two studies (2003–2007: 4.1% & 2008–2013: 7.9% among veterans with bacteremia; and 2009: 5.4% & 2016: 12.9% for IED-related visits). One study reported higher prevalence of E. coli AMR among older as opposed to younger patients for ESC-R (18-49 years: 6%; > 65 years: 10%) and FQ-R (18-49 years: 18%; > 65 years: 31%). Similar trends were observed for E. coli multidrug resistance (≤69 years: 10% vs > 69 years: 19%) in one study. FQ/ESC co-resistance increased over time, from 11% in 2013 to 14% in 2017 (p < .0001). In one study, AMR rates were lower during Summer for amoxicillin/clavulanic acid (17% vs 29%; p=.02), cefazolin (6% vs 19%; p < .001), trimethoprim/sulfamethoxazole (9% vs 27%; p < .001) and ceftriaxone (2% vs 6%; p=.04). Prevalence of ampicillin resistance was not seasonal. Regional variation in AMR was observed, with FQ-R varying between 10.5% in Denver Health Clinic to 28.9% in Cleveland Clinic. Prevalence of FQ/ESC co-resistance varied geographically; highest prevalence ( > 13%) occurred in several regions. Conclusion Prevalence of AMR E. coli in the US increased overall, in certain high-risk groups, over time, with also regional and seasonal variation. There is an unmet need for additional data on AMR prevalence in IED, and a critical need for preventive measures. Disclosures Sanjukta Basu, Ph.D, Amaris Consulting: Advisor/Consultant Ziyan (Jenny) Wei, Msc, Amaris Consulting: Advisor/Consultant Atara Laor, BSc., Amaris Consulting: Advisor/Consultant Liga Bennetts, PhD, Amaris Consulting: Advisor/Consultant Antoine El Khoury, PhD, Janssen Global Services: Advisor/Consultant|Janssen Global Services, LLC: Employee of Janssen Global Services, LLC Nina Ahmad, MD, Janssen Global Services, LLC: Employee of Janssen Global Services, LLC Jeroen Geurtsen, PhD, Janssen Vaccines & Prevention BV: Advisor/Consultant|Janssen Vaccines & Prevention BV: Employee of Janssen Vaccines & Prevention BV Maureen P. Neary, PhD, MS, Janssen Global Services, LLC: Employee of Janssen Global Services, LLC

Inflammation contributes to the development of type 2 diabetes mellitus (T2DM). While South Asians are more prone to develop T2DM than Europids, the inflammatory phenotype of the South Asian population remains relatively unknown. Therefore, we aimed to investigate potential differences in circulating levels of inflammation-related proteins in South Asians compared with Europids with T2DM. In this secondary analysis of three randomized controlled trials, relative plasma levels of 73 inflammation-related proteins were measured using an Olink Target Inflammation panel and the serum fibroblast growth factor 21 (FGF21) concentration using an ELISA kit in Dutch South Asians (n = 47) and Dutch Europids (n = 49) with T2DM. Of the 73 inflammation-related proteins, the relative plasma levels of six proteins were higher (stem cell factor, caspase-8, C-C motif chemokine ligand 28, interferon-gamma, sulfotransferase 1A1 and cystatin D; q-value <0.05), while relative levels of six proteins were lower (FGF21, human fibroblast collagenase, interferon-8, C-C motif chemokine ligand 4, C-X-C motif chemokine ligand 6 and monocyte chemoattractant protein-1; q-value <0.05) in South Asians compared with Europids. Of these, the effect size of FGF21 was the largest, particularly in females. We validated this finding by assessing the FGF21 concentration in serum. The FGF21 concentration was indeed lower in South Asians compared with Europids with T2DM in both males (-42.2%; P < 0.05) and females (-58.5%; P < 0.001). Relative plasma levels of 12 inflammation-related proteins differed between South Asians and Europids with T2DM, with a significantly pronounced reduction in FGF21. In addition, the serum FGF21 concentration was significantly lower in South Asian males and females compared with Europids. Whether low FGF21 is an underlying cause or consequence of T2DM in South Asians remains to be determined. ClinicalTrials.gov (NCT01761318, registration date 20-12-2012; NCT02660047, registration date 21-03-2018; and NCT03012113, registration date 06-01-2017).

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and older people. Current RSV subunit vaccines are based on a fusion protein that is stabilized in the prefusion conformation and linked to a heterologous foldon trimerization domain to obtain a prefusion F (preF) trimer. Here we show that current RSV vaccines induce undesirable anti-foldon antibodies in non-human primates, mice and humans. To overcome this, we designed a foldon-free RSV preF trimer by elucidating the structural basis of trimerization-induced preF destabilization through molecular dynamics simulations and by introducing amino acid substitutions that negate hotspots of charge repulsion. The highly stable prefusion conformation was validated using antigenic and cryo-electron microscopy analysis. The preF is immunogenic and protective in naive mouse models and boosts neutralizing antibody titres in RSV-pre-exposed mice and non-human primates, while achieving similar titres to approved RSV vaccines in mice. This stable preF design is a promising option as a foldon-independent candidate for a next-generation RSV vaccine immunogen.

The urgency and importance of organizing a global effort to harmonize clinical assay validation specific to the vaccine industry was identified during the drafting of the 2020 White Paper in Bioanalysis due to the lack of clarity and regulatory guidance/guidelines in vaccine immunoassay validation. Indeed, the Workshop on Recent Issues in Bioanalysis (WRIB) issues the White Paper in Bioanalysis yearly, which is one of the high-profile articles of the Bioanalysis Journal focused on detailed discussions and recommendations on vaccine assay validation. Since 2017, participation in the WRIB working groups by vaccine assay validation experts and regulators has rapidly increased due to its unique format where industry leaders and regulators can meet and exchange ideas on topics of interest to both groups. In early 2021, Vaccine manufacturers approached WRIB for sponsoring/supporting the authorship and publication of an overarching vaccine assay validation document based on the 2017-2020 discussions and consensus starting from immunogenicity assays first and followed by future papers on molecular and cell-based assay validation. Using industry and WRIB vaccine network, a vaccine immunogenicity assay validation working group was assembled consisting of 16 companies. The work on the first white paper started officially in April 2021 focusing on Vaccine LBA Validation (Part 1), and the drafting of Vaccine LBA Development (Part 2) and Vaccine LBA Monitoring & Transfer (Part 3) are presently ongoing and expected to be published shortly after this paper. Moreover, recommendations on Vaccine Cell-Based Assays Validation (ELISpot and Flow cytometry) and Vaccine Molecular Assays Validation (PCR, NGS, NanoString) are also on the WRIB publications agenda and the drafting is planned to start in mid-2024. For too long, vaccine scientists have not had a clear validation guidance for clinical vaccine immunogenicity assays. We hope that this common effort will help close this regulatory gap.

ObjectivesX-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease with no available treatment. Gene therapies in clinical trials will pose challenges for health technology assessment (HTA) if found to be safe and effective. We evaluated 2 of these challenges, namely acceptability and difficulties in assessing value beyond short-term patient health and healthcare savings and discounting in economic evaluation. MethodsWe conducted a narrative literature review on the socioeconomic burden of XLRP to identify relevant components of value for a hypothetical gene therapy from a societal perspective and to assess their relative importance. We compared the resulting value profile against the value frameworks of three European HTA agencies. We also reviewed their guidelines on discounting and potential discounting issues specific to XLRP. ResultsMuch of the societal value of an XLRP gene therapy is likely to originate from productivity effects, carer spillovers, and value elements related to patient uncertainty. The evidence on these effects, however, is often limited, making it difficult for HTA agencies to assess them. Cost-effectiveness results are likely to be highly sensitive to the discount rate, and discounting will compound the effects of omitting important sources of value. ConclusionsWe have identified and detailed important components of societal value, key evidence gaps, and potential discounting issues for an XLRP gene therapy, which can inform future value assessments. Many of these may apply to gene therapies in other disease areas. Revisiting existing HTA approaches is recommended to ensure these are fit for purpose for such new classes of treatment.

2.5 × 1010 vp Ad26.COV2.S elicited robust SARS-CoV-2–specific antibody responses in adolescents through 6 months, with acceptable safety and reactogenicity profiles. Compared with adults immunized with 5 × 1010 vp Ad26.COV2.S, adolescents had higher antibody levels, despite being vaccinated with a lower dose.