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- 2019
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Journal article (peer-reviewed)
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| 2. |
- Gonzalez Dias Carvalho, Patrícia Conceição, et al.
(author)
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Baseline gene signatures of reactogenicity to Ebola vaccination: a machine learning approach across multiple cohorts
- 2023
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In: Frontiers in Immunology. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- Introduction: The rVSVDG-ZEBOV-GP (Ervebo®) vaccine is both immunogenic and protective against Ebola. However, the vaccine can cause a broad range of transient adverse reactions, from headache to arthritis. Identifying baseline reactogenicity signatures can advance personalized vaccinology and increase our understanding of the molecular factors associated with such adverse events. Methods: In this study, we developed a machine learning approach to integrate prevaccination gene expression data with adverse events that occurred within 14 days post-vaccination. Results and Discussion: We analyzed the expression of 144 genes across 343 blood samples collected from participants of 4 phase I clinical trial cohorts: Switzerland, USA, Gabon, and Kenya. Our machine learning approach revealed 22 key genes associated with adverse events such as local reactions, fatigue, headache, myalgia, fever, chills, arthralgia, nausea, and arthritis, providing insights into potential biological mechanisms linked to vaccine reactogenicity.
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| 3. |
- Huttner, Angela, et al.
(author)
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Antibody responses to recombinant vesicular stomatitis virus-Zaire Ebolavirus vaccination for Ebola virus disease across doses and continents: 5-year durability
- 2023
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In: CLINICAL MICROBIOLOGY AND INFECTION. - 1198-743X .- 1469-0691. ; 29:12, s. 1587-1594
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Journal article (peer-reviewed)abstract
- Objectives: To report 5-year persistence and avidity of antibodies produced by the live-attenuated recombinant vesicular stomatitis virus (rVSV) expressing the Zaire Ebolavirus (ZEBOV) glycoprotein (GP), known as rVSV-ZEBOV (Ervebo (R)).Methods: Healthy adults vaccinated with 300,000 or 10-50 million plaque-forming units of rVSV-ZEBOV in the WHO-coordinated trials of 2014-2015 were followed for up to 4 (Lambar & eacute;n & eacute;, Gabon) and 5 (Geneva, Switzerland) years. We report seropositivity rates, geometric mean titres (GMTs), and population distribution of ZEBOV-GP ELISA IgG antibodies, neutralizing antibodies (pseudovirus and live-virus neutralization) and antibody avidity; the primary outcome was ZEBOV-GP ELISA IgG GMTs at 4 or 5 years compared with 1 year (Y1) after immunization.Results: Among the 168 eligible vaccinees (Geneva: 97 and Lambar & eacute;n & eacute;: 71) enrolled 1 year post-immunization, 146 (87%) remained enrolled at 4 years (Geneva: n = 88, Lambar & eacute;n & eacute;: n = 58), and 84 (87%, Geneva) at 5 years post-vaccination. ZEBOV-GP ELISA IgG GMTs plateaued, with no declining trend from 1 year through the last time point assessed (1147.8 [95% CI 874.3-1507.0] at Y1 versus 1548.1 [95% CI 1136.6-2108.5] at Y5 in Geneva volunteers receiving >= 10 million plaque-forming units of rVSV-ZEBOV), their avidity matching that of ZEBOV convalescents. Live-virus neutralizing antibodies were detected for shorter periods and in fewer vaccinees (53/95 [56%] at Y1 versus 35/84 [42%] at Y5 in Geneva volunteers, all dose levels).Discussion: Titres at Y1 emerged as a correlate of antibody persistence at Y5. The findings of persistent ZEBOV-GP ELISA IgG titres yet shorter-lasting, lower titres of live-virus neutralizing antibodies suggest the contribution of antibody-mediated protective mechanisms other than neutralization. Long-term clinical efficacy of rVSV-ZEBOV, however, requires further study.
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| 4. |
- Martinez-Murillo, Paola Andrea, et al.
(author)
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Refined innate plasma signature after rVSVΔG-ZEBOV-GP immunization is shared among adult cohorts in Europe and North America
- 2024
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In: FRONTIERS IN IMMUNOLOGY. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- Background: During the last decade Ebola virus has caused several outbreaks in Africa. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV Delta G-ZEBOV-GP) vaccine has proved safe and immunogenic but is reactogenic. We previously identified the first innate plasma signature response after vaccination in Geneva as composed of five monocyte-related biomarkers peaking at day 1 post-immunization that correlates with adverse events, biological outcomes (haematological changes and viremia) and antibody titers. In this follow-up study, we sought to identify additional biomarkers in the same Geneva cohort and validate those identified markers in a US cohort.Methods: Additional biomarkers were identified using multiplexed protein biomarker platform O-link and confirmed by Luminex. Principal component analysis (PCA) evaluated if these markers could explain a higher variability of the vaccine response (and thereby refined the initial signature). Multivariable and linear regression models evaluated the correlations of the main components with adverse events, biological outcomes, and antibody titers. External validation of the refined signature was conducted in a second cohort of US vaccinees (n=142).Results: Eleven additional biomarkers peaked at day 1 post-immunization: MCP2, MCP3, MCP4, CXCL10, OSM, CX3CL1, MCSF, CXCL11, TRAIL, RANKL and IL15. PCA analysis retained three principal components (PC) that accounted for 79% of the vaccine response variability. PC1 and PC2 were very robust and had different biomarkers that contributed to their variability. PC1 better discriminated different doses, better defined the risk of fever and myalgia, while PC2 better defined the risk of headache. We also found new biomarkers that correlated with reactogenicity, including transient arthritis (MCP-2, CXCL10, CXCL11, CX3CL1, MCSF, IL-15, OSM). Several innate biomarkers are associated with antibody levels one and six months after vaccination. Refined PC1 correlated strongly in both data sets (Geneva: r = 0.97, P < 0.001; US: r = 0.99, P< 0.001).Conclusion: Eleven additional biomarkers refined the previously found 5-biomarker Geneva signature. The refined signature better discriminated between different doses, was strongly associated with the risk of adverse events and with antibody responses and was validated in a separate cohort.
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| 5. |
- Tängdén, Thomas, et al.
(author)
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How preclinical infection models help define antibiotic doses in the clinic
- 2020
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In: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 56:2, s. 106008-
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Journal article (peer-reviewed)abstract
- Appropriate dosing of antibiotics is key in the treatment of bacterial infections to ensure clinical efficacy while avoiding toxic drug concentrations and minimizing emergence of resistance. As collection of sufficient clinical evidence is difficult for specific patient populations, infection types and pathogens, market authorization, dosing strategies and recommendations often rely on data obtained from in vitro and animal experiments. The aim of this review is to provide an overview of commonly used preclinical infection models, including their strengths and limitations. In vitro, static and dynamic time-kill experiments are the most frequently used methods for assessing pharmacokinetic/pharmacodynamic (PK/PD) associations. Limitations of in vitro models include the inability to account for the effects of the immune system, and uncertainties in clinically relevant bacterial concentrations, growth conditions and the implications of emerging resistant bacterial populations during experiments. Animal experiments, most commonly murine lung and thigh infections models, are considered a necessary link between in vitro data and the clinical situation. However, there are differences in pathophysiology, immunology, and PK between species. Mathematical modeling in which preclinical data are integrated with human population PK can facilitate translation of preclinical data to the patient's clinical situation. Moreover, PK/PD modeling and simulations can help in the design of clinical trials aiming to establish optimal dosing regimens to improve patient outcomes. (C) 2020 The Authors. Published by Elsevier B.V.
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| 6. |
- Vianello, Eleonora, et al.
(author)
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Global blood miRNA profiling unravels early signatures of immunogenicity of Ebola vaccine rVSVΔG-ZEBOV-GP
- 2023
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In: iScience. - 2589-0042. ; 26:12
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Journal article (peer-reviewed)abstract
- The vectored Ebola vaccine rVSVΔG-ZEBOV-GP elicits protection against Ebola Virus Disease (EVD). In a study of forty-eight healthy adult volunteers who received either the rVSVΔG-ZEBOV-GP vaccine or placebo, we profiled intracellular microRNAs (miRNAs) from whole blood cells (WB) and circulating miRNAs from serum-derived extracellular vesicles (EV) at baseline and longitudinally following vaccination. Further, we identified early miRNA signatures associated with ZEBOV-specific IgG antibody responses at baseline and up to one year post-vaccination, and pinpointed target mRNA transcripts and pathways correlated to miRNAs whose expression was altered after vaccination by using systems biology approaches. Several miRNAs were differentially expressed (DE) and miRNA signatures predicted high or low IgG ZEBOV-specific antibody levels with high classification performance. The top miRNA discriminators were WB-miR-6810, EV-miR-7151-3p, and EV-miR-4426. An eight-miRNA antibody predictive signature was associated with immune-related target mRNAs and pathways. These findings provide valuable insights into early blood biomarkers associated with rVSVΔG-ZEBOV-GP vaccine-induced IgG antibody responses.
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