Abstract:Increasing antibiotic resistance in bacteria causing endogenous infections has entailed a need for innovative approaches to therapy and prophylaxis of these infections and raised a new interest in vaccines for prevention of colonization and infection by typically antibiotic resistant pathogens. Nevertheless, there has been a long history of failures in late stage clinical development of this type of vaccines, which remains not fully understood. This article provides an overview on present and past vaccine deve… Show more
“…Antimicrobial resistance is recognized as one of the greatest threats to human health ( World Health Organization [WHO], 2017 ; Morehead and Scarbrough, 2018 ; Murray et al, 2022 ). Thus, new antimicrobial therapies are urgently needed, although few are currently being developed ( Hughes and Karlén, 2014 ; Bekeredjian-Ding, 2020 ; Theuretzbacher et al, 2020 ). Due to numerous challenges, including long research timelines and limited financial reward, most large pharmaceutical companies are no longer investing in research and development of new antibiotics.…”
Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded “Collaboration for prevention and treatment of MDR bacterial infections” (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.
“…Antimicrobial resistance is recognized as one of the greatest threats to human health ( World Health Organization [WHO], 2017 ; Morehead and Scarbrough, 2018 ; Murray et al, 2022 ). Thus, new antimicrobial therapies are urgently needed, although few are currently being developed ( Hughes and Karlén, 2014 ; Bekeredjian-Ding, 2020 ; Theuretzbacher et al, 2020 ). Due to numerous challenges, including long research timelines and limited financial reward, most large pharmaceutical companies are no longer investing in research and development of new antibiotics.…”
Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded “Collaboration for prevention and treatment of MDR bacterial infections” (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.
“…Hence, there is a need for the accelerated development of new agents to treat and prevent infections caused by AMR pathogens ( WHO, 2021 ). Despite increasing interest in the development of new or alternative therapies, there is a high attrition rate, and new therapies that often fail to reach the market ( Hughes and Karlén, 2014 ; Bekeredjian-Ding, 2020 ).…”
The rise in antimicrobial resistance (AMR), and increase in treatment-refractory AMR infections, generates an urgent need to accelerate the discovery and development of novel anti-infectives. Preclinical animal models play a crucial role in assessing the efficacy of novel drugs, informing human dosing regimens and progressing drug candidates into the clinic. The Innovative Medicines Initiative-funded “Collaboration for prevention and treatment of MDR bacterial infections” (COMBINE) consortium is establishing a validated and globally harmonized preclinical model to increase reproducibility and more reliably translate results from animals to humans. Toward this goal, in April 2021, COMBINE organized the expert workshop “Advancing toward a standardized murine model to evaluate treatments for AMR lung infections”. This workshop explored the conduct and interpretation of mouse infection models, with presentations on PK/PD and efficacy studies of small molecule antibiotics, combination treatments (β-lactam/β-lactamase inhibitor), bacteriophage therapy, monoclonal antibodies and iron sequestering molecules, with a focus on the major Gram-negative AMR respiratory pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Here we summarize the factors of variability that we identified in murine lung infection models used for antimicrobial efficacy testing, as well as the workshop presentations, panel discussions and the survey results for the harmonization of key experimental parameters. The resulting recommendations for standard design parameters are presented in this document and will provide the basis for the development of a harmonized and bench-marked efficacy studies in preclinical murine pneumonia model.
“… Challenges of developing vaccines against pathogens causing hospital-acquired infections Many of the WHO bacterial priority pathogens cause hospital-acquired infections, in particular Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus , extra-intestinal pathogenic Escherichia coli, Clostridioides difficile, Enterococcus faecium , and Enterobacter spp. There are multiple challenges 35 for the clinical development of vaccines against these pathogens: The relatively low incidence of infections in the vaccine target population makes efficacy trials prohibitively large in terms of trial sites and patient numbers, and expensive 3 Potential target populations tend to be critically ill, with multiple comorbidities and severely compromised immune systems, making clinical endpoints hard to establish 36 , 37 Identification of populations at risk of hospital-acquired infections at intensive care unit admission is impracticable, due to the little time available to mount an effective immune response 38 At present there is no regulatory or policy precedent for a vaccine against hospital-acquired infections Despite these limitations, it could be possible to identify patients at high risk, such as those scheduled for elective surgery or hospital treatment, which would allow enough time for their immune systems to respond to vaccine administration. Given these challenges, regulators could explore the use of correlates of protection in phase 3 trials followed by the collection of post-licensure effectiveness data and real-world evidence.…”
Section: Group B: Pathogens With Vaccines In Late-stage Clinical Tria...mentioning
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