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Coenraad F.m. Hendriksen - One of the best experts on this subject based on the ideXlab platform.
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Humane Endpoints in vaccine potency testing
Procedia in Vaccinology, 2011Co-Authors: Coenraad F.m. HendriksenAbstract:Abstract Vaccine potency and safety testing is characterized by extensive use of laboratory animals and a relatively high percentage of test methods that involve severe pain and distress. This is particularly true for tests that are based on infection or challenge with a virulent microorganism. Traditionally, vaccine potency tests on inactivated vaccines require a vaccination–challenge procedure using severe clinical signs or even lethality as Endpoints. For several of these vaccines, 3R methods have been developed that include a nonclinical endpoint, ultimately resulting in reduction of animal numbers and a significant decrease in severity level. An example is the use of serology in potency testing of tetanus and diphtheria toxoid vaccines. For some potency tests, however, replacement of the challenge procedure is not (yet) possible, and the implementation of Humane Endpoints might be an approach to limit the level and duration of pain and distress. The application of these Endpoints is now allowed in most pharmacopoeias. Establishing Humane Endpoints in vaccine potency testing requires the identification of parameters that are predictive of death, or severe clinical signs, in the animal during the observation period. As a case study, we present the results of work we performed on the identification of Humane Endpoints in whole cell pertussis (wP) vaccine potency testing (the mouse protection test or the Kendrick test). In this potency test, mice are challenged by intracerebral route 14 days after immunization with a lethal dose of virulent B. pertussis microorganisms. Animals are observed for 14 days, and the number of mice per dose group surviving this period is used for probit analysis and estimation of potency. We have studied two types of Humane Endpoints: clinical signs and pathophysiological parameters (body weight and body temperature). Clinical signs in a wP potency test range from piloerection, hunched back posture, apathy, and convulsions to moribund condition. Also body temperature drops, and animals lose up to 50% of their body weight post-challenge. Parameters were “validated” for relevance (prediction of death within the observation period) and reliability. Recommendations are given for implementation of Humane Endpoints in vaccine potency testing, also taking into account potential obstacles.
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application of the three rs to challenge assays used in vaccine testing tenth report of the bvaawf frame rspca ufaw joint working group on refinement
Biologicals, 2010Co-Authors: Maggy Jennings, Coenraad F.m. Hendriksen, David B. Morton, Emmanuelle Charton, Jane Cooper, Stella Martin, Michael C Pearce, Scott Price, Keith Redhead, Nick ReedAbstract:This report aims to facilitate the implementation of the Three Rs (reduction, refinement and replacement) in the testing of vaccines for regulatory and other purposes. The focus is predominantly on identification of reduction and refinement opportunities in batch potency testing but the principles described are widely applicable to other situations that involve experimental infections of animals. The report should also help to interpret the requirements of the European Pharmacopoeia with regard to the use of alternative tests, Humane Endpoints and other refinements. Two specific worked examples, for batch potency testing of Clostridium chauvoei and canine leptospira, with recommendations for harmonisation of international test requirements for these and other vaccines, are provided as appendices online.
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Humane Endpoints in the efficacy testing of swine erysipelas vaccines.
ALTEX, 2003Co-Authors: S. Johannes, Joachim Hartinger, Coenraad F.m. Hendriksen, David B. Morton, Klaus CusslerAbstract:For licensing the efficacy of vaccines for veterinary use has to be demonstrated by well-controlled laboratory experiments in which vaccinated and untreated animals of the target species are challenged. Erysipelas challenge tests cause extreme suffering of the unprotected animals with high fever, apathy, large skin lesions, and even death. This paper describes a standardised procedure for the vaccination challenge test and gives due consideration to the welfare of the animals. By monitoring and using clinical signs observed during the test it is possible to minimise animal pain and distress, thus preventing unnecessary animal suffering.
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refinement of vaccine potency testing with the use of Humane Endpoints
Ilar Journal, 2000Co-Authors: Coenraad F.m. Hendriksen, Bjorn SteenAbstract:Published results of a poll taken in the United Kingdom about public views on animal experimentation (Aldhous et al. 1999) reveal that people provided with impartial informa- tion appear to weigh the pros and cons of each experiment carefully before deciding whether they are willing to support the use of animals in research. The results also reveal that potential distress is an important factor in the public's sup- port of specific uses of animals. Death may be used as the experimental endpoint in can- cer research, studies of infectious disease, carcinogenicity and toxicology (e.g., the LD50 test), drug comparisons, and vaccine potency testing (Hamm 1995). In this article, we discuss Humane Endpoints that can replace lethality as an endpoint in vaccine potency testing.
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Humane Endpoints as a replacement for the estimation of lethality rates in the potency testing of rabies vaccines
ALTEX-Alternatives to Animal Experimentation, 1998Co-Authors: Klaus Cubetaler, David B. Morton, Coenraad F.m. HendriksenAbstract:Vaccines are successfully used to prevent rabies infections in humans and animals. The quality requirements for these products are high. After licensing it is still necessary for batch release to perform animal challenge tests to demonstrate the potency of the vaccines. In these experiments it is registered how many animals in the immunised groups die or show symptoms of rabies within a defined time frame. An ECVAM working group has examined whether clinical signs can be used in challenge tests for vaccine control to replace lethality as criterion. The severe distress and the typical signs of the disease made the rabies infection a promising example for this study. Clinical signs, body temperature and body weight were the criteria used to define Humane Endpoints. It could be shown, that the reduction of body weight and the appearance of typical clinical signs are suitable to define Humane Endpoints. Pain and distress could be considerably reduced by the implementation of these criteria in to the legal requirements for potency tests of rabies vaccines.
William S. Stokes - One of the best experts on this subject based on the ideXlab platform.
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Humane Endpoints for laboratory animals used in regulatory testing
2016Co-Authors: William S. StokesAbstract:Laboratory animals are used for regulatory testing to assess the safety, efficacy, and/or potential adverse health effects of new chemicals and products such as vaccines, medicines, food additives, pesticides, and industrial chemicals. Testing results are used for risk assessment decisions intended to safeguard human and animal health. However, chemical toxicity and vaccine testing can cause injury, disease, and mortality involving significant pain and distress. Alleviation of pain and distress in animals during testing is problematic because regulations allow treatment only if the treatment does not interfere with the study. One approach to this prob-lem has been to identify criteria that can serve as the basis for ending a test procedure sooner in an effort to terminate or avoid pain and distress while still allowing attainment of study objectives. These criteria are referred to as Humane Endpoints because they reduce the severity and/or duration of pain and distress experienced by an animal. New and revised test methods and approaches that incorporate hu-mane Endpoints are being considered and adopted by na-tional and international regulatory testing authorities. The prerequisite for adoption of these methods is a determina-tion that the methods have been adequately validated and that they provide equivalent or better information for risk assessment. Further progress in reducing animal pain and distress resulting from regulatory testing is expected as sci-entific and technological advances are incorporated into testing procedures and strategies. Key Words: alternatives; Humane Endpoints; laboratory animals; pain and distress; refinement; regulatory testing; toxicolog
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report on the international workshop on alternative methods for human and veterinary rabies vaccine testing state of the science and planning the way forward
Biologicals, 2012Co-Authors: William S. Stokes, Richard Mcfarland, J Kulpaeddy, R Levis, M Halder, G Pulle, Donna M Gatewood, Hajime Kojima, Warren Casey, Alexander GaydamakaAbstract:Potency testing of most human and veterinary rabies vaccines requires vaccination of mice followed by a challenge test using an intracerebral injection of live rabies virus. NICEATM, ICCVAM, and their international partners organized a workshop to review the availability and validation status of alternative methods that might reduce, refine, or replace the use of animals for rabies vaccine potency testing, and to identify research and development efforts to further advance alternative methods. Workshop participants agreed that general anesthesia should be used for intracerebral virus injections and that Humane Endpoints should be used routinely as the basis for euthanizing animals when conducting the mouse rabies challenge test. Workshop participants recommended as a near-term priority replacement of the mouse challenge with a test validated to ensure potency, such as the mouse antibody serum neutralization test for adjuvanted veterinary rabies vaccines for which an international collaborative study was recently completed. The workshop recommended that an in vitro antigen quantification test should be a high priority for product-specific validation of human and non-adjuvanted veterinary rabies vaccines. Finally, workshop participants recommended greater international cooperation to expedite development, validation, regulatory acceptance, and implementation of alternative test methods for rabies vaccine potency testing.
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report on the international workshop on alternative methods for human and veterinary rabies vaccine testing state of the science and planning the way forward
Biologicals, 2012Co-Authors: William S. Stokes, Richard Mcfarland, J Kulpaeddy, R Levis, M Halder, G Pulle, Donna M Gatewood, Hajime Kojima, Warren Casey, Alexander GaydamakaAbstract:Potency testing of most human and veterinary rabies vaccines requires vaccination of mice followed by a challenge test using an intracerebral injection of live rabies virus. NICEATM, ICCVAM, and their international partners organized a workshop to review the availability and validation status of alternative methods that might reduce, refine, or replace the use of animals for rabies vaccine potency testing, and to identify research and development efforts to further advance alternative methods. Workshop participants agreed that general anesthesia should be used for intracerebral virus injections and that Humane Endpoints should be used routinely as the basis for euthanizing animals when conducting the mouse rabies challenge test. Workshop participants recommended as a near-term priority replacement of the mouse challenge with a test validated to ensure potency, such as the mouse antibody serum neutralization test for adjuvanted veterinary rabies vaccines for which an international collaborative study was recently completed. The workshop recommended that an in vitro antigen quantification test should be a high priority for product-specific validation of human and non-adjuvanted veterinary rabies vaccines. Finally, workshop participants recommended greater international cooperation to expedite development, validation, regulatory acceptance, and implementation of alternative test methods for rabies vaccine potency testing.
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The International Workshop on Alternative Methods to Reduce, Refine, and Replace the Use of Animals in Vaccine Potency and Safety Testing: Introduction and summary
Procedia in Vaccinology, 2011Co-Authors: William S. Stokes, Jodie Kulpa-eddy, Richard McfarlandAbstract:Vaccines contribute to improved animal and human health and welfare by preventing diseases and deaths from infectious diseases. However, testing necessary to ensure vaccine effectiveness and safety can involve large numbers of animals and significant pain and distress. NICEATM and ICCVAM recently convened an international workshop to review the state of the science of available alternative methods and approaches that can further reduce, refine, and replace the use of animals for human and veterinary vaccine potency and safety testing, and to identify research, development, and validation efforts necessary to further advance new and improved alternative methods. Workshop participants identified human and veterinary vaccines that should have the highest priority for future efforts. Prioritization criteria included testing that involves significant pain and distress, large numbers of animals, and pathogens that are dangerous to people and animals. Participants noted that in vitro antigen quantification assays have replaced animals for potency testing for some killed vaccines, and recommended that this approach be expanded to other vaccines. Recommendations to support more Humane animal use included development and use of Humane Endpoints for all challenge tests, development of serologic assays to replace challenge tests, and development of in vitro toxin neutralization tests (TNT) to replace in vivo TNTs. Workshop participants recommended several approaches that might further reduce the number of animals required for specific potency tests. Participants also recommended priority vaccines for which alternative safety testing methods should be pursed and that would have the greatest impact on avoiding pain and distress and reducing animal numbers. Finally, workshop participants recommended enhanced international harmonization and cooperation efforts and closer collaborations between human and veterinary researchers to expedite progress. Implementation of the workshop recommendations is expected to advance new methods for vaccine testing that will reduce animal use, benefit animal welfare, and ensure continued and improved protection of human and animal health. © 2011.
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Improving Animal Welfare and Reducing Animal Use for Veterinary Vaccine Potency Testing: State-Of-The-Science and Future Directions
Procedia in Vaccinology, 2011Co-Authors: William S. Stokes, Geetha Srinivas, Jeffrey Galvin, Ivo Claassen, Glen Gifford, Hans Draayer, Marlies Halder, Jodie Kulpa-eddy, Karen Brown, Ralph WoodlandAbstract:Veterinary vaccines contribute to improved human and animal health and welfare by preventing diseases and deaths caused by a wide range of infectious agents. However, testing necessary to ensure vaccine effectiveness and safety can involve large numbers of animals and significant pain and distress. NICEATM and ICCVAM convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing methods and to identify opportunities to advance new and improved methods that can further reduce, refine, and replace animal use. This workshop report is the fourth in a series of six, and addresses methods and strategies for veterinary vaccine potency testing that can avoid or lessen pain and distress, improve animal welfare, and reduce animal use. Vaccine potency tests considered to have the highest priority for further reduction and refinement were those that require an infectious agent challenge test or an in vivo toxin neutralization test, those that require large numbers of animals, and those that require the use of infectious agents hazardous to laboratory workers and/or animals. Vaccines identified as high priorities for improved alternative test methods were rabies, Clostridium spp., Leptospira spp., foreign animal diseases (e.g., foot and mouth disease), and poultry and fish vaccines. The workshop recommended priority research, development, and validation activities to address critical knowledge and data gaps, including opportunities to apply new science and technology. Recommendations to support more Humane animal use included development and use of Humane Endpoints for all challenge tests, development of serologic assays to replace challenge tests, and development of in vitro toxin neutralization tests to replace in vivo TNTs. Workshop participants recommended approaches to reduce the number of animals required for potency testing, and recommended enhanced international harmonization and cooperation, and closer collaborations between human and veterinary researchers to expedite progress in the development and application of alternative methods. Implementation of the workshop recommendations is expected to advance new methods for veterinary vaccine potency testing that will benefit animal welfare and reduce animal use while ensuring continued protection of human and animal health. © 2011.
Bjorn Steen - One of the best experts on this subject based on the ideXlab platform.
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refinement of vaccine potency testing with the use of Humane Endpoints
Ilar Journal, 2000Co-Authors: Coenraad F.m. Hendriksen, Bjorn SteenAbstract:Published results of a poll taken in the United Kingdom about public views on animal experimentation (Aldhous et al. 1999) reveal that people provided with impartial informa- tion appear to weigh the pros and cons of each experiment carefully before deciding whether they are willing to support the use of animals in research. The results also reveal that potential distress is an important factor in the public's sup- port of specific uses of animals. Death may be used as the experimental endpoint in can- cer research, studies of infectious disease, carcinogenicity and toxicology (e.g., the LD50 test), drug comparisons, and vaccine potency testing (Hamm 1995). In this article, we discuss Humane Endpoints that can replace lethality as an endpoint in vaccine potency testing.
Klaus Cussler - One of the best experts on this subject based on the ideXlab platform.
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Humane Endpoints in the efficacy testing of swine erysipelas vaccines.
ALTEX, 2003Co-Authors: S. Johannes, Joachim Hartinger, Coenraad F.m. Hendriksen, David B. Morton, Klaus CusslerAbstract:For licensing the efficacy of vaccines for veterinary use has to be demonstrated by well-controlled laboratory experiments in which vaccinated and untreated animals of the target species are challenged. Erysipelas challenge tests cause extreme suffering of the unprotected animals with high fever, apathy, large skin lesions, and even death. This paper describes a standardised procedure for the vaccination challenge test and gives due consideration to the welfare of the animals. By monitoring and using clinical signs observed during the test it is possible to minimise animal pain and distress, thus preventing unnecessary animal suffering.
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suitability of temperature sensitive transponders to measure body temperature during animal experiments required for regulatory tests
ALTEX-Alternatives to Animal Experimentation, 2003Co-Authors: Joachim Hartinger, Daniela Kulbs, Peter Volkers, Klaus CusslerAbstract:Body temperature is a clinical parameter in vaccine quality control to detect systemic side-effects or to monitor progression of infectious diseases. Moreover, changes in body temperature are used as clinical parameters to define Humane Endpoints in animal experiments. However, measuring body temperature via the rectal route can be troublesome and distressing to the animal. Non-invasive measurement methods were developed in recent years. The aim of this investigation was to study and to compare rectally measured body temperature with data obtained with implanted temperature-sensitive transponders (TST) in mice, guinea pigs, rabbits and pigs under the controlled conditions of regulatory testing.
Elizabeth D Brooks - One of the best experts on this subject based on the ideXlab platform.
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long term complications of glycogen storage disease type ia in the canine model treated with gene replacement therapy
Journal of Inherited Metabolic Disease, 2018Co-Authors: Elizabeth D Brooks, Dustin J Landau, Jeffrey I Everitt, T T Brown, Kylie M Grady, Lauren R Waskowicz, Cameron R Bass, John Dangelo, Yohannes G Asfaw, K D WilliamsAbstract:Glycogen storage disease type Ia (GSD Ia) in dogs closely resembles human GSD Ia. Untreated patients with GSD Ia develop complications associated with glucose-6-phosphatase (G6Pase) deficiency. Survival of human patients on intensive nutritional management has improved; however, long-term complications persist including renal failure, nephrolithiasis, hepatocellular adenomas (HCA), and a high risk for hepatocellular carcinoma (HCC). Affected dogs fail to thrive with dietary therapy alone. Treatment with gene replacement therapy using adeno-associated viral vectors (AAV) expressing G6Pase has greatly prolonged life and prevented hypoglycemia in affected dogs. However, long-term complications have not been described to date. Five GSD Ia-affected dogs treated with AAV-G6Pase were evaluated. Dogs were euthanized due to reaching Humane Endpoints related to liver and/or kidney involvement, at 4 to 8 years of life. Necropsies were performed and tissues were analyzed. Four dogs had liver tumors consistent with HCA and HCC. Three dogs developed renal failure, but all dogs exhibited progressive kidney disease histologically. Urolithiasis was detected in two dogs; uroliths were composed of calcium oxalate and calcium phosphate. One affected and one carrier dog had polycystic ovarian disease. Bone mineral density was not significantly affected. Here, we show that the canine GSD Ia model demonstrates similar long-term complications as GSD Ia patients in spite of gene replacement therapy. Further development of gene therapy is needed to develop a more effective treatment to prevent long-term complications of GSD Ia.
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701 long term complications of glycogen storage disease type ia in the dog model treated with gene replacement therapy
Molecular Therapy, 2015Co-Authors: Elizabeth D Brooks, Dustin J Landau, T T Brown, Yohannes G Asfaw, Dwight D KoeberlAbstract:Glycogen storage disease type Ia (GSD-Ia) in dogs closely resembles human GSD-Ia where untreated patients develop complications associated with glucose-6-phosphatase (G6Pase) deficiency (hypoglycemia, hyperlipidemia, growth retardation, and early death). For the past 3 decades survival of human patients that are placed under intensive nutritional management with uncooked corn starch has improved; however, long-term complications persist including renal failure, nephrolithiasis, hepatic adenomas, and a high risk for hepatocellular carcinoma. Affected dogs fail to thrive with dietary therapy alone, but treatment with gene replacement therapy using adeno-associated viral vectors (AAV) expressing G6Pase has greatly prolonged life and prevented hypoglycemia. In this study, 7 GSD-Ia affected dogs treated with AAV-G6Pase were followed up to 8 years of life to describe long-term complications. All required readministration of AAV vector(s) pseudotyped as a new serotype to avoid anti-AAV antibodies, due to decreased ability to maintain normoglycemia during fasting. Two dogs developed chronic renal disease as denoted by polyuria, polydipsia, and azotemia at 6 and 8 years of age. Calcium oxalate and phosphate urolithiasis was detected in 2 dogs; 1 dog had evidence of polycystic ovarian disease. Four of the 7 dogs were euthanized due to reaching Humane Endpoints related to liver and/or kidney disease, at 3 to 8 years of life, and 1 dog succumbed to acute hypoglycemia. Necropsy revealed several focal hepatic lesions in all deceased dogs; 2 dogs had lesions confirmed histologically as hepatocellular carcinoma, the largest tumor reached 8 cm in diameter (Fig. 1). One dog demonstrated lesions consistent with hepatocellular adenoma and in the other 2, there was hepatocellular hyperplasia. There was no significant difference in amount of vector DNA in hepatic tumors compared with normal tissue (n=4 dogs), suggesting that insertional mutagenesis by the AAV vector was not the mechanism for tumor formation (Fig. 2). View Large Image | Download PowerPoint Slide View Large Image | Download PowerPoint SlideGlomerular sclerosis, fibrosis of Bowman's capsules and focal interstitial nephritis were found in the 2 dogs with clinical renal disease. Two dogs, both female, remain in good health with no evidence of liver masses appreciable on ultrasound examination; they are 4 and 5 years of age. Hepatocellular carcinoma, kidney disease, polycystic ovaries and urolithiasis are common findings among GSD-Ia patients. Here we show that the canine GSD-Ia model demonstrates similar long-term complications in spite of AAV-mediated gene replacement therapy. Further development of gene therapy is needed to prevent long-term complications of GSD-Ia.
