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Use of primates and alternatives for vaccine production and testing

The use of primates and alternatives
GlaxoSmithKline’s (GSK) aim is to discover and develop medicines and vaccines that will help alleviate the suffering caused by disease. Research, development and manufacturing of medicines and vaccines all involve the use of laboratory animals to some extent. Animals are used in the medicine and vaccine development process to understand disease mechanisms, to discover novel ways to treat disease, and evaluate the efficacy and safety of potential new vaccines and medicines before they are tested in clinical studies in humans and approved for marketing. The vast majority of animals used by GSK, about 98 per cent, are rodents with less than 1 per cent being primates. 

For biological products, such as vaccines, additional safety and quality measures must also be met. In some cases, regulatory authorities responsible for the safety of such vaccines, including oral polio vaccine, currently require that some of this testing be done using non-human primates.

As the major supplier of oral polio vaccine to the developing world, GSK manufactures approximately 1 billion oral polio vaccine doses per year. In accordance with WHO and European Pharmacopoeia specifications, as well as the US Code of Federal Regulations, batch testing of live polio viral vaccines still remains mandatory for public health reasons. This testing assesses if attenuated viruses remain safe and effective to be given to humans and is therefore an essential safety and quality measure. In addition, new primary batches (‘seeds’) of other live attenuated viral vaccines need to be tested before they are approved for use in people. Current legal and regulatory requirements mandate that this testing be conducted in animals, specifically in non-human primates.

Prior to 2005, a small proportion of primates used for safety and quality testing of oral polio vaccine were ‘wild caught’ African Green Monkeys (Cercopithecus aethiops) from Barbados. African Green Monkeys also were used before 2002 to provide kidney cells for oral polio vaccine production. ‘Wild caught’ is defined as animals captured from a free ranging environment. ‘Purpose bred’ is defined as animals specifically bred for use in biomedical research, either in large contained areas such as small islands or in enclosures.

GSK used wild-caught primates from Barbados as they were a reliable high quality source of animals with well-defined background data and favourable health status. For example, these monkeys are free of several contaminating infectious agents such as TB, Ebola & Marburg viruses, SV40, Herpes B and SIV. The monkeys were taken from the natural population on the island under the supervision of the local government. 

GSK acknowledges that the use of wild-caught primates is an issue of sensitivity for some people and recently has replaced its use of wild caught primates.

This paper specifically addresses why GSK used of wild-caught primates and why we have been able to move to using purpose-bred primates. It describes how GSK continues to develop alternatives in the context of the historical use of wild-caught primates and its current use of primates in vaccine development and testing. (Additional information concerning GSK's use of animals in research).

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GSK's position

• GSK continues to use primates as they remain essential for testing the safety and quality of vaccines, and the safety of medicines, before they are given to people. They continue to be required by regulators for this purpose.
• GSK uses animals in research only when no alternative exists and is actively seeking to develop and implement alternatives. 
• GSK actively supports the development and approval of alternative testing methods in cooperation with the European Pharmacopoeia and other regulatory bodies.
• All animal research by GSK is performed to the highest standards and in full compliance with national authorities. GSK voluntarily undergoes accreditation by the Association for the Assessment and Accreditation of Laboratory Animal Care International.
• GSK has already significantly reduced its use of primates and is committed to reinforcing its efforts to develop and implement use of alternatives.
• The overwhelming benefit to public health, in the view of GSK and international regulatory authorities, justifies the use of these animals.
• GSK will continue to use purpose bred primates for polio safety evaluation until there is regulatory approval of the transgenic mouse test (or another alternative validated test is available).
• Primates will continue to be used for the safety evaluation of new master seeds of other attenuated viral vaccines such as mumps, measles, and varicella.
• GSK has now replaced its use of wild caught primates for polio vaccine production and testing
• GSK will only use wild caught primates under exceptional circumstances and only with specific authorisations by national authorities.

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Background
GSK has actively contributed to developing ways to test vaccines in ways that Replace, Reduce and Refine (3Rs) the use of primates but importantly will not compromise human safety. Crucial to this is the development of new alternative methods, their scientific validation and then authorisation of alternative methods by regulatory authorities.

Polio eradication is a WHO priority; GSK is helping in this initiative as the world's largest supplier of polio vaccines to developing countries. Very large volumes of vaccine are required in these final years of the eradication campaign.  Any changes in production and testing methodology affecting vaccine volumes could jeopardize the success of the eradication campaign.  In 2002, after extensive research efforts, GSK changed the production method of the polio vaccine. This alternative cell culture production method did not require the use of cells taken from animals, but crucially maintained the high production capacity that is needed for the worldwide disease eradication campaign. This important step allowed GSK to replace primate use in the production of the polio vaccine.
 
GSK also committed to the replacement of the use of wild-caught primates for quality and safety testing of oral polio vaccine used for worldwide polio eradication programmes. From 2002 to 2005, whilst development of non primate tests for quality and safety continued, there was still a requirement to use primates for safety testing of these vaccines as required by law. Some of these primates continued to be wild-caught due to the small number of purpose bred animals available at that time. Before 2005, the post-implementation validation for the alternative cell culture production method also required the use of some primates.  Since 2005, GSK has replaced the use of wild caught primates, first because the overall number of primates used to test the oral polio vaccine has been reduced following the full implementation of the new cell culture production method, and second because the availability of purpose bred monkeys has increased. GSK now only uses purpose bred animals for quality and safety testing of oral polio vaccine

In addition, as part of its continued effort for the replacement of all primates for safety testing of oral polio vaccine, GSK is actively collaborating with regulatory authorities to develop and implement a transgenic mouse test to replace testing using primates. This replacement of primates for quality and safety testing of oral polio vaccine is complex and challenging. Oral Polio Vaccine is a mixture of three types of polio virus which are produced and tested separately. The virus used in the vaccine is not killed, but rather attenuated (i.e. rendered non-virulent or weakened) to allow it to create an immune response but not give the person taking the vaccine the disease. To ensure that each batch of the vaccine has been properly attenuated, each batch of these three types of oral polio vaccine is separately subjected to safety testing. Until recently it had not been possible to use species other than primates because these other species lack the receptor for polio virus and so are not susceptible to the polio virus.  Consequently, African Green Monkeys (polio Types 1 and 2) and cynomologous macaque monkeys (Macaca fasicularis) (polio Type 3), both species being susceptible to the poliovirus, must be used for testing separately the three components of the vaccine before they are pooled at the end of the production cycle. Safety testing serves to ensure that the attenuated strain of polio has not reverted to a strain that could result in very serious side effects.

GSK has participated in and contributed to the development of alternative animal models for all three oral polio vaccine types using mice genetically altered (transgenic mice) to make them susceptible to the polio virus. The genetic alteration adds the polio virus receptor. These studies have now been published and have helped to generate a wealth of data which allow the acceptance of tests using mice by the European Pharmacopoeia. GSK has been training its staff for these tests ahead of the formal processes of authorisation and qualification of these new methods by the European authorities.

The European Pharmacopoeia recently approved the transgenic mouse test for safety testing of oral polio vaccine. GSK is submitting all the necessary applications to the relevant Authorities to enable the Company to switch to the new testing methods and hopes to obtain approval of the new methodology for all three types of polio by end 2007. As the replacement tests for each type of polio virus are approved by the relevant Authorities, GSK will then promptly replace the tests using primates with tests that use transgenic mice.

GSK recognises that this replacement still involves the use of animals. Until a non animal test is available and approved by the Authorities, this approach of using species of lower neurophysiological sensitivity will remain necessary.

GSK strives to achieve best practice as it continues to refine the husbandry and care of primates. 'Best practice' is defined as a combination of what is currently known from the scientific literature, from published recommendations, and from the knowledge of experts from within and outside GSK. The export of primates for medical and/or scientific use is strictly controlled and monitored under the supervision of the national authorities where animals are bred and in accordance with the CITES Convention and national legislation. GSK staff also regularly audits our suppliers and transporters.

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