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The EUPRIM-Net Project

WP10: Development of in vitro technologies to replace, reduce and refine non-human primate studies

The general aim of this joint research activity is to develop and apply new in vitro technologies leading to the
Replacement, Reduction and Refinement (the 3Rs) of the use of non-human primates (NHP) in biomedical
research. The specific objectives for this research activity are:

To develop in vitro model systems for research on the central nervous system.
To develop in vitro test methods for vaccine research.

The EUPRIM-Net members within this Joint Research Activity represent the largest NHP breeding centres
and research institutes in Europe and are committed to the development and implementation of the 3Rs in
biomedical research. Studies using NHP are important in various research fields. The high numbers of NHP in
central nervous system (CNS) and vaccine studies provide a strong impetus to develop 3R methodology for
these fields in particular.

There are additional important reasons for the development of alternatives for CNS studies. First, studies on
the CNS that use NHP often go accompanied with moderate to severe discomfort for the animals. This is often
due to the invasive nature of the studies or to the very long preclinical incubation times of e.g. transmissible
neurodegenerative diseases. Second, the negative public perception of CNS studies provides an extra
motivation for the development of alternatives. The development and validation of in vitro primary cell cultures,
transgenic cells and specified cell culture systems will provide researchers with the possibility to predict the
outcome of in vivo experiments and to screen compounds or therapeutics that directly target resident CNS
cells as a pre-in vivo test phase, reducing the number of NHP needed for in vivo studies. The development and
validation of slice culture techniques can be used to address even more complex research questions, further
reducing animal numbers for in vivo studies. Importantly, no animals will be sacrificed for the exclusive purpose
of any of these studies as ‘left-over’ material from other experiments is used. This project thereby also directly
contributes to the refinement of the use of experimental animals.

Development of safe and potent vaccines is still a major task in biomedical research and many NHP are used in
vaccine research. In HIV vaccine research, controlled prime-boost regimen strategies followed by experimental
exposure (challenge) to simian or human/simian immunodeficiency viruses (SIV or SHIV) is, as yet, only feasible
in NHP. The protective outcome of SIV vaccination can only be measured in vivo, leading to studies where
NHP are kept under experimental conditions for extended periods of time. We will develop and validate in
methods to predict the clinical outcome of vaccination ex vivo, ideally rendering the experimental in vivo
challenge with virus unnecessary leading to a considerable reduction of the duration of in vivo experiments.

One of the major obstacles in the development of vaccines is the selection of potent adjuvants that are safe
and licensed for human application. Adjuvants and vaccine formulations are tested in various animal models,
including NHP, causing significant degrees of discomfort in the form of unwanted side-effects. We will develop
and employ in vitro technology to select and develop new adjuvants with good adjuvating potential, but with
minimal side-effects. Although this project contributes mainly to refinement, the topic is so general and involves
so many animals that even slight improvements will generate considerable effects regarding animal welfare.

The techniques developed in this joint research activity will have considerable impact on future studies using
NHP for neuroscience/neuroimmunology and vaccine research. The development and availability of in vitro
technologies that enable basic research and/or identification of new drug candidates and therapies will reduce
and refine the use of NHP, possibly also leading to replacement. Findings will actively be shared between all
members of EUPRIM-Net, but also be disseminated to other NHP research centres and the overall scientific
community by means of publication in peer-reviewed scientific journals, presentations at scientific conferences
and during a workshop on “Alternative methods for the use of NHP in biomedical research”.