Karolinska Institutet is the last university in Scandanavia to use primates in research.

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2 Karolinska Institutet is the last university in Scandanavia to use primates in research. Animal Justice Project is partnering with Djurrättsalliansen, to stop the import of 120 macaque monkeys into the university from the United States for inhumane malaria research. The Swedish researchers will infect 120 macaque monkeys with malaria parasites and then perform multiple invasive procedures on the monkeys over a period of at least one year. The procedures will include bone marrow biopsies, repeated vaccinations and blood sampling (up to 25 times per year). Lymph node biopsies will be obtained from the armpit or groin. Although the biopsies will be performed under general anaesthesia the monkeys will nevertheless experience pain and discomfort afterwards. All of the monkeys will be kept in cages, some with a floor area as small as two square meters. Stress and fear is imposed on monkeys used in experiments as a result of being caged, their inability to express normal behavior and separation from their family groups, something not accounted for when researchers put studies such as this into categories of severity. Not only is using monkeys in this research at Karolinska Institutet unethical, EU law set down in Directive 2010/63/EU states that it is essential, both on moral and scientific grounds, to ensure that each use of an animal is carefully evaluated as to the scientific or educational validity, usefulness and relevance of the expected result of that use. We believe the experiments at Karolinska Institutet contravene this EU law because: On the basis of current science, including genetics and evolutionary biology, the monkey model is not reliable or relevant for the study of human disease On the basis of current science, the likely harm to the monkeys far outweighs the hypothetical benefits to human medical progress (0.004%) Macaque monkeys are largely immune to the common form of human malaria Non-animal methods, including MIMIC and VACCINOMICS are available today and are relevant to the development of human vaccines Please, contact Karolinska Institutet today and urge them to END the use of monkeys in cruel experiments like this. info@ki.se Facebook: Karolinska Institutet For more information, visit This report, written by Science Advisor, Dr. Andre Menache, outlines why the primate experiments at Karolinska Institutet are not only unethical, but also of dubious legal standing. Together we aim to END the use of monkeys in cruel experiments like this. Animal Justice Project Djurrättsalliansen

3 A group of Swedish animal researchers at the Karolinska Institute has received ethical approval to conduct a series of invasive experiments on macaque monkeys in order to develop a vaccine against human malaria. Nobody would argue against the benefits of developing a vaccine against malaria, a disease that, according to the World Health Organisation, resulted in the deaths of between 584,000 and 855,000 people worldwide in 2013, of which the majority (90%) occurred in Africa (1). The Swedish researchers will infect 120 macaque monkeys with malaria parasites and then perform multiple invasive procedures on the monkeys over a period of at least one year. The procedures will include bone marrow biopsies, repeated vaccinations and blood sampling (up to 25 times per year). Lymph node biopsies will be obtained from the armpit or groin. Although the biopsies will be performed under general anaesthesia the monkeys will nevertheless experience pain and discomfort afterwards. All of the monkeys will be kept in cages, some with a floor area as small as two square meters. The study project will begin in 2015 and end in It unclear whether the monkeys will be killed at the end of the study although that is the normal outcome of such experiments. The researchers have categorised the level of animal suffering in this experiment as moderate on a three-point scale of mild, moderate and severe. However, the moderate classification does not take into account the added stress and fear imposed on the monkeys as a result of being caged, their inability to express normal behaviour and separation from their family groups. When all of these factors are taken into consideration, the level of suffering is likely to be in the severe category. Animal researchers tend to subjectively select a lower category of animal suffering in order to face less criticism during the ethical review process. In addition, the Animal Welfare and Ethical Review Body (AWERB) responsible for overseeing animal experiments often overlooks these hidden forms of animal suffering and may subsequently be less critical of an animal study. An inherent weakness in all European Union AWERBs (as described in articles 26 and 27 of Directive 2010/63/EU) is the 3Rs framework (replacement, reduction, refinement), which does not challenge the validity of animals as models of human disease research. This legislative loophole effectively allows researchers to conduct animal experiments in the absence of scientific proof that animals are predictive and relevant with respect to human health (2, 3). This major flaw in EU legislation carries with it huge consequences for animal welfare and human disease research. The Swedish monkey study illustrates this point very clearly. In terms of animal suffering, the researchers themselves describe the painful procedures that the monkeys will undergo. However, in addition to the animal welfare concerns, there are also powerful scientific arguments against using monkeys for the study of human disease. These

4 scientific arguments are based on genetic and evolutionary differences between apes, monkeys and humans, as well as between different monkey species. The Swedish researchers make the claim that, macaque monkeys are very valuable model systems for immunology studies because of their genetic resemblance to humans. The researchers also state that, There are no alternatives. The (monkey) model is the only one where the immune system and pathogens are similar to a human situation. It is important to examine each of these claims in detail. Response: According to this logic, chimpanzees are even more valuable than monkeys because humans are evolutionarily closer to chimpanzees (5 million years), than they are to monkeys (25 million years). However, since 2011 invasive experiments on chimpanzees have essentially been abandoned by the scientific research community. This significant decision was based on the conclusions of a report published by the Institute of Medicine and adopted by the US National Institutes of Health, which stated that, most current use of chimpanzees for biomedical research is unnecessary (4). Not only do chimpanzees suffer as a result of captivity but, they are also poor models for the study of human disease. Chimpanzees are essentially immune to HIV/AIDS, hepatitis B and C, common malaria, and are far less susceptible to some human cancers (5). If the chimpanzee is such a poor model for the study of human disease, what does that say about other animals (including monkeys) with whom we share even less DNA? A peer reviewed article published in 2010 clearly states, Humans respond differently than other primates to a large number of infections. Differences in susceptibility to infectious agents between humans and other primates are probably due to inter-species differences in immune response to infection (6). The Swedish researchers seem to miss the point that even our closest relatives are not good models for the study of human disease. What is even more surprising is that the Swedish researchers appear to ignore the fact that there are important genetic differences between different species of monkeys. In their application form, the researchers list the animal species to be used in their experiments as Macaca mulatta OR Macaca fascicularis (Macaca mulatta is commonly known as the rhesus macaque while Macaca fascicularis is commonly known as the long-tailed macaque).

5 It is usual for researchers to accurately list the exact species, subspecies and even strain of animal to be used in an experiment. Given the international standing of the Karolinska Institute, it is surprising that their AWERB should grant ethical approval for an experiment without knowing the exact species of animal to be used. In addition to important genetic differences between rhesus macaques and long-tailed macaques, which could result in different immune response to the experimental malaria infection, there are also significant genetic differences within each species. For example, Indian-origin and Chinese-origin rhesus macaques differ in their immune response to monkey AIDS (Simian Immunodeficiency Virus), (7). In the field of vaccine development, the use of nonhuman primates (including chimpanzees and monkeys), has been a spectacular failure. Out of 100 AIDS vaccines that protected laboratory animals against HIV/AIDS not one was effective in protecting humans against the disease (8). It is therefore bizarre for the Swedish researchers to justify the current monkey study by stating in their application that they, have previously worked with a number of HIV vaccine studies, and have therefore built up competence and experience in vaccine research on primates. What the Swedish researchers also appear to ignore is the fact that, although humans and monkeys share many genes, it is the way in which those genes are regulated that accounts for much of the difference between human and monkey anatomy and physiology. Thus, although monkeys and humans both have a gene for a tail, the gene is switched on in monkeys but is switched off in humans. This crucial finding is supported by a recent study published in the journal Nature in 2014, which concluded that, most of the differences between mice and humans come from regulation of gene activity, not from genes themselves (9). There is yet more evidence that basic biological research using animals (also referred to as fundamental research ), is not an effective way to achieve medical progress. An analysis of 25,000 basic research articles that claimed to have some future applicability in humans, yielded a success of 0.004% (10).

6 Response: Once again, the Swedish researchers appear to ignore current science. The best way to develop human vaccines is by studying human populations and the human immune system, not monkeys. An example of an in vitro system for developing human vaccines is the in vitro MIMIC system (11), which was selected by the US government to develop an effective vaccine against the Ebola virus (12, 13). The other major advance in human vaccine technology is called Vaccinomics (14). Now, guided in part by advances in personalized medicine as applied to the use of drugs, the field of vaccinomics provides a conceptual framework for both understanding, (and predicting), immune responses to vaccines, and allows the development of new vaccines informed by advances in immunology, immunogenetics, (the study of individual host genetic variation associated with individual differences in immune responses to the same antigen(s)) and immunogenomics, (the study of population-level genetic variations associated with population-level variations in immune responses), bioinformatics, virology, systems biology, metagenomics, (host and non-host), and other fields (15).

7 As an EU member state, Sweden is required to adhere to the EU guidelines set down in Directive 2010/63/EU on the, Protection of Animals used for Experimental and other Scientific Purposes. Paragraph 39 of the Directive states: It is also essential, both on moral and scientific grounds, to ensure that each use of an animal is carefully evaluated as to the scientific or educational validity, usefulness and relevance of the expected result of that use. The likely harm to the animal should be balanced against the expected benefits of the project. Therefore, an impartial project evaluation independent of those involved in the study should be carried out as part of the authorisation process of projects involving the use of live animals. Effective implementation of a project evaluation should also allow for an appropriate assessment of the use of any new scientific experimental techniques as they emerge (16). The Swedish monkey experiment appears to contravene the above guideline, since: on the basis of current science, including genetics and evolutionary biology, the monkey model is not reliable or relevant for the study of human disease (see references below) on the basis of current science, the likely harm to the monkeys far outweighs the hypothetical benefits to human medical progress (0.004%) macaque monkeys are largely immune to the common form of human malaria non-animal methods, including MIMIC and VACCINOMICS are available today and are relevant to the development of human vaccines Animal research is now increasingly challenged within the scientific community and as such, should at the very least be the subject of a public inquiry (17).

8 1. en.wikipedia.org/wiki/malaria genome.cshlp.org/content/10/8/1065.full 6. journals.plos.org/plosgenetics/article?id= /journal.pgen biomedcentral.com/ /8/43/ eur-lex.europa.eu/lexuriserv/lexuriserv.do?uri=oj:l:2010:276:0033:0079:en:pdf 17.

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