Animal experiments and animal welfare at Fraunhofer IZI

Animal testing in research

Developing a new technology for the resource-efficient manufacture of killed vaccines

Killed vaccines consist of inactivated, i.e. killed, pathogens (e.g. viruses) that are no longer able to replicate. Up to now, pathogens have always been deactivated using toxic chemicals such as formaldehyde.

This is a safe method that has been established for decades. However, it also poses a number of challenges.

First, the chemicals have to be taken back out of the vaccine during the manufacturing process, which is a complicated procedure in itself. Second, using and disposing of large quantities of toxic substances places a burden on people and the environment. Third, this kind of chemical treatment also weakens and modifies the antigens that form part of the pathogens, thus reducing the efficacy of the immune response triggered in the vaccine recipient.

Together with colleagues from Fraunhofer FEP and Fraunhofer IPA, researchers from Fraunhofer IZI have developed a new technology for the gentle inactivation of pathogens.

This draws on low-energy electrons, which selectively and reliably destroy the genetic makeup of the pathogens. The antigens, however, remain practically unchanged, allowing a more specific immune response. The process does not use any toxic or environmentally harmful substances whatsoever, making it both cheaper and quicker than the current method.

Animal experiments were conducted to help develop the technology. They were required in order to verify whether vaccines manufactured using the new method were safe and induced immunity. As the complex connections and reactions of the mammalian immune system cannot be reproduced in cell cultures and computer models, animal experiments were drawn upon in the form of various infection models in mice. These studies typically investigated how the new vaccine takes effect compared to conventionally manufactured vaccines and placebo controls. To do this, different groups of mice were first immunized with the respective vaccine (usually via injection) and then infected with the pathogen (by inhalation or injection, depending on the pathogen).

Researchers then observed and examined whether and to what extent the mice developed the expected disease symptoms. The results clearly showed that the vaccines which had been inactivated by means of electron treatment led to an effective and partially improved immunization of the animals. In the next stage, the procedure now has to be adapted in line with pharmaceutical manufacturing processes and tested on human subjects in clinical trials.

SARS-CoV-2 infection model for evaluating new drugs and vaccines to combat coronavirus

Coronavirus and the related pandemic have claimed countless lives around the world, placed severe restrictions on public life, and caused economic damage on a monumental scale.

Luckily, coronaviruses were well researched even before the pandemic. This meant existing knowledge could be built upon when it came to developing vaccines and active agents.

The “spike” protein, a molecule on the virus’ surface, was thus quickly identified as an effective target structure for vaccines and drugs.

In order to be able to investigate new vaccines and active agents to combat the coronavirus, measures were taken at an early stage of the pandemic at Fraunhofer IZI and a respective infection model was established in the mouse. As the SARS-CoV-2 virus is a human pathogen that is easily transmitted via aerosols, any work conducted with the active virus, including the associated animal experiments, is done in the institute’s S3 safety laboratory.

Besides the early vaccine development projects, such work also focuses on therapeutic antibodies as a potential medicine for treating or avoiding severe COVID-19 infections.

To this end, researchers from Fraunhofer IZI and various partners immunized transgenic mice* against the virus’ spike protein and looked at the resulting antibodies. Two antibodies were identified here that could potentially prevent severe COVID-19 infections.  

* Transgenic mice were genetically modified to produce partially human proteins (in this case, relevant antibody structures). This procedure is being used to examine human target structures and to improve the transferability of the results to humans.

Preclinical testing of a cell therapy for treating cartilage defects

Patient safety takes top priority when developing new drugs and therapies. Especially when dealing with new classes of drugs such as ATMPs (Advanced Therapy Medicinal Products), which are based on cell and gene therapies, all risks have to be minimized where possible before the drugs are first used on human subjects as part of clinical trials.

These types of investigations are conducted in the GLP test facility at Fraunhofer IZI in close cooperation with regulatory authorities.

Cartilage defects, in the knee for example, have always been difficult to treat as cartilage in the body regenerates itself only to a limited degree and the affected areas are usually placed under a heavy mechanical load. One way of facilitating the regeneration of cartilage defects is to manufacture respective cartilage grafts based on the body’s own cells.

The company Codon AG developed precisely this type of procedure and had it safety tested in the GLP test facility at Fraunhofer IZI. The tests conducted here focused specifically on biodistribution, i.e. where the implant’s cells migrate to in the body, as well as tumorigenicity, i.e. whether the implant’s cells trigger the formation of tumors in the body.

These complex questions can only be explored in a living organism. Immunodeficient mice were used and given a corresponding implant. The molecular biological and immunological analyses showed no evidence that the implanted cells had migrated to other structures or organs. Nor was there any indication that the implants had led to the formation of tumors.

Based on this and many other research results, the procedure subsequently underwent clinical testing and was ultimately approved in the EU in 2017. According to the manufacturer, the method is applied in over 200 German clinics and has already been used on over 16,000 patients.

Development of specific immunotherapies for the treatment of Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia, with 300,000 new cases diagnosed every year. Over a period of several years, this as yet incurable disease leads to a progressive loss of memory and changes in personality, culminating in a total loss of autonomy. Alzheimer’s therefore poses a tremendous challenge for patients and their relatives.

Huge efforts are being made all around the globe to develop therapies to treat the disease. Therapeutic antibodies in particular play an important role here, the idea being that they remove deposits in the brain that are causally linked to the emergence of Alzheimer’s. It is hoped that this therapy will stabilize the memory function of those affected by the disease.

Therapeutic antibodies are being developed at Fraunhofer IZI that will allow researchers to work on new therapies to combat toxic proteins in the brains of Alzheimer’s patients. In order to investigate their efficacy, the antibodies will be tested in transgenic mice, which develop amyloid deposits similar to those seen in Alzheimer’s patients.

The first antibodies for treating Alzheimer’s were recently approved for use as a drug in the USA or are currently awaiting approval. All of these active agents were tested on mice in the early stages of development. This is a necessary step in achieving the objective of finally having access to effective drugs that stabilize patients’ cognitive abilities (for example memory function). As therapeutic antibodies fall under a class of drugs that is partly associated with strong side effects, the research at Fraunhofer IZI also aims to discover new mechanisms for Alzheimer’s treatments that will help develop drugs which are more effective yet have fewer side effects in the future. This involves creating new and improved mouse models to help gain an even better understanding of Alzheimer’s disease besides investigating new drugs and drug classes in these models.