Humanised mice: a test system for vaccine development

Around 170 million people worldwide are infected with the hepatitis C virus (HCV), most of them in developing countries. Anti-viral treatments are very expensive, have serious side effects and are only effective for some patients. Most of the victims carry the infection for the rest of their lives, with the threat of later developing liver cirrhosis and cancer. The most effective way to combat Hepatitis C would be with a vaccine against the virus – but so far, no vaccine exists.

One of the main reasons for this is the lack of appropriate animal models for the development of the vaccine. HCV can only infect the liver cells (hepatocytes), of humans and certain primates, but using great apes for testing purposes is ethically controversial and expensive as well. Mice, on the other hand, cannot be infected with HCV. This is the starting point for the researchers of the Helmholtz Centre for Infection Research around Professor Carlos A. Guzmán and their colleagues in the Human Vaccine Consortium, which, along with the Brunswick scientists, includes researchers from the Hanover Medical School, the Institut Pasteur and the Institute National de la Santé et de la Recherche Médical (both in France), the Academic Medical Center at the University of Amsterdam (Netherlands) and the Rockefeller University (USA). Their joint aim is to develop humanised mouse models: mice engrafted with human hepatocytes and immune system cells, to evaluate the efficacy of vaccine candidates against HCV. For the successful transplantation of human tissues and cells into mice their immune system should be deactivated.

In order to transplant the human immune system as completely as possible to the mice, human genes, essential for various immune system functions, must be provided as well as human blood stem cells. So researchers are developing strains of mice with a defective immune systems carrying different human genes. The second step is to transplant either human blood stem cells or hepatocytes into these mice. The aim is to optimise the conditions for organ transfer: In which recipient mice do the human immune system components function most effectively? What conditions are most suitable for an effective engraftment of human hepatocytes in mouse livers? Guzmán explains that all procedures must be standardised and validated to ensure that they can be reproduced in any laboratory, which is essential if the animal models are to be used to test vaccines.

After three years’ work, the consortium researchers reached an important milestone in 2008. They now have a validated process of generating mice which are either engrafted with the cells of the human immune system (HIS mice) or whose livers contain human hepatocytes (HuHEP mice). Mice like these are researchers’ preferred tools to predict human immune responses to vaccine candidates. The humanised mice are also much cheaper than primates, despite the high breeding costs, and permit a variety of other applications. HIS mice can be used to test vaccines and thereby predicting human immune responses whereas HuHEP mice can provide answers on toxicological and infection biology. Furthermore, both models can be used to test toxicity and efficacy of drugs against various infectious agents.

Work is continuing on optimising the two models and at the same time, the consortium aims to combine the HIS and the HuHEP mice. Guzmán explains the importance of transplanting human immune and liver cells into the same mice. The human hepatocytes are necessary in order to infect the mice with HCV and other hepatotrophic agents, whereas the human immune cells give information about the immune responses to the infection. Both of these processes are necessary in order to test a vaccine against HCV. If researchers succeed in producing such mice, that would be a huge milestone. The mouse model would be a suitable test system to help achieve the goal of developing vaccines against a number of human pathogens for which up to now, there were no alternatives to primate models. It would also enable much more accurate testing of the efficacy and toxicity for humans of possible vaccines than in conventional mice or other animal models.