Thursday, 23 September 2021 09:00

Jena: Research to combat infectious diseases Featured

As part of the EU project Inno4Vac (Innovations to accelerate vaccine development and manufacture), the "Inspire" working group from Jena University Hospital will develop immunocompetent organ models. InVitro+Jobs spoke with the head of the Inspire working group at Jena University Hospital, private lecturer Dr. Alexander Mosig.


Inno4Vac is a project of the Innovative Medicines Initiative (IMI), a European partnership initiative. It will bring together experts from a wide range of disciplines to exploit technological advances with the aim of developing and bringing vaccines to market faster and more efficiently1.

In the project, the scientists will work on computer developments, but also develop new in vitro models to study certain infectious diseases based on human stem cells. The total project amount is 38,542,552 euros, where IMI will contribute a little more than 18 million euros. Nearly 20 million will be covered by EFPIA, an association of the European pharmaceutical industry.

Dr. Alexander Mosig is head of the research group INSPIRE - In Vitro Sepsis Research, at the Center for Sepsis Control and Care of Jena University Hospital and one of the participating scientists. For his project research, he has 800,000 euros at his disposal. We spoke with him about his planned research in the Inno4Vac project.

InVitro+Jobs:
Dr. Mosig: What exactly will be investigated and which in vitro methods will be used?

Dr. Mosig:
Inno4vac addresses four core areas: in the first, artificial intelligence is used for in silico prediction of immune response and vaccine efficacy. In the second, a modular computational platform is being developed for in silico modeling of vaccine bioproduction and stability testing. In the third, new and improved controlled human infection models will be developed for influenza virus (CHIM), respiratory syncytial virus2 (RSV), and Clostridium difficile research, among others, to enable early assessment of vaccine efficacy. In the fourth core area, new cell-based human in vitro 3D models are being developed for reliable prediction of immune protection.

Our research group is involved in the fourth project, where we are developing infection models for viruses and bacteria based on artificial models of the intestine and lung. The tissue models are generated from human stem cells. For the development of the infection models, we cooperate in Jena with the Institute of Medical Microbiology and within the consortium with colleagues from Germany, the Netherlands, Italy, and the United Kingdom.

InVitro+Jobs:
Will this involve the development of a two-organ model on the chip?

Dr. Mosig:
No, we are developing organ-specific infection models for different pathogens. Initially, there are no plans to interconnect the organs.

InVitro+Jobs:
Do immune cells also play a role in this research?

Dr. Mosig:
Immune cells play a very important role. That is why we develop isogenic3, immunocompetent organ models for our infection studies and the testing of specific drugs with them.

InVitro+Jobs:
Why exactly is the intestine being examined?

Dr. Mosig:
Among other things, we work with human noroviruses and the bacterium Clostridioides difficile. Both pathogens primarily play a role in the intestine.

InVitro+Jobs:
What exactly is the study of this diarrheal pathogen about?  

Dr. Mosig:
Our goal is first to develop a reliable and reproducible infection model for human norovirus in the laboratory. Subsequently, different approaches to protect against norovirus infections will be investigated. These should help to mitigate or possibly even protect against the annual waves of infection by the virus.

InVitro+Jobs:
Which immune cell types can be already integrated into the models and how are these isogenic cells isolated or generated?

Dr. Mosig:
We initially focus here on immune cells of the innate immune system, especially natural killer cells, macrophages, monocytes and dendritic cells. These are differentiated from iPSC lines, from which we also differentiate the appropriate endothelial and epithelial cells.

InVitro+Jobs:
Can you say that the in vitro models can now well replicate the situation in the human body?

Dr. Mosig:
You can't give a blanket answer to that. All models, whether in vitro or animal models, have limitations and can only reproduce the in vivo situation in the patient to a limited extent. This is due to the reductionist approach of a model, which, however, also offers advantages when it comes to the detailed investigation of partial aspects of diseases. Therefore, we develop our in vitro models for specific questions and defined pathogens. It is important to precisely define the capabilities of the model, i.e. to evaluate which questions can be reliably answered and which cannot. Knowing these limitations and the individual strengths of each investigative approach is necessary to develop a strategy for the sensible use of all available approaches, in order to ultimately help patients by testing and developing safe agents for the treatment of infections. In vitro 3D infection models offer exciting opportunities in this regard, for example, to take into account species-specific differences between animals and humans and thus help to test drugs more quickly and safely in the future.

InVitro+Jobs:
So before vaccine candidates are tested, the models are first infected with the various pathogens. What immune responses are measured and are there specific expectations in this process so that the infection model is considered meaningful?

Dr. Mosig:
We measure immune responses at different levels, from changes in cellular metabolism and production of proteins in tissues to immigration and differentiation of immune cells and release of chemokines as the infection progresses. We correlate these observations with data from clinical studies. The situation in the patient is the gold standard and we aim to replicate these responses as well and reliably as possible in the laboratory.

InVitro+Jobs:
How does the (hypothetical) immune response occur in the model, and what can't yet be represented in it compared to the whole organism?

Dr. Mosig:
Replicating the whole organism in every detail is very difficult and currently not within reach. We are currently unable to reproduce the full complexity of the human immune system in vitro and therefore focus on selected cells of the immune system and individual organ functions. However, stem cell research is making rapid progress and it remains to be seen how detailed the human immune system can be replicated in vitro in the future.

InVitro+Jobs:
What are the advantages of the human immunocompetent infection model over animal experiments?

Dr. Mosig:
The advantage of the animal model is certain to be able to consider systemic interactions taking into account all essential cellular and humoral parameters. This is not yet possible in full in vitro and remains a challenge for the coming years and possibly decades. There are also limitations of animal models in biomedical research: some pathogens, for example, are specific to humans and infection can only be artificially reproduced in animal models, if at all. Furthermore, there are differences between animals and humans in the immune system and the recognition and strategy to fight the infection. In vitro models can make important contributions to the understanding of infections and mechanisms involved by allowing studies on human tissues under controlled conditions. Moreover, by using stem cell-based models, they hold the potential to at least partially reproduce patient-specific characteristics relevant to infection progression in vitro. In the future, these models could support the development of individualized therapeutic approaches tailored to each patient.  

InVitro+Jobs:
To what extent can infection models replace or reduce animal testing if developed successfully?

Dr. Mosig:
A reduction of animal experiments is already possible with the current models and many mechanistic questions can be investigated well and reliably in them. However, animal experiments are still necessary to answer statements on the effectiveness of therapies at a higher level of complexity before studies in humans are possible. The challenge for the future is to make current in vitro models even better, i.e. to increase their informative value and to increase cellular complexity in a controlled and reproducible manner. Stem cells offer enormous potential here, and we want to contribute with our work to be able to completely replace animal experiments in the future. However, when this will be possible depends on the disease and the therapeutic approach. Many working groups are working on this and there is still a lot of joint work ahead of us.

InVitro+Jobs:
Thank you for the interview.

1 https://www.imi.europa.eu/projects-results/project-factsheets/inno4vac

2 Syncytial viruses: Respiratory syncytial virus (RSV) is a DNA virus that belongs to the pneumoviruses. It causes diseases of the deep respiratory tract. Source: https://www.msdmanuals.com/de-de/profi/p%C3%A4diatrie/verschiedene-virusinfektionen-bei-s%C3%A4uglingen-und-kindern/infektionen-mit-dem-respiratorischen-synzytialvirus-rsv-und-dem-humanen-metapneumovirus

3 Isogenic: Genetically similar cell lines. Source: http://www.laborundmore.com/archive/253559/bioconfident-grade%3A-ZytokineWachstumsfaktoren.html



More Sources:
https://www.rtl.de/cms/forschung-fuer-bekaempfung-von-covid-19-erhaelt-foerderungen-4826524.html
http://www.mosig-lab.com/Home/