Logo der Universitätsmedizin Mainz

Experimental Vaccinology

The development of mRNA vaccines for preventive and therapeutic applications has made significant progress over the last decade. The therapeutic efficacy of mRNA vaccines has already been demonstrated in a number of applications, including infectious diseases, immunotherapy, genetic disorders, regenerative medicine and cancer. Therefore, mRNA vaccines are predicted to have a promising future. We utilise these flexible possibilities for the preclinical development of innovative vaccine concepts.

Hepatitis B virus (HBV) is one of the major etiologic agents of human viral hepatitis, cirrhosis and hepatocellular carcinoma (HCC). According to WHO, there are currently more than 250 million people who are chronically infected with HBV worldwide, with more than 780,000 deaths per year. Despite the availability of the commercial anti-hepatitis B vaccine, its three-dose schedule of intramuscular injections is often not achievable in populations of high endemicity for HBV, it has a 10-15% rate of non-responders, and it is ineffective in limiting viral replication in patients with chronic hepatitis B. Since cellular immunity is essential for an effective immune response against viral infections by promoting the elimination of virus-infected cells, it is desirable to develop antiviral vaccines capable of inducing a cell-mediated immune response that complements the antibody-mediated immune response. Genetic vaccines represent one of the best immunization alternatives as they are capable of inducing both humoral and cellular immune responses. The focus of our research group is focused on the development of subunit and genetic vaccine formulations that are transported by nanoparticle-based delivery systems in order to generate anti-HBV specific T-cell responses that complements the specific humoral immune response.

 

·         Cacicedo ML, Limeres MJ, Gehring S. mRNA-based Approaches to Treating Liver Diseases. Cells. 2022 Oct;11(20):3328. doi: 10.3390/cells11203328.

·         Gehring S, Pietrzak-Nguyen A, Fichter M, Landfester K. Novel strategies in vaccine design: can nanocapsules help prevent and treat hepatitis B? Nanomedicine(Lond). 2017 Jun;12(11):1205-1207. doi: 10.2217/nnm-2016-0064. Epub 2017 May 18.

·         Pietrzak-Nguyen A, Piradashvili K, Fichter M, Pretsch L, Zepp F, Wurm FR, Landfester K, Gehring S. MPLA-coated hepatitis B virus surface antigen (HBsAg) nanocapsules induce vigorous T cell responses in cord blood derived human T cells. Nanomedicine. 2016 Nov;12(8):2383-2394. doi: 10.1016/j.nano.2016.07.010.

During the last years, the use of nanotechnology in the development of new therapeutic approaches for the treatment of different illnesses become a relevant tool in the medical field. The aim of our laboratory is the production of new pharmaceutical nanoparticles for the treatment of pathologies related to liver inflammation. The composition, surface signal patterns, charge, type of cargo molecules and co-loading with different macromolecules can be optimized according to the therapeutic need. The targeted delivery of the drugs into particular liver cells has been explored to minimize systemic undesirable side effects. The immunosuppressive activity and biological effects of these nanoparticles are being investigated in mouse models of biliary atresia and hepatic inflammation.

Contact
Department of Paediatrics and Adolescent Medicine
Laboratory for Paediatric Immunology
University Medicine Mainz
Disposition Building 911 / R.01-349
Obere Zahlbacher Str. 63
55131 Mainz

Contact person: Dr. Germán Islan

 

Publication(s)

  • Medina-Montano, C., Rivero Berti, I., Gambaro, R. C., Limeres, M. J., Svensson, M., Padula, G., Chain, C. Y., Cisneros, J. S., Castro, G. R., Grabbe S., Bros M., Gehring S., Islan G. A., & Cacicedo, M. L. (2022). Nanostructured lipid carriers loaded with dexamethasone prevent inflammatory responses in primary non-parenchymal liver cells. Pharmaceutics, 14(8), 1611.
  • Gambaro, R. C., Berti, I. R., Cacicedo, M. L., Gehring, S., Alvarez, V. A., Castro, G. R., Seoane A., Padula G. & Islan, G. A. (2022). Colloidal delivery of vitamin E into solid lipid nanoparticles as a potential complement for the adverse effects of anemia treatment. Chemistry and Physics of Lipids, 249, 105252.
  • Rodenak-Kladniew, B., Castro, M. A., Gambaro, R. C., Girotti, J., Cisneros, J. S., Viña, S., Padula G., Crespo R., Castro G. R., Gehring S., Chain C. Y., & Islan, G. A. (2023). Cytotoxic Screening and Enhanced Anticancer Activity of Lippia alba and Clinopodium nepeta Essential Oils-Loaded Biocompatible Lipid Nanoparticles against Lung and Colon Cancer Cells. Pharmaceutics, 15(8), 2045.


Biliary atresia is a fibro-inflammatory disease present in children and is characterized by inflammation and sclerosis of intrahepatic bile ducts in combination with blockage of the extrahepatic bile ducts. This very special form of cholangiopathy is cause number one for children to receive a liver transplantation. Till today the cause of biliary atresia is not known. Possible factors for the occurrence of this diseases could be besides genetic factors and errors in embryonic development also virus infections and hepatotoxins. Due to this lack of knowledge about the causes of this disease only limited treatment options are available.

Based on recent research on mRNA therapeutics, we want to develop a vaccine which decelerates the immunological processes leading to the cholangiopathy and in that way slowing down the procession of this disease. This should ultimately give the patients more time until a liver transplantation is needed and thereby improve the patient’s outcome of the transplantation.

Recent breakthroughs in vaccinology have proven the relevance of mRNA technology in treating infectious diseases. Moreover, mRNA based approaches shown promising results as immunotherapies against different types of cancer. Besides finding the right target, mRNA optimization plays a crucial role for the development of a successful vaccine. From the cap to the tail, the mRNA molecule gives you a plethora of different possibilities on how to construct it. Aim of the optimization should always be a good protein translation and a low immunogenicity of the mRNA molecule. Therefore our lab is working with different UTR-sequences, cap structures and tail lengths to develop the best possible mRNA for our different vaccine approaches.

Hepatocellular carcinoma (HCC) is among the most common malignancies worldwide and a leading cause of cancer-related deaths. Occurrence is characterized by a poor prognosis and a high rate of mortality. Therapeutic options are limited due to high rates of metastasis and recurrence. Identifying innovative therapeutic approaches that target the factors that affect malignant cell migration and invasion are critical.

Aspartyl/asparaginyl-β-hydroxylase (ASPH) is a highly-conserved, Type II transmembrane protein (2). It plays key roles in regulating cell growth, differentiation, migration and adhesion. The elevated expression of ASPH on the surface of essentially all HCC tumor cells, but not cells located in the surrounding, noninvolved liver tissue suggests that ASPH could serve as an immunotherapeutic target.

The liver is inherently tolerogenic, an environment exacerbated by chronic inflammation and developing neoplasia in HCC patients. An elevated CD4+CD25+FoxP3+ regulatory T(reg) cell population in the peripheral blood and infiltrating the malignant tissue observed in HCC patients contributes to a ineffective tumor-specific T cell response. Analysis of ASPH identified four epitopes that are cross-conserved at the T cell receptor (TcR) facing aspect with a large number of proteins, and, therefore, are predicted to induce Treg cell activity. Recently, we reported that abolishing these putative Treg cell epitopes and de-tolerizing ASPH as a consequence enhanced both the CD4+ and CD8+ effector T(eff) cell responses while simultaneously decreasing the Treg cell number in ex vivo tissue cultures (Wirsching et al., 2022).

To this end, the goal of our research is to generate a de-tolerized aspartyl/asparaginyl β-hydroxylase anti-cancer vaccine and demonstrate its capacity to elicit the ASPH protein-specific responses of human CD4+ and CD8+ T cells ex vivo and tumor immunity in humanized mice challenged with ASPH-expressing human hepatocellular carcinoma cells.

  

Contact

Department of Paediatrics and Adolescent Medicine
Laboratory for Paediatric Immunology
University Medicine Mainz
Disposition Building 911 / R.01-336
Obere Zahlbacher Str. 63
55131 Mainz
Contact person: Dr. MaJo Limeres  /  Dr. C. Meyer

Publications:

Wirsching S, Fichter M, Cacicedo ML, Landfester K, Gehring S. Modification of Regulatory T Cell Epitopes Promotes Effector T Cell Responses to Aspartyl/Asparaginyl β-Hydroxylase. Int J Mol Sci. 2022 Oct 18;23(20):12444. doi: 10.3390/ijms232012444.


Klinik und Poliklinik für Kinder- und Jugendmedizin

Hausanschrift:
Universitätsmedizin Mainz
Klinik und Poliklinik für Kinder- und Jugendmedizin

Gebäude 109

Langenbeckstr. 1

55131 Mainz

Tel.: 06131 17-2557
 E-Mail

www.unimedizin-mainz.de/kinderklinik

Logo_PaedImmu.jpg
AG Pädiatrische Immunologie und Impfstoffentwicklung

Anschrift:
Klinik und Poliklinik für Kinder- und Jugendmedizin
Labor für Pädiatrische Immunologie

Universitätsmedizin Mainz
Verfügungsgebäude 911/R.01-336
Obere Zahlbacher Str. 63
55131 Mainz

Tel.: +49 6131 17-9753
Fax: +49 6131 17-9658
 paed-cmi-labor@uni-mainz.de