Research Group Tumorvirus-specific Vaccination Strategies
apl. Prof. Dr. Martin Müller
Cells expressing HPV L1 and L2 capsid proteins (pink and red labeled).
Besides the development of papillomavirus vaccine strategies we are interested to study the functions of the structural proteins L1 and L2 in the course of the viral life cycle. With the help of VLPs we are able to investigate interactions of the viruses with the cells at early steps of infection. The L2 protein plays a central role in the packaging of the viral genome into the capsids. By packaging heterologous DNA into capsids we are able to produce so called pseudovirions. With these we can detect virus-neutralizing antibodies in the sera of immunized animals but also in human sera. In addition, pseudovirions allow to study the host range of the papillomaviruses.
The N-terminal region of the human papillomavirus (HPV) L2 protein has been shown to contain epitopes able to induce the production of neutralizing and cross-neutralizing antibodies. Using bacterial thioredoxin as a scaffold, we managed to significantly enhance the immunogenicity of putative L2 neutralizing epitopes. Before we can apply a thioredoxin L2 antigen in humans, we need to address cross-protective vaccine efficacy as well as safety issues e.g. in regard to thioredoxin scaffold. These issues are currently in the focus of our work.
Jointly with the European Molecular Biology Laboratory (EMBL) in Heidelberg we have developed a standardized validated assay system which allows us the high-throughput detection of neutralizing antibodies against HPV16, HPV18, and other oncogenic HPV types (automated pseudovirion-based HPV-neutralization assay). This assay can be used for a multitude of epidemiological studies. In particular, the duration of the immunization-protection after the introduction of a new vaccine could be monitored with our assay in large study groups.
Another important question we are dealing with is the immune response against the viral capsid in the course of natural HPV infections. This includes to study the relevance of maternal antibodies in the infant.
Selected Publications
Rubio I, Seitz H, Canali E, Sehr P, Bolchi A, Tommasino M, Ottonello S, Mueller M.: The N-terminal region of the human papillomavirus L2 protein contains overlapping binding sites for neutralizing, cross-neutralizing and non-neutralizing antibodies. Virology 409 (2), 348-359, 2011.
Pokorna,D., Rubio,I., Mueller,M.: DNA-vaccination via tattooing induces stronger humoral and cellular immune responses than intramuscular delivery supported by molecular adjuvants. Genetic Vaccines and Therapy 6, Art.Nr. 4, 2008.
Schaedlich,L., Senger,T., Gerlach,B., Muecke,N., Klein,C., Bravo,I.G., Mueller,M., Gissmann,L.: Analysis of Modified Human Papillomavirus Type 16 L1 Capsomeres: the Ability To Assemble into Larger Particles Correlates with Higher Immunogenicity. Journal of Virology 83 (15), 7690-7705, 2009.
Nieto,K, Kern,A, Leuchs,B, Gissmann,L, Mueller,M, Kleinschmidt,JA: Combined prophylactic and therapeutic intranasal vaccination against human papillomavirus type-16 using different adeno-associated virus serotype vectors. Antiviral Therapy 14 (8), 1125-1137, 2010.
