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New Cytomegaloviral Vaccine Vector Concepts

Full title: New Cytomegaloviral Vaccine Vector Concepts

Grantors: Helmholtz Association’s Helmholtz European Partnering Grant

Grant number:  PIE-0008

Grantor’s website:   https://www.helmholtz.de/en/

Duration: 2018-2023

CoordinatorProf. Dr. Luka Cicin-Sain, HZI Helmholtz Centre for Infection Research

No. of participants: 6

Partners:  Prof. Dr. Stipan Jonjic, Faculty of Medicine University of Rijeka

Dr. Christine Goffinet, Charité – Universitätsmedizin Berlin

Prof. Dr. Alemka Markotic, University Hospital for Infectious Diseases (BFM) Zagreb

Prof. Dr. Stefan Pohlmann, Deutsches Primatenzentrum GmbH (DPZ), Leibniz-Institut für Primatenforschung

Prof. Dr. Albert Osterhaus Sitftung Tierärztliche Hochschule Hannover (TiHo)

Coordinator’s web sitehttps://www.helmholtz-hzi.de/en/

Brief description:

Numerous viruses causing vast global disease burden (e.g. HCV, HIV, and numerous emerging and re-emerging viruses) have resisted efforts to develop a vaccine by well-established, conventional methods. Immune protection from infection by these pathogens requires a very strong vaccine-induced immunity, typically triggered by live-attenuated vaccines. However, attenuated HCV or HIV vaccines may mutate or recombine into deadly strains, raising critical safety concerns. An attractive and safe solution would be to use well-characterized viral vectors expressing antigens of pathogenic viruses. Prominent examples of this approach include adeno- and pox- vectors, yet their deployment in clinical settings has yielded only limited success. Therefore, novel approaches for vaccine vector development are urgently required.

We propose to develop and test vaccine vectors based on the genetic platform and unique properties of the murine cytomegalovirus (MCMV), a virus that naturally replicates only in murine cells. Immune responses to experimental MCMV infection are exceedingly robust and sustained for life, because the virus establishes a depot of latently infected cells that slowly release antigen, boosting the immune response over time. We have shown that the continuous stimulation of immune responses depends on the expression context of the antigen in the immediate early (ie) locus of MCMV, and this effect is evoked even by replication-defective viral mutants. MCMV abortively infects human cells, failing to replicate and spread, but robustly expressing ie antigen.

Consequently, the replication defect of MCMV in primate cells does not have to preclude it from establishing latency and inducing a life-long immunity in humans or non-human primates. To validate this hypothesis, we will develop MCMV vectors expressing antigenic determinants from several viruses against which prophylactic vaccines are urgently needed. These include hepatitis C virus, hantavirus, chikungunya virus and influenza virus. We will test their ability to induce humoral or cellular immune responses in mice or in human cells, define their virulence in human tissue culture, validate the key results in vivo in ferrets and non-human primates.