| dc.contributor.advisor | Stahl-Hennig, Christiane Dr. | |
| dc.contributor.author | Gan, Li Lin | |
| dc.date.accessioned | 2018-04-10T08:46:52Z | |
| dc.date.available | 2018-04-10T08:46:52Z | |
| dc.date.issued | 2018-04-10 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002E-E3B1-C | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-6818 | |
| dc.language.iso | deu | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Pathogenesis of orthopoxvirus (OPXV) infection in common CM and identification of immune correlates after vaccination with differently attenuated vaccines | de |
| dc.type | doctoralThesis | de |
| dc.title.translated | Pathogenesis of orthopoxvirus (OPXV) infection in common CM and identification of immune correlates after vaccination with differently attenuated vaccines | de |
| dc.contributor.referee | Czerny, Claus-Peter Prof. Dr. Dr. | |
| dc.date.examination | 2018-01-17 | |
| dc.description.abstracteng | After the successful eradication of smallpox, mass vaccination stopped and the herd immunity against orthopoxvirus (OPXV) infections has been waning. In the light of bioterrorism, the interest in the development of antiviral drugs and safer vaccines against OPXVs increases. Therefore, a non-human primate model for OPXVs was established. Common CM (CM, Callithrix jacchus) are intranasally infected with a cowpox virus that is lethal for this non-human primate species and designated calpox virus.
A pathogenesis study was performed to determine the portal of viral entry and to analyze the early dissemination of the virus and the pathological sequelae. Groups of three animals were infected with either 3.5x105 plaque forming units (pfu) calpox virus and euthanized on day 3, or with 8.3x103 pfu and euthanized on 5, 7, 10 and 12 days post infection (dpi). Blood and various organs were analyzed for infectious virus using the endpoint dilution assay and for viral DNA by real-time PCR. To detect the calpox virus infection in immune cells, PBMCs and buffy coat were analyzed by flow cytometry for calpox virus. Two vaccination studies aimed at identifying immune correlates of protection. Two attenuated smallpox vaccines, i.e. modified VACV Tian Tan (MVTT) and modified VACV Ankara (MVA) were tested for their efficacy after a 4- and 10-week waiting period. Humoral and cellular responses were analysed during immunization and after challenge, as well as viral DNA copy numbers and replicating virus after challenge. Occurrance of viremia (DNA copies in blood) was dose dependent and already observed at 3 dpi (with the high inoculation dose) and after inoculation with the low viral dose at 7 dpi. The data suggests that the calpox virus initially replicated in the upper respiratory tract followed by systemic spread. In the prefinal phase, all organs became infected. Calpox antigen was detected in immune cells at different time points. With respect to the vaccine studies, overall, 67 % protection was observed following immunization with MVTT and 13 % after MVA vaccination independently of the waiting period. All vaccine failures became virus positive. Virus-specific T-cell proliferation was observed in some animals vaccinated with MVTT. However, binding and neutralizing antibodies as well as the proliferative activity were not associated with the protection of the CM from calpox virus challenge. Peptide microarrays revealed antibodies against linear B cell epitope regions in different proteins (A33, B5 and L1) that were present almost exclusively in protected animals post challenge. Phenotyping of innate and adaptive immune cells by flow cytometric staining revealed no significant differences between vaccine groups in T and B cell numbers as well as in their expression of activation markers.
In conclusion, intranasal infection of CM with calpox virus led to a first local viral replication in nasal tissue. From there, the virus spread to various organs and in the prefinal phase all organs became infected. Highest protection was mediated by MVTT which therefore is superior to MVA in this model. So far, no obvious correlates of immune protection were identified. | de |
| dc.contributor.coReferee | Becker, Stephan Prof. Dr. | |
| dc.contributor.thirdReferee | Pöhlmann, Stefan Prof. Dr. | |
| dc.subject.eng | Calpox virus | de |
| dc.subject.eng | pathogenesis | de |
| dc.subject.eng | non-human primate model | de |
| dc.subject.eng | calpox virus/marmoset model | de |
| dc.subject.eng | smallpox vaccine | de |
| dc.subject.eng | MVTT | de |
| dc.subject.eng | MVA | de |
| dc.subject.eng | New World | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E3B1-C-3 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1018321683 | |