Development and characterization of Lassa virus vaccines and mouse model
| dc.contributor.author | Camus, Gaelle | |
| dc.contributor.examiningcommittee | Feldmann, Heinz (Medical Microbiology) Moqbel, Redwan (Immunology) Hensley, Lisa (U.S. Army medical research institute of infectious diseases) | en_US |
| dc.contributor.supervisor | Uzonna, Jude (Immunology) Alimonti, Judie (Medical Microbiology) | en_US |
| dc.date.accessioned | 2012-09-06T13:38:34Z | |
| dc.date.available | 2012-09-06T13:38:34Z | |
| dc.date.issued | 2012-09-06 | |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Lassa virus (LASV) is the causative agent of a hemorrhagic fever endemic in West Africa, which results in over 200,000 infections and 3000 to 5000 deaths annually. It has previously been demonstrated that a live attenuated recombinant Vesicular Stomatitis Virus expressing the LASV glycoproteins (VSVΔG/LVGPC) is protective in a lethal non-human primate model of Lassa fever. The objective of the present study was to compare the immune response to the VSVΔG/LVGPC vaccine to a novel non-replicating vaccine candidate based on Lassa virus-like particles (VLPs) in the mouse. Additionally, there is a lack of an adequate small animal model for Lassa fever, and LASV is not lethal in immunocompetent mice. We thus investigated the role of the immune system during LASV infection using various immunodeficient mice. In the present study, the VSVΔG/LVGPC vaccine was shown to induce an adaptive immune response, as determined by ELISA and a cytokine ELISPOT assay in immunocompetent mice. The response was stronger with increasing vaccine doses and the number of booster injections. Additionally, the cytokine response preferentially shifted towards epitopes from the N-terminal part of the LASV glycoprotein following the booster injections. A novel vaccine based on Lassa VLPs was also generated, but the immune response to this vaccine candidate was much lower than for the VSVΔG/LVGPC vaccine, even when the VLPs were combined with an adjuvant. Furthermore, we found that mice deficient in the interferon system are susceptible to lethal LASV infection. Complete lethality was observed in STAT1 deficient mice, which are unresponsive to Type I and Type II interferons. Moreover, partial lethality was observed in IFN-[gamma] deficient mice. In contrast, mice lacking major components of the adaptive immune system, as well as wild-type mice, did not show any apparent signs of disease. In conclusion, these results suggest that both the VSVΔG/LVGPC and Lassa VLP vaccine candidates can stimulate an adaptive immune response in the mouse, although the immune response is stronger for the VSVΔG/LVGPC vaccine than for Lassa VLPs. Furthermore, we have established a novel mouse model of LASV infection and lethality, which could potentially be used for vaccine and drug testing against LASV. | en_US |
| dc.description.note | October 2012 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/8609 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | immunology | en_US |
| dc.subject | virology | en_US |
| dc.title | Development and characterization of Lassa virus vaccines and mouse model | en_US |
| dc.type | doctoral thesis | en_US |