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Balanced immunity to Lassa virus glycoprotein and nucleoprotein is associated with full protection of macaques after a single shot of different vaccines

ABSTRACT: Lassa fever is a major threat in Western Africa. The large number of people living at risk for this disease calls for the development of a vaccine against Lassa virus (LASV). We compared the efficacy of measles-based and Mopeia-based vaccine platforms against LASV in cynomolgus monkeys. The vaccines were well tolerated and protected the animals from Lassa virus infection and disease after a single immunization but with different efficacy. Analyses of immune responses demonstrated that complete protection was associated with early and robust T-cell responses against LASV but not humoral responses nor neutralizing antibodies. Transcriptomic and proteomic analyses performed during the immunization phase confirmed the role of early innate immunity and T-cell priming in vaccine efficacy and showed specific profiles detectable as early as two days after immunization. The most efficient candidate, measles vector expressing simultaneously LASV glycoprotein and nucleoprotein, will be soon evaluated in phase I clinical trial.

ORGANISM(S): Macaca fascicularis

PROVIDER: GSE132998 | GEO | 2019/06/20

REPOSITORIES: GEO

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Project description:Lassa fever virus (LASV) is a significant human pathogen that is endemic to several countries in West Africa. Infection with Lassa leads to the development of hemorrhagic fever in a significant number of public health cases and it is considered a potential bioweapon. Little is known about the complex immune mechanisms governing response to LASV infection, or the genetic determinants of susceptibility and resistance to infection. In the study presented here, we have used a whole-genome, microarray-based approach to determine the temporal host response to infection in the peripheral blood mononuclear cells of non-human primates (NHP) infected with LASV. Sequential sampling over the entire disease course showed that there are specific transcription signatures of the immune response to LASV infection, including the rapid up- regulation of interferon-responsive genes and toll-like receptor signaling pathways. However, this increase in early innate responses was coupled with a lack of pro- inflammatory cytokine response in LASV infected NHPs. There was a distinct lack of cytokines such as IL1b and IL23a, while immune suppressive cytokines such as IL27 and IL6 were upregulated. Comparison of cytokine gene expression with the amount of detectable protein in Lassa infected NHPs suggests that gene expression precedes the protein detection and thus is possibly a better tool for early diagnostics of the disease. Our results provide a comprehensive picture of the immune response to hemorrhagic LASV infection and provide a foundation for biomarker identification to allow clinical diagnosis of Lassa infection through analysis of the host response. RNA was isolated from a total of 46 PBMC samples from 15 cynomologus macaques infected with Lassa Virus. Samples were obtained at sequential timepoints post-infection, and included a pre-infection specimen from each animal. A subset of 30 samples (11 animals) were then processed and hybridized onto the Agilent 2-color arrays.

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Balanced immunity to Lassa virus glycoprotein and nucleoprotein is associated with full protection of macaques after a single shot of different vaccines

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