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Preclinical efficacy of a live vesicular stomatitis virus-based Lassa virus vaccine candidate advanced for human clinical trials

ABSTRACT: We advanced a promising experimental vaccine for immunizing against the Lassa virus surface glycoprotein as a candidate for human trials. Preclinical evaluation of the vaccine candidate based on a live vesicular stomatitis virus (VSV) vector showed that it was highly efficacious in cynomolgus macaques consistent with earlier research studies, and that the animals developed serum antibodies that could mediate antiviral effector functions including direct neutralization of virus infectivity. As part of this evaluation, we analyzed whole-blood transcriptomes from each study subject prior to vaccination and at 1 day and 3 days post-vaccination.

ORGANISM(S): Macaca fascicularis

PROVIDER: GSE246148 | GEO | 2024/11/30

REPOSITORIES: GEO

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Project description:Lassa fever (LF) is a rodent-borne viral disease that can be fatal for human beings. In this study, an attenuated Lassa vaccine candidate, ML29, was tested in SIV-infected rhesus macaques for its ability to elicit immune responses without instigating signs of virulent disease. ML29 is a reassortant between Lassa and Mopeia viruses that causes a transient infection in non-human primates and confers sterilizing protection from lethal Lassa viral challenge. However, since the LF endemic area of West Africa also has high HIV seroprevalence, it is important to determine whether vaccination could be safe in the context of AIDS. SIV-infected and uninfected rhesus macaques were vaccinated with the ML29 virus and monitored for classical and non-classical signs of arenavirus disease. Classical disease signs included viremia, rash, weight loss, high liver enzyme levels, and virus invasion of the central nervous system. Non-classical signs derived from profiling the blood transcriptome of virulent and non-virulent arenavirus infections included increased expression of interferon response genes and decreased expression of COX2, IL-1?, coagulation intermediates and nuclear receptors needed for stress signaling. Here it is demonstrated that SIV-infected and uninfected rhesus macaques responded similarly to ML29 vaccination, and that none developed signs of arenavirus disease or persistence. Furthermore, 5 of 5 animals given a heterologous challenge with a lethal dose of LCMV-WE survived without developing disease signs. 30 RNA samples from Monkey PBMC: 4 uninf. Monkey PBMC, 8 SIV-infected Monkey PBMC(From 8 Monkeys), 5 SIV+ML29-sc infected week1(Monkey PBMC), 5 SIV+ML29-sc infected week2(Monkey PBMC), 1 SIV+ML29-ig infected week1(Monkey PBMC), 1 SIV+ML29-ig infected week2(Monkey PBMC), 2 SIV+Arm-sc infected week1(Monkey PBMC), 2 SIV+Arm-sc infected week2(Monkey PBMC), 1 only ML29-iv infected week1(Monkey PBMC), 1 only ML29-iv infected week2(Monkey PBMC)

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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Preclinical efficacy of a live vesicular stomatitis virus-based Lassa virus vaccine candidate advanced for human clinical trials

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