Project description:The study was undertaken to define correlates of protection against repeated low dose rectal SIVmac251 challenges in rhesus macaques (RMs) vaccinated with two regimens. Two groups of six RMs were immunized with either the attenuated SIVdeltanef virus, which establishes a persistent low-level infection and induces protective immunity against high dose challenges with SIVmac, or with two doses of an AdHu5 vector expressing Gag of SIVmac239 (AdHu5gag), that was given at a two-month interval.
Project description:An efficacious vaccine to HIV-1 remains elusive. We tested two vaccine regimens based on prime-boosting with two chimpanzee-origin adenovirus (Ad) vectors (SAdV) of serotypes SAdV24 and SAdV23 or two distinct human serotype Ad vectors (HAdV), i.e., HAdV5 and HAdV26, expressing Gag and gp160 of SIVmac239 for induction of protection against repeated low dose rectal SIVmac251 challenges in Indian rhesus macaques (RMs). Animals were rendered seropositive to the HAdV vectors prior to vaccination. In RMs with non-controller genotypes, the SAdV vectors achieved significant reduction in viral acquisition. In RMs with controller genotypes, both vaccine regimens reduced set-point and peak viral loads and accelerated viral clearance. In SAdV-vaccinated RMs resistance against infection correlated with levels of circulating envelope (Env)-specific antibody (Ab) titers. In both vaccine groups CD8+T cells controlled viral loads upon infection. Circulating CD4+ and CD8+ T cells showed significant changes in their transcriptome over time following vaccination, which differed between the vaccine groups. T cells from SIV-resistant RMs had unique transcriptional profiles indicating that both follicular T helper (TFH) cell responses and highly activated CD8+ T cells may play a role in protection. Our results demonstrate that SAdV-based candidate AIDS vaccines provide protection from virus acquisition and replication in a stringent SIV challenge model in RMs and may thus outperform HIV-1 vaccines that have undergone large-scale clinical efficacy testing in humans.
Project description:The primary objective of this study was to evaluate response to a SIV DNA-based vaccine that was adminstered via vivo electroporation (EP) in rhesus macaques to further understand the molecular correlates of protection against SIV. In this study, rhesus macaques were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. At eight month post-vaccination, animals were challenged with SIV. Standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis were performed to determine the host response to each vaccine regimen.
Project description:To determine the blood transcriptional response to intravenous (IV) BCG vaccination in rhesus macaques and identify correlates of vaccine-mediated protection against Mycobacterium tuberculosis (Mtb) challenge.
Project description:To determine the blood transcriptional response to BCG vaccination administered via different routes in rhesus macaques and identify correlates of vaccine-mediated protection against Mycobacterium tuberculosis (Mtb) challenge.
Project description:Rhesus macaques vaccinated by rhesus cytomegalovirus vectors expressing simian immunodeficiency virus proteins (RhCMV/SIV) activate gene expression signature associated with IL15. To examine the gene expression signature activated by IL15, we performed longitudinal examinations of rhesus macaques during IL15 treament.
Project description:Immunization of macaques with simian immunodeficiency virus with deletions in nef (SIV?nef) has been shown to elicit protective immunity to infection by pathogenic SIV, yet our understanding of the mechanisms that orchestrate protection and prevent pathogenesis remains limited. In the study, we utilize whole-genome transcriptional profiling to reveal molecular signatures of protective immunity in circulating CD8+ T cells of rhesus macaques vaccinated with SIVmac239?nef and challenged with pathogenic SIVmac251. Microarrays were used to characterize changes in gene expression in blood CD8+ T cells that occur following vaccination of rhesus macaques with attenuated SIV?nef and subsequent challenge with pathogenic SIVmac251, in comparison to corresponding changes in healthy controls and unvaccinated animals infected with pathogenic SIVmac251 CD8+ T cells were isolated by magnetic beads from the blood of healthy uninfected macaques, macaques vaccinated with SIV?nef, and unvaccinated controls infected with SIVmac251, and used for RNA extraction and hybridization on Affymetrix microarrays. Blood samples from vaccinated animals were collected prior to vaccination, at 3, 20, and 40 weeks following vaccination. After the 40 week vaccination period, macaques were challenged with SIVmac251, and blood was again collected at 3 weeks following challenge. Blood was collected from the unvaccinated controls at 3 weeks following infection with SIVmac251
Project description:Systemic vaccination with the attenuated virus SIVmac239-∆Nef provides sterilizing or partial protection to rhesus monkeys challenged with WT SIV strains, providing important opportunities to study key immunological components of a protective host response. Here we show that intravenous vaccination with SIVmac239-∆Nef provides two potentially crucial immunological barriers localized at mucosal surfaces that correlate with the vaccine’s protective effects against WT SIVmac251 vaginal challenge: 1) a conditioned and coordinated response from the mucosal epithelium that blunts the early inflammatory and chemotactic signalling cascade that aids virus propagation and expansion; 2) early on-site generation/diversification of SIV-specific Abs from ectopic germinal center-like lymphoid aggregates. This unique host response to WT SIVmac251 in the female reproductive tract of SIVmac239-∆Nef-vaccinated animals points to a multi-layered strategy for a protective host response during immunodeficiency virus exposure—rapid induction of humroal immunity at mucosal surfaces without the deleterious inflammatory side effects tied to innate recognition of virus. This vaccine-induced host response highlights potential key protective mechanisms needed for an effective HIV vaccine Total RNA was isolated from the cervix of 17 Indian Rhesus macaques (3 uninfected animals; 5 unvaccinated animals 4-5 days post vaginal exposure with SIVmac251; 4 SIVmac239-∆Nef-vaccinated animals before challenge; 5 SIVmac239-∆Nef-vaccinated animals 4-5 days post vaginal exposure with SIVmac251) and prepared for hybridization on Affymetrix GeneChip Rhesus Macaque Genome Arrays. Replicate arrays were performed for a number of the samples to minimize assay noise and significant host genes altered during virus exposure in female reproductive tract tissue were identified by their associated q-values (< 0.2) and fold change in expression (> 1.2).
Project description:Gene expression profiles in PPD-stimulated and unstimulated peripheral blood mononuclear cells isolated from rhesus macaques before and after M. tuberculosis challenge were compared in animals able to control TB infection and those that developed TB disease in order to identify potential correlates of protection and/or biomarkers of disease.