Microarray analysis to identify optimal timepoint post-ALVAC vaccintation to investigate innate immune pathways
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ABSTRACT:
ORGANISM(S): Homo sapiens Macaca mulatta
PROVIDER: GSE181996 | GEO | 2021/08/13
REPOSITORIES: GEO
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Project description:The Canarypox/gp120/Alum vaccines decreased the risk of HIV acquisition in humans. We demonstrate here the efficacy of this vaccine regimen also in the SIVmac251 macaque model when we used the alum but not the MF59 adjuvant. Analysis of innate and adaptive cell responses, envelope antibodies Fc profiles and glycoforms demonstrated a lower inflammatory response with alum than MF59. Alum elicited mucosal V2 peptide-specific IgG associated with vaccine efficacy whereas the MF59 induced mucosal V2 peptide-specific IgG associated with increased risk of infection. Alum modulated the expression of 12 genes, 7 of which are part of the RAS pathway, that correlates with vaccine efficacy and were linked to innate responses that preserve mucosal integrity and adaptive mucosal antibody response to V2. Thus, activation of the RAS pathway, preservation of mucosal integrity and mucosal antibody to V2 in concert, reduce the risk of SIVmac251 acquisition. Fifty-four (54) rhesus macaques were randomized into two vaccination groups. One group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in MF59 adjuvant (at week 12 and week 24). The second group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in Alum adjuvant (at week 12 and week 24). Blood samples were taken pre-vaccination, 24 hours after the first prime (post-1st imunization at week 0) and 24 hours after the first boost (post-3rd immunization at week 12). All the samples were taken before SIV challenge. Blood samples were conserved in PAXgene tubes. RNA was extracted and hybridized to Illumina beadchips. technical replicate: P162_P382_post1st, P162_P382_post1st_rep1
2016-05-29 | E-GEOD-72624 | biostudies-arrayexpress
Project description:We contrasted innate and adaptive immune responses of HIV vaccine candidates of varying efficacy in macaques that shared the ALVAC+gp120 protein boost with an ALVAC, DNA or Ad26 prime modality. The vaccine efficacies of the DNA/ALVAC+gp120 and ALVAC/ALVAC+gp120 vaccine regimens, both protective, were associated with qualitative temporal-spatial differences in the innate CD14+ and CD16+ cells in blood and tissues. The activation of hypoxia and the inflammasome in CD14+ DR+ CD16- classical monocytes and CD4+ Th2 responses correlated with a decreased risk of SIVmac251 acquisition. CD4+ Th2 cells, in turn, correlated with mucosal NKp44+ cells and mucosal protective antibodies to V2. In contrast, the Ad26/ALVAC+gp120 vaccine resulted in increased de novo differentiated CX3CR1+ CD163+ macrophages in lymph nodes, increased CD4+ Th17 cells in blood and rectal mucosa, and a lack vaccine efficacy. These data posit that the engagement of classical monocytes and inflammasome activation is central for the elicitation of protective innate and adaptive responses by the ALVAC-based HIV vaccine platform.
2018-02-23 | GSE108011 | GEO
Project description:Microarray analysis to identify optimal timepoint post-ALVAC vaccintation to investigate innate immune pathways
| PRJNA754159 | ENA
Project description:The RV144 HIV vaccine trial remains the only study to demonstrate significant protection from future HIV-1 acquisition. One of the key components of the RV144 vaccine was the use of the canarypox vector ALVAC as the priming component. Since AIDSVAX, the booster component, alone failed to provide protection we hypothesized that the ALVAC prime contributed significantly to the generation of protection. To test this, we designed a NHP immunogenicity trial to mechanistically link ALVAC vaccination with the magnitude of V1V2 titers, the most significant immune correlate of reduced HIV-1 acquisition in RV144. Our objective was to use a systems biology approach to identify the transcription factors, target genes and immune pathways which were being induced by ALVAC vaccination and associated with higher V1V2 titers. We identified the transcription factor CREB1 and its target genes as rapidly induced by ALVAC in multiple immune subsets and that CREB1 drives the expression and activation of a network of other TFs which are critical for modulating immune responses. Pathways induced by this ALVAC-CREB1 axis include lymphocyte/leukocyte migration, lymphocyte differentiation, antigen processing and presentation, T cell co-stimulation and cytokine signaling.
2021-07-25 | GSE180748 | GEO
Project description:The RV144 HIV vaccine trial remains the only study to demonstrate significant protection from future HIV-1 acquisition. One of the key components of the RV144 vaccine was the use of the canarypox vector ALVAC as the priming component. Since AIDSVAX, the booster component, alone failed to provide protection we hypothesized that the ALVAC prime contributed significantly to the generation of protection. To test this, we designed a NHP immunogenicity trial to mechanistically link ALVAC vaccination with the magnitude of V1V2 titers, the most significant immune correlate of reduced HIV-1 acquisition in RV144. Our objective was to use a systems biology approach to identify the transcription factors, target genes and immune pathways which were being induced by ALVAC vaccination and associated with higher V1V2 titers. We identified the transcription factor CREB1 and its target genes as rapidly induced by ALVAC in multiple immune subsets and that CREB1 drives the expression and activation of a network of other TFs which are critical for modulating immune responses. Pathways induced by this ALVAC-CREB1 axis include lymphocyte/leukocyte migration, lymphocyte differentiation, antigen processing and presentation, T cell co-stimulation and cytokine signaling.
2021-07-25 | GSE180747 | GEO
Project description:The RV144 HIV vaccine trial remains the only study to demonstrate significant protection from future HIV-1 acquisition. One of the key components of the RV144 vaccine was the use of the canarypox vector ALVAC as the priming component. Since AIDSVAX, the booster component, alone failed to provide protection we hypothesized that the ALVAC prime contributed significantly to the generation of protection. To test this, we designed a NHP immunogenicity trial to mechanistically link ALVAC vaccination with the magnitude of V1V2 titers, the most significant immune correlate of reduced HIV-1 acquisition in RV144. Our objective was to use a systems biology approach to identify the transcription factors, target genes and immune pathways which were being induced by ALVAC vaccination and associated with higher V1V2 titers. We identified the transcription factor CREB1 and its target genes as rapidly induced by ALVAC in multiple immune subsets and that CREB1 drives the expression and activation of a network of other TFs which are critical for modulating immune responses. Pathways induced by this ALVAC-CREB1 axis include lymphocyte/leukocyte migration, lymphocyte differentiation, antigen processing and presentation, T cell co-stimulation and cytokine signaling.
2021-07-26 | GSE180677 | GEO
Project description:We analyzed innate and adaptive immune responses elicited by the V1-deleted DNA/ALVAC/gp120/alum vaccine in non-human primates. Following SIVmac251 challenge exposure, we observed reduced risk of SIV acquisition comparing vaccinated animals to controls, confirming th ability of this vaccine strategy in decreasing the risk of SIV acquisition against vaginal exposure. Transcriptome and chromatin accessibility in CD14+ cells were analyzed by RNA-seq and ATAC-seq. Epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway correlated with vaccine efficacy. The efficacy of V1-delted DNA/ALVAC/gp120/alum vaccine, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Our data support the protective role for CREB1 expression in monocytes and posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.
2023-01-06 | GSE189032 | GEO
Project description:We analyzed innate and adaptive immune responses elicited by the V1-deleted DNA/ALVAC/gp120/alum vaccine in non-human primates. Following SIVmac251 challenge exposure, we observed reduced risk of SIV acquisition comparing vaccinated animals to controls, confirming th ability of this vaccine strategy in decreasing the risk of SIV acquisition against vaginal exposure. Transcriptome and chromatin accessibility in CD14+ cells were analyzed by RNA-seq and ATAC-seq. Epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway correlated with vaccine efficacy. The efficacy of V1-delted DNA/ALVAC/gp120/alum vaccine, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Our data support the protective role for CREB1 expression in monocytes and posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.
2023-01-06 | GSE188879 | GEO
Project description:Using specimens from a phase 1b trial of the RV144 regimen in HIV-1-uninfected South Africans (HVTN 097), we profiled innate responses to the first ALVAC-HIV immunization. PBMC transcriptional responses peaked 1 day post-vaccination. Type I and II interferon signaling pathways were activated, as were innate pathways critical for adaptive immune priming.
2021-03-17 | GSE164366 | GEO
Project description:We contrasted innate and adaptive immune responses elicited by the DNA/ALVAC/gp120/alum vaccine in non-human primates differing in age. We performed several analyses. MicroRNA profiling in Extracellular Vesicles (EVs) isolated from plasma collected prior and 1 week following vaccination identified 109 miRNAs that differed significantly between age groups at the end of immunization. Several miRNAs correlated with risk of virus acquisition in young and old animals, but none remained significant following correction for FDR. In young animals, we identified 3 miRNAs which were modified by vaccination and correlated with decreased risk of SIV acquisition (unadjusted p-values). Of these three miRNAs, two, miR-139-5p and miR-29b-1-5p, were increased by vaccination, whereas one, mir 98, decreased by vaccination. MiR-139-5p has several validated targets, including: CXCR4, important for egress of CXCR4+ cells and monocytes from bone marrow and HIV entry in target T-cells; the cAMP-specific PDE4D gene which decreases CREB1-mediated transcription by degrading cAMP; and the IGF-1/AKT/Glut1 gene receptor, central for glucose utilization and cellular metabolism. The validated target of miR-29b-1-5p is the NF-kB pathway. Mir-98 has several validated targets, inhibits IL-10 production, modulates M1-M2 polarization of macrophages towards the M1 phenotype, and its CCL2-induced downregulation increases IL-6 production. These data suggest the importance of CREB1-mediated transcription in vaccine efficacy, identified in the study, is likely assisted by miR-139-5p targeting the cAMP-degrading PDE4D gene, and downregulation of the NF-kB pathway, targeted by miR-29b-1-5p.
2023-01-06 | GSE188575 | GEO