Posted in Adenovirus, Resource

Merck Ad5/HIV induces broad innate immune activation that predicts CD8+ T-cell responses but is attenuated by preexisting Ad5 immunity

Figure (top) showing the protein–protein interaction network that links between CD8+ T-cell response-associated genes and constituents of functional gene modules differentially regulated by MRKAd5/HIV. Study is done by Zak DE et al., PNAS, 2012.

The Step Study revealed that the MRKAd5/HIV had poor efficacy in protecting against HIV-1 infection, especially in subjects with pre-existing Ad5 immunity. However, no clear mechanisms have been identified to date why the seropositive subjects showed reduced efficacy. In this manuscript, Zak DE et al., describe the possible mechanisms of vaccine failure using a systems biology approach

35 healthy HIV-1-uninfected adults, 20–50 years old were recruited for the study. 10 subjects (3 seropositive and 7 seronegative subjects) PBMCs were isolated and transcript levels were analysed by microarray at 4–6, 24, 72, and 168 h post-vaccination.

Strong induction of innate immune responses were detected at the gene and protein level, peaking at 24 hours post-vaccination and resolving at 72 hours post-vaccination. In addition, protein levels of CXCL-10, ITAC, monocyte chemoattractant protein-1 (MCP-1), and MCP-2, as well as immunoregulatory IL-10 and IL-1Ra, were upregulated.

92% concordance between the in vivo and in vitro induction of IFN response genes was observed, indicating that these immune responses observed were modulated by viral infection. Genes not captured in vitro are related to cell lineages, possibly due to lack of cell trafficking in vitro.

When comparing subjects with Ad5 nAb titers ≤ 200 and >200, significant attenuation of the innate immune responses were seen in seropositive subjects compared to the seronegative subjects.

Two chemokines, MCP-1 and MCP-2, discriminated between the strong and moderate CD8-responders as compared to those subjects with poor or no CD8 responses.

Interestingly, the gene signatures that correlated with CD8 T-cell responses were seen at day 3, where members of the “Cytotoxicity,” “T cells,” and “Lymphoid lineage” modules were positively correlated (see above figure). This finding may support the notion that prolonged upregulation of the innate immune gene transcripts could influence CD8 responses.

Data is deposited in the Gene Expression Omnibus (GEO) database, GSE22822.

Posted in Meningococcal vaccines, Resource

Molecular signatures of antibody responses derived from a systems biological study of 5 human vaccines

Volcano plots comparing the differentially expressed genes after 3 days and 7 days post-vaccination with MCV4, MPSV4, YF-17D, TIV or LAIV vaccines. Source taken from Li et al., Nature Immunology, 2014.

Neisseria meningitidis is a leading cause of meningitis and septicemia with 1.2 million cases per year worldwide. Of note, bacterial polysaccharides do not trigger the same receptors that are involved in viral sensing. This brings an interesting question: Do carbohydrate vaccines induce the same or distinct molecular signatures as viral vaccines? To address this question, Shuzhao Li et al., 2014, compared the molecular signatures induced by meningococcal vaccines with yellow fever (YF-17D) and influenza vaccines (TIV and LAIV).

The two major classes of meningococcal vaccines tested are:

  1. The quadrivalent polysaccharide vaccine (MPSV4) containing polysaccharides from serogroups A, C, Y and W-135. Vaccine is given intramuscularly.
  2. The polysaccharide-protein conjugate vaccines, such as the quadrivalent conjugate vaccine (MCV4) that contains the same four polysaccharides conjugated to diphtheria toxoid. MCV4 given subcutaneously.

13 healthy subjects (age 18-45) received MPSV4 and 17 subjects received MCV4. Direct transcriptomic analysis on PBMCs was performed on days 0, 3 and 7 after vaccination.

The magnitude and duration of the polysaccharide-specific IgG response was greater with MPSV4 compared to a single dose of MCV4.

Peak levels of peripheral blood antibody secreting cells (ASCs) detected at day 7 post-vaccination.

Most DEGs for both vaccines were detected at day 7, with more DEGs in MCV4 vaccinees compared to MPSV4 vaccinees. Many of these DEGs were transcripts related to ASCs, which coincided with the increase in ASCs at day 7. XBP1 gene network was also enriched in MCV4 at day 7 post vaccination, similar to antibody signatures seen in subjects given the influenza inactivated vaccine. The signatures produced by MCV4 and MPSV4 were clearly distinct from the live-attenuated yellow fever and influenza vaccines.

Blood transcriptomic modules was used to decrypt immune responses produced by MCV and MPSV. Dendritic cell surface signature module, together with activation, complement and pro-inflammatory cytokines was correlated with anti-polysaccharide IgG in both MCV4 and MPSV4 vaccinees, suggesting the role of myeloid dendritic cells in antibody production. However, how these vaccines lead to myeloid dendritic cell activation still remains to be elucidated.

Data is deposited at Gene Expression Omnibus: GSE52245

Posted in Resource, shingles vaccine

Metabolic Phenotypes Of Response to Vaccination in Humans

Metabolic responses to Zostavax vaccines over time (days 1, 3, 7). Source: Li et al., Cell, 2018

Zostavax is a licensed live-attenuated vaccine for prevention of HZ (shingles) in individuals aged 50 and above. HZ is caused by varicella zoster virus (VZV) reactivation, and Zostavax has been previously shown to confer ~50% reduction in HZ. Interestingly, the efficacy against HZ was 63.9% in subjects who were 60–69 years old but only 37.6% in subjects older than 70 years. In this article published in Cell, Li et al investigates why the efficacy of Zostavax could be different in the young and old subjects, using a multi-omics approach. Main findings are summarised below:

77 participants enrolled. 33 were young adults between the ages of 25 and 40 years and 44 were older subjects between the ages of 60 and 79 years.

PBMCs collected at baseline prior to vaccination and at days 1, 3, 7, 14, 28, 90, and 180 post-vaccination

Weak CD8+ T-cell responses seen in all subjects, but CD4 T-cell responses detected in the majority of subjects. Blood Tfh-like cells (CD4+CXCR5+CXCR3+ICOS+ T cells), known to be important in providing B-cell help, was also increased in both the young and elderly adults after vaccination.

The younger subjects had a greater increase of VZV-specific IgG antibody after vaccination compared to the elderly subjects.

Transcriptomics show increased interferon-stimulated genes at days 1 and 3, but the induction of these innate immune genes were of a smaller magnitude than the Yellow Fever live-attenuated vaccine. This is then followed by increased immunoglobulin transcripts at day 7. Of note, the increase in immunoglobulin genes coincided with the increase in antigen-specific plasmablast cells.

Comparing between young and elderly subjects, most differences were seen at baseline, including increased expression of genes in gene modules related to inflammation, cytosolic DNA sensing, and NK cells.

Among the different cell population phenotypes measured, day 7 IFN-γ+ T cells is the most significant predictor of IgG response. High activity in inositol phosphate metabolism is also associated with reduced T cell and B cell responses.

Sterol regulatory binding protein 1 and its targets is most predictive of Tfh response, IgG response, and the associations between genes and metabolite networks, including chemokine signaling (CCL23, CCL19, and CCR3), TNF/MAPK signaling (TNFSF11, VACM1, and DUSP6), complement genes (C1QA and C1QB), killer cell immunoglobulin-like receptors (KIR3DL3, KIR2DL3, and KIR2DS5), and lipid metabolic enzymes (ACSM2A, ACSM2B, and DGAT2).

Data is available at GEO: GSE79396