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Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response.

Matsumiya M, Harris SA, Satti I, Stockdale L, Tanner R, O'Shea MK, Tameris M, Mahomed H, Hatherill M, Scriba TJ, Hanekom WA, McShane H, Fletcher HA - BMC Infect. Dis. (2014)

Bottom Line: One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples.Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination.The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults.

View Article: PubMed Central - HTML - PubMed

Affiliation: Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, UK. magali.matsumiya@ndm.ox.ac.uk.

ABSTRACT

Background: Tuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population.

Methods: We investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis.

Results: One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A.

Conclusion: The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies.

Trial registration: ClinicalTrials.gov number NCT00953927.

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Related in: MedlinePlus

Heatmap of differential gene expression 1 day post vaccination. Heatmap showing changes in gene expression one day post-vaccination with either MVA85A or a Candin placebo. Colors at the top show vaccination: MVA85A (blue) or Candin (red). Genes were selected on the basis of differential expression between the two groups (fdr < 0.05). Clustering using euclidean distance and average clustering methods. Red indicates up-regulated mRNA, blue indicates downregulated.
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Figure 1: Heatmap of differential gene expression 1 day post vaccination. Heatmap showing changes in gene expression one day post-vaccination with either MVA85A or a Candin placebo. Colors at the top show vaccination: MVA85A (blue) or Candin (red). Genes were selected on the basis of differential expression between the two groups (fdr < 0.05). Clustering using euclidean distance and average clustering methods. Red indicates up-regulated mRNA, blue indicates downregulated.

Mentions: Illumina microarray gene expression analysis of 82 whole blood samples taken one day post-vaccination (37 MVA85A, 45 Candin placebo) identified 32 differentially expressed genes. These genes were largely associated with the immune response (differentially expressed genes are shown in Table 2 with genes associated with the immune response highlighted in bold). Hierarchical clustering showed that infants fall into three clusters with a mixed MVA85A/Candin cluster exhibiting a moderate level of expression of inflammatory genes (Figure 1). This analysis shows MVA85A-vaccinated infants exhibit a more inflammatory gene expression profile than those in the placebo group however the range is large in both groups and there is an overlap between the two groups. This overlap could be due to the immunomodulatory properties of Candin, which induces inflammation and may lead to functional reprogramming of monocytes associated with protection from subsequent infection[34].


Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response.

Matsumiya M, Harris SA, Satti I, Stockdale L, Tanner R, O'Shea MK, Tameris M, Mahomed H, Hatherill M, Scriba TJ, Hanekom WA, McShane H, Fletcher HA - BMC Infect. Dis. (2014)

Heatmap of differential gene expression 1 day post vaccination. Heatmap showing changes in gene expression one day post-vaccination with either MVA85A or a Candin placebo. Colors at the top show vaccination: MVA85A (blue) or Candin (red). Genes were selected on the basis of differential expression between the two groups (fdr < 0.05). Clustering using euclidean distance and average clustering methods. Red indicates up-regulated mRNA, blue indicates downregulated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061512&req=5

Figure 1: Heatmap of differential gene expression 1 day post vaccination. Heatmap showing changes in gene expression one day post-vaccination with either MVA85A or a Candin placebo. Colors at the top show vaccination: MVA85A (blue) or Candin (red). Genes were selected on the basis of differential expression between the two groups (fdr < 0.05). Clustering using euclidean distance and average clustering methods. Red indicates up-regulated mRNA, blue indicates downregulated.
Mentions: Illumina microarray gene expression analysis of 82 whole blood samples taken one day post-vaccination (37 MVA85A, 45 Candin placebo) identified 32 differentially expressed genes. These genes were largely associated with the immune response (differentially expressed genes are shown in Table 2 with genes associated with the immune response highlighted in bold). Hierarchical clustering showed that infants fall into three clusters with a mixed MVA85A/Candin cluster exhibiting a moderate level of expression of inflammatory genes (Figure 1). This analysis shows MVA85A-vaccinated infants exhibit a more inflammatory gene expression profile than those in the placebo group however the range is large in both groups and there is an overlap between the two groups. This overlap could be due to the immunomodulatory properties of Candin, which induces inflammation and may lead to functional reprogramming of monocytes associated with protection from subsequent infection[34].

Bottom Line: One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples.Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination.The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults.

View Article: PubMed Central - HTML - PubMed

Affiliation: Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, UK. magali.matsumiya@ndm.ox.ac.uk.

ABSTRACT

Background: Tuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population.

Methods: We investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis.

Results: One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A.

Conclusion: The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies.

Trial registration: ClinicalTrials.gov number NCT00953927.

Show MeSH
Related in: MedlinePlus