New approach to vaccine discovery and development.

<p><a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002344#ppat-1002344-g001" target="_blank">Figure 1</a> illustrates the differences between the one-size-fits-all approach of empiric vaccine development with a more directed and personal approach that relies upon vaccinomics and high-dimensional “omics” technologies. By analogy, empiric vaccine development represents the undifferentiated light entering the prism from the left. Individual aspects of directed vaccine development can be seen when viewed through the prism of vaccinomics. Several examples of these components are illustrated in the rainbow on the right side of the figure. These aspects may or may not be appropriate for all vaccines and are used here to illustrate the wide range of possibilities that a “discover – validate – characterize – deploy” approach allows one to independently investigate, optimize, and fully utilize. Below the vaccinomics prism are listed some examples (by no means complete or definitive) representing a range of potential components that can be assembled into a comprehensive, systems-level examination of infection/vaccination of a given pathogen. Please refer to the text for examples of how different components might be used in the development of specific vaccines.</p

Distribution of measles vaccine–induced antibody levels.

<p>This graph represents the distribution of antibody levels determined by an EIA assay on healthy grade-school children immunized with a single dose of MMR-II vaccine. The inter-individual variation in antibody levels among this healthy cohort illustrates the importance of determining the mechanisms for heterogeneity in vaccine response.</p

Demographic characteristics of the study population (n = 714).

<p>Demographic characteristics of the study population (n = 714).</p

Associations between extended class I-HLA-LTA-TNF-LST1 haplotypes and class I HLA-only haplotypes, and rubella-specific cytokine responses.

<p>Only haplotypes with estimated frequencies ≥0.01 and <i>p</i>-values ≤0.15 are presented.</p>a<p>Haplotype effects estimated using a haplotype t-statistic that assesses associations of cytokine levels across haplotypes. Allele <i>p</i>-value compares the haplotype of interest to all other haplotypes combined. Statistically significant findings (<i>p</i><0.05) are shown in bold. Analyses adjust for age at blood draw, gender, race, age at first rubella vaccine, age at second rubella vaccine, and cohort status.</p>b<p>Common SNPs from the LTA gene: [rs2857602 (A>G), rs2857708 (G>A), rs915654 (T>A), rs2844482 (G>A), rs1041981 (C>A), rs1799964 (A>G), rs1799724 (G>A)]; TNF gene: rs1800629 (G>A); LST1 gene: [rs2256965 (G>A), and rs2256974 (C>A)].</p

Associations between extended class I HLA-LTA-TNF-LST1-class II HLA haplotypes and class I-class II HLA-only haplotypes, and rubella-specific cytokine responses.

<p>Only haplotypes with estimated frequencies ≥0.01 and <i>p</i>-values ≤0.15 are presented.</p>a<p>Haplotype effects estimated using a haplotype t-statistic that assesses associations of cytokine levels across haplotypes. Allele <i>p</i>-value compares the haplotype of interest to all other haplotypes combined. Statistically significant findings (<i>p</i><0.05) are shown in bold. Analyses adjust for age at blood draw, gender, race, age at first rubella vaccine, age at second rubella vaccine, and cohort status.</p>b<p>Common SNPs from the LTA gene: [rs2857602 (A>G), rs2857708 (G>A), rs915654 (T>A), rs2844482 (G>A), rs1041981 (C>A), rs1799964 (A>G), rs1799724 (G>A)]; TNF gene: rs1800629 (G>A); LST1 gene: [rs2256965 (G>A), and rs2256974 (C>A)].</p

A schematic overview of the extended human leukocyte antigen (HLA) complex, encompassing the lymphotoxin alpha (LTA), tumor necrosis factor (TNF) and leukocyte specific transcript -1 (LST1) genes on chromosome 6 (6p21.3).

<p>A 3,145 kb segment of the extended HLA gene region is shown. The LTA, TNF, and LST1 loci encoded in the class III region of the HLA complex in relation to HLA-B and HLA-DRB1 loci. The positions of single nucleotide polymorphisms (SNPs) selected from LTA [rs2857602 (31641357), rs2857708 (31641585), rs915654 (31646476), rs2844482 (31647746), rs1041981 (31648763), rs1799964 (31650287), rs1799724 (31650461)], TNF [rs1800629 (31651010)], and LST1 [rs2256965 (31663109), rs2256974 (31663371)] gene families and used for haplotype estimation are shown. Targeted sets of extended haplotypes used in this study: (1) haplotypes containing the three class I HLA loci (A-C-B) and the set of ten-SNP haplotypes, (2) haplotypes containing ten-SNP haplotypes and the class II HLA loci (DRB1-DQA1-DQB1-DPA1-DPB1), and (3) haplotypes containing class I HLA loci (A-C-B), the set of ten-SNP haplotypes, and alleles of class II HLA loci (DRB1-DQA1-DQB1-DPA1-DPB1). Note: the figure is not to scale.</p

Associations between extended haplotypes and HLA-only haplotypes, and rubella virus-specific antibody responses.

<p>Only haplotypes with estimated frequencies ≥0.01 and <i>p</i>-values ≤0.15 are presented.</p>a<p>Haplotype effects estimated using a haplotype t-statistic that assesses associations of antibody levels across haplotypes. Allele <i>p</i>-value compares the haplotype of interest to all other haplotypes combined. Statistically significant findings (<i>p</i><0.05) are shown in bold. Analyses adjust for age at blood draw, gender, race, age at first rubella vaccine, age at second rubella vaccine, and cohort status.</p>b<p>Common SNPs from the LTA gene: [rs2857602 (A>G), rs2857708 (G>A), rs915654 (T>A), rs2844482 (G>A), rs1041981 (C>A), rs1799964 (A>G), rs1799724 (G>A)]; TNF gene: rs1800629 (G>A); LST1 gene: [rs2256965 (G>A), and rs2256974 (C>A)].</p

RXR network predicted by IMP using <i>THRB</i> (square node) as a seed from the empirical epistasis network analysis.

<p>Empirical seed was chosen from the top enriched pathway from the epistasis network analysis of the smallpox vaccine GWAS. Variants in <i>RXRA</i> (purple node) have been previously associated with variation in smallpox vaccination response using an epistasis network centrality approach.</p

Positive/negative epistasis degree plot shows the overall epistatic network effect and main effect of the top variants for smallpox vaccine immune response.

<p>For each variant (mapped to gene symbol), the sum of positive interaction coefficients (positive epistasis degree) versus negative epistasis degree is plotted. The diagonal is the line of zero sum of epistasis degree. Plot symbols (size and color) are labeled by their main effect (magnitude and direction of effect on vaccine immune response). The gray box highlights the <i>THBR</i> variant.</p

SNPrank centrality score elbow plot.

<p>The SNPrank scores are plotted for the top 500 variants. The red dashed line represents the null centrality line.</p