Article

Genetic basis for adverse events after smallpox vaccination.

Computational Genetics Laboratory, Dartmouth Medical School, Lebanon, New Hampshire, USA.
The Journal of Infectious Diseases (Impact Factor: 5.78). 07/2008; 198(1):16-22. DOI: 10.1086/588670
Source: PubMed

ABSTRACT Identifying genetic factors associated with the development of adverse events might allow screening before vaccinia virus administration. Two independent clinical trials of the smallpox vaccine (Aventis Pasteur) were conducted in healthy, vaccinia virus-naive adult volunteers. Volunteers were assessed repeatedly for local and systemic adverse events (AEs) associated with the receipt of vaccine and underwent genotyping for 1,442 singlenucleotide polymorphisms (SNPs). In the first study, 36 SNPs in 26 genes were associated with systemic AEs (P <or= .05); these 26 genes were tested in the second study. In the final analysis, 3 SNPs were consistently associated with AEs in both studies. The presence of a nonsynonymous SNP in the methylenetetrahydrofolate reductase (MTHFR)gene was associated with the risk ofAEin both trials (odds ratio [OR], 2.3 [95% confidence interval {CI}, 1.1-5.2] [P = .04] and OR, 4.1 [95% CI, 1.4 -11.4] [P<.01]). Two SNPs in the interferon regulatory factor-1 (IRF1) gene were associated with the risk of AE in both sample sets (OR, 3.2 [95% CI, 1.1-9.8] [P = .03] andOR, 3.0 [95% CI, 1.1- 8.3] [P = .03]). Genetic polymorphisms in genes expressing an enzyme previously associated with adverse reactions to a variety of pharmacologic agents (MTHFR) and an immunological transcription factor (IRF1) were associated with AEs after smallpox vaccination in 2 independent study samples.

Download full-text

Full-text

Available from: James E Crowe, Jun 28, 2015
0 Followers
 · 
116 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The pharmaceutical industry is spending increasingly large amounts of money on the discovery and development of novel medicines, but this investment is not adequately paying off in an increased rate of newly approved drugs by the FDA. The post-genomic era has provided a wealth of novel approaches for generating large, high-dimensional genetic and transcriptomic data sets from large cohorts of preclinical species as well as normal and diseased individuals. This systems biology approach to understanding disease-related biology is revolutionizing our understanding of the cellular pathways and gene networks underlying the onset of disease, and the mechanisms of pharmacological treatments that ameliorate disease phenotypes. In this article, we review a number of approaches being used by pharmaceutical and biotechnology companies, e.g., high-throughput DNA genotyping, sequencing, and genome-wide gene expression profiling, to enable drug discovery and development through the identification of new drug targets and biomarkers of disease progression, drug pharmacodynamics, and predictive markers for selecting the patients most likely to respond to therapy.
    Current topics in microbiology and immunology 08/2012; 363. DOI:10.1007/82_2012_252 · 3.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: For decades, the search for new vaccine adjuvants has been largely empirical. A series of new adjuvants and related formulations are now emerging that are acting through identified immunological mechanisms. Understanding adjuvant mechanism of action is crucial for vaccine design, since this allows for directing immune responses towards efficacious disease-specific effector mechanisms and appropriate memory. It is also of great importance to build new paradigms for assessing adjuvant safety at development stages and at regulatory level. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference, organized by the International Association for Biologicals (IABS), on the mode of action of adjuvants on 29-30 April 2010 in Bethesda, Maryland, USA, particularly focusing on how understanding adjuvants mode of action can impact on the assessment of vaccine safety and help to develop target-specific vaccines. More information on the conference output can be found on the IABS website, http://www.iabs.org/.
    Biologicals 09/2010; 38(5):594-601. DOI:10.1016/j.biologicals.2010.06.002 · 1.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the development of adverse events (AEs) in patients after smallpox vaccination. As vaccination was successful in all of the patients under study, the AE outcomes reported likely represent the result of interactions among immune system components that result in excessive or prolonged immune stimulation. In this study, we examined 1442 genetic variables (single nucleotide polymorphisms) and 108 proteomic variables (serum cytokine concentrations) to model AE risk. To accomplish this daunting analytical task, we employed the Random Forests (RF) method to filter the most important attributes, then we used the selected attributes to build a final decision tree model. This strategy is well suited to integrated analysis, as relevant attributes may be selected from categorical or continuous data. Importantly, RF is a natural approach for studying the type of gene-gene, gene-protein and protein-protein interactions we hypothesize to be involved in the development of clinical AEs. RF importance scores for particular attributes take interactions into account, and there may be interactions across data types. Combining information from previous studies on AEs related to smallpox vaccination with the genetic and proteomic attributes identified by RF, we built a comprehensive model of AE development that includes the cytokines intercellular adhesion molecule-1 (ICAM-1 or CD54), interleukin-10 (IL-10), and colony stimulating factor-3 (CSF-3 or G-CSF) and a genetic polymorphism in the cytokine gene interleukin-4 (IL4). The biological factors included in the model support our hypothesized mechanism for the development of AEs involving prolonged stimulation of inflammatory pathways and an imbalance of normal tissue damage repair pathways. This study shows the utility of RF for such analytical tasks, while both enhancing and reinforcing our working model of AE development after smallpox vaccination.
    Genes and immunity 11/2008; 10(2):112-9. DOI:10.1038/gene.2008.80 · 3.79 Impact Factor