Available online at www.sciencedirect.com Systems biology approaches to new vaccine development Ann L Oberg 1,2 , Richard B Kennedy 2,3 , Peter Li 1,2 , Inna G Ovsyannikova 2,3 and Gregory A Poland 2,3 The current ‘isolate, inactivate, inject’ vaccine development strategy has served the field of vaccinology well, and such empirical vaccine candidate development has even led to the eradication of smallpox. However, such an approach suffers from limitations, and as an empirical approach, does not fully utilize our knowledge of immunology and genetics. A more complete understanding of the biological processes culminating in disease resistance is needed. The advent of high-dimensional assay technology and ‘systems biology’ along with a vaccinomics approach [1,2  ] is spawning a new era in the science of vaccine development. Here we review recent developments in systems biology and strategies for applying this approach and its resulting data to expand our knowledge base and drive directed development of new vaccines. We also provide applied examples and point out new directions for the field in order to illustrate the power of systems biology. Addresses 1 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States 2 Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN, United States 3 The Program in Translational Immunovirology and Biodefense and the Department of Medicine, Mayo Clinic, Rochester, MN, United States Corresponding author: Poland, Gregory A (poland.gregory@mayo.edu) Current Opinion in Immunology 2011, 23:436–443 This review comes from a themed issue on Vaccines Edited by Jeffrey Ulmer and Marcelo Sztein Available online 11 May 2011 0952-7915/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2011.04.005 Vaccines and the promise of systems biology Vaccines have been among the most successful public health interventions to date with most vaccine-preven- table diseases having declined in the United States by 95– 99% or more [3]. As we move into the 21st century; however, it is apparent that future vaccine development will be more difficult as more complex organisms become vaccine targets. To date, vaccine development has been empiric, often characterized by an ‘isolate, inactivate, inject’ paradigm of development. Such an approach ignores both pathogen and host variability and as a result, significant limitations ensue such as inadequate immune protection, the inability to develop vaccines against hypervariable viruses (e.g. HIV, HCV, etc.), and an insufficient understanding of how protective immune responses develop and persist over time in response to vaccine antigens. The past several years have seen an increasing emphasis on systems biology science that is expected to aid researchers in elucidating the pathways and networks involved in diverse biological processes. While the defi- nition is evolving, systems biology has been described as ‘‘an interdisciplinary approach that systematically describes the complex interactions between all the parts in a biological system, with a view to elucidating new biological rules capable of predicting the behavior of the biological system’’ [4]. Biological systems are more than simple collections of genes/proteins; they are complex, intricately interacting sets of functional and sometimes redundant pathways that collectively produce coherent behaviors [5], of which the innate and adaptive immune responses are perfect examples. For this reason, vaccinol- ogists in the 21st century must not only use increasingly high throughput technology to understand immune pro- filing after vaccination, but must also consider strategies designed to understand how such data can be harnessed toward new vaccine development. With the remarkable advances in technology it is appropriate to review how new technology, systems biology, and the analytic and bioinformatic approaches used to make sense of the data generated, can be best harnessed toward the goal of new vaccine development. We frame our review with a new paradigm to vaccine development with four phases: organize, analyze, utilize and immunize (Figure 1). Organize Over the past decade or so, many high dimensional assays have become available to researchers allowing interrogation of thousands to millions of endpoints. These can be orga- nized according to biological system or network within an organism. Importantly, these ‘omics’ technologies are avail- able for the large-scale characterization of many of the essential components of biological systems such as: 1) DNA including: single nucleotide polymorphisms (SNPs), genetic insertions and deletions, chromosomal copy num- ber variation (CNV), and DNA methylation, 2) RNA including: mRNA expression, microRNA expression, differential transcript detection, RNA interference screen- ing, and 3) Protein including: protein expression and local- ization, protein–protein interaction using yeast 2-hybrid screening. The list will only grow with newly emerging fields, such as lipidomics, metabolomics, interactomics, Current Opinion in Immunology 2011, 23:436–443 www.sciencedirect.com