Systems biology approaches to new vaccine development

Abstract

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.

Figure 1. An iterative systems biology approach to vaccine development

Movement from one phase to the next involves updating known biological knowledge with implications for study design, analytical strategies, study endpoints and laboratory techniques. Organize: Includes selecting the appropriate high-dimensional ‘omics’ technologies to interrogate the appropriate biological systems (DNA, RNA, protein, lipid, cell subset, etc…) as well as organizing and integrating a priori known knowledge regarding pathways and networks. Analyze: Includes strategies for study design and modeling methods to truly integrate data spanning each of the assayed biological systems. This step also includes statistical techniques to maximize power and minimize false discoveries while modeling the complex interactions and developing a greater understanding of both the host and pathogen biologies underlying the immune process. Utilize: Applying the new knowledge gained from the systems-level analysis to logically target areas for vaccine improvement. These could impact vaccine composition (an adjuvant driving appropriate Th1/Th2 balance), or efficacy testing (early immune signatures predictive of vaccine response). Immunize: Includes the physical steps necessary to implement the needed changes for novel vaccine development (moving from egg-based to cell-line based vaccine production) and to introduce the new vaccine into the population (clinical trials to confirm improved safety profiles or enhanced immunogenicity using newly discovered biomarkers).

Figure 2. Application of systems biology to vaccine development

From Jenner's initial work with cowpox forward, vaccine development was an empirical science based on incomplete understanding of immune processes leading to protection. Pathogenic organisms were attenuated, inactivated, or killed and then injected. Success led to large-scale use of the vaccine, while failure meant repeating the process with a new pathogen strain or different inactivation procedure. The factors controlling success or failure were largely unknown. With a systems biology approach, modern high-dimensional data acquisition techniques allow researchers to comprehensively characterize the epigenetic, transcriptomic, proteomic, metabolomic, and other essential features of host-pathogen interactions and immune regulatory networks and processes in order to more fully elucidate the biological rules governing “immunity” enhancing our understanding of the “black box”. Cutting-edge bioinformatic algorithms and statistical methods are used to gain a deeper understanding of the data, which is then applied to develop next-generation vaccines which appropriately stimulate the key drivers of immune response.

Figure 3. Two pronged systems biology approach to understanding influenza vaccine response in the elderly

Our primary biology to gene approach is a deductive approach relying on known biological information to construct gene sets known to be involved in key immune processes. Integrated transcriptomic/proteomic/cellular data from our profiling assays will be used to develop immunologic profiles related to defined immune response outcomes as described. Our secondary gene to biology approach is an inductive, evidence based approach which will rely on individual variables. Modules in this approach are genes with co-regulated gene expression. This has historically been the primary analytical approach in the gene expression literature.