Systems vaccinology

Abstract

Vaccination is one of the greatest triumphs of modern medicine, yet we remain largely ignorant of the mechanisms by which successful vaccines stimulate protective immunity. Two recent advances are beginning to illuminate such mechanisms: realization of the pivotal role of the innate immune system in sensing microbes and stimulating adaptive immunity, and advances in systems biology. Recent studies have used systems biology approaches to obtain a global picture of the immune responses to vaccination in humans. This has enabled the identification of early innate signatures that predict the immunogenicity of vaccines, and identification of potentially novel mechanisms of immune regulation. Here, we review these advances and critically examine the potential opportunities and challenges posed by systems biology in vaccine development.

Figure 1. Using Systems Biology to predict the immunogenicity of the YF-17D vaccine

Schematic representation of the systems biology approach used to predict the T and B cell responses of YF-17D vaccinees (Querec et al., 2009). Healthy humans vaccinated with YF-17D are bled at the indicated time points and the innate and adaptive responses studied. Innate signatures obtained using microarrays are found to correlate with the later adaptive immune responses. The predictive power of such signatures are tested in an independent trial (trial 2).

Figure 2. Construction of a Generic Vaccine Chip

Top: Systems biology approaches allow the identification of predictive gene signatures of immunogenicity for many vaccines. Vaccines with similar correlates of protection may or may not share the same gene markers. The identification of predictive signatures of many vaccines would enable the development of a vaccine chip. Bottom: This chip would consist of perhaps a few hundred genes, subsets of which would predict a particular type of innate or adaptive immune response (e.g. magnitude of effector CD8⁺ T cell response, frequency of polyfunctional T cells, balance of T helper 1 (Th1), Th2 and Th17 cells, high-affinity antibody titers and so on). This would allow the rapid evaluation of vaccinees for the strength, type, duration and quality of protective immune responses stimulated by the vaccine. Thus, the vaccine chip is a device that could be used to predict immunogenicity and protective capacity of virtually any vaccine in the future.

Figure 3. Integrating systems biology approaches into clinical trials

Top: For vaccines for which correlates or protection are known (Table 1), systems approaches can be used to identify early signatures of protection in a phase 1 trial. The key genes from these signatures can be incorporated into a vaccine chip or ELISA kit, which can then be used to identify non responders or sub-optimal responders, particularly in special populations such as immunocompromised patients, elderly and infants. Bottom: For new and emerging vaccines, for which correlates of protection were unknown, signatures that predict various aspects of immunogenicity (e.g. CD8⁺ T cell responses or neutralizing antibody responses) can be assessed in phase I trials. Such signatures can then be incorporated into a vaccine chip or ELISA kit that can then be used in phase II and III trials to determine their capacity to predict protection. Alternatively, a retrospective nested case controlled study could be done in a phase II and III trial to identify signatures of protection.

Figure 4. A framework for systems vaccinology

Systems biology approaches applied to clinical trials can lead to the generation of new hypotheses which can be tested and ultimately lead to developing better vaccines. For example, immune responses to vaccination in clinical trials can be profiled in exquisite depth, using technologies such as microarrays, deep sequencing and proteomics. The high throughput data generated can be mined using bioinformatics tools, and used to create hypotheses about the biological mechanisms underlying vaccine induced immunity. Such hypotheses can then be tested using animal models or in vitro human systems. The insights gained from experimentation, can then guide the design and development of new vaccines. Such a framework seeks to bridge the so called gaps between clinical trials and discovery based science, between human immunology and mouse immunology, between translational and basic science, and offers a seamless continuum of scientific discovery and vaccine invention.