Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? From Data to Understanding through Systems Biology

Abstract

The advent of high-throughput "omics" technologies, combined with the computational and statistical methods necessary to analyze such data, have revolutionized biology, enabling a global view of the complex molecular processes and interactions that occur within a biological system. Such systems-based approaches have begun to be used in the evaluation of immune responses to vaccination, with the promise of identifying predictive biomarkers capable of rapidly evaluating vaccine efficacy, transforming our understanding of the immune mechanisms responsible for protective responses to vaccination and contributing to a new generation of rationally designed vaccines. Here we present our opinion that systems biology does indeed have a critical role in the future of vaccinology. Such approaches have shown potential in identifying transcriptional and cellular signatures of responsiveness to vaccination using diverse vaccines, adjuvants, and human populations. These findings, coupled with further mechanistic evaluation in animal models, will guide development of targeted vaccine and adjuvant formulations designed to optimally induce protective responses in populations of differing immune status.

Figure 1.

Systems biology–driven pipeline of vaccine development. In the context of clinical vaccine trials, systems-based analyses can be used to integrate immunological measurements of correlates of protection such as neutralizing antibody titers with high-throughput transcriptional, cellular, and metabolic data to establish biomarkers of protection in specific populations. Simultaneously, these approaches may also be used to identify the biological pathways activated by candidate adjuvants. This information can guide experimental validation in animal models to understand the unique mechanisms by which each adjuvant elicits protective immune responses. Together, this knowledge can be used to develop targeted vaccine–adjuvant combinations that are designed to enhance the most protective immune pathways unique to various at-risk populations. HIV, Human immunodeficiency virus; TB, tuberculosis; TLR, Toll-like receptor.

Figure 2.

Challenges of systems vaccinology. Systems-based approaches to understanding vaccine-driven immune responses face several important challenges. First, constraints on the feasibility of biopsy collection during clinical trials has led to limited development of molecular signatures associated with tissue-based responses such as germinal center activity and affinity maturation. In addition, analysis of molecular responses to vaccination has thus far been largely focused on transcriptional data. The high-throughput technologies and computational algorithms necessary to integrate diverse data types and foster a true systems-level understanding of vaccine responses are just beginning to be developed. Another important obstacle that has emerged is the difficulty in identifying robust predictive signatures of protective immune responses caused by various sources of biological and technical variability, which must be overcome if clinically relevant diagnostic tools are to be established. Finally, the foremost challenge in systems vaccinology is the need to successfully convert knowledge extracted by high-throughput data analysis into a meaningful understanding of the biological mechanisms that generate protective immune responses through hypothesis-driven animal models, in vitro experiments, and intimate collaboration between data scientists and immunologists.