Systems Vaccinomics: The Road Ahead for Vaccinology

Abstract

In 1985, an Institute of Medicine report (Division of Health Promotion and Disease Prevention and Institute of Medicine, 1985) stated: “Vaccines are an elegant solution to one of the perennial problems of the human race—infectious disease. The body's own protective mechanisms are primed by specific interventions to thwart the invasion of or multiplication of pathogenesis.” Vaccines are indeed one of the great triumphs of modern medicine and public health: they prevent disease, they are relatively inexpensive, easy to deliver and their effects long lasting, and their mechanism of action relies entirely on activation of our body's own protective immunological mechanisms. Yet, despite the historic successes of vaccines, or perhaps because of these successes, vaccinology has evolved to rely almost entirely on an empirical, trial-and-error process, in which the pathways to protective immunity—the early events that lead to the development of long-lived protection against infection by a given pathogen—remain largely unknown, and for those successful vaccines, largely unnecessary to know (D'Argenio and Wilson, 2010). Despite this, vaccinology is undoubtedly the most powerful public health intervention available, saving millions of lives and preventing disease in hundreds of millions of people worldwide. However, a better understanding of the immune response, coupled with an improved ability to elicit these responses by immunization, appears to be key to future success in vaccine development against pathogens such as HIV, tuberculosis (TB), and malaria, that have, to date, been resistant to traditional trial-and-error approaches. These three pathogens—the big three—account for a significant proportion of premature deaths and morbidity worldwide. In addition, the burden of treating these diseases has siphoned significant financial and health care resources away from other urgent global health needs. Over 11 million people live with TB, almost 250 million cases of malaria, including approximately 1 million deaths in children, were reported in 2008, whereas over 33 million people worldwide are living with HIV/AIDS, including 2.5 million people who became newly infected with HIV in 2009. Recent advances in our understanding of the human immune system and the intertwined functions of the innate and adaptive immune response, as well as new insights into host–pathogen interactions, and the development of powerful new postgenomic technologies, are now available to be focused on developing, testing, and improving vaccine candidates. One indirect and largely unanticipated side effect of the Human Genome Project has been a transformation in the power of modern biology, driven by the development of powerful new “omic” technologies (genomics, proteomics, etc.), and associated computational and high-throughput technologies. Together, these advances are fueling the development of a new science of systems biology that has opened up the ability to understand the overall architecture of complex biological systems. These advances have led to the development of new clinical investigative tools, which has made the human a robust experimental organism for discovery research (Brenner, 2003). It is timely, therefore, to undertake the development of a new science of vaccinomics that is grounded in leading edge science, including systems biology, and a culture of science-driven clinical trials and clinical research. The goals of this new science of vaccinomics or systems vaccinology (Pulendran et al., 2010) are to develop new vaccines through understanding the global architecture of the human immune response and the changes that occur following vaccination, and to define the correlates of protection, or more appropriately, the signatures of protection that are required to elicit a protective immune response. Vaccine development has largely been focused on trying to identify a specific immune response that might be exploited to develop a vaccine capable of eliciting long-lived protection against a pathogen (Plotkin, 2008). However, the power of a systems approach in unraveling potentially novel mechanisms of vaccine action, and in enabling the prediction of the immunogenicity and efficacy of vaccines, has been highlighted by recent studies (Gaucher et al., 2008; Querec et al., 2009; Young et al., 2008). With the development of high-throughput approaches that allow exploration of the interconnected networks that control and drive the immune response, vaccine development is on the verge of a fundamental shift from the search for a single correlate (or multiple, independent correlates), to the identification of multifactorial signatures associated with immunological protection. This new science of vaccinomics also promises to close the current gap between clinical trials and discovery science, a gap that has compromised vaccine development. As highlighted in the 2010 Scientific Strategic Plan of the Global HIV Vaccine Enterprise (The Council of the Global HIV Vaccine Enterprise, 2010), human clinical trials no longer need be considered as separate from fundamental research but rather can be viewed and conducted as an integral part of the research continuum between discovery and clinical testing. This transformation in thinking has been made possible by the development of robust systems biology approaches to aid both in the design and testing of novel vaccine concepts and the analysis of the complexity of the immune response in humans. With powerful new laboratory and computational techniques, the design and testing of novel vaccine candidates in humans has become feasible. Capturing the full advantage of these advances, however, will require real-time laboratory analysis in order to extract the full depth of immunological, epidemiological, and clinical information that a well-conceived and conducted trial can yield. This objective will only be realized through close partnership between basic and translational scientists, computational biologists, clinicians, statisticians, industry, regulatory authorities, and funders.