Systems vaccinology and big data in the vaccine development chain

Raeven, René H. M.; van Riet, Elly; Meiring, Hugo D.; Metz, Bernard; Kersten, Gideon F. A.

There are many effective vaccines available to protect humans against infectious diseases. However, the development of vaccines against 'difficult' pathogens remains challenging. For example, vaccines against human immunodeficiency virus (HIV) and respiratory syncytial virus (RSV) are still under development. Furthermore, some existing vaccines require improved efficacy, e.g. vaccines against Bordetella pertussis, influenza viruses, Mycobacterium tuberculosis and Plasmodium species causing malaria. In addition, new infectious diseases such as severe acute respiratory syndrome and Ebola virus disease will continue to emerge, which require new vaccines to prevent epidemics. Also, therapeutic vaccines against noninfectious diseases, such as cancer, are needed. The lack of in-depth knowledge of the pathogen and requirements for protective immunity often hamper development. 1 Application of systems biology during the development of vaccines, or systems vaccinology, can be an important tool to enhance insight into immune responses induced by (candidate) vaccines or identification of (early) correlates of protection. 2,3 Alan Aderem defined systems biology as a 'comprehensive quantitative analysis of the manner in which all the components of a biological system interact functionally over time and space that is executed by an interdisciplinary team of investigators.' 4 This definition can readily be applied to study the responses to vaccination. Systems-based approaches are often labeled unbiased and broad (sometimes even the word 'holistic' is used). However, that is only true to a certain extent, as defining a research objective is already introducing bias. Often only a few analytical techniques are used (as described in the next section) to address the objectives (Fig. 1) . Usually, there are also limitations in availability of materials. For example, in preclinical studies using mice the amount of blood that can be collected is very limited, whereas in clinical studies mainly body fluids can be used, although biopsies and mucosal lavages are sometimes available. Also, time is an essential parameter of systems vaccinology for studying kinetics and cause-effect relations, but repeated sampling is limited in humans. In this review, we describe current developments of the techniques that form the pillars of systems vaccinology and discuss the implementation of systems vaccinology in the vaccine research and development chain.