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.

While the main focus in systems vaccinology is on vaccine-induced responses, pathogen-induced responses during infection are also of great interest, as these can enable the discovery of potential markers of, or mechanisms involved in, protective immunity, or unwanted immunological effects such as immune evasion (Fig. 2) . Systems biology can assist to investigate host-pathogen interactions by looking at pathogen behavior and clearance after infection. A natural infection sometimes induces effective protection, e.g. mumps, that may serve as a benchmark for a vaccine, whereas other pathogens may display immune evasive or suppressive responses, which one would like to avoid in a vaccine-induced response. A systems-based approach was for instance used to investigate infection-induced responses during sepsis. 98 In terms of vaccine-preventable diseases, investigators have looked at infection-induced responses for pathogens such as RSV, [99] [100] [101] M. tuberculosis, 102 B. pertussis 12,78,103 and influenza. 104, 105 The course of a B. pertussis infection was investigated in mice to unravel molecular and cellular signatures of the effective infection-induced immunity. 12, 106 Results indicated that a B. pertussis infection induced T helper type 17 (Th17) cells and mucosal IgA responses that were preceded by a prolonged acute-phase response, broad pathogen recognition and early gene signatures of subsequent T-cell recruitment in the lungs. 12 In addition, the infection led to enhanced activation of pulmonary innate immune cells and markers indicating recruitment of CCR6 + B-cells and Th17 cells. 106 These promising markers of infection-induced responses should ideally be confirmed in human B. pertussis challenge models. 107 In a comparative network analysis of two data sets, the pulmonary molecular signatures that preceded the effector cells in B. pertussis infection-induced-immunity 12 were compared with signatures induced upon pulmonary immunization with a novel Outer Membrane Vesicle Pertussis vaccine (omvPV). 15 Network analysis demonstrated that similar genes and pathways were involved in both responses but that the intensity and kinetics between infection-induced and vaccine-induced responses were different. Both responses did, however, result in induction Systems approaches have also been used to investigate innate responses, for example responses induced by adjuvants. 108 In vitro studies were performed to investigate monocyte-specific responses induced by alum salts using a proteomics approach 109 and to study subset-specific dendritic cell responses following lipopolysaccharide stimulation using a transcriptomics approach. 110 These extensive in vitro studies provide insight into novel markers, pathways and cell subsets activated by adjuvants. Yet the complexity of cell-to-cell interaction during immune Relevant animal models to study infection are not always available. In such cases, the application of systems approaches in vaccination studies can provide valuable information on the mechanism of action of candidate vaccines. G omez et al. unraveled transcriptomic activation markers of human myeloid and plasmacytoid dendritic cells upon stimulation with a vaccine candidate against HIV/AIDS, based on an MVA-based vector. Subsequently, HIV-1-specific CD4 + and CD8 + T-cell memory responses were demonstrated in vivo. 114 Strouts et al. 115 were able to link early specific gene transcripts related to T-cell activation and type I inter