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.

After vaccines have been licensed and introduced on the market, post-marketing surveillance studies are performed to monitor vaccine safety and efficacy in larger populations (Fig. 2) . At this point in the vaccine life cycle, correlates of protection, or surrogates thereof, are sometimes known, however the mechanism of action is often underexposed. Systems approaches in this phase are not routinely applied, as far as we know. The validation of the methods is complex and expensive, with the added value not yet proven convincingly. However, pioneering studies have demonstrated that vaccine efficacy after yellow fever and influenza vaccination could be predicted in an early stage after immunization by analyzing molecular signatures. 14, 126, 127 For the yellow fever vaccine, the enhanced levels of specific gene expression profiles in blood obtained 1 to 7 days after vaccination were predictive for antigen-specific CD8 + T-cell levels and antibody titers usually obtained 60 days after immunization, thus inducing a significant time advantage. In a clinical phase, regulators might want to see positive classical end-points but for post-marketing purposes this approach of looking at early correlates may be valuable. Furthermore, these studies are of value in comparative studies of different vaccine formulations. Nakaya et al. 128 compared two different vaccine formulations, trivalent inactivated influenza vaccine (TIV) and MF59-adjuvanted TIV (ATIV), in children and predicted influenza antibody titers 1 month after vaccination with a seasonal influenza vaccine across five consecutive seasons by analyzing specific signatures of innate immunity and plasma blasts. 129 In addition, a systems biology approach could also be applied to investigate the differences in vaccine responsiveness in different target groups. For example, researchers predicted age-related vaccine hypo-responses against a hepatitis B vaccine in the elderly with a gene marker 130 and exposed transcriptomic signatures of vaccine-induced immunity, both cellular and humoral immune responses, after seasonal influenza vaccination specifically in older adults. 131 Obviously, these post-marketing surveillance studies facilitate further clinical development of improved vaccines or provide insight into general mechanisms that will enhance future vaccine development, even if correlates of protection are unknown. 132 Finally, a great benefit of systems vaccinology studies is the ability to combine data sets from vaccine responses against different pathogens in integrative network modeling to reveal detailed insight into universal signatures of vaccine responsiveness. 78, 79, 118, 133 Li et al. 79 compared molecular signatures, induced by five different human vaccines against specific bacterial or viral infections, which could predict antibody responses. This indicates that investigating responses against a single pathogen can lead to universal markers that serve as benchmark for vaccine development against new emerging diseases. This also supports the desire for data obtained in systemsapproaches to be publicly available (open access) for future large meta-analyses.