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.

Predictive markers that have been found in the exploratory studies (described in the previous section) can be applied in subsequent clinical studies. Moreover, systems vaccinology analyses are also useful in a clinical study itself to obtain better insight into safety and efficacy (Fig. 2) . However, to our knowledge in only a few clinical studies has systems vaccinology been performed to assess signatures that correlate to adverse effects, such as fever and seizures. In the public-private project BIOVACSAFE, systems approaches are applied to investigate markers correlating to vaccine safety in human and animal models potentially providing novel markers. 119 Investigators have conducted systems-based studies in humans investigating vaccine candidates against Ebola (rVSV-ZEBOV), 120 HIV-1, 121 malaria (RTS,S) 122, 123 and M. tuberculosis (M72/ AS01). 124 For Ebola (rVSV-ZEBOV), IP-10 and CXCR6 + natural killer (NK) cells were independently correlating with antibody titers, suggesting that IP-10 could be a potential target to influence vaccine-induced responses. 120 Anderson et al. 121 investigated transcriptome profiles in the blood of healthy volunteers following immunization with a novel HIV-1 vaccine adjuvanted with a Toll-like receptor 4 agonist. High responders, based on serum antibodies, contained modules of genes expressed in NK cells, whereas modules of genes related to myeloid cells, monocytes and integrin cell surface interactions were detected in low responders. These signatures enable vaccine responses to be distinguished in an early phase and perhaps even allows steering of immune responses in low responders by adjustment of the vaccine. In a phase I randomized controlled trial using AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines, the effect of adjuvant on vaccine-induced responses, such as serum cytokines, antibody titers, and gene expression levels, was investigated. This led to novel insights into antigen processing, presentation markers in neutrophils and revealed the correlation of serum IP-10 levels with proliferation of NK cells. 125 Interestingly, for the prediction of protection induced by malaria (RTS,S) immunization, NK cells correlated negatively whereas positive correlations were detected for molecular signatures of B-cells and plasma cells 122 factor-jB and interferon-c pathways. 123 These findings indicate that different vaccine-adjuvant combinations may induce different immune (non)effective responses.