Systems Vaccinology Identifies an Early Innate Immune Signature as a Correlate of Antibody Responses to the Ebola Vaccine rVSV-ZEBOV

Rechtien, Anne; Richert, Laura; Lorenzo, Hadrien; Martrus, Gloria; Hejblum, Boris; Dahlke, Christine; Kasonta, Rahel; Zinser, Madeleine; Stubbe, Hans; Matschl, Urte; Lohse, Ansgar; Krähling, Verena; Eickmann, Markus; Becker, Stephan; Thiébaut, Rodolphe; Altfeld, Marcus; Addo, Marylyn

Recent outbreaks of emerging infections, caused by viruses such as Ebola, Middle East Respiratory Syndrome (MERS), Coronavirus, and Zika Virus, represent a global threat and emphasize the critical need for new vaccine concepts and vectors and for rapid clinical development. However, predicting and achieving vaccine efficacy remains a major challenge in the acceleration of vaccine development. Systems vaccinology approaches can assist with the identification of early immune signatures predictive of vaccine immunogenicity (Pulendran et al., 2010) . Previous studies have investigated the potential of early innate immune signatures to predict the antibody response to vaccines, such as the yellow fever or influenza vaccines (Nakaya et al., 2011; Querec et al., 2009; Gaucher et al., 2008; Furman et al., 2013) , among others (Li et al., 2014) , but it remains unknown whether molecular signatures can be identified that can be used to predict immune responses to novel vaccines. Here we applied a systems vaccinology approach to disentangle the early innate immune responses elicited by the Ebola vaccine rVSV-Zaire Ebola virus (ZEBOV) to identify innate immune responses correlating with Ebola virus (EBOV)-glycoprotein (GP)specific antibody induction. This replication-competent recombinant vaccine candidate is based on the vesicular stomatitis virus (rVSV)-based vaccine vector, for which limited data on immune responses and no innate immunity profiles in humans have been reported thus far. rVSV-ZEBOV represents one of the most promising Ebola vaccine candidates to date, with anticipated licensure expected soon. This vaccine has shown to be protective in relevant EBOV animal challenge models, including nonhuman primates (NHPs), where it conferred 100% protection (Jones et al., 2005; Qiu et al., 2009; Geisbert et al., 2008 Geisbert et al., ,2009 . Furthermore, it is the only EBOV candidate vaccine for which an efficacy evaluation against the risk of infection in humans was possible. A cluster-randomized ring vaccination trial conducted in Guinea in 2015 showed promising results, demonstrating that a strategy of contact tracing and immediate ring vaccination of contacts with the rVSV-ZEBOV vaccine protects against Ebola virus disease compared with controls (Henao-Restrepo et al., 2017) . While this ring vaccination trial was focused on clinical endpoints only and did not assess immune responses induced by the vaccine, the safety and immunogenicity of vaccination with rVSV-ZEBOV were evaluated in 2014-2015 in a number of investigator-initiated dose-escalation phase 1 clinical trials coordinated through a World Health Organization (WHO)-led African and European VSV-Ebola Consortium (VEBCON), which informed dose selection for the efficacy trials. These harmonized but independent investigatorinitiated phase I trials were completed in 2015 and took place at four different international sites, including the University Medical Center Hamburg-Eppendorf (UKE) in Germany (Agnandji et al., 2016) . In these trials, vaccination with rVSV-ZEBOV was shown to be immunogenic and induced GP-specific antibodies in all participants (Agnandji et al., 2016) . However, the immunological mechanisms leading to antibody induction, in particular the role of early innate immune responses to this vaccine vector, remain to be elucidated.