Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

Fathi, Anahita; Dahlke, Christine; Addo, Marylyn M.

Animal models can be crucial to decipher immune response mechanisms important for protection. In the past, guinea pig as well as non-human-primate EBOV models were used to unravel protective mechanisms. Andrea Marzi and colleagues comprehensively analyzed EBOV challenges in cynomolgus macaques after vaccination. Depletion methods, in which CD4+ and CD8+ T cells as well as B-cells were blocked, revealed a critical role for EBOV GP-specific antibodies. 66 The pivotal role of VSV-EBOV-induced innate immunity in conferring early antiviral control and generating effective humoral immune responses was demonstrated in an NHP challenge model. Transcriptional whole blood profiling from vaccinated animals challenged at different timepoints (28, 21, 14, 7 and 3 days p.v.) uncovered that genes associated with antiviral innate responses were upregulated at early timepoints, and were delayed in an animal that did not survive challenge at day 3 p.v. 50, 67 The collection of samples obtained during the West African epidemic and the ongoing outbreak in the DRC together with numerous individuals vaccinated with VSV-EBOV can now generate a highly valuable body of information to fill critical knowledge gaps regarding mechanisms crucial for immune protection. A first meta-analysis has now been published by Gross and colleagues summarizing antibody responses of all clinical trials in which VSV-EBOV was tested. 68 All studies observed induction of EBOV GP-specific antibody responses following immunization with VSV. Antibody responses developed at 14 days p.v., peaked around day 28 and remained detectable for at least 2 years. 28, 29, 40 Besides evaluating humoral responses, clinical trials also evaluated all other arms of immune responses. One study focused on T follicular helper (TFH) cells and observed a correlation with antibody titers. 69 Cellular immune responses were observed in the cohort receiving a dose of 2 × 10 7 PFU. Here, EBOV GP specific T-cells secreted mainly CD107a and TNFα, while lower dose groups showed antigen-specific T-cell responses. 70 Recent advances in our understanding of the innate immune system and the use of systems biology approaches are beginning to reveal the fundamental mechanisms by which the innate immune system orchestrates protective immune responses to vaccination. We investigated innate immune responses following VSV-EBOV immunization and our data revealed an innate immune signature that correlated with antibody responses in the Hamburg VSV-EBOV vaccine trial. 71 In addition, changes in expression levels of circulating miRNAs have been associated with increased EBOV GP-specific antibody titers. Furthermore, innate immune signatures were assessed in vaccinees from Europe and Africa, revealing an early induction at day 1 p.v. of chemokines and cytokines, associated with monocyte functionality. 72 Comprehensive evaluations of immunogenicity following VSV-EBOV vaccination are still ongoing. Systems vaccinology approaches in which clinical, immunological, transcriptomic and metabolomic data from clinical vaccine studies can now be integrated and analyzed with data from survivors will be instrumental to further identify EBOV vaccine correlates of protection.