Predicting and achieving vaccine efficacy remains a major challenge. Here, Rechtien et al used 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. Of note, this replication-competent recombinant vaccine candidate is based on the vesicular stomatitis virus (rVSV)-based vaccine vector, which has been shown safe and immunogenic in a number of phase I trials.
The vaccine rVSV-ZEBOV induced a rapid and robust increase in cytokine levels, with a maximum peak at day 1, especially for CXCL10, MCP-1 and MIP-1β. Assessment of PBMCs revealed significant induction of co-stimulatory molecules, monocyte/DC activation and NK cell activation at day 1 post-vaccination. The expression of these molecules begin to decline at day 3.
Interestingly, CXCL10 plasma levels and frequency of activated NK cells at day 3 were found to be positively correlated with antibody responses. CD86+ expression in monocytes and mDCs at day 3 are negatively correlated with antibody responses (See figure on top).
The most number of upregulated genes were detected at day 1 post-vaccination. Critically, the early gene signature linked to CXCL10 pathway, including TIFA (TRAF-interacting protein with forkhead-associated domain) on day 1, SLC6A9 (solute carrier family 6 member 9) on day 3, NFKB1 and NFKB2 were most predictive of antibody responses.
rVSV∆G-ZEBOV-GP is a recombinant vaccine based on the Vesicular Stomatitis Virus (VSV), where the original VSV glycoprotein encoding gene was deleted and replaced with the surface glycoprotein (GP) encoding gene from the Ebolavirus Zaire strain (ZEBOV).
The vaccine was shown to be safe, although occasionally associated with transient reactogenicity. However, the host response to the vaccine has not been thoroughly investigated.
In this manuscript by F Santoro et al., 2021, the blood transcriptomic response to high dose vaccination (107 and 5 × 107 pfu) with rVSV∆G- ZEBOV-GP was analysed in 51 volunteers. Whole blood data was taken from day 0, 1, 2, 3, 7, 14, 21 and 28.
Vaccination resulted in greatest host transcriptomic changes at day 1, which lasts till day 3 (see top figure). Notably, the massive transcriptomic changes on days 1-2 corresponds to the timing of occurrence of mild to moderate reactogenicity events (chills, fever, headache, fatigue or myalgia) in 50 out of 51 vaccinees
Viral load differences did not affect host responses to vaccine, except for the MZB1 gene, coding for Marginal Zone B And B1 Cell Specific Protein.
Most blood transcriptomic module correlations with anti-ZEBOV GP IgGs were detected at day 14 post-vaccination. As expected, B cell activation and BCR signaling modules were observed to correlate with vaccine immunogenicity. Other modules that were significantly correlated at day 14 involve pathways such as calcium signalling, cell adhesion and activating transcription factor networks, which are possibly related to signal transduction.