Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy

Area of Science:

• Immunology
• Vaccinology
• Virology

Background:

• Simian immunodeficiency virus (SIV) challenge in rhesus macaques (RMs) vaccinated with Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) yields a binary outcome: ~55% achieve SIV control and clearance, while 45% remain unprotected.
• Previous studies identified SIV-specific, effector-memory (EM)-biased CD8+ T cell responses as necessary for vaccine efficacy, but response magnitude does not predict protection, leaving the basis of protection versus non-protection unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying vaccine efficacy and non-efficacy in RhCMV/SIV vector-vaccinated rhesus macaques.
• To identify host immune response pathways that correlate with protection against SIV challenge.
• To investigate the role of interleukin-15 (IL-15) signaling in mediating vaccine-induced protection.

Main Methods:

• Whole blood transcriptome analysis of vaccinated rhesus macaques to identify immune-related gene expression pathways.
• Correlation analysis between gene expression signatures and vaccine efficacy (SIV control/clearance).
• Intervention study involving IL-15 treatment in a separate RM cohort to confirm its role in the protection signature.

Main Results:

• RhCMV/SIV vector administration induced sustained changes in the whole blood transcriptome, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and IL-15 signaling pathways, which significantly correlated with vaccine efficacy.
• IL-15 treatment confirmed its central role in the protection signature, linking innate and adaptive immune gene expression networks to RhCMV/SIV vaccine efficacy.
• A robust de novo vaccine-induced IL-15 signaling response, correlated with reduced baseline IL-15 pathway activity, was necessary for vaccine protection.

Conclusions:

• The RhCMV/SIV vaccine elicits a coordinated and persistent induction of innate and adaptive immune pathways, notably IL-15 signaling.
• IL-15, a regulator of CD8+ T cell function, is critical for programming vaccine efficacy by supporting the protective capacity of vaccine-elicited CD8+ T cells.
• Understanding these IL-15-mediated immune signatures provides insights into developing effective SIV vaccines.