Characterization of "Off-Target" Immune Modulation Induced by Live Attenuated Yellow Fever Vaccine

Area of Science:

• Immunology
• Vaccinology
• Molecular Biology

Background:

• Live attenuated vaccines are known to modulate immune functions, often leading to beneficial outcomes.
• Previous in vitro studies showed the live attenuated yellow fever virus (YFV) vaccine (LA-YF-Vax) suppresses T-cell receptor (TCR) signaling through an RNA-based mechanism.
• This study investigates the in vivo effects of LA-YF-Vax on TCR-mediated functions.

Purpose of the Study:

• To assess the in vivo impact of LA-YF-Vax on TCR-mediated immune functions.
• To investigate the role of serum extracellular vesicles in mediating vaccine-induced immune changes.
• To elucidate mechanisms behind the beneficial 'off-target' effects of live attenuated vaccines.

Main Methods:

• Collected serum and peripheral blood mononuclear cells (PBMCs) from participants before and after vaccination (LA-YF-Vax or quadrivalent influenza vaccine).
• Assessed TCR-mediated activation via interleukin-2 release and lymphocyte-specific Src kinase phosphorylation.
• Measured expression levels of TCR-regulating phosphatase (protein tyrosine phosphatase receptor type E [PTPRE]).

Main Results:

• LA-YF-Vax recipients showed a transient reduction in IL-2 release and PTPRE levels post-vaccination compared to pre-vaccination levels.
• Yellow fever virus (YFV) RNA was detected in 8 of 14 LA-YF-Vax recipients.
• Extracellular vesicles from the serum of LA-YF-Vax recipients reduced TCR signaling and PTPRE levels in healthy donor PBMCs, irrespective of detectable YFV RNA.

Conclusions:

• LA-YF-Vax administration leads to reduced TCR functions and PTPRE levels.
• Serum extracellular vesicles are identified as mediators of these vaccine-induced immune modulations.
• These findings suggest a mechanism contributing to the reduced immunogenicity of subsequent heterologous vaccines and highlight beneficial effects of live vaccines.