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. 2024 Mar 14;229(3):786-794.
doi: 10.1093/infdis/jiad086.

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

J Xiang  1 , Q Chang  1 , J H McLinden  1 , N Bhattarai  2 , J L Welch  1 , T M Kaufman  1 , Jack T Stapleton  1
Affiliations

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

J Xiang et al. J Infect Dis. .

Abstract

Background: Live attenuated vaccines alter immune functions and are associated with beneficial outcomes. We previously demonstrated that live attenuated yellow fever virus (YFV) vaccine (LA-YF-Vax) dampens T-cell receptor (TCR) signaling in vitro via an RNA-based mechanism. We examined study participants before and after LA-YF-Vax to assess TCR-mediated functions in vivo.

Methods: Serum samples and peripheral blood mononuclear cells (PBMCs) were obtained before and after LA-YF-Vax (with or without additional vaccines) or quadrivalent influenza vaccine. TCR-mediated activation was determined by interleukin 2 release or phosphorylation of the lymphocyte-specific Src kinase. TCR-regulating phosphatase (protein tyrosine phosphatase receptor type E [PTPRE]) expression was also measured.

Results: Compared with prevaccination findings, LA-YF-Vax recipient PBMCs demonstrated transient reduction in interleukin 2 release after TCR stimulation and PTPRE levels, unlike in control participants who received quadrivalent influenza vaccine. YFV was detected in 8 of 14 participants after LA-YF-Vax. After incubation of healthy donor PBMCs in serum-derived extracellular vesicles prepared from LA-YF-Vax recipients, TCR signaling and PTPRE levels were reduced after vaccination, even in participants without detectable YFV RNA.

Conclusions: LA-YF-Vax reduces TCR functions and PTPRE levels after vaccination. Extracellular vesicles from serum recapitulated this effect in healthy cells. This likely contributes to the reduced immunogenicity for heterologous vaccines after LA-YF-Vax administration. Identification of specific immune mechanisms related to vaccines should contribute to understanding of the "off-target," beneficial effects of live vaccines.

Keywords: Off-target vaccine effects; PTPRE; T lymphocyte; T-cell receptor; live attenuated yellow fever vaccine; vaccine; yellow fever virus.

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Conflict of interest statement

Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Live attenuated yellow fever virus vaccine (LA-YF-Vax) specifically reduces T-cell receptor (TCR)–mediated interleukin 2 (IL-2) release after vaccination. A, All 14 study participants receiving LA-YF-Vax had significantly less IL-2 released from their peripheral blood mononuclear cells 4–21 days after vaccination, compared with their prevaccination values. IL-2 was measured 16 hours after TCR stimulation. B, In contrast, none of the controls who received quadrivalent influenza vaccine (QIV) had significant changes in TCR-mediated IL-2 release. Arrows identify participants who received LA-YF-Vax ≥10 years before this immunization (participants 2, 5, and 9). *P < .05; **P < .01.
Figure 2.
Figure 2.
Live attenuated yellow fever virus vaccine (LA-YF-Vax) specifically reduces the Src kinase–activating protein tyrosine phosphatase receptor type E (PTPRE). A, PTPRE levels relative to actin within samples in circulating peripheral blood mononuclear cells were reduced in study participants receiving LA-YF-Vax 4–14 days after vaccination, compared with their prevaccination values. B, In contrast, none of the controls who received quadrivalent influenza vaccine (QIV) had significant changes in PTPRE levels relative to actin within samples. Arrows identify participants who received LA-YF-Vax ≥10 years before this immunization (participants 2, 5, and 9). *P < .05; **P < .01.
Figure 3.
Figure 3.
Serum extracellular vesicles (EVs) from live attenuated yellow fever virus (YFV) vaccine (LA-YF-Vax) recipients dampen T-cell receptor–mediated T-cell function and reduce protein tyrosine phosphatase receptor type E (PTPRE) expression. A, YFV titer in stock virus, the pellet, and supernatant from a commercial exosome purification method (ExoQuick). B–D, Incubation of healthy donor peripheral blood mononuclear cells with EVs in serum before and after vaccination led to reduction in interleukin 2 (IL-2) release (B), PTPRE expression relative to actin (C), and Lck activation (Lck-p) (D) after vaccination compared with prevaccination values. Arrows identify study participants who received LA-YF-Vax ≥10 years before this immunization (participants 2, 5, and 9). *P < .05; **P < .01. Abbreviation: TCID50, median tissue culture infective dose.
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