Poxvirus Vectors Activate Human NK and MAIT Cells in a Type I Interferon, IL-18, and Monocyte-Dependent Manner

TL;DR

The study shows that poxvirus vaccines activate important immune cells like NK and MAIT cells through specific immune signals.

Contribution

The study identifies a conserved mechanism of immune activation by poxvirus vectors involving NK and MAIT cells.

Findings

ALVAC-HIV activates NK and MAIT cells via monocytes, cGAS, IL-18, and type I IFN.

Activation of NK and MAIT cells by ALVAC-HIV leads to B cell activation.

MVA also activates NK and MAIT cells, suggesting a conserved mechanism across poxviral vectors.

Abstract

Recombinant poxviruses have been extensively studied as vaccine vectors, yet the specific mechanisms by which they engage the immune system remain incompletely understood. ALVAC is a poxviral vector that was a component of the HIV vaccine used in the Thai RV144 trial, showing modest efficacy in reducing HIV acquisition. Here, we show that in vitro ALVAC-HIV infection of peripheral blood mononuclear cells (PBMCs) activates natural killer (NK) and mucosal-associated invariant T (MAIT) cells. This activation was partially dependent on monocytes, cGAS sensing, and production of IL-18 and type I IFN. Furthermore, ALVAC-HIV-mediated activation of NK and MAIT cells contributed to the activation of B cells. Modified vaccinia Ankara (MVA), another poxviral vector used for prevention of smallpox and mpox, similarly activated NK and MAIT cells. Overall, this suggests a conserved mechanism by which NK and MAIT cells could contribute to the immunogenicity of poxviral vectors.

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