Type I Interferon Promotes Humoral Immunity in Viral Vector Vaccination

Abstract

Recombinant viral vectors are an important platform for vaccine delivery. Our recent study has demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus vs. poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type-I IFN and inflammasome activation. However, impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we showed that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated type-I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type-I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo . Following vaccination, type-I IFN receptor knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to the wild-type (WT) mice. Consistent with the antibody response, type-I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to those in WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type-I IFN signaling also promoted the generation of vaccine-specific CD4 T-cell response and T follicular helper (Tfh) response in mice. Together, our data indicate a role of type-I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type-I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and its impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1-/- mice as a model, our study reports that type-I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Findings of the present study provide insights not only for basic understanding of host-viral vector interactions, but also for improving vaccine design by potentially modulating type-I IFN and its associated innate immune pathways in viral vector vaccination.

Disruption of the cGAS/STING axis does not impair sensing of MVA in BHK21 cells

“…As poxviruses replicate their DNA genomes in the cytoplasm, they must avoid detection by a number of DNA sensors. It has been demonstrated that MVA triggers an antiviral response in several human and mouse cell types in a cGAS-and STING-dependent manner [32][33][34][35]. This is in agreement with the absence of multiple viral immunomodulators in the virus as a result of multiple genomic alterations that occurred during its extensive passage in avian cells.…”

“…Poxin is highly conserved in orthopoxviruses (OPXV) but it is inactivated in MVA [29,30]. Whilst viruses carrying poxin effectively prevent STING activation, MVA infection of human and mouse cells results in strong induction of IFN and pro-inflammatory cytokines that is dependent on cGAS and STING [31][32][33] that is crucial for the establishment of cytotoxic T cell responses and memory T cell formation [34,35]. The cGAS/STING axis is therefore essential for the antiviral response against MVA.…”

Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies

“…Subsequently, these transcriptional changes lead to a coordinated and sustained anti-tumor immune response across multiple cell types ( 17 ). In addition, type I IFN is a potent adjuvant for inducing primary Ab responses ( 18 , 19 ) and plays an essential role in linking innate and adaptive immunity ( 20 ). In the context of tumoral immunity, type I IFNs can inhibit tumor cell survival, suppress angiogenesis, and stimulate the activity of T, natural killer, and dendritic cells (DCs).…”

Characterizing the cellular and molecular variabilities of peripheral immune cells in healthy recipients of BBIBP-CorV inactivated SARS-CoV-2 vaccine by single-cell RNA sequencing

“…The upregulated DEGs in CD16 + monocytes in the 2V7 and 2V14 groups were enriched in “type I interferon production”, “positive regulation of cytokine production”, “response to interferon gamma”, “toll-like receptor signaling pathway” and “antigen processing and exogenous antigen” pathways ( Figure 2 E, F). Notably, type I interferon signalling promotes humoral immunity following vaccination, including vaccine-induced antibody, B cell and follicular helper T (Tfh) cell responses [ 33 ]. Additionally, we analyzed the expression of type I interferon production-related pathway in innate immune cells across four time points.…”