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Review
. 2020 Feb 17;10(2):316.
doi: 10.3390/biom10020316.

Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement

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Free PMC article
Review

Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement

Alexander Batista-Duharte et al. Biomolecules. .
Free PMC article

Abstract

: Antisense oligonucleotides (ASOs) are synthetically prepared short single-stranded deoxynucleotide sequences that have been validated as therapeutic agents and as a valuable tool in molecular driving biology. ASOs can block the expression of specific target genes via complementary hybridization to mRNA. Due to their high specificity and well-known mechanism of action, there has been a growing interest in using them for improving vaccine efficacy. Several studies have shown that ASOs can improve the efficacy of vaccines either by inducing antigen modification such as enhanced expression of immunogenic molecules or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extended use, some problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe ASO-based vaccines. In this review, we analyze the molecular bases and the research that has been conducted to demonstrate the potential use of ASOs in vaccines.

Keywords: adjuvants; antisense oligonucleotide; cancer; infectious disease; vaccines.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Main mechanisms of action of antisense oligonucleotides. (A) Normal gene and protein expression in the absence of ASO. (B) In cytoplasm, ASOs can bind to a complementary mRNA region. ASO-mRNA heteroduplex can induce the activation of RNase H, leading to mRNA degradation. Alternatively, ASOs can block the translation process without promoting RNA degradation by steric interference of ribosomal assembly. (C) ASO can enter the nucleus and hinder mRNA maturation by inhibition of 5′ cap formation, RNase H-mediated pre-RNA cleavage, and inhibition of mRNA splicing.
Figure 2
Figure 2
Types of ASOs-mediated toxicity: (1) Hybridization-independent toxicity represent those effects that are not due to Watson–Crick base pairing between an ASO and RNA. This type of toxicity occurs by three possible mechanisms: (A) ASOs accumulation effect is manifested as cytoplasmic granule accumulation, degenerative changes in kidney or liver epithelium, and presence of vacuolated macrophages. (B) Proinflammatory mechanisms due to ASOs interaction with innate immune receptors, inducing macrophages activation, complement activation, and immunocomplex formation. (C) Aptameric binding to intracellular cell surface or extracellular proteins. (2) Hybridization-dependent toxicity can be caused by partial or complete ASO interaction with unintended transcripts (hybridization-dependent off-target effects [OTEs]); or with intended transcripts (on-target toxicity).
Figure 3
Figure 3
Tumor cells are forced to present their own tumor antigens to the immune system by anti-li ASO treatment. Left, MHC class I presents endogenous tumor antigens to CD8+ cytotoxic T cells (CTL). Ii protein blocks the binding of endogenous antigens to MHC class II in the endoplasmic reticulum (ER). Right, anti li-ASO blocks Ii protein expression, and endogenous tumor antigens are also presented by MHC class II molecules and recognized by specific Th1 lymphocytes. The simultaneous presentation of tumor antigens by both MHC class I to CTL and MHC II to Th1 lymphocytes induces a stronger antitumor response. (Adapted from [117]).
Figure 4
Figure 4
Some examples of the use of ASOs as vaccine adjuvant by modulating the regulatory T cells (Tregs) response. Left, molecules involved in Tregs function that are currently being studied as target for vaccine improvement with ASOs. CTLA-4, T-lymphocyte antigen4; DC, dendritic cells; IL-, interleukin; LAG-3, lymphocyte activation gene-3; TGFβ, transforming growth factor beta; TCR, T cells receptor. Right, (A) Normal post-vaccination immune response without Tregs modulation. (B) ASO-mediated transitory Tregs depletion/inhibition elicit a stronger vaccine immune response.

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