Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement

Batista-Duharte, Alexander; Sendra, Luis; Herrero, Marí­a José; Téllez-Martínez, Damiana; Carlos, Iracilda Zeppone; Aliño, Salvador F.

doi:10.3390/biom10020316

Cited by 21 publications

(20 citation statements)

References 144 publications

(181 reference statements)

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“…Several studies have shown that oligonucleotides can improve the efficacy of vaccines, either by inducing antigen modification (i.e., by enhancing expression of immunogenic molecules) or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extensive use, problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe oligonucleotide-based vaccines [ 66 ]. For many years, nucleic acids and short nucleotide molecules have been used as vaccine components.…”

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confidence: 99%

SARS-CoV-2 will constantly sweep its tracks: a vaccine containing CpG motifs in ‘lasso’ for the multi-faced virus

et al. 2020

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During the current COVID-19 pandemic, the global ratio between the dead and the survivors is approximately 1 to 10, which has put humanity on high alert and provided strong motivation for the intensive search for vaccines and drugs. It is already clear that if we follow the most likely scenario, which is similar to that used to create seasonal influenza vaccines, then we will need to develop improved vaccine formulas every year to control the spread of the new, highly mutable coronavirus SARS-CoV-2. In this article, using well-known RNA viruses (HIV, influenza viruses, HCV) as examples, we consider the main successes and failures in creating primarily highly effective vaccines. The experience accumulated dealing with the biology of zoonotic RNA viruses suggests that the fight against COVID-19 will be difficult and lengthy. The most effective vaccines against SARS-CoV-2 will be those able to form highly effective memory cells for both humoral (memory B cells) and cellular (cross-reactive antiviral memory T cells) immunity. Unfortunately, RNA viruses constantly sweep their tracks and perhaps one of the most promising solutions in the fight against the COVID-19 pandemic is the creation of 'universal' vaccines based on conservative SARS-CoV-2 genome sequences (antigen-presenting) and unmethylated CpG dinucleotides (adjuvant) in the composition of the phosphorothioate backbone of single-stranded DNA oligonucleotides (ODN), which can be effective for long periods of use. Here, we propose a SARS-CoV-2 vaccine based on a lasso-like phosphorothioate oligonucleotide construction containing CpG motifs and the antigen-presenting unique ACG-containing genome sequence of SARS-CoV-2. We found that CpG dinucleotides are the least rare dinucleotides in the genomes of SARS-CoV-2 and other known human coronaviruses, and hypothesized that their higher frequency could be responsible for the unwanted increased lethality to the host, causing a ‘cytokine storm’ in people who overexpress cytokines through the activation of specific Toll-like receptors in a manner similar to TLR9-CpG ODN interactions. Interestingly, the virus strains sequenced in China (Wuhan) in February 2020 contained on average one CpG dinucleotide more in their genome than the later strains from the USA (New York) sequenced in May 2020. Obviously, during the first steps of the microevolution of SARS-CoV-2 in the human population, natural selection tends to select viral genomes containing fewer CpG motifs that do not trigger a strong innate immune response, so the infected person has moderate symptoms and spreads SARS-CoV-2 more readily. However, in our opinion, unmethylated CpG dinucleotides are also capable of preparing the host immune system for the coronavirus infection and should be present in SARS-CoV-2 vaccines as strong adjuvants.

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confidence: 99%

SARS-CoV-2 will constantly sweep its tracks: a vaccine containing CpG motifs in ‘lasso’ for the multi-faced virus

et al. 2020

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“…This location allowed us to estimate that its possible site of action could be at the pre-RNA level, still containing the non-coding sequences. Therefore, the probable silencing mechanism could occur through the action of an RNAse-H, which cleaves the heterodimer, or also by a steric hindrance mechanism and splicing inhibition [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…Given the known deleterious effects of Tregs in vaccine immunogenicity and efficacy, one of the current directions of this approach is the development of subunit vaccines and molecular adjuvants targeting immune regulatory networks to improve vaccine immunogenicity [ 15 ]. The use of ASOs targeting important regulatory mechanisms is one of the most promising molecular adjuvants for vaccine improvement [ 16 ]. Several ASOs have been designed against immunomodulatory components, such as cytokines [ 29 , 30 ], immune checkpoints [ 31 , 32 ], or transcription factors [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, there has been great interest in developing molecular adjuvants with inhibitory effects on Tregs, aiming to improve the immunogenicity and vaccine efficacy [ 14 , 15 ] against deleterious foreign antigens. One of the newer strategies for depletion/inhibition of Tregs in vaccines has been the use of antisense oligonucleotides (ASOs) targeting important immunosuppressor pathways or immune checkpoints [ 16 ]. ASOs are small-sized (around 20 nucleotides) single-stranded oligonucleotides designed to bind specifically to the RNA or DNA target, based on their sequence homology, and bring about gene silencing [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Foxp3 Silencing with Antisense Oligonucleotide Improves Immunogenicity of an Adjuvanted Recombinant Vaccine against Sporothrix schenckii

Batista-Duharte

Sendra

Herrero

et al. 2021

IJMS

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Background: In recent years, there has been great interest in developing molecular adjuvants based on antisense oligonucleotides (ASOs) targeting immunosuppressor pathways with inhibitory effects on regulatory T cells (Tregs) to improve immunogenicity and vaccine efficacy. We aim to evaluate the immunostimulating effect of 2′OMe phosphorothioated Foxp3-targeted ASO in an antifungal adjuvanted recombinant vaccine. Methods: The uptake kinetics of Foxp3 ASO, its cytotoxicity and its ability to deplete Tregs were evaluated in murine splenocytes in vitro. Groups of mice were vaccinated with recombinant enolase (Eno) of Sporothix schenckii in Montanide Gel 01 adjuvant alone or in combination with either 1 µg or 8 µg of Foxp3 ASO. The titers of antigen-specific antibody in serum samples from vaccinated mice (male C57BL/6) were determined by ELISA (enzyme-linked immunosorbent assay). Cultured splenocytes from each group were activated in vitro with Eno and the levels of IFN-γ and IL-12 were also measured by ELISA. The results showed that the anti-Eno antibody titer was significantly higher upon addition of 8 µM Foxp3 ASO in the vaccine formulation compared to the standard vaccine without ASO. In vitro and in vivo experiments suggest that Foxp3 ASO enhances specific immune responses by means of Treg depletion during vaccination. Conclusion: Foxp3 ASO significantly enhances immune responses against co-delivered adjuvanted recombinant Eno vaccine and it has the potential to improve vaccine immunogenicity.

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“…A review article about the use of ASOs for vaccine improvement based on the strategy of antigen modification has recently been published [7]. The first attempts using ASOs for antigen manipulation started in 1990.…”

Section: Inhibition Of Hiv-1 Rnamentioning

confidence: 99%

Phosphate-Methylated Oligonucleotides Past, Present and Future

Buck¹

2020

JBPC

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At the moment, we see a great interest for application of Anti Sense Oligonucleotides (ASOs) in order to regulate the expression of genes related to certain diseases. These nucleotides obtained a number of fascinating properties by means of chemical manipulation of natural DNA and RNA under conservation of Watson-Crick base-pairing. About 35 years ago for our research in this field, we selected synthetically (short) phosphate-methylated DNA and RNA. It was concluded that there is an exclusive selection in hybridization affinity with natural DNA and RNA. These (bio)chemical and physical-chemical properties are extensively published. ASOs have found their way in public health as is clearly shown in the treatment of (progressive) neurological diseases. We focus specifically on the past, present and future of the phosphate-methylated oligonucleotides, illustrated with different research studies in chemistry and biophysics. A new field of application of modified DNAs is based on interactive improvements of sensitivity and specificity of nanowire field effect transistor gene chip by designing phosphate-methylated DNA as probe.

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Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement

Cited by 21 publications

References 144 publications

SARS-CoV-2 will constantly sweep its tracks: a vaccine containing CpG motifs in ‘lasso’ for the multi-faced virus

SARS-CoV-2 will constantly sweep its tracks: a vaccine containing CpG motifs in ‘lasso’ for the multi-faced virus

Foxp3 Silencing with Antisense Oligonucleotide Improves Immunogenicity of an Adjuvanted Recombinant Vaccine against Sporothrix schenckii

Phosphate-Methylated Oligonucleotides Past, Present and Future

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