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Current Opinion in Immunology Oct 2023Oral vaccines have a distinctive advantage of stimulating immune responses in the mucosa, where numerous pathogens gain entry and cause disease. Although various efforts... (Review)
Review
Oral vaccines have a distinctive advantage of stimulating immune responses in the mucosa, where numerous pathogens gain entry and cause disease. Although various efforts have been attempted to create recombinant mucosal vaccines that provoke strong immunogenicity, the outcomes in clinical trials have been weak or inconsistent. Therefore, next-generation mucosal vaccines are needed that are more immunogenic. Here, we discuss oral vaccines with an emphasis on a next-generation mucosal vaccine that utilizes a nonreplicating human recombinant adenovirus type-5 (rAd5) vector. Numerous positive clinical results investigating oral rAd5 vaccines are reviewed, with a summary of the immunogenicity and efficacy results for specific vaccine indications of influenza, norovirus, and SARS-CoV-2. The determination of correlates of protection for oral vaccination and the potential impact this novel vaccine formulation may have on disease transmission are also discussed. In summary, successful oral vaccination can be accomplished and would have major public health benefits if approved.
Topics: Humans; COVID-19; SARS-CoV-2; Adenoviridae; Vaccines, Synthetic; Vaccination; Antibodies, Viral
PubMed: 37562075
DOI: 10.1016/j.coi.2023.102374 -
Viruses Jul 2023Worldwide, acute gastroenteritis (AGE) is a major cause of morbidity and mortality in children under 5 years of age. Viruses, including norovirus, rotavirus, and enteric...
Worldwide, acute gastroenteritis (AGE) is a major cause of morbidity and mortality in children under 5 years of age. Viruses, including norovirus, rotavirus, and enteric adenovirus, are the leading causes of pediatric AGE. In this prospective cohort study, we investigated the viral load and duration of shedding of norovirus, rotavirus, and adenovirus in stool samples collected from 173 children (median age: 15 months) with AGE who presented to emergency departments (EDs) across Canada on Day 0 (day of enrollment), and 5 and 28 days after enrollment. Quantitative RT-qPCR was performed to assess the viral load. On Day 0, norovirus viral load was significantly lower compared to that of rotavirus and adenovirus ( < 0.001). However, on Days 5 and 28, the viral load of norovirus was higher than that of adenovirus and rotavirus ( < 0.05). On Day 28, norovirus was detected in 70% (35/50) of children who submitted stool specimens, while rotavirus and adenovirus were detected in 52.4% (11/24) and 13.6% (3/22) of children ( < 0.001), respectively. Overall, in stool samples of children with AGE who presented to EDs, rotavirus and adenovirus had higher viral loads at presentation compared to norovirus; however, norovirus was shed in stool for the longest duration.
Topics: Child; Humans; Infant; Child, Preschool; Rotavirus; Adenoviridae; Norovirus; Prospective Studies; Gastroenteritis; Adenoviridae Infections; Feces; Rotavirus Infections; Caliciviridae Infections
PubMed: 37515227
DOI: 10.3390/v15071541 -
Pathogenicity and virulence of human adenovirus F41: Possible links to severe hepatitis in children.Virulence Dec 2023Over 100 human adenoviruses (HAdVs) have been isolated and allocated to seven species, A-G. Species F comprises two members-HAdV-F40 and HAdV-F41. As their primary site... (Review)
Review
Over 100 human adenoviruses (HAdVs) have been isolated and allocated to seven species, A-G. Species F comprises two members-HAdV-F40 and HAdV-F41. As their primary site of infection is the gastrointestinal tract they have been termed, with species A, enteric adenoviruses. HAdV-F40 and HAdV-F41 are a common cause of gastroenteritis and diarrhoea in children. Partly because of difficulties in propagating the viruses in the laboratory, due to their restrictions on growth in many cell lines, our knowledge of the properties of individual viral proteins is limited. However, the structure of HAdV-F41 has recently been determined by cryo-electron microscopy. The overall structure is similar to those of HAdV-C5 and HAdV-D26 although with some differences. The sequence and arrangement of the hexon hypervariable region 1 (HVR1) and the arrangement of the C-terminal region of protein IX differ. Variations in the penton base and hexon HVR1 may play a role in facilitating infection of intestinal cells by HAdV-F41. A unique feature of HAdV-F40 and F41, among human adenoviruses, is the presence and expression of two fibre genes, giving long and short fibre proteins. This may also contribute to the tropism of these viruses. HAdV-F41 has been linked to a recent outbreak of severe acute hepatitis "of unknown origin" in young children. Further investigation has shown a very high prevalence of adeno-associated virus-2 in the liver and/or plasma of some cohorts of patients. These observations have proved controversial as HAdV-F41 had not been reported to infect the liver and AAV-2 has generally been considered harmless.
Topics: Humans; Child; Child, Preschool; Adenoviruses, Human; Virulence; Cryoelectron Microscopy; Adenovirus Infections, Human; Hepatitis; Hepatitis A; Phylogeny
PubMed: 37543996
DOI: 10.1080/21505594.2023.2242544 -
Molecular Therapy : the Journal of the... Jul 2023OBP-301 is an oncolytic adenovirus modified to replicate within cancer cells and lyse them. This open-label, non-comparative, phase I dose-escalation trial aimed to...
OBP-301 is an oncolytic adenovirus modified to replicate within cancer cells and lyse them. This open-label, non-comparative, phase I dose-escalation trial aimed to assess its safety and optimal dosage in 20 patients with advanced hepatocellular carcinoma. Good tolerance was shown with a maximum tolerated dose of 6 × 10 viral particles. The most common treatment-emergent adverse events were influenza-like illness, pyrexia, fatigue, decreased platelet count, abdominal distension, and anemia. Cohorts 4 and 5 had approximately 50% higher levels of CD8+ T cells in the peripheral blood after injection. The best target response occurred in 14 patients, 4 of whom had progressive disease. Multiple intratumoral injections of OBP-301 were well tolerated in patients with advanced hepatocellular carcinoma. The stable disease rate for the injected tumors was greater than the overall response rate, even with no obvious tumor response. OBP-301 might have a greater impact on local response as histological examination revealed that the presence of OBP-301 was consistent with the necrotic area at the injection site. Increased infiltration of CD8+ T cells and <1% PD-L1 expression were observed in tumors after injection. Improved antitumor efficacy might be achieved in future studies via viral injection with volume adjustment and in combination with other immuno-therapeutics.
Topics: Humans; Adenoviridae; Carcinoma, Hepatocellular; Liver Neoplasms; Cell Line, Tumor; Oncolytic Virotherapy; Oncolytic Viruses; Telomerase
PubMed: 37060176
DOI: 10.1016/j.ymthe.2023.04.006 -
PloS One 2023In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/mutTKSR39rep-hIL-12) was...
In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/mutTKSR39rep-hIL-12) was administered in 15 subjects with localized recurrent prostate cancer (T1c-T2) at increasing doses (1 × 1010, to 1 × 1012 viral particles) followed by 7-day treatment of 5-fluorocytosine (5-FC) and valganciclovir (vGCV). The primary endpoint was toxicity through day 30 while the secondary and exploratory endpoints were quantitation of IL-12, IFNγ, CXCL10 and peripheral blood mononuclear cells (PBMC). The study maximum tolerated dose (MTD) was not reached indicating 1012 viral particles was safe. Total 115 adverse events were observed, most of which (92%) were grade 1/2 that did not require any treatment. Adenoviral DNA was detected only in two patients. Increase in IL-12, IFNγ, and CXCL10 was observed in 57%, 93%, and 79% patients, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in the highest-dose cohorts. PBMC analysis revealed immune system activation after gene therapy in cohort 5. The PSA doubling time (PSADT) pre and post treatment has a median of 1.55 years vs 1.18 years. This trial confirmed that replication-competent Ad5-IL-12 adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) was well tolerated when administered locally to prostate tumors.
Topics: Humans; Male; Adenocarcinoma; Adenoviridae; Genetic Therapy; Interleukin-12; Leukocytes, Mononuclear; Prostate; Prostatic Neoplasms; Genes, Transgenic, Suicide; Oncolytic Virotherapy
PubMed: 37713401
DOI: 10.1371/journal.pone.0291315 -
Journal of Translational Medicine Oct 2023Systemic administration of oncolytic adenovirus for cancer therapy is still a challenge. Mesenchymal stem cells as cell carriers have gained increasing attention in drug...
BACKGROUND
Systemic administration of oncolytic adenovirus for cancer therapy is still a challenge. Mesenchymal stem cells as cell carriers have gained increasing attention in drug delivery due to their excellent tumor tropism, immunosuppressive modulatory effects, and paracrine effects. However, the potential of human dental pulp stem cells (hDPSCs) loaded with oncolytic adenovirus for cancer biotherapy has not been investigated yet.
METHODS
The stemness of hDPSCs was characterized by FACS analysis and Alizarin red staining, Oil Red O staining, and immunofluorescence assays. The biological fitness of hDPSCs loaded with oncolytic adenovirus YSCH-01 was confirmed by virus infection with different dosages and cell viability CCK-8 assays. Additionally, the expression of CAR receptor in hDPSCs was detected by qPCR assay. Tumor tropism of hDPSC loaded with YSCH-01 in vitro and in vivo was investigated by Transwell assays and living tumor-bearing mice imaging technology and immunohistochemistry, Panoramic scanning of frozen section slices assay analysis. Furthermore, the antitumor efficacy was observed through the different routes of YSCH-01/hPDSCs administration in SW780 and SCC152 xenograft models. The direct tumor cell-killing effect of YSCH-01/hDPSCs in the co-culture system was studied, and the supernatant of YSCH-01/hDPSCs inhibited cell growth was further analyzed by CCK-8 assays.
RESULTS
hDPSCs were found to be susceptible to infection by a novel oncolytic adenovirus named YSCH-01 and were capable of transporting this virus to tumor sites at 1000 VP/cell infectious dosage in vitro and in vivo. Moreover, it was discovered that intraperitoneal injection of hDPSCs loaded with oncolytic adenovirus YSCH-01 exhibited potential anti-tumor effects in both SW780 and SCC152 xenograft models. The crucial role played by the supernatant secretome derived from hDPSCs loaded with YSCH-01 significantly exerted a specific anti-tumor effect without toxicity for normal cells, in both an active oncolytic virus and an exogenous protein-independent manner. Furthermore, the use of hDPSCs as a cell carrier significantly reduced the required dosage of virus delivery in vivo compared to other methods.
CONCLUSIONS
These findings highlight the promising clinical potential of hDPSCs as a novel cell carrier in the field of oncolytic virus-based anti-cancer therapy.
Topics: Humans; Mice; Animals; Adenoviridae; Dental Pulp; Sincalide; Oncolytic Viruses; Oncolytic Virotherapy; Mesenchymal Stem Cells; Xenograft Model Antitumor Assays
PubMed: 37789452
DOI: 10.1186/s12967-023-04539-z -
Journal of Virology Aug 2023Human adenovirus (HAdV) is ubiquitous in the human population, constituting a significant burden of global respiratory diseases. Children and individuals with low...
Human adenovirus (HAdV) is ubiquitous in the human population, constituting a significant burden of global respiratory diseases. Children and individuals with low immunity are at risk of developing severe infections without approved antiviral treatment for HAdV. Our study demonstrated that TRIM35 inhibited HAdV-C5 early gene transcription, early protein expression, genome replication, and infectious virus progeny production. Furthermore, TRIM35 was found to inhibit HAdV replication by attenuating E1A expression. Mechanistically, TRIM35 interacts with and degrades E1A by promoting its K48-linked ubiquitination. Additionally, K253 and K285 are the key sites necessary for TRIM35 degradation. Moreover, an oncolytic adenovirus carrying shTRIM35 was constructed and observed to exhibit improved oncolysis , providing new ideas for clinical tumor treatment. Our results expand the broad antiviral activity of TRIM35 and mechanically support its application as a HAdV replication inhibitor. IMPORTANCE E1A is an essential human adenovirus (HAdV) protein responsible for the early replication of adenovirus while interacting with multiple host proteins. Understanding the interaction between HAdV E1A and TRIM35 helps identify effective antiviral therapeutic targets. The viral E1A protein is a crucial activator and regulator of viral transcription during the early infection stages. We first reported that TRIM35 interacts with E1A to resist adenovirus infection. Our study demonstrated that TRIM35 targets E1A to resist adenovirus, indicating the applicability of targeting virus-dependent host factors as a suitable antiviral strategy.
Topics: Humans; Adenovirus E1A Proteins; Adenoviruses, Human; Antiviral Agents; Apoptosis Regulatory Proteins; Virus Replication
PubMed: 37578239
DOI: 10.1128/jvi.00700-23 -
Current Opinion in Virology Jun 2024Oncogenic viruses contribute to 15% of global human cancers. To achieve that, virus-encoded oncoproteins deregulate cellular transcription, antagonize common cellular... (Review)
Review
Oncogenic viruses contribute to 15% of global human cancers. To achieve that, virus-encoded oncoproteins deregulate cellular transcription, antagonize common cellular pathways, and thus drive cell transformation. Notably, adenoviruses were the first human viruses proven to induce cancers in diverse animal models. Over the past decades, human adenovirus (HAdV)-mediated oncogenic transformation has been pivotal in deciphering underlying molecular mechanisms. Key adenovirus oncoproteins, encoded in early regions 1 (E1) and 4 (E4), co-ordinate these processes. Among the different adenovirus species, the most extensively studied HAdV-C5 displays lower oncogenicity than HAdV-A12. A complete understanding of the different HAdV-A12 and HAdV-C5 oncoproteins in virus-mediated cell transformation, as summarized here, is relevant for adenovirus research and offers broader insights into viral transformation and oncogenesis.
PubMed: 38865835
DOI: 10.1016/j.coviro.2024.101413 -
The Journal of Gene Medicine Dec 2023Adenovirus expresses two non-coding virus-associated (VA) RNAs: VA I RNA and VA II RNA. Adenovirus-expressed VA RNAs interfere with the microRNA (miRNA) pathway by...
BACKGROUND
Adenovirus expresses two non-coding virus-associated (VA) RNAs: VA I RNA and VA II RNA. Adenovirus-expressed VA RNAs interfere with the microRNA (miRNA) pathway by competing with precursor miRNAs. The processing pattern of primary miRNA (pri-miRNA) and factors to affect its processing are not exactly known when using adenovirus for the delivery of pri-miRNA.
METHODS
To observe pri-miRNA processing, plasmid construct encoding pri-miRNA was co-transfected with VA I/II RNA expression plasmid, or recombinant adenovirus encoding pri-miRNA was generated and infected. Levels of miRNAs, VA I RNA and VA II RNA were analyzed by a quantitative real-time PCR (RT-PCR). VA I-II full-length RNA was analyzed by a RT-PCR. RNA immunoprecipitation analysis to pull-down the VA I-II full-length RNA binding with Drosha was conducted with Drosha antibody.
RESULTS
pri-miRNA was normally processed into mature miRNA when it was expressed in cells using plasmid. However, miRNA maturation was impaired when pri-miRNA was delivered and expressed using adenovirus. Of note, pri-miRNA processing was observed to be blocked by VA RNA expression. Such blocked processing could be recovered by introducing antisense RNA of VA RNA, anti-3'VA RNA. In addition, VA RNAs were transcribed into VA I-II full-length RNA, which was found to bind and sequester Drosha.
CONCLUSIONS
Adenovirus infection downregulated the processing of pri-miRNAs in cells, and such downregulation could be derived from VA I-II full-length RNAs in pri-miRNA-like form through competitively binding to Drosha protein. These results indicated that the expression of adenovirus VA RNAs should be inhibited for successful delivery and expression of pri-miRNA or shRNA in cells using adenovirus.
Topics: RNA Processing, Post-Transcriptional; MicroRNAs; RNA, Viral; Adenoviridae
PubMed: 37434327
DOI: 10.1002/jgm.3564 -
The EMBO Journal Oct 2023Within the virion, adenovirus DNA associates with the virus-encoded, protamine-like structural protein pVII. Whether this association is organized, and how genome...
Within the virion, adenovirus DNA associates with the virus-encoded, protamine-like structural protein pVII. Whether this association is organized, and how genome packaging changes during infection and subsequent transcriptional activation is currently unclear. Here, we combined RNA-seq, MNase-seq, ChIP-seq, and single genome imaging during early adenovirus infection to unveil the structure- and time-resolved dynamics of viral chromatin changes as well as their correlation with gene transcription. Our MNase mapping data indicates that the adenoviral genome is arranged in precisely positioned nucleoprotein particles with nucleosome-like characteristics, that we term adenosomes. We identified 238 adenosomes that are positioned by a DNA sequence code and protect about 60-70 bp of DNA. The incoming adenoviral genome is more accessible at early gene loci that undergo additional chromatin de-condensation upon infection. Histone H3.3 containing nucleosomes specifically replaces pVII at distinct genomic sites and at the transcription start sites of early genes. Acetylation of H3.3 is predominant at the transcription start sites and precedes transcriptional activation. Based on our results, we propose a central role for the viral pVII nucleoprotein architecture, which is required for the dynamic structural changes during early infection, including the regulation of nucleosome assembly prior to transcription initiation. Our study thus may aid the rational development of recombinant adenoviral vectors exhibiting sustained expression in gene therapy.
Topics: Nucleosomes; Transcriptional Activation; Chromatin; DNA; Chromatin Assembly and Disassembly; Adenoviridae
PubMed: 37641864
DOI: 10.15252/embj.2023114162