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Viruses Feb 2024Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important... (Review)
Review
Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important to comprehend the signaling cascades during an infection and to initiate appropriate diagnostic and therapeutic interventions. In addition, Ad vector-based vaccines have revealed significant potential in generating robust immune protection and recombinant Ad vectors facilitate efficient gene transfer to treat genetic diseases and are used as oncolytic viruses to treat cancer. Continuous improvements in gene delivery capacity, coupled with advancements in production methods, have enabled widespread application in cancer therapy, vaccine development, and gene therapy on a large scale. This review provides a comprehensive overview of the virus biology, and several aspects of recombinant Ad vectors, as well as the development of Ad vector, are discussed. Moreover, we focus on those Ads that were used in preclinical and clinical applications including regenerative medicine, vaccine development, genome engineering, treatment of genetic diseases, and virotherapy in tumor treatment.
Topics: Humans; Adenoviridae; Genetic Vectors; Genetic Therapy; Vaccines; Neoplasms; Oncolytic Virotherapy
PubMed: 38543743
DOI: 10.3390/v16030377 -
Vaccine Jul 2023Countermeasures against Zika virus (ZIKV) epidemics are urgently needed. In this study we generated a ZIKV virus-like particle (VLP) based vaccine candidate and assessed...
Countermeasures against Zika virus (ZIKV) epidemics are urgently needed. In this study we generated a ZIKV virus-like particle (VLP) based vaccine candidate and assessed the immunogenicity of these particles in mice. The ZIKV-VLPs were morphologically similar to ZIKV by electron microscopy and were recognized by anti-Flavivirus neutralising antibodies. We observed that a single dose of unadjuvanted ZIKV-VLPs, or inactivated ZIKV, generated an immune response that lasted over 6 months, but did not neutralize ZIKV infection of cells in vitro. However, when we co-administered the ZIKV VLPs with either Aluminium hydroxide (Alhydrogel®; Alum), AddaVax or PamCys we observed that Alum was the most effective in a single dose regime, since it not only produced antibodies that neutralized the virus, but also generated a greater number of antigen-specific memory B cells. We additionally observed that the generation of the neutralising antibodies persisted for up to 6 months. Our results suggest that a single dose ZIKV VLPs could be a suitable single dose vaccine candidate for use in outbreak settings.
Topics: Animals; Mice; Zika Virus; Antibodies, Neutralizing; Zika Virus Infection; Antibodies, Viral; Viral Vaccines; Adenoviridae
PubMed: 37391311
DOI: 10.1016/j.vaccine.2023.06.068 -
Diseases (Basel, Switzerland) Sep 2023Respiratory infections constitute a major reason for infants and children seeking medical advice and visiting health facilities, thus remaining a significant public...
Respiratory infections constitute a major reason for infants and children seeking medical advice and visiting health facilities, thus remaining a significant public threat with high morbidity and mortality. The predominant viruses causing viral respiratory infections are influenza A and B viruses (Flu-A, Flu-B), respiratory syncytial virus (RSV), adenovirus and coronaviruses. We aimed to record the proportion of RSV, SARS-CoV-2, influenza A/B and adenovirus cases with rapid antigen tests and validate the results with RT-PCR assays of upper respiratory specimens with a wide range of viral loads and (co)-infection patterns in children. Clinical samples were collected from early symptomatic children (presenting with fever and/or cough and/or headache within 5-7 days). The surveillance program was conducted in five private pediatric dispensaries and one pediatric care unit, from 10 January 2023 to 30 March 2023 in central Greece. The total sample of specimens collected was 784 young children and infants, of which 383 (48.8%) were female and 401 were male (51.2%). The mean age of participants was 7.3 + 5.5 years. The sensitivity of the FLU A & B test was 91.15% (95% CI: 84.33-95.67%), and the specificity was 98.96% (95% CI: 97.86-99.58%). The sensitivity and specificity of the adenovirus and RSV test was {92.45% (95% CI: 81.79-97.91%), 99.32% (95% CI: 98.41-99.78%)} and {92.59% (95% CI: 75.71-99.09%), 99.47% (95% CI: 98.65-99.86%)} respectively. Lastly, the sensitivity of the SARS-CoV-2 test was 100.00% (95% CI: 79.41-100.00%) and the specificity was 99.74% (95% CI: 99.06-99.97%). We recorded a proportion of 14.3% and 3.44% for influenza A and B, respectively, followed by a proportion of 6.9% for adenovirus, a proportion of 3.7% for RSV, and finally, a proportion of 2.3% for SARS-CoV-2. The combination of a new multiple rapid test with multiple antigens will probably be a useful tool with a financial impact for health systems targeting the early detection and appropriate treatment of respiratory infections in emergency departments in primary health care facilities.
PubMed: 37754318
DOI: 10.3390/diseases11030122 -
International Journal of Stroke :... Oct 2023Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to...
BACKGROUND
Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs.
AIMS
We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs.
METHODS
We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs).
RESULTS
Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20-37) versus 47 (IQR 32-58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95% confidence interval (CI) 11-40]) than in HICs (44/102 [43%, 95% CI 34-53], = 0.039).
CONCLUSIONS
The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.
Topics: Humans; Female; Young Adult; Adult; COVID-19 Vaccines; Developing Countries; Stroke; Thrombocytopenia; Vaccines; Sinus Thrombosis, Intracranial
PubMed: 37277922
DOI: 10.1177/17474930231182901 -
Vaccines Dec 2023Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare autoimmune condition associated with recombinant adenovirus (rAV)-based COVID-19 vaccines. It is...
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare autoimmune condition associated with recombinant adenovirus (rAV)-based COVID-19 vaccines. It is thought to arise from autoantibodies targeting platelet factor 4 (aPF4), triggered by vaccine-induced inflammation and the formation of neo-antigenic complexes between PF4 and the rAV vector. To investigate the specific induction of aPF4 by rAV-based vaccines, we examined sera from rAV vaccine recipients (AZD1222, AD26.COV2.S) and messenger RNA (mRNA) based (mRNA-1273, BNT162b2) COVID-19 vaccine recipients. We compared the antibody fold change (FC) for aPF4 and for antiphospholipid antibodies (aPL) of rAV to mRNA vaccine recipients. We combined two biobanks of Dutch healthcare workers and matched rAV-vaccinated individuals to mRNA-vaccinated controls, based on age, sex and prior history of COVID-19 (AZD1222: 37, Ad26.COV2.S: 35, mRNA-1273: 47, BNT162b2: 26). We found no significant differences in aPF4 FCs after the first (0.99 vs. 1.08, mean difference (MD) = -0.11 (95% CI -0.23 to 0.057)) and second doses of AZD1222 (0.99 vs. 1.10, MD = -0.11 (95% CI -0.31 to 0.10)) and after a single dose of Ad26.COV2.S compared to mRNA-based vaccines (1.01 vs. 0.99, MD = 0.026 (95% CI -0.13 to 0.18)). The mean FCs for the aPL in rAV-based vaccine recipients were similar to those in mRNA-based vaccines. No correlation was observed between post-vaccination aPF4 levels and vaccine type (mean aPF difference -0.070 (95% CI -0.14 to 0.002) mRNA vs. rAV). In summary, our study indicates that rAV and mRNA-based COVID-19 vaccines do not substantially elevate aPF4 levels in healthy individuals.
PubMed: 38140254
DOI: 10.3390/vaccines11121851 -
Microbiology Spectrum Aug 2023Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes....
Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes. Presently, there are no approved antiviral drugs against enteroviruses. Here, we studied the potency of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAF mutant-related melanoma, as an antiviral against enteroviruses. We showed that vemurafenib prevented enterovirus translation and replication at low micromolar dosage in an RAF/MEK/ERK-independent manner. Vemurafenib was effective against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect was related to a cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevented infection efficiently in acute cell models, eradicated infection in a chronic cell model, and lowered virus amounts in pancreas and heart in an acute mouse model. Altogether, instead of acting through the RAF/MEK/ERK pathway, vemurafenib affects the cellular PI4KB and, hence, enterovirus replication, opening new possibilities to evaluate further the potential of vemurafenib as a repurposed drug in clinical care. Despite the prevalence and medical threat of enteroviruses, presently, there are no antivirals against them. Here, we show that vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAF mutant-related melanoma, prevents enterovirus translation and replication. Vemurafenib shows efficacy against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect acts through cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevents infection efficiently in acute cell models, eradicates infection in a chronic cell model, and lowers virus amounts in pancreas and heart in an acute mouse model. Our findings open new possibilities to develop drugs against enteroviruses and give hope for repurposing vemurafenib as an antiviral drug against enteroviruses.
Topics: Animals; Mice; Humans; Vemurafenib; Enterovirus; 1-Phosphatidylinositol 4-Kinase; Proto-Oncogene Proteins B-raf; Melanoma; Protein Kinase Inhibitors; Enterovirus Infections; Mitogen-Activated Protein Kinase Kinases; Mutation
PubMed: 37436162
DOI: 10.1128/spectrum.00552-23 -
International Journal of Molecular... Sep 2023The present review article presents the key messages of the 8th Workshop on Paediatric Virology organised virtually by the Institute of Paediatric Virology based on the... (Review)
Review
The present review article presents the key messages of the 8th Workshop on Paediatric Virology organised virtually by the Institute of Paediatric Virology based on the island of Euboea in Greece. The major topics covered during the workshop were the following: i) New advances in antiviral agents and vaccines against cytomegalovirus; ii) hantavirus nephropathy in children; iii) human rhinovirus infections in children requiring paediatric intensive care; iv) complications and management of human adenovirus infections; v) challenges of post‑coronavirus disease 2019 (COVID‑19) syndrome in children and adolescents; and vi) foetal magnetic resonance imaging in viral infections involving the central nervous system. The COVID‑19 era requires a more intensive, strategic, global scientific effort in the clinic and in the laboratory, focusing on the diagnosis, management and prevention of viral infections in neonates and children.
Topics: Infant, Newborn; Humans; Child; Adolescent; COVID-19; Virus Diseases; Antiviral Agents; Cytomegalovirus; Greece
PubMed: 37503745
DOI: 10.3892/ijmm.2023.5286 -
Immunology and Cell Biology 2023Mucosal antibodies play a key role in protection against breakthrough COVID-19 infections and emerging viral variants. Intramuscular adenovirus-based vaccination...
Mucosal antibodies play a key role in protection against breakthrough COVID-19 infections and emerging viral variants. Intramuscular adenovirus-based vaccination (Vaxzevria) only weakly induces nasal IgG and IgA responses, unless vaccinees have been previously infected. However, little is known about how Vaxzevria vaccination impacts the ability of mucosal antibodies to induce Fc responses, particularly against SARS-CoV-2 variants of concern (VoCs). Here, we profiled paired mucosal (saliva, tears) and plasma antibodies from COVID-19 vaccinated only vaccinees (uninfected, vaccinated) and COVID-19 recovered vaccinees (COVID-19 recovered, vaccinated) who both received Vaxzevria vaccines. SARS-CoV-2 ancestral-specific IgG antibodies capable of engaging FcγR3a were significantly higher in the mucosal samples of COVID-19 recovered Vaxzevria vaccinees in comparison with vaccinated only vaccinees. However, when IgG and FcγR3a engaging antibodies were tested against a panel of SARS-CoV-2 VoCs, the responses were ancestral-centric with weaker recognition of Omicron strains observed. In contrast, salivary IgA, but not plasma IgA, from Vaxzevria vaccinees displayed broad cross-reactivity across all SARS-CoV-2 VoCs tested. Our data highlight that while intramuscular Vaxzevria vaccination can enhance mucosal antibodies responses in COVID-19 recovered vaccinees, restrictions by ancestral-centric bias may have implications for COVID-19 protection. However, highly cross-reactive mucosal IgA could be key in addressing these gaps in mucosal immunity and may be an important focus of future SARS-CoV-2 vaccine development.
Topics: Humans; COVID-19 Vaccines; Antibody Formation; ChAdOx1 nCoV-19; Vaccination; COVID-19; Antibodies, Viral; Immunoglobulin A; Immunoglobulin G; Antibodies, Neutralizing
PubMed: 37670482
DOI: 10.1111/imcb.12685 -
Vaccine Nov 2023Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. The aim of this...
Superior immunogenicity of mRNA over adenoviral vectored COVID-19 vaccines reflects B cell dynamics independent of anti-vector immunity: Implications for future pandemic vaccines.
Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. The aim of this study was to validate whether immunogenicity differs for adenoviral vectored (AdV) versus mRNA vaccines against SARS-CoV-2, and to investigate how anti-vector immunity and B cell dynamics modulate immunogenicity. We enrolled SARS-CoV-2 infection-naïve health care workers who had received two doses of either AdV AZD1222 (n = 184) or mRNA BNT162b2 vaccine (n = 274) between April and October 2021. Blood was collected at least once, 10-48 days after vaccine dose 2 for antibody and B cell analyses. Median ages were 42 and 39 years, for AdV and mRNA vaccinees, respectively. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p < 0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine, which reflected greater B cell expansion and targeting of the RBD rather than an attenuating effect of anti-vector antibodies. ClinicalTrials.gov Identifier: NCT05110911.
Topics: Humans; COVID-19 Vaccines; Pandemics; BNT162 Vaccine; ChAdOx1 nCoV-19; COVID-19; SARS-CoV-2; Viral Vaccines; Antibodies; Antibodies, Viral
PubMed: 37903679
DOI: 10.1016/j.vaccine.2023.10.034 -
Hematology, Transfusion and Cell Therapy Feb 2024Detecting anti-PF4 antibodies remains the golden diagnostic method for heparin-induced thrombocytopenia (HIT) diagnosis with high sensitivity and specificity. Various... (Review)
Review
Detecting anti-PF4 antibodies remains the golden diagnostic method for heparin-induced thrombocytopenia (HIT) diagnosis with high sensitivity and specificity. Various lab tests detect anti-PF4 antibodies, including immunoassays and functional assays. Even with positive detection of the anti-PF4 antibody, several factors are involved in the result. The concept of anti-PF4 disorders was recently brought to light during the COVID pandemic since the development of vaccine-induced thrombotic thrombocytopenia (VITT) with the adenovirus-vectored-DNA vaccine during the pandemic. Circumstances that detect anti-PF4 antibodies are classified as anti-PF4 disorders, including VITT, autoimmune HIT and spontaneous HIT. Some studies showed a higher percentage of anti-PF4 antibody detection among the population infected by COVID-19 without heparin exposure and some supported the theory that the anti-PF4 antibodies were related to the disease severity. In this review article, we provide a brief review of anti-PF4 disorders and summarize the current studies of anti-PF4 antibodies and COVID-19 infection.
PubMed: 38388299
DOI: 10.1016/j.htct.2023.11.012