Reduction In Viral Load Research Articles

The neurological damage caused by enterovirus 71 infection is associated with hsa_circ_0069335/miR-29b/PMP22 pathway.

Enterovirus 71 (EV71) infection is usually accompanied by neurological damage, which is the leading cause of death in children with hand-foot-mouth disease. In this study, we demonstrated that EV71 infection can cause pathological damage in the nervous system, such as neuronal vacuolar degeneration, shrinkage of some neurons, edema of brain tissues in the hippocampus, and a decreased number of Nissl bodies in the infarction area. Also, EV71 infection caused apparent structural damage to Schwann cells, including a decreased number of cytoplasmic organelles and severe damage of rough endoplasmic reticulum and mitochondria. However, the pathological damage was alleviated with the decrease of EV71 viral load. The cell experiment in vitro showed that EV71 infection significantly reduced ATP levels and promoted Schwann cell apoptosis, thus inhibiting cell growth. The extended infection time and the decreased viral load resulted in the gradual improvement of cell growth status. Meanwhile, EV71 inhibited the expression of miR-29b and promoted the expression of PMP22 in a time-dependent manner at both mRNA and protein levels, with the most significant change at 36 h of infection. Subsequently, the expression of miR-29b and PMP22 was gradually restored with the reduction of EV71 viral load. In addition, EV71 regulated the expression of hsa_circ_0069335, which could bind and co-localize with miR-29b. Therefore, EV71 infection can cause significant damage to the nervous system and may be related to hsa_circ_0069335/miR-29b/PMP22 pathway. The present study provides a new therapeutic target for neurological damage induced by EV71 infection.IMPORTANCEEV71 can cause severe neurological damage and even death, but the mechanism remains unclear. In this study, we exhibited the pathological changes of nervous system in EV71 infection and revealed that the damage degree was consistent with the EV71 viral load. From the molecular perspective, EV71 infection up-regulated the PMP22 expression in Schwann cells, which is accompanied by apparent structural damage of Schwann cells and myelin sheaths. Furthermore, EV71 promoted the expression of PMP22 and inhibited the expression of miR-29b in a time-dependent manner, with the most significant change at 36 h of infection. Otherwise, the hsa_circ_0069335, which binds and co-localizes with miR-29b, was also regulated by EV71 infection. The hsa_circ_0069335/miR-29b/PMP22 axis may be a potential molecular mechanism involved in EV71 infection-induced fatal neuronal damage. Drug development targeting this pathway may bring clinical improvement of EV71-infected patients.

Compassionate access to virus-specific T cells for adoptive immunotherapy over 15 years

Adoptive T-cell immunotherapy holds great promise for the treatment of viral complications in immunocompromised patients resistant to standard anti-viral strategies. We present a retrospective analysis of 78 patients from 19 hospitals across Australia and New Zealand, treated over the last 15 years with “off-the-shelf” allogeneic T cells directed to a combination of Epstein–Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKV), John Cunningham virus (JCV) and/or adenovirus (AdV) under the Australian Therapeutic Goods Administration’s Special Access Scheme. Most patients had severe post-transplant viral complications, including drug-resistant end-organ CMV disease, BKV-associated haemorrhagic cystitis and EBV-driven post-transplant lymphoproliferative disorder. Adoptive immunotherapy is well tolerated with few adverse effects. Importantly, 46/71 (65%) patients show definitive clinical improvement including reduction in viral load, clinical symptoms and complete resolution of end-organ disease. In addition, seven high-risk patients remain disease free. Based on this long-term encouraging clinical experience, we propose that a dedicated nationally funded centre for anti-viral cellular therapies should be considered to provide T cell therapies for critically ill patients for compassionate use.

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLpro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLpro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discover a series of novel potent non-covalent PLpro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLpro with lead compounds reveal that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor’s potency. The lead compound GZNL-P36 not only inhibits SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibits HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 μM, respectively. Oral administration of the GZNL-P36 results in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro inhibitors represent a promising SARS-CoV-2 therapy.

Real world effectiveness of early ensitrelvir treatment in patients with SARS-CoV-2, a retrospective case series

BackgroundEnsitrelvir, a 3C-like protease inhibitor, received emergency approval in Japan in November 2022 for treating non-hospitalized patients with mild-to-moderate COVID-19. However, confirmation of its real-world clinical effectiveness is limited. MethodsThis retrospective study evaluated 18 vaccinated outpatients (15 men; median age, 39.5 years; range, 26–56), treated with a 5-day oral ensitrelvir regimen (375 mg loading dose, followed by 125 mg daily) between December 1, 2022, and January 31, 2023. Nasal swabs were collected on days 0, 3, 6, and 9 for RT-qPCR to assess viral load. Variants were identified by Sanger sequencing, and outcomes were compared to historical controls. Patients were followed for 60 days to monitor for post-acute sequelae of COVID-19 (PASC). ResultsSymptoms such as mild fever and sore throat improved rapidly after one day of ensitrelvir treatment, with 66 % of patients recovering within six days. All individuals were infected with the BA.5 Omicron variant. Viral loads, as measured by Ct values, increased significantly from 21.82 at symptom onset to 37.65 b y day 6, with SARS-CoV-2 RNA undetectable in most patients by day 9. Those treated within 48 h of symptom onset showed the viral load reduction. Compared to historical controls, where symptom resolution took 8.5 days, ensitrelvir shortened recovery time to as little as 1.4 days for over 66 % of patients. ConclusionEnsitrelvir treatment resulted in rapid symptom relief and significant viral load reduction, with no adverse events, viral rebound, or PASC symptoms, demonstrating its potential efficacy and safety. Larger studies are needed for further confirmation.

Directly Isolated Allogeneic Virus–Specific T Cells in Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a life-threatening viral infection with no approved antiviral treatment. To determine whether restoring the compromised immune system of patients with PML with directly isolated allogeneic virus-specific (DIAVIS) T cells is a promising therapeutic strategy, especially if other curative options are absent. A retrospective case series of patients with PML who were treated with DIAVIS T cells was conducted between March 2020 and February 2022. T cells were isolated from healthy donors within 24 hours and targeted against the BK polyomavirus. Patients with PML were treated monocentrically. Eligibility for treatment with DIAVIS T cells was assessed for patients with confirmed PML, and exclusion criteria included stable PML disease and previous treatment with natalizumab. Fresh DIAVIS T cells were administered with a maximum dose of 2 × 104 CD3+ cells/kg body weight. Remaining T cells were cryopreserved in divided doses and administered in additional treatments approximately 2 and 6 weeks later. Primary outcome measures were clinical response and survival of patients, compared with the outcomes of a historical reference group of PML cases receiving best supportive treatment (BST) and with recently published real-world data of patients with PML who were treated with immune checkpoint inhibition. The study cohort consisted of 28 patients (median [IQR] age, 60 [51-72] years; 20 male [71.4%]). Twenty-two patients (79%) treated with DIAVIS T cells showed response, resulting in significant clinical stabilization or improvement and a reduction in viral load. Six individuals (21%) were classified as nonresponders, deteriorated rapidly, and died, as did 2 other patients during a 12-month follow-up. Older age was the only predictor of a poor treatment response. Survival analysis revealed better 12-month survival rates (hazard ratio, 0.42; 95% CI, 0.24-0.73; P =.02) from diagnosis for patients treated with DIAVIS T cells (18 of 26 [69%]; 12-mo survival rate, 69%) compared with historical controls with BST (57 of 113 [50%]; 12-mo survival rate, including censored data, 45%). This case series of DIAVIS T-cell therapy in PML provides first class IV evidence suggesting efficacy to reduce mortality and improve functional outcome. Further prospective studies are required to confirm these results.

Unveiling ancestral threads: Exploring CCR5 ∆32 mutation frequencies in Colombian populations for HIV/AIDS therapeutics

AIDS remains a significant global health challenge since its emergence in 1981, with millions of deaths and new cases every year. The CCR5 ∆32 genetic deletion confers immunity to HIV infection by altering a cell membrane protein crucial for viral entry. Stem cell transplants from homozygous carriers of this mutation to HIV-infected individuals have resulted in viral load reduction and disease remission, suggesting a potential therapeutic avenue. This study aims to investigate the relationship between genetic ancestry and the frequency of the CCR5 ∆32 mutation in Colombian populations, exploring the feasibility of targeted donor searches based on ancestry composition. Utilizing genomic data from the CÓDIGO-Colombia consortium, comprising 532 individuals, the study assessed the presence of the CCR5 ∆32 mutation and examined if the population was on Hardy-Weinberg equilibrium. Individuals were stratified into clusters based on African, American, and European ancestry percentages, with logistic regression analysis performed to evaluate the association between ancestry and mutation frequency. Additionally, global genomic databases were utilized to visualize the worldwide distribution of the mutation. The findings revealed a significant positive association between European ancestry and the CCR5 ∆32 mutation frequency, underscoring its relevance in donor selection. African and American ancestry showed negative but non-significant associations with CCR5 ∆32 frequency, which may be attributed to the study's limitations. These results emphasize the potential importance of considering ancestry in donor selection strategies, reveal the scarcity of potential donors in Colombia, and underscore the need to consider donors from other populations with mainly European ancestry if the CCR5 ∆32 stem cell transplant becomes a routine treatment for HIV/AIDS in Colombia.

Ziresovir in Hospitalized Infants with Respiratory Syncytial Virus Infection

BackgroundRespiratory syncytial virus (RSV) is a leading cause of severe illness in infants, with no effective treatment. Results of a phase 2 trial suggested that ziresovir may have efficacy in the treatment of infants hospitalized with RSV infection.MethodsIn a phase 3, multicenter, double-blind, randomized, placebo-controlled trial conducted in China, we enrolled participants 1 to 24 months of age who were hospitalized with RSV infection. Participants were randomly assigned, in a 2:1 ratio, to receive ziresovir (at a dose of 10 to 40 mg, according to body weight) or placebo, administered twice daily, for 5 days. The primary end point was the change from baseline to day 3 (defined as 48 hours after the first administration) in the Wang bronchiolitis clinical score (total scores range from 0 to 12, with higher scores indicating greater severity of signs and symptoms). The intention-to-treat population included all the participants with RSV-confirmed infection who received at least one dose of ziresovir or placebo; the safety population included all the participants who received at least one dose of ziresovir or placebo.ResultsThe intention-to-treat population included 244 participants, and the safety population included 302. The reduction from baseline in the Wang bronchiolitis clinical score at day 3 was significantly greater with ziresovir than with placebo (−3.4 points [95% confidence interval {CI}, −3.7 to −3.1] vs. −2.7 points [95% CI, −3.1 to −2.2]; difference, −0.8 points [95% CI, −1.3 to −0.3]; P=0.002). The reduction in the RSV viral load at day 5 was greater in the ziresovir group than in the placebo group (−2.5 vs. −1.9 log10 copies per milliliter; difference, −0.6 log10 copies per milliliter [95% CI, −1.1 to −0.2]). Improvements were observed in prespecified subgroups, including in participants with a baseline bronchiolitis score of at least 8 and in those 6 months of age or younger. The incidence of adverse events related to the drug or placebo was 16% with ziresovir and 13% with placebo. The most common adverse events that were assessed by the investigator as being related to the drug or placebo were diarrhea (in 4% and 2% of the participants, respectively), an elevated liver-enzyme level (in 3% and 3%, respectively), and rash (in 2% and 1%). Resistance-associated mutations were identified in 15 participants (9%) in the ziresovir group.ConclusionsZiresovir treatment reduced signs and symptoms of bronchiolitis in infants and young children hospitalized with RSV infection. No safety concerns were identified. (Funded by Shanghai Ark Biopharmaceutical; AIRFLO ClinicalTrials.gov number, NCT04231968.)

ICOS limits memory-like properties and function of exhausted PD-1 + CD8 T cells.

During persistent antigen stimulation, PD-1 + CD8 T cells are maintained by progenitor exhausted PD-1 + TCF-1 + CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1 + CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory-like features of Tpex. In mice with established chronic infection, ICOS-Ligand blockade resulted in expansion of effector-like Tex and reduction in viral load. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1 + CD8 T cells and delayed tumor growth. Overall, we show that ICOS limits CD8 T cell responses during chronic antigen exposure.

Antiviral effect of oversulfated kappa-carrageenan derivatives against COVID-19 for spray coating application on facemasks

The COVID-19 pandemic caused by SARS-CoV-2 has spurred the urgent need for effective antiviral strategies. In this work, we explored the potential of oversulfated kappa-carrageenan (OSKC) in spray-coated facemasks for SARS-CoV-2 inhibition pathway. The sulfated derivative was synthesized with sulfur trioxide pyridine complex in dimethylformamide solution. The antiviral efficacy of OSKC at different concentrations and spray-coated facemasks was evaluated using betacoronavirus Murine Hepatitis Virus strain 3, revealing a significant reduction in viral load compared to commercial kappa-carrageenan. Furthermore, the characterization techniques assessed the effect of the position of the introduced sulfate groups on the antiviral activity and on the physicochemical characteristics. OSKC is able to bind specific proteins of enveloped viruses, preventing viral attachment into target cells. Overall, this study demonstrates the feasibility and effectiveness of OSKC spray coating for breathable facemasks with antimicrobial properties, offering a promising approach to enhancing personal protective equipment against viral transmission in healthcare and community settings.

Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance.

In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of nirmatrelvir-ritonavir near the time of symptom onset, coupled with incomplete viral clearance, appear to be the main factors leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. Finally, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment, in particular to a 10-day regimen, may greatly diminish the risk for rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2.

Platycodin D: A promising anti tilapia lake virus natural compound from Platycodon grandiflorus

Tilapia lake virus (TiLV) poses a significant threat to the worldwide tilapia aquaculture sector, and there currently exists no efficient method of containment for this lethal pathogen. Given the widespread utilization of herbal medicines in the treatment of various aquatic animal diseases, it becomes imperative to evaluate and identify herbs that can be used for developing effective drugs against TiLV. We evaluated the efficacy of 20 herbs to inhibit TiLV proliferation in a TiLV infection model (Oreochromis niloticus) through two rounds of screening, with Platycodon grandiflorus extract showing the strongest inhibitory effect on TiLV replication (IC50 = 72.619 mg/L), survival of TiLV-infected tilapia was also improved in individual experiments. Platycodin D (PD), the principal bioactive compound found in Platycodon grandiflorus, demonstrated a dose-dependent reduction in viral load when used for treatment and enhanced the survival rate of tilapia infected with TiLV (42.3 %). The results of serum enzyme activity showed that PD treatment at a concentration of 5 mg/kg significantly enhance the non-specific parameters in tilapia (GSH, ACP, and AKP) (**p < 0.01). Additionally, immune-related gene analysis indicated that PD up-regulated IFN-I, CC2 and other genes expression while down-regulated the expression of pro-inflammatory factors (TNF-α, IL-1β) and TLR2 in the spleen and kidney of tilapia, implying that PD could induce IFN-I expression resulting in potential antiviral effects and inhibit some pro-inflammatory factors to alleviate oxidative stress and inflammatory responses in tilapia. The aforementioned findings suggest that Platycodon grandiflorus could potentially serve as a promising candidate for the development of drugs targeting TiLV. In particular, the bioactive component PD showed a strong anti-TiLV effect, which needs to be further explored.

Efficacy and Safety of Low-Dose, Rapidly Infused Bamlanivimab and Etesevimab: Phase 3 BLAZE-1 Trial for Mild-to-Moderate COVID-19.

The monoclonal antibody therapies bamlanivimab (BAM) + etesevimab (ETE) received emergency use authorization (EUA) from the US Food and Drug Administration (February 9, 2021) for treatment of mild-to-moderate COVID-19. The EUA of BAM + ETE was revoked (December 14, 2023) due to the high prevalence of BAM + ETE-resistant variants of SARS-CoV-2. Efficacy and safety of 700/1400mg and 2800/2800mg BAM + ETE are well established and published; however, efficacy and safety of 350/700 mg BAM + ETE have not been disclosed to date. This portion of phase 3, BLAZE-1 trial (J2X-MC-PYAB) enrolled patients (between June 17, 2020 and April 9, 2021) with mild-to-moderate COVID-19 within 3 days of laboratory diagnosis of SARS-CoV-2 infection. In total, 354 patients with at least one risk factor for severe COVID-19 were enrolled, randomized (2:3), and infused with placebo (N = 141) or 350/700mg BAM + ETE (N = 213), over ~ 8 min. Primary endpoint was to assess proportion of patients with persistently high SARS-CoV-2 viral load (PHVL) (log viral load > 5.27) 7 days after infusion. Patients were aged (mean) 53 years, 49.7% female, and 82.7% White. Seven days after drug infusion, 10.8% (95% confidence interval: 6.6, 15.0; p < 0.001) of BAM + ETE-treated patients and 34.8% (26.9, 42.6) of placebo-treated patients had PHVL, and the viral load change from baseline (least square mean [standard error]) was - 3.50 (0.15; p < 0.001) in BAM + ETE-treated patients versus - 2.51 (0.19) in placebo-treated patients. The majority of treatment-emergent adverse events were considered mild or moderate in severity (BAM + ETE: 6.6%; placebo: 14.2%). No deaths were reported. Consistent with previous studies, patients treated with BAM + ETE (350/700 mg) had a significantly lower proportion of PHVL and greater reduction in viral load compared with placebo. The overall safety profile is consistent with higher doses of BAM + ETE. Infusions of over ~ 8 min did not result in meaningful increase in incidence of TEAEs compared to higher doses of BAM + ETE administered over 30-60 min. Clinical trial.gov identifier, NCT04427501.

Association Between SARS-CoV-2 Viral Load and COVID-19 Vaccination in 4 Phase 3 Trials.

Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.38-4.18; n = 60 placebo, 11 vaccine) and 2.12 log10 copies/mL (95% CI, 1.44-2.80; n = 594 placebo, 36 vaccine) for NVX-CoV2373 and mRNA-1273, respectively. Associations were not significant for AZD1222 (0.59 log10 copies/mL; 95% CI, -.19 to 1.36; n = 90 placebo, 78 vaccine) or Ad26.COV2.S (0.23 log10 copies/mL; 95% CI, -.01 to .47; n = 916 placebo, 424 vaccine). Thus, vaccines potentially decreased transmission when ancestral SARS-CoV-2 predominated. Clinical Trials Registration. NCT04470427, NCT04505722, NCT04516746, NCT04611802.

Efficacy and safety of Ibalizumab for the treatment of HIV-1 infected patients: A systematic review

Objectives: Human immunodeficiency virus (HIV) infection is a significant global health concern, due to the emerging complexity in the management of infection. The emergence of novel therapeutic agents, such as ibalizumab, has provided a ray of hope for individuals living with HIV. This systematic review provides a comprehensive analysis of the efficacy and safety of ibalizumab for the treatment of HIV-1-infected patients. Material and Methods: Using online medical literature databases and the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines, four of the 86 articles met the acceptance criteria to be analyzed. Details such as author name, year of publication, demographic characteristics, mode, and dose of drug administration, duration of treatment, comparator if any, baseline CD4 counts, and viral load, change in CD4 count and viral load, and the adverse events were noted in the studies. Results: The total number of patients enrolled in each study ranged from 22 to 82 with a median age ranging from 39 to 53. Except for the open-label dose-ranging cohort study, baseline CD4 counts and post-intervention CD4 counts were assessed in all the studies. The patients who received a higher dose of ibalizumab showed an early significant rise in CD4+T-cell count at week 16 and week 48. Although the viral reduction after ibalizumab injection increases from the dose of 3 mg/kg, it was noted that beyond 10mg/kg the viral load reduction was not increasing proportionately with 25 mg/kg. The adverse effects encountered among the four studies ranged from 45% to 91%. The commonly observed adverse effects were headache, diarrhea, nausea, fatigue, somnolence, and rash. Conclusion: Ibalizumab demonstrates promise as a therapeutic option for individuals with multidrug-resistant HIV-1. Its unique mechanism of action and positive impact on viral load reduction and CD4 cell counts make it a valuable addition to the armamentarium of HIV treatment options.

Development of quaternized agar-based materials for the coronavirus inactivation

The COVID-19 pandemic has revealed weaknesses in healthcare systems and underscored the need for advanced antimicrobial materials. This study investigates the quaternization of agar, a seaweed-derived polysaccharide, and the development of electrospun membranes for air filtration in facemasks and biomedical applications. Using the betacoronavirus MHV-3 as a model, quaternized agar and membranes achieved a 90–99.99 % reduction in viral load, without associated cytotoxicity. The quaternization process reduced the viscosity of the solution from 1.19 ± 0.005 to 0.64 ± 0.005 Pa.s and consequently the electrospun fiber diameter ranged from 360 to 185 nm. Membranes synthesized based on polyvinyl alcohol and thermally cross-linked with citric acid exhibited lower water permeability. Avoiding organic solvents in the electrospinning technique ensured eco-friendly production. This approach offers a promising way to develop biocompatible and functional materials for healthcare and environmental applications.

Intranasal Administration of Recombinant Newcastle Disease Virus Expressing SARS-CoV-2 Spike Protein Protects hACE2 TG Mice against Lethal SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged as a global outbreak in 2019, profoundly affecting both human health and the global economy. Various vaccine modalities were developed and commercialized to overcome this challenge, including inactivated vaccines, mRNA vaccines, adenovirus vector-based vaccines, and subunit vaccines. While intramuscular vaccines induce high IgG levels, they often fail to stimulate significant mucosal immunity in the respiratory system. We employed the Newcastle disease virus (NDV) vector expressing the spike protein of the SARS-CoV-2 Beta variant (rK148/beta-S), and evaluated the efficacy of intranasal vaccination with rK148/beta-S in K18-hACE2 transgenic mice. Intranasal vaccination with a low dose (106.0 EID50) resulted in an 86% survival rate after challenge with the SARS-CoV-2 Beta variant. Administration at a high dose (107.0 EID50) led to a reduction in lung viral load and 100% survival against the SARS-CoV-2 Beta and Delta variants. A high level of the SARS-CoV-2 spike-specific IgA was also induced in vaccinated mice lungs following the SARS-CoV-2 challenge. Our findings suggest that rK148/beta-S holds promise as an intranasal vaccine candidate that effectively induces mucosal immunity against SARS-CoV-2.

Modeling hepatocyte apoptosis in chronic HCV infection with impulsive drug control

Chronic hepatitis C virus (HCV) infection is one of the leading life-threatening diseases owing to its non-cytopathic nature and scarcity of vaccines to combat. Hepatocyte apoptosis casts extensive impact in regulating chronic HCV infection. We propose a four dimensional deterministic model scheming the role of hepatocyte apoptosis and significance of HCV-specific CTL response in the intermediate stages of chronic HCV infection. Numerical simulation indicates that unregulated behavior of hepatocyte apoptosis triggers hepatocellular carcinoma and prolonged continuation of apoptosis induces liver damages. The system undergoes backward bifurcation and the value of the basic reproduction number R0=0.98<1 shows recurrence of infection. Local sensitivity analysis has been performed to reveal the most sensitive parameters responsible for the progression and mitigation of infection. In order to control of chronic HCV infection through pan-genotypic direct acting antiviral drugs (DAAs), impulsive differential equations are considered to study the effect of perfect drug adherence to both fixed and non-fixed dosing. For possible eradication of the chronic HCV infection, impulsive drug control suggests significant viral load reduction. The analytical results obtained for both non-impulsive and impulsive models are quantified biologically.

Update on Hepatitis C Virus (HCV) Vaccine Candidates in Clinical Trials: A Systematic Literature Review

Introduction: Hepatitis C virus (HCV) infection remains a significant global health challenge, affecting over 71 million people worldwide and leading to severe liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Despite the availability of highly effective direct-acting antiviral (DAA) therapies achieving sustained virologic response (SVR) rates exceeding 90%, high costs and limited accessibility impede global eradication efforts. Additionally, DAAs do not confer immunity against reinfection, highlighting the need for a prophylactic vaccine. Methods: This systematic literature review follows the PRISMA guidelines. A comprehensive search was conducted in PubMed, Scopus, and Web of Science for articles published between January 2010 and March 2024, focusing on HCV vaccine candidates in clinical trials. Data on study characteristics, participant demographics, vaccine characteristics, vaccine platforms and key outcomes were extracted. Results: Nine studies met the eligibility criteria, covering various phases of clinical trials (Phase I, II, and II/III). Key findings included: Vaccine platforms: The studies primarily utilized three types of vaccine platforms: Viral Vector-Based Vaccines, Peptide-Based Vaccines and Recombinant Protein Vaccines Immunogenicity: Vaccines targeting non-structural proteins (NS3, NS4, NS5) induced robust T-cell responses. Chimpanzee adenovirus (ChAd) and Modified Vaccinia Ankara (MVA) vector-based vaccines showed high polyfunctional CD8+ and CD4+ T-cell levels. Safety: Most adverse events were mild to moderate, including flu-like symptoms and injection site reactions. Severe adverse events were noted with TG4040 when combined with PEG-IFNα and RBV. Efficacy: Significant reductions in viral load and improvements in liver function were reported. Personalized peptide vaccines demonstrated enhanced immune responses and improved overall survival in HCV-positive advanced HCC patients. Conclusion: HCV vaccine development has made significant strides, with several candidates demonstrating strong immunogenicity, acceptable safety, and promising efficacy in clinical trials. Continued research is essential to address challenges such as viral genetic variability, durability of immune responses, and global accessibility.

Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice

RNA vaccines elicit protective immunity against SARS-CoV-2, but the use of mRNA as an antiviral immunotherapeutic is unexplored. Here, we investigate the activity of lipidoid nanoparticle (LNP)-formulated mRNA encoding human IFNλ1 (ETH47), which is a critical driver of innate immunity at mucosal surfaces protecting from viral infections. IFNλ1 mRNA administration promotes dose-dependent protein translation, induction of interferon-stimulated genes without relevant signs of unspecific immune stimulation, and dose-dependent inhibition of SARS-CoV-2 replication in vitro. Pulmonary administration of IFNλ1 mRNA in mice results in a potent reduction of virus load, virus-induced body weight loss and significantly increased survival. These data support the development of inhaled administration of IFNλ1 mRNA as a potential prophylactic option for individuals exposed to SARS-CoV-2 or at risk suffering from COVID-19. Based on the broad antiviral activity of IFNλ1 regardless of virus or variant, this approach might also be utilized for other respiratory viral infections or pandemic preparedness.

A multidisciplinary approach for people with HIV failing antiretroviral therapy in South Africa.

South Africa (SA) has the largest antiretroviral therapy (ART) programme worldwide. Multiple factors contribute to virological failure (VF), including poor adherence and viral resistance mutations. A multidisciplinary team (MDT) clinic dedicated to those with VF may be of benefit; however, very little data from SA exist. To assess whether an MDT approach achieved virological suppression (VS) in patients failing second-line-ART (2LART); assess the number of MDT sessions required to achieve VS; assess local resistance mutation patterns and whether the MDT reduced the number of genotypic resistance testing (GRT) required. An observational, retrospective, cross-sectional chart review study was conducted between January 2018 and December 2019 at a Target High Viral Load (VL) MDT clinic in KwaZulu-Natal, SA. Ninety-seven medical records were eligible. Women accounted for 63% of patients, with a mean age of 37 years. A significant reduction in the first VL measurement following the MDT was seen (median reduction 2374 c/mL; P < 0.001). This was maintained at the second VL measurement post-MDT (median reduction 2957 c/mL; P < 0.001). Patients attended a mean of 2.71 MDT sessions and 73.2% achieved VS, resulting in 61.86% fewer GRTs required. Of the GRTs performed, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitor-related mutations were noted most frequently. The MDT approach resulted in a significant reduction in VL, with most participants achieving VS. The MDT was successful in reducing the need for GRT. Resistance mutations were similar to those found in other studies conducted across SA.