MVA-MERS-S, a vaccine candidate against Middle East respiratory syndrome (MERS), was recently evaluated in a randomized, placebo-controlled, double-blind phase 1b clinical trial to assess its safety, immunogenicity, and optimal dosing in healthy adults in Hamburg and Rotterdam. A three-dose regimen was safe and elicited robust spike-specific antibody responses. We extended this trial to assess the two-year durability of MERS-CoV-specific antibody and T cell responses in 48 study participants of the Hamburg cohort. Our findings show that immune responses remain detectable for at least 24 months after the third vaccination. Antibodies persisted at levels comparable to the peak response observed after the second vaccination and were able to cross-neutralize MERS-CoV spike mutants. Although the immune correlates of protection against MERS remain unknown, the observed durability of humoral and cellular immune responses supports the potential of MVA-MERS-S as a promising MERS vaccine candidate and highlights the importance of a booster dose in sustaining long-term immunity.
BACKGROUND:The emergence of Plasmodium falciparum strains with reduced susceptibility to the artemisinin component of artemisinin combination therapies poses a serious threat to the treatment and control of malaria in sub-Saharan Africa. Regimens consisting of combinations of three or more conventional antimalarials have been proposed as a new treatment paradigm to overcome the impending problem of drug-resistant malaria. It was the aim of the MultiMal study to assess the safety, tolerability, and efficacy of the two novel multidrug antimalarial combination therapies, artesunate-pyronaridine-atovaquone-proguanil (APAP) and artesunate-fosmidomycin-clindamycin (AFC), in comparison with standard artesunate-pyronaridine (AP). METHODS:This open-label, randomised, controlled, clinical, phase 2 trial was done in Lambaréné, Gabon, and Kumasi, Ghana. Patients with uncomplicated malaria who had fever or a history of fever in the preceding 24 h and a parasitaemia in the range of 1000-100 000 per μL of blood were enrolled. Random permuted blocks of variable block sizes stratified by country were computed to generate a treatment allocation sequence. Recruitment was done across three age groups: children aged 6 months to 10 years, adolescents aged 11-17 years, and adults aged 18-65 years. Weight-adjusted oral, once-daily therapy was administered for 3 consecutive days for AP and APAP regimens dosed according to the recommendations of the manufacturer and twice daily for AFC (dose: artesunate 2 mg/kg, fosmidomycin 30 mg/kg, and clindamycin 10 mg/kg). Participants were followed up over a 42-day period. The primary endpoints of the trial, related to pharmacokinetic analyses, are being reported elsewhere; this Article reports the secondary endpoints-safety, tolerability, and efficacy of the treatment regimens (defined as adequate clinical and parasitological response [ACPR]) at days 28 and 42 after treatment initiation. ACPRs were calculated in the intention-to-treat and PCR-corrected per-protocol populations at these timepoints, whereas safety and tolerability outcomes were assessed continuously over the 42-day follow-up period in the safety population. This trial is registered with pactr.samrc.ac.za, PACTR202008909968293 and is complete. FINDINGS:Recruitment and follow-up took place between Jan 5 and Nov 5, 2021. Of 309 screened individuals, 100 patients with uncomplicated malaria were recruited into this clinical trial: 20 semi-immune patients aged 18-65 years, 40 adolescents aged between 11 and 17 years, and finally 40 patients aged 6 months to 10 years. PCR-corrected ACPR in the per-protocol set was 100% (95% CI 80-100) for AP, 100% (90-100) for APAP, and 97% (86-100) for AFC for day 28, and 87·5% (62-98) for AP, 85·3% (69-95) for APAP, and 94·4% (81-99) for AFC on day 42. Uncorrected ACPR in the intention-to-treat set was 85% (95% CI 62-97%) for AP, 87·5% (73-96) for APAP, and 82·5% (67-93) for AFC on day 28, and 70% (46-88) for AP, 75% (59-87) for APAP, and 75% (59-87) for AFC on day 42. There was no evidence for a differential efficacy across AP, APAP, and AFC. The proportion of patients with treatment-emergent adverse events (TEAEs) did not differ across study groups (p=0·37) and all treatment regimens were safe. Three (7%) of 46 TEAEs in the APAP group were severe compared with two (10%) of 20 in the AP control group and zero of 56 in the AFC group; all severe TEAEs were haematological alterations. The other TEAEs were mild or moderate. Moreover, there were two serious adverse events (SAEs) in the APAP group (peptic ulcer disease and chest contusion) and none in the other groups; these SAEs were rated as not related to the study medication. INTERPRETATION:Antimalarial regimens of APAP and AFC have unique characteristics to tackle the development and spread of drug-resistant P falciparum malaria. Given that APAP and AFC were safe, well tolerated, and highly efficacious in this clinical phase 2 study, they constitute promising multidrug combination regimens for further clinical development. FUNDING:German Center for Infection Research.
Background & Aims BK polyomavirus (BKPyV) reactivation is a serious complication in kidney transplant recipients (KTRs), with biopsy-proven BK virus nephropathy (BKVN) occurring in 1–10% of patients. Among these, 15–50% experience graft loss or return to dialysis. Currently, no effective antiviral therapy exists, and reduction of immunosuppression remains the standard approach, albeit with the risk of rejection. Virus-specific Tcells (VSTs) have shown clinical efficacy in hematopoietic stem cell transplant (HSCT) settings against multiple viruses, including BKPyV, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and Adenovirus, with response rates up to 86% in BK viremia.Aim of this study is to evaluate the safety and tolerability of third-party BK virus-specific T-cell therapy in kidney transplant recipients with biopsy-proven BKVN and to assess its impact on BK viral load and renal function over a 2-years follow-up. Methodology This retrospective study included eight KTRs treated with a total of 18 third-party BK-VST infusions (median 2 per patient) between 2019 and 2025 with a 2-years follow up. Safety endpoints included the incidence of graft-versus-host disease (GVHD) and graft loss. Efficacy was evaluated based on serial measurements of BK viral load (whole blood PCR), estimated glomerular filtration rate (eGFR), proteinuria, and dialysis dependency. Assessments were performed 6 and 3 mothts prior to the first T-cell infusion, at baseline and every three months during the first year and every six months during the second year following T-cell infusion. Results BK-VST therapy was well tolerated. No GVHD, graft loss, or severe adverse events were observed. One patient developed a new onset autoimmune-myositis, with possible relation to the therapy, resolving without specific therapy. At 12 months, 6 of 8 of patients demonstrated a ≥1-log reduction in BK viral load, maintained through 24 months. Renal function remained stable throughout follow-up in all patients. None of the dialysis-independent patients at baseline progressed to dialysis dependency, and the one dialysis-dependent patient remained on dialysis. Conclusion Third-party BK virus-specific T-cell therapy was safe and well tolerated in KTRs with biopsy-confirmed BKVN and may contribute to stabilization of disease progression. These findings support further investigation in prospective, controlled trials to define the therapeutic role of BK-VSTs in solid organ transplantation.
Objective:To assess the feasibility of fixed-dose, praziquantel preventive chemotherapy against schistosomiasis in young children in rural Madagascar, focusing on treatment uptake and sustainability. Methods:We used the Consolidated Framework for Implementation Research to guide the study. Between November 2022 and December 2023, children aged 9 to 24 months at various venues were offered 300 mg of praziquantel as a crushed half tablet mixed with water and sugar. We conducted a cross-sectional survey among caregivers to assess treatment uptake and acceptability, children's compliance with drug administration, anxiety about adverse events, and praziquantel's tolerability and safety. Factors associated with uptake and acceptability were identified using Poisson regression. Findings:The study analysis included 5142 child-caregiver pairs. The praziquantel uptake rate was 86.2% (95% confidence interval, CI: 85.3-87.1) and 80.2% (95% CI: 79.1-81.3) of caregivers regarded repeated preventive chemotherapy acceptable. Clear anxiety, and uncertainty, about adverse events were the most significant factors associated with refusal of both initial and repeated treatment. No children experienced serious adverse events or choking. Of the 4434 children who received praziquantel, 152 (3.4%) swallowed a partial dose, whereas 2467 (55.6%) cried and 1833 (41.3%) initially resisted treatment, but ultimately received it. Conclusion:Fixed-dose praziquantel preventive chemotherapy using a crushed half tablet with water and sugar was feasible in preschool-aged children and was potentially sustainable. This approach has a strong potential for scaling up in areas where schistosomiasis is highly endemic.
BACKGROUND:Placental schistosomiasis (PS) is underdiagnosed and may compromise maternal and neonatal health. This study estimated the prevalence of PS in a rural Gabonese population of pregnant women with confirmed S. haematobium infection using light microscopy of macerated placental tissue. METHODS:This is a cross-sectional, diagnostic proof-of-concept study which applied an improved placenta maceration technique in real-world conditions to diagnose PS. Performing light microscopic assessment of a single sample of 10 mL urine, we screened pregnant women for S. haematobium infection who sought antenatal care in Lambaréné (Gabon) between January 2022 and January 2023. Women positive for S. haematobium infection were followed up until delivery. Additionally, a subsample of women with negative urine samples was recruited as a non-infected control group (1:1 ratio infected and non-infected groups) and followed up until delivery. Only participants with available macerated placental samples were considered for final analysis. Placental samples were subjected to light-microscopy-based screening for S. haematobium eggs and PS was considered present if a least one S. haematobium egg was detected. Positive light microscopic placental samples were confirmed by qPCR. RESULTS:Among 318 women screened for S. haematobium in urine, we found 40 (12.6%; 95% CI: 9.1-16.7%) to be positive. Together with 40 women in the non-infected control group all women were followed up until delivery. After loss-to-follow-up, 28 (70%; 28/40) women with S. haematobium infection and 20 (50%; 20/40) without infection provided placenta samples at delivery. In the group with S. haematobium infection, 14% (4/28; 95% CI: 4.0-32.7%) of women were positive for S. haematobium eggs in macerated placenta tissue. In the non-infected control group, one woman (5%; 1/20; 95% CI: 0.1-24.9%) had a positive microscopy result for PS. All five women with positive S. haematobium egg microscopy in placental tissue received a concordant qPCR result. CONCLUSION:14% of women with S. haematobium infection also had PS. Notably, PS was also observed in 5% of women without detectable S. haematobium eggs in urine. This suggests that PS could be an underestimated phenomenon in highly endemic regions and warrants further investigations of its implications for mother-and-child health.
