A randomized, controlled Phase 1b trial of the Sm-TSP-2 Vaccine for intestinal schistosomiasis in healthy Brazilian adults living in an endemic area.

BACKGROUND: Recombinant Schistosoma mansoni Tetraspanin-2 formulated on Alhydrogel (Sm-TSP-2/Alhydrogel) is being developed to prevent intestinal and hepatic disease caused by S. mansoni. The tegumentary Sm-TSP-2 antigen was selected based on its unique recognition by cytophilic antibodies in putatively immune individuals living in areas of ongoing S. mansoni transmission in Brazil, and preclinical studies in which vaccination with Sm-TSP-2 protected mice following infection challenge. METHODS: A randomized, observer-blind, controlled, Phase 1b clinical trial was conducted in 60 healthy adults living in a region of Brazil with ongoing S. mansoni transmission. In each cohort of 20 participants, 16 were randomized to receive one of two formulations of Sm-TSP-2 vaccine (adjuvanted with Alhydrogel only, or with Alhydrogel plus the Toll-like receptor-4 agonist, AP 10-701), and 4 to receive Euvax B hepatitis B vaccine. Successively higher doses of antigen (10 µg, 30 µg, and 100 µg) were administered in a dose-escalation fashion, with progression to the next dose cohort being dependent upon evaluation of 7-day safety data after all participants in the preceding cohort had received their first dose of vaccine. Each participant received 3 intramuscular injections of study product at intervals of 2 months and was followed for 12 months after the third vaccination. IgG and IgG subclass antibody responses to Sm-TSP-2 were measured by qualified indirect ELISAs at pre- and post-vaccination time points through the final study visit. RESULTS: Sm-TSP-2/Alhydrogel administered with or without AP 10-701 was well-tolerated in this population. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. No vaccine-related serious adverse events or adverse events of special interest were observed. Groups administered Sm-TSP-2/Alhydrogel with AP 10-701 had higher post-vaccination levels of antigen-specific IgG antibody. A significant dose-response relationship was seen in those administered Sm-TSP-2/Alhydrogel with AP 10-701. Peak anti-Sm-TSP-2 IgG levels were observed approximately 2 weeks following the third dose, regardless of Sm-TSP-2 formulation. IgG levels fell to low levels by Day 478 in all groups except the 100 µg with AP 10-701 group, in which 57% of subjects (4 of 7) still had IgG levels that were ≥4-fold higher than baseline. IgG subclass levels mirrored those of total IgG, with IgG1 being the predominant subclass response. CONCLUSIONS: Vaccination of adults with Sm-TSP-2/Alhydrogel in an area of ongoing S. mansoni transmission was safe, minimally reactogenic, and elicited significant IgG and IgG subclass responses against the vaccine antigen. These promising results have led to initiation of a Phase 2 clinical trial of this vaccine in an endemic region of Uganda. TRIAL REGISTRATION: NCT03110757.

PfSPZ-CVac malaria vaccine demonstrates safety among malaria-experienced adults: A randomized, controlled phase 1 trial.

Background: Plasmodium falciparum (Pf) Sporozoite (SPZ) Chemoprophylaxis Vaccine (PfSPZ-CVac) involves concurrently administering infectious PfSPZ and malaria drug, often chloroquine (CQ), to kill liver-emerging parasites. PfSPZ-CVac (CQ) protected 100% of malaria-naïve participants against controlled human malaria infection. We investigated the hypothesis that PfSPZ-CVac (CQ) is safe and efficacious against seasonal, endemic Pf in malaria-exposed adults. Methods: Healthy 18-45 year olds were enrolled in a double-blind, placebo-controlled trial in Bougoula-Hameau, Mali, randomized 1:1 to 2.048 × 105 PfSPZ (PfSPZ Challenge) or normal saline administered by direct venous inoculation at 0, 4, 8 weeks. Syringes were prepared by pharmacy staff using online computer-based enrolment that randomized allocations. Clinical team and participant masking was assured by identical appearance of vaccine and placebo. Participants received chloroquine 600mg before first vaccination, 10 weekly 300mg doses during vaccination, then seven daily doses of artesunate 200mg before 24-week surveillance during the rainy season. Safety outcomes were solicited adverse events (AEs) and related unsolicited AEs within 12 days of injections, and all serious AEs. Pf infection was detected by thick blood smears performed every four weeks and during febrile illness over 48 weeks. Primary vaccine efficacy (VE) endpoint was time to infection at 24 weeks. NCT02996695. Findings: 62 participants were enrolled in April/May 2017. Proportions of participants experiencing at least one solicited systemic AE were similar between treatment arms: 6/31 (19.4%, 95%CI 9.2-36.3) of PfSPZ-CVac recipients versus 7/31 (22.6%, 95%CI 29.2-62.2) of controls (p value = 1.000). Two/31 (6%) in each group reported related, unsolicited AEs. One unrelated death occurred. Of 59 receiving 3 immunizations per protocol, fewer vaccinees (16/29, 55.2%) became infected than controls (22/30, 73.3%). VE was 33.6% by hazard ratio (p = 0.21, 95%CI -27·9, 65·5) and 24.8% by risk ratio (p = 0.10, 95%CI -4·8, 54·3). Antibody responses to PfCSP were poor; 28% of vaccinees sero-converted. Interpretation: PfSPZ-CVac (CQ) was well-tolerated. The tested dosing regimen failed to significantly protect against Pf infection in this very high transmission setting. Funding: U.S. National Institutes of Health, Sanaria. Registration number: ClinicalTrials.gov identifier (NCT number): NCT02996695.

EVITA Dengue: a cluster-randomized controlled trial to EValuate the efficacy of Wolbachia-InfecTed Aedes aegypti mosquitoes in reducing the incidence of Arboviral infection in Brazil.

BACKGROUND: Arboviruses transmitted by Aedes aegypti including dengue, Zika, and chikungunya are a major global health problem, with over 2.5 billion at risk for dengue alone. There are no licensed antivirals for these infections, and safe and effective vaccines are not yet widely available. Thus, prevention of arbovirus transmission by vector modification is a novel approach being pursued by multiple researchers. However, the field needs high-quality evidence derived from randomized, controlled trials upon which to base the implementation and maintenance of vector control programs. Here, we report the EVITA Dengue trial design (DMID 17-0111), which assesses the efficacy in decreasing arbovirus transmission of an innovative approach developed by the World Mosquito Program for vector modification of Aedes mosquitoes by Wolbachia pipientis. METHODS: DMID 17-0111 is a cluster-randomized trial in Belo Horizonte, Brazil, with clusters defined by primary school catchment areas. Clusters (n = 58) will be randomized 1:1 to intervention (release of Wolbachia-infected Aedes aegypti mosquitoes) vs. control (no release). Standard vector control activities (i.e., insecticides and education campaigns for reduction of mosquito breeding sites) will continue as per current practice in the municipality. Participants (n = 3480, 60 per cluster) are children aged 6-11 years enrolled in the cluster-defining school and living within the cluster boundaries who will undergo annual serologic surveillance for arboviral infection. The primary objective is to compare sero-incidence of arboviral infection between arms. DISCUSSION: DMID 17-0111 aims to determine the efficacy of Wolbachia-infected mosquito releases in reducing human infections by arboviruses transmitted by Aedes aegypti and will complement the mounting evidence for this method from large-scale field releases and ongoing trials. The trial also represents a critical step towards robustness and rigor for how vector control methods are assessed, including the simultaneous measurement and correlation of entomologic and epidemiologic outcomes. Data from this trial will inform further the development of novel vector control methods. TRIAL REGISTRATION: ClinicalTrials.gov NCT04514107 . Registered on 17 August 2020 Primary sponsor: National Institute of Health, National Institute of Allergy and Infectious Diseases.

PfSPZ-CVac efficacy against malaria increases from 0% to 75% when administered in the absence of erythrocyte stage parasitemia: A randomized, placebo-controlled trial with controlled human malaria infection.

PfSPZ-CVac combines 'PfSPZ Challenge', which consists of infectious Plasmodium falciparum sporozoites (PfSPZ), with concurrent antimalarial chemoprophylaxis. In a previously-published PfSPZ-CVac study, three doses of 5.12x104 PfSPZ-CVac given 28 days apart had 100% vaccine efficacy (VE) against controlled human malaria infection (CHMI) 10 weeks after the last immunization, while the same dose given as three injections five days apart had 63% VE. Here, we conducted a dose escalation trial of similarly condensed schedules. Of the groups proceeding to CHMI, the first study group received three direct venous inoculations (DVIs) of a dose of 5.12x104 PfSPZ-CVac seven days apart and the next full dose group received three DVIs of a higher dose of 1.024x105 PfSPZ-CVac five days apart. CHMI (3.2x103 PfSPZ Challenge) was performed by DVI 10 weeks after the last vaccination. In both CHMI groups, transient parasitemia occurred starting seven days after each vaccination. For the seven-day interval group, the second and third vaccinations were therefore administered coincident with parasitemia from the prior vaccination. Parasitemia was associated with systemic symptoms which were severe in 25% of subjects. VE in the seven-day group was 0% (7/7 infected) and in the higher-dose, five-day group was 75% (2/8 infected). Thus, the same dose of PfSPZ-CVac previously associated with 63% VE when given on a five-day schedule in the prior study had zero VE here when given on a seven-day schedule, while a double dose given on a five-day schedule here achieved 75% VE. The relative contributions of the five-day schedule and/or the higher dose to improved VE warrant further investigation. It is notable that administration of PfSPZ-CVac on a schedule where vaccine administration coincided with blood-stage parasitemia was associated with an absence of sterile protective immunity. Clinical trials registration: NCT02773979.

Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study.

Neurocysticercosis and trichuriasis are difficult-to-treat parasitic infections that affect more than 1.5 billion people worldwide. Oxfendazole, a potent broad-spectrum benzimidazole anthelmintic approved for use in veterinary medicine, has shown substantial antiparasitic activity against neurocysticercosis and intestinal helminths in preclinical studies. As part of a program to transition oxfendazole from veterinary medicine to human use, phase I multiple ascending dose and food effect studies were conducted. Thirty-six healthy adults were enrolled in an open-label study which evaluated (i) the pharmacokinetics and safety of oxfendazole following multiple ascending doses of oxfendazole oral suspension at 3, 7.5, and 15 mg/kg once daily for 5 days and (ii) the effect of food on oxfendazole pharmacokinetics and safety after a single 3-mg/kg dose administered following an overnight fast or the consumption of a fatty breakfast. Following multiple oral dose administration, the intestinal absorption of oxfendazole was rapid, with the time to maximum concentration of drug in serum (Tmax) ranging from 1.92 to 2.56 h. A similar half-life of oxfendazole (9.21 to 11.8 h) was observed across all dose groups evaluated, and oxfendazole exhibited significantly less than a dose-proportional increase in exposure. Oxfendazole plasma exposures were higher in female subjects than in male subjects. Following daily administration, oxfendazole reached a steady state in plasma on study day 3, with minimal accumulation. Food delayed the oxfendazole Tmax by a median of 6.88 h and resulted in a 49.2% increase in the maximum observed drug concentration in plasma (Cmax) and an 86.4% increase in the area under the concentration-time curve (AUC). Oxfendazole was well tolerated in all study groups, and there were no major safety signals identified in this study. (This study has been registered at ClinicalTrials.gov under identifier NCT03035760.).

Dose-Dependent Infectivity of Aseptic, Purified, Cryopreserved Plasmodium falciparum 7G8 Sporozoites in Malaria-Naive Adults.

Direct venous inoculation of 3.2 × 103 aseptic, purified, cryopreserved, vialed Plasmodium falciparum (Pf) strain NF54 sporozoites, PfSPZ Challenge (NF54), has been used for controlled human malaria infection (CHMI) in the United States, 4 European countries, and 6 African countries. In nonimmune adults, this results in 100% infection rates. We conducted a double-blind, randomized, dose-escalation study to assess the infectivity of the 7G8 clone of Pf (PfSPZ Challenge [7G8]). Results showed dose-dependent infectivity from 43% for 8 × 102 PfSPZ to 100% for 4.8 × 103 PfSPZ. PfSPZ Challenge (7G8) will allow for more complete assessment by CHMI of antimalarial vaccines and drugs.