The Candidate Blood-stage Malaria Vaccine P27A Induces a Robust Humoral Response in a Fast Track to the Field Phase 1 Trial in Exposed and Nonexposed Volunteers.

Background: P27A is an unstructured 104mer synthetic peptide from Plasmodium falciparum trophozoite exported protein 1 (TEX1), the target of human antibodies inhibiting parasite growth. The present project aimed at evaluating the safety and immunogenicity of P27A peptide vaccine in malaria-nonexposed European and malaria-exposed African adults. Methods: This study was designed as a staggered, fast-track, randomized, antigen and adjuvant dose-finding, multicenter phase 1a/1b trial, conducted in Switzerland and Tanzania. P27A antigen (10 or 50 µg), adjuvanted with Alhydrogel or glucopyranosil lipid adjuvant stable emulsion (GLA-SE; 2.5 or 5 µg), or control rabies vaccine (Verorab) were administered intramuscularly to 16 malaria-nonexposed and 40 malaria-exposed subjects on days 0, 28, and 56. Local and systemic adverse events (AEs) as well as humoral and cellular immune responses were assessed after each injection and during the 34-week follow-up. Results: Most AEs were mild to moderate and resolved completely within 48 hours. Systemic AEs were more frequent in the formulation with alum as compared to GLA-SE, whereas local AEs were more frequent after GLA-SE. No serious AEs occurred. Supported by a mixed Th1/Th2 cell-mediated immunity, P27A induced a marked specific antibody response able to recognize TEX1 in infected erythrocytes and to inhibit parasite growth through an antibody-dependent cellular inhibition mechanism. Incidence of AEs and antibody responses were significantly lower in malaria-exposed Tanzanian subjects than in nonexposed European subjects. Conclusions: The candidate vaccine P27A was safe and induced a particularly robust immunogenic response in combination with GLA-SE. This formulation should be considered for future efficacy trials. Clinical Trials Registration: NCT01949909, PACTR201310000683408.

Recent shifts in the occurrence, cause, and magnitude of animal mass mortality events.

Mass mortality events (MMEs) are rapidly occurring catastrophic demographic events that punctuate background mortality levels. Individual MMEs are staggering in their observed magnitude: removing more than 90% of a population, resulting in the death of more than a billion individuals, or producing 700 million tons of dead biomass in a single event. Despite extensive documentation of individual MMEs, we have no understanding of the major features characterizing the occurrence and magnitude of MMEs, their causes, or trends through time. Thus, no framework exists for contextualizing MMEs in the wake of ongoing global and regional perturbations to natural systems. Here we present an analysis of 727 published MMEs from across the globe, affecting 2,407 animal populations. We show that the magnitude of MMEs has been intensifying for birds, fishes, and marine invertebrates; invariant for mammals; and decreasing for reptiles and amphibians. These shifts in magnitude proved robust when we accounted for an increase in the occurrence of MMEs since 1940. However, it remains unclear whether the increase in the occurrence of MMEs represents a true pattern or simply a perceived increase. Regardless, the increase in MMEs appears to be associated with a rise in disease emergence, biotoxicity, and events produced by multiple interacting stressors, yet temporal trends in MME causes varied among taxa and may be associated with increased detectability. In addition, MMEs with the largest magnitudes were those that resulted from multiple stressors, starvation, and disease. These results advance our understanding of rare demographic processes and their relationship to global and regional perturbations to natural systems.

Coping with stress: Salt type, concentration, and exposure history limit life history tradeoffs in response to road salt salinization.

Substantial increases in the salinity of freshwater ecosystems has occurred around the globe from causes such as climate change, industrial operations, and the application of road deicing salts. We know very little about how plastic responses in life history traits or rapid evolution of new traits among freshwater organisms could promote stability in ecological communities affected by salinization. We performed a cohort life history analysis from birth to death with 180 individuals of a ubiquitous freshwater zooplankter to understand how life history traits are affected by exposure to two common salt types causing salinization-sodium chloride (NaCl) and calcium chloride (CaCl2)-across two environmentally relevant concentrations. We also tested if a multi-generational exposure history to high salinity altered life-history responses. We tracked and measured lifespan, time to maturation, brood size, brood interval, and body size. We found smaller brood sizes but slightly longer lifespans occurred at a low concentration of NaCl (230 mg Cl-/L). The longer lifespans led to more, albeit smaller broods, which generated a similar lifetime reproductive output compared to the no-salt control populations. At higher concentrations of NaCl and CaCl2, we found lifetime reproductive output was reduced by 23 % to 83 % relative to control populations because no tradeoff among life history traits occurred. In CaCl2, we observed shorter life spans, longer time intervals between smaller broods, and smaller body sizes leading to reduced lifetime reproductive output. We also found that a multi-generational exposure to the salt types did not convey any advantages for lifetime reproductive output. In some cases, the exposure history worsened the life history trait responses suggesting maladaptation. Our findings suggest that life history tradeoffs for freshwater species can occur in response to salinization, but these tradeoffs will largely depend on salt type and concentration, which will have implications for biodiversity and ecological stability.

Freshwater salinization reduces vertical movement rate and abundance of Daphnia: Interactions with predatory stress.

Contaminants in human-dominated landscapes are changing ecological interactions. The global increase in freshwater salinity is likely to change predator-prey interactions due to the potential interactive effects between predatory stress and salt stress. We conducted two experiments to assess the interactions between the non-consumptive effects of predation and elevated salinity on the abundance and vertical movement rate of a common lake zooplankton species (Daphnia mendotae). Our results revealed an antagonism rather than a synergism between predatory stress and salinity on zooplankton abundance. Elevated salinity and predator cues triggered a >50% reduction in abundance at salt concentrations of 230 and 860 mg Cl-/L, two thresholds designed to protect freshwater organisms from chronic and acute effects due to salt pollution. We found a masking effect between salinity and predation on vertical movement rate of zooplankton. Elevated salinity reduced zooplankton vertical movement rate by 22-47%. A longer exposure history only magnified the reduction in vertical movement rate when compared to naïve individuals (no prior salinity exposure). Downward movement rate under the influence of predatory stress in elevated salinity was similar to the control, which may enhance the energetic costs of predator avoidance in salinized ecosystems. Our results suggest antagonistic and masking effects between elevated salinity and predatory stress will have consequences for fish-zooplankton interactions in salinized lakes. Elevated salinity could impose additional energetic constraints on zooplankton predator avoidance behaviors and vertical migration, which may reduce zooplankton population size and community interactions supporting the functioning of lake ecosystems.

Efficacy, safety, and palatability of arpraziquantel (L-praziquantel) orodispersible tablets in children aged 3 months to 6 years infected with Schistosoma in Côte d'Ivoire and Kenya: an open-label, partly randomised, phase 3 trial.

BACKGROUND: WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, palatability, and pharmacokinetics of arpraziquantel (L-praziquantel) orodispersible tablets for preschool-aged children. METHODS: This open-label, partly randomised, phase 3 study was conducted at two hospitals in Côte d'Ivoire and Kenya. Children with a minimum bodyweight of 5 kg in those aged 3 months to 2 years and 8 kg in those aged 2-6 years were eligible. In cohort 1, participants aged 4-6 years infected with Schistosoma mansoni were randomly assigned (2:1) to receive a single dose of oral arpraziquantel 50 mg/kg (cohort 1a) or oral praziquantel 40 mg/kg (cohort 1b) using a computer-generated randomisation list. Cohorts 2 (aged 2-3 years) and 3 (aged 3 months to 2 years) infected with S mansoni, and the first 30 participants in cohort 4a (aged 3 months to 6 years) infected with Schistosoma haematobium, received a single dose of oral arpraziquantel 50 mg/kg. After follow-up assessments, arpraziquantel was increased to 60 mg/kg (cohort 4b). Laboratory personnel were masked to the treatment group, screening, and baseline values. S mansoni was detected using a point-of-care circulating cathodic antigen urine cassette test and confirmed using the Kato-Katz method. The primary efficacy endpoint was clinical cure rate at 17-21 days after treatment in cohorts 1a and 1b, measured in the modified intention-to-treat population and calculated using the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, NCT03845140. FINDINGS: Between Sept 2, 2019, and Aug 7, 2021, 2663 participants were prescreened and 326 were diagnosed with S mansoni or S haematobium. 288 were enrolled (n=100 in cohort 1a, n=50 in cohort 1b, n=30 in cohort 2, n=18 in cohort 3, n=30 in cohort 4a, and n=60 in cohort 4b), but eight participants received antimalarial drugs and were excluded from the efficacy analyses. The median age was 5·1 years (IQR 4·1-6·0) and 132 (47%) of 280 participants were female and 148 (53%) were male. Cure rates with arpraziquantel were similar to those with praziquantel (87·8% [95% CI 79·6-93·5] in cohort 1a vs 81·3% [67·4-91·1] in cohort 1b). No safety concerns were identified during the study. The most common drug-related treatment-emergent adverse events were abdominal pain (41 [14%] of 288 participants), diarrhoea (27 [9%]), vomiting (16 [6%]), and somnolence (21 [7%]). INTERPRETATION: Arpraziquantel, a first-line orodispersible tablet, showed high efficacy and favourable safety in preschool-aged children with schistosomiasis. FUNDING: The Global Health Innovative Technology Fund, the European and Developing Countries Clinical Trials Partnership, and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

Comparative palatability of orally disintegrating tablets (ODTs) of Praziquantel (L-PZQ and Rac-PZQ) versus current PZQ tablet in African children: A randomized, single-blind, crossover study.

BACKGROUND: Praziquantel (PZQ) is currently the only recommended drug for infection and disease caused by the schistosome species that infects humans; however, the current tablet formulation is not suitable for pre-school age children mainly due to its bitterness and the large tablet size. We assessed the palatability of two new orally disintegrating tablet (ODT) formulations of PZQ. METHODOLOGY: This randomized, single-blind, crossover, swill-and-spit palatability study (NCT02315352) was carried out at a single school in Tanzania in children aged 6-11 years old, with or without schistosomiasis infection as this was not part of the assessment. Children were stratified according to age group (6-8 years or 9-11 years) and gender, then randomized to receive each formulation in a pre-specified sequence. Over 2 days, the children assessed the palatability of Levo-Praziquantel (L-PZQ) ODT 150 mg and Racemate Praziquantel (Rac-PZQ) ODT 150 mg disintegrated in the mouth without water on the first day, and L-PZQ and Rac-PZQ dispersed in water and the currently available PZQ 600 mg formulation (PZQ-Cesol) crushed and dispersed in water on the second day. The palatability of each formulation was rated using a 100 mm visual analogue scale (VAS) incorporating a 5-point hedonic scale, immediately after spitting out the test product (VASt = 0 primary outcome) and after 2-5 minutes (VASt = 2-5). PRINCIPAL FINDINGS: In total, 48 children took part in the assessment. Overall, there was no reported difference in the VASt = 0 between the two ODT formulations (p = 0.106) without water. Higher VASt = 0 and VASt = 2-5 scores were reported for L-PZQ ODT compared with Rac-PZQ ODT in older children (p = 0.046 and p = 0.026, respectively). The VASt = 0 and VASt = 2-5 were higher for both ODT formulations compared with the standard formulation (p<0.001 for both time points). No serious adverse events were reported. CONCLUSIONS/SIGNIFICANCE: The new paediatric-friendly formulations dispersed in water were both found to be more palatable than the existing standard formulation of PZQ. There may be gender and age effects on the assessment of palatability. Further research is needed for assessing efficacy and tolerability of the newly ODTs Praziquantel drug in younger children. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT02315352) and in the Pan African Clinical Trials Registry (PACTR201412000959159).

Challenges and Lessons From Conducting A Paediatric Clinical Trial in Sub-Saharan Africa: The Case of the Praziquantel Oral Dispersible Tablets Phase II Study in Côte d'Ivoire.

The importance of implementing paediatric clinical trials for neglected tropical diseases (NTDs) in compliance with the Good Clinical Practices of the International Conference of Harmonisation (ICH-GCP) and other applicable regulatory and ethics guidelines is increasingly being recognised as an essential pathway to provide safe and effective medicines for millions of untreated children living in sub-Saharan Africa (SSA). This paper describes the learnings and challenges faced by the Pediatric Praziquantel Consortium team during the implementation of an industry-sponsored Phase II clinical study in pre-school-aged children infected with schistosomiasis, conducted in remote rural settings in Côte d'Ivoire. The importance of close interactions with the ethics committee, the regulatory and administrative authorities and the rural communities are highlighted. The difficulties faced included obtaining a valid informed consent from the child's parent or guardian, the collection of blood samples from children during the study while respecting cultural beliefs as well as the weak medical research infrastructure. The paper illustrates how a public-private collaborative partnership can promote capacity-building and high-quality NTD paediatric clinical research in SSA.

Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites.

Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa. Aseptic, purified, cryopreserved Pf sporozoites, PfSPZ Challenge, were used to infect Dutch volunteers by intradermal injection. We conducted a double-blind, placebo-controlled trial to assess safety and infectivity of PfSPZ Challenge in adult male Tanzanians. Volunteers were injected intradermally with 10,000 (N = 12) or 25,000 (N = 12) PfSPZ or normal saline (N = 6). PfSPZ Challenge was well tolerated and safe. Eleven of 12 and 10 of 11 subjects, who received 10,000 and 25,000 PfSPZ respectively, developed parasitemia. In 10,000 versus 25,000 PfSPZ groups geometric mean days from injection to Pf positivity by thick blood film was 15.4 versus 13.5 (P = 0.023). Alpha-thalassemia heterozygosity had no apparent effect on infectivity. PfSPZ Challenge was safe, well tolerated, and infectious.

Rapid microarray-based method for monitoring of all currently known single-nucleotide polymorphisms associated with parasite resistance to antimalaria drugs.

Parasite drug resistance is partly conferred by single-nucleotide polymorphisms (SNPs), and monitoring them has been proposed as an alternative to monitoring drug resistance. Therefore, techniques are required to facilitate analyses of multiple SNPs on an epidemiological scale. We report a rapid and affordable microarray technique for application in epidemiological studies of malaria drug resistance. We have designed a multiwell microarray that is used in conjunction with PCR-amplified target genes implicated in the drug resistance of malaria with subsequent one-tube minisequencing using two fluorochromes. The drug-resistance-associated genes pfdhfr, pfdhps, pfcrt, pfmdr1, and pfATPase were amplified and analyzed for cultured Plasmodium falciparum strains and from field samples. We obtained a specificity of 94%, and comparison of field sample results to those of restriction fragment length polymorphism (RFLP) typing resulted in an overall consistency of >90%, except for pfdhfr51, for which most discrepancies were due to false determinations by RFLP of mixed infections. The system is sufficiently sensitive to assay parasites in clinical malaria cases and in most asymptomatic cases, and it allows high throughput with minimal hands-on time. The cost for the assay has been calculated as 0.27 euros/SNP (US $0.33), which is below the cost incurred with other systems. Due to the simplicity of the approach, newly identified SNPs can be incorporated rapidly. Such a monitoring system also makes it possible to identify the reemergence of drug-susceptible parasites once a drug has been withdrawn.

Robonaut: a robot designed to work with humans in space.

The Robotics Technology Branch at the NASA Johnson Space Center is developing robotic systems to assist astronauts in space. One such system, Robonaut, is a humanoid robot with the dexterity approaching that of a suited astronaut. Robonaut currently has two dexterous arms and hands, a three degree-of-freedom articulating waist, and a two degree-of-freedom neck used as a camera and sensor platform. In contrast to other space manipulator systems, Robonaut is designed to work within existing corridors and use the same tools as space walking astronauts. Robonaut is envisioned as working with astronauts, both autonomously and by teleoperation, performing a variety of tasks including, routine maintenance, setting up and breaking down worksites, assisting crew members while outside of spacecraft, and serving in a rapid response capacity.