In Schistosoma-endemic regions a lack of natural sterilizing immunity means individuals are repeatedly infected, treated and reinfected. Due to difficulties in tracking natural infection, kinetics of host immune response during these reinfections have not been elucidated. Here, we use repeated (3x) controlled-human-Schistosoma mansoni infection (CHI) to study how antigen-specific T cells develop during reinfection (NCT05085470 study). We compared these responses to naturally infected endemic Ugandan individuals (HALLMARK study). A mixed Th1/Th2/regulatory CD4+ T cell response develops in repeated CHI. Adult-worm-specific responses after repeated CHI were similar to endemic-natural infection. However, endemic participants showed differential responses to egg- and cercariae-antigens. Repeated CHI with sequential exposure to cercariae of different sexes (male-female-male) revealed an elevated CD4+ T cell cytokine response to adult-worm and egg-antigens. Our findings demonstrate that single-sex schistosome infection elicits adult-worm-specific T cell cytokine responses that reflect endemic-natural infection. This study advances our understanding of the immunology of schistosome (re)infection in the human host.

Malaria vaccines consisting of metabolically active Plasmodium falciparum (Pf) sporozoites can offer improved protection compared with currently deployed subunit vaccines. In a previous study, we demonstrated the superior protective efficacy of a three-dose regimen of late-arresting genetically attenuated parasites administered by mosquito bite (GA2-MB) compared with early-arresting counterparts (GA1-MB) against a homologous controlled human malaria infection. Encouraged by these results, we explored the potency of a single GA2-MB immunization in a placebo-controlled randomized trial. Primary outcomes were safety and tolerability, time-to-parasitemia and protective efficacy. Humoral and cellular immunological results were considered secondary outcomes. Here we report the safe administration of GA2-MB with no breakthrough malaria and sterile protection in nine of ten participants at 6 weeks after a single immunization with 50 GA2-infected mosquitoes, compared with none of five mock-immunized participants, against a homologous controlled human malaria infection. Immunization increased circulating Pf-specific polyfunctional effector memory CD4+ T cells coexpressing tumor necrosis factor and interleukin-2. This unprecedented 90% protective efficacy after a single low-dose immunization holds great promise for the potency of GA2 immunization. Future studies should demonstrate whether GA2 is similarly efficacious in pre-exposed populations and whether the favorable safety profile reported here holds up in larger groups. ClinicalTrials.gov registration: NCT05468606.

BACKGROUNDPartial protective immunity to schistosomiasis develops over time, following repeated praziquantel (PZQ) treatment. Moreover, animals develop protective immunity after repeated immunization with irradiated cercariae. Here, we evaluated the development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni in healthy, Schistosoma-naive participants using single-sex, controlled human S. mansoni infection.METHODSTwenty-four participants were randomized in a double-blinded (1:1) manner to either the reinfection group, which received 3 exposures (weeks 0, 9, and 18) to 20 male cercariae, or to the infection control group, which received 2 mock exposures with water (weeks 0 and 9) prior to cercariae exposure (week 18). Participants were treated with PZQ (or placebo) at weeks 8, 17, and 30. Attack rates (ARs) after the final exposure (weeks 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events (AEs) were collected for safety.RESULTSTwenty-three participants completed the follow-up. No protective efficacy was observed, given an 82% (9 of 11) AR after the final exposure in the reinfection group and 92% (11 of 12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; P = 0.5). Related AEs were higher after the first infection (45%) compared with the second (27%) and third (28%) infections. Severe acute schistosomiasis was observed after the first infections only (2 of 12 in the reinfection group and 2 of 12 in the infection control group).CONCLUSIONRepeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported following subsequent infections, but did not result in protection against reinfection.TRIAL REGISTRATIONClinicalTrials.gov NCT05085470.FUNDINGEuropean Research Council (ERC) Starting Grant (no. 101075876).

Fractional dosing can be a cost-effective vaccination strategy to accelerate individual and herd immunity in a pandemic. We assessed the immunogenicity and safety of primary intradermal (ID) vaccination, with a 1/5th dose compared with the standard intramuscular (IM) dose of mRNA-1273 in SARS-CoV-2 naïve persons. We conducted an open-label, non-inferiority, randomized controlled trial in the Netherlands between June and December 2021. One hundred and fifty healthy and SARS-CoV-2 naïve participants, aged 18–30 years, were randomized (1:1:1) to receive either two doses of 20 µg mRNA-1273 ID with a standard needle (SN) or the Bella-mu® needle (BM), or two doses of 100 µg IM, 28 days apart. The primary outcome was non-inferiority in seroconversion rates at day 43 (D43), defined as a neutralizing antibody concentration threshold of 465 IU/mL, the lowest response in the IM group. The non-inferiority margin was set at −15%. Neutralizing antibody concentrations at D43 were 1789 (95% CI: 1488–2150) in the IM and 1263 (951–1676) and 1295 (1020–1645) in the ID-SN and ID-BM groups, respectively. The absolute difference in seroconversion proportion between fractional and standard-dose groups was −13.95% (−24.31 to −3.60) for the ID-SN and −13.04% (−22.78 to −3.31) for the ID-BM group and exceeded the predefined non-inferiority margin. Although ID vaccination with 1/5th dose of mRNA-1273 did not meet the predefined non-inferior criteria, the neutralizing antibody concentrations in these groups are far above the proposed proxy for protection against severe disease (100 IU/mL), justifying this strategy in times of vaccine scarcity to accelerate mass protection against severe disease.

Schistosomiasis is an infection caused by contact with Schistosoma -contaminated water and affects more than 230 million people worldwide with varying morbidity. The roles of T helper 2 (T H 2) cells and regulatory immune responses in chronic infection are well documented, but less is known about human immune responses during acute infection. Here, we comprehensively map immune responses during controlled human Schistosoma mansoni infection using male or female cercariae. Immune responses to male or female parasite single-sex infection were comparable. An early T H 1-biased inflammatory response was observed at week 4 after infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. By week 8 after infection, inflammatory responses were followed by an expansion of T H 2 and regulatory cell subsets. This study demonstrates the shift from T H 1 to both T H 2 and regulatory responses, typical of chronic schistosomiasis, in the absence of egg production and provides immunological insight into the clinical manifestations of acute schistosomiasis.

BACKGROUND Currently licensed and approved malaria subunit vaccines provide modest, short-lived protection against malaria. Immunization with live-attenuated Plasmodium falciparum malaria parasites is an alternative vaccination strategy that has potential to improve protection. METHODS We conducted a double-blind, controlled clinical trial to evaluate the safety, side- effect profile, and efficacy of immunization, by means of mosquito bites, with a second-generation genetically attenuated parasite (GA2) - a mei2 single knockout P. falciparum NF54 parasite (sporozoite form) with extended development into the liver stage. After an open-label dose-escalation safety phase in which participants were exposed to the bites of 15 or 50 infected mosquitoes (stage A), healthy adults who had not had malaria were randomly assigned to be exposed to 50 mosquito bites per immunization of GA2, an early-arresting parasite (GA1), or placebo (bites from uninfected mosquitoes) (stage B). After the completion of three immunization sessions with 50 mosquito bites per session, we compared the protective efficacy of GA2 against homologous P. falciparum controlled human malaria infection with that of GA1 and placebo. The primary end points were the number and severity of adverse events (in stages A and B) and blood-stage parasitemia greater than 100 P. falciparum parasites per milliliter after bites from GA2-infected mosquitoes (in stage A) and after controlled human malaria infection (in stage B). RESULTS Adverse events were similar across the trial groups. Protective efficacy against subsequent controlled human malaria infection was observed in 8 of 9 participants (89%) in the GA2 group, in 1 of 8 participants (13%) in the GA1 group, and in 0 of 3 participants in the placebo group. A significantly higher frequency of P. falciparum- specific polyfunctional CD4+ and V delta 2+ gamma delta T cells were observed among participants who received GA2 than among those who received GA1, whereas GA2 and GA1 induced similar antibody titers targeting the P. falciparum circumsporozoite protein. CONCLUSIONS In this small trial, GA2 was associated with a favorable immune induction profile and protective efficacy, findings that warrant further evaluation. (Funded by the Bontius Foundation; ClinicalTrials.gov number, NCT04577066.)

Objectives: The aim of this study was to assess the safety and immunogenicity of a dose -sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine. Methods: COVID-19 naive adults aged 18-30 years were recruited from a previous study on primary vaccination regimens that compared 20 mu g ID vaccinations with 100 mu g intramuscular (IM) vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 mu g) or the standard-of-care intramuscular (IM) booster dose (50 mu g) of the mRNA-1273 vaccine, 6 months after completing their primary series (ID -ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). In addition, COVID-19 naive individuals aged 18-40 years who had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti -spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored. Results: In January 2022,129 participants were included in the study. Fractional ID boosting was safe and well tolerated, with fewer systemic adverse events compared with IM boosting. At day 28 post -booster, anti -spike S1 IgG geometric mean concentrations were 9106 (95% CI, 7150-11 597) binding antibody units (BAU)/mL in the IM-IM group and 4357 (3003-6322) BAU/mL; 6629 (4913-8946) BAU/mL; and 5264 (4032-6873) BAU/mL in the ID-IM, ID -ID, and IM-ID groups, respectively. Discussion: Intradermal boosting provides robust immune responses and is a viable dose -sparing strategy for mRNA COVID-19 vaccines. The favourable side-effect pro file supports its potential to reduce vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness. Geert V.T. Roozen, dlin Microbiol Infect 2024;30:930 (c) 2024 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Background: Travellers visiting rabies-endemic countries are at risk of rabies infection. Assessing travellers' knowledge and risk perception of rabies and risk behaviour during travel can help identify knowledge gaps and improve pre-travel risk education. Methods: Cohort study in Dutch adult travellers, using two surveys: one before travel to assess knowledge and perception of rabies, and one after return to identify risk behaviour during travel. Results: The pre-travel and post-travel survey were completed by 301 and 276 participants, respectively. 222 participants had travelled to a high-risk rabies-endemic country. 21.6 % of the participants scored their rabies knowledge as poor. Some participants were unaware cats or bats can transmit rabies (26.6 % and 13.6 %, respectively), or that post-exposure prophylaxis (PEP) is required for certain exposures such as skin abrasions without bleeding or licks on damaged skin (35.5 % and 18.9 %, respectively), while 27.9 % of participants did not know PEP needs to be administered within one day. 115 participants (51.8 %) reported any form of contact with any animal during travel. Two participants reported animal exposure, of which one took adequate PEP measures. Risk factors for animal contact abroad were regularly touching cats or dogs at home or abroad, longer travel duration, having pets during childhood and being an animal lover. Conclusions: Pre-travel rabies risk education currently does not meet travellers' needs, which is reflected in knowledge gaps and engagement in risk behaviour during travel. During pre-travel health advice, avoiding animal contact abroad should be emphasized, and additional education is required about indications for PEP.

Schistosomiasis is a parasitic disease affecting over 200 million people in multiple organs, including the lungs. Despite this, there is little understanding of pulmonary immune responses during schistosomiasis. Here, we show type-2 dominated lung immune responses in both patent (egg producing) and pre-patent (larval lung migration) murine Schistosoma mansoni ( S. mansoni) infection. Human pre-patent S. mansoni infection pulmonary (sputum) samples revealed a mixed type-1/type-2 inflammatory cytokine profile, whilst a case-control study showed no significant pulmonary cytokine changes in endemic patent infection. However, schistosomiasis induced expansion of pulmonary type-2 conventional dendritic cells (cDC2s) in human and murine hosts, at both infection stages. Further, cDC2s were required for type-2 pulmonary inflammation in murine pre-patent or patent infection. These data elevate our fundamental understanding of pulmonary immune responses during schistosomiasis, which may be important for future vaccine design, as well as for understanding links between schistosomiasis and other lung diseases.

Control of schistosomiasis depends on a single drug, praziquantel, with variable cure rates, high reinfection rates, and risk of drug resistance. A vaccine could transform schistosomiasis control. Preclinical data show that vaccine development is possible, but conventional vaccine efficacy trials require high incidence, long-term follow-up, and large sample size. Controlled human infection studies (CHI) can provide early efficacy data, allowing the selection of optimal candidates for further trials. A Schistosoma CHI has been established in the Netherlands but responses to infection and vaccines differ in target populations in endemic countries. We aim to develop a CHI for Schistosoma mansoni in Uganda to test candidate vaccines in an endemic setting. This is an open-label, dose-escalation trial in two populations: minimal, or intense, prior Schistosoma exposure. In each population, participants will be enrolled in sequential dose-escalating groups. Initially, three volunteers will be exposed to 10 cercariae. If all show infection, seven more will be exposed to the same dose. If not, three volunteers in subsequent groups will be exposed to higher doses (20 or 30 cercariae) following the same algorithm, until all 10 volunteers receiving a particular dose become infected, at which point the study will be stopped for that population. Volunteers will be followed weekly after infection until CAA positivity or to 12 weeks. Once positive, they will be treated with praziquantel and followed for one year. The trial registry number is ISRCTN14033813 and all approvals have been obtained. The trial will be subjected to monitoring, inspection, and/or audits.

Background Vaccine development against hookworm is hampered by the absence of the development of protective immunity in populations repeatedly exposed to hookworm, limiting identification of mechanisms of protective immunity and new vaccine targets. Immunisation with attenuated larvae has proven effective in dogs and partial immunity has been achieved using an irradiated larvae model in healthy volunteers. We aimed to investigate the protective efficacy of immunisation with short-term larval infection against hookworm challenge.Methods We did a single-centre, placebo-controlled, randomised, controlled, phase 1 trial at Leiden University Medical Center (Leiden, Netherlands). Healthy volunteers (aged 18-45 years) were recruited using advertisements on social media and in publicly accessible areas. Volunteers were randomly assigned (2:1) to receive three short-term infections with 50 infectious Necator americanus third-stage filariform larvae (50L3) or placebo. Infection was abrogated with a 3-day course of albendazole 400 mg, 2 weeks after each exposure. Subsequently all volunteers were challenged with two doses of 50L3 at a 2-week interval. The primary endpoint was egg load (geometric mean per g faeces) measured weekly between weeks 12 and 16 after first challenge, assessed in the per-protocol population, which included all randomly assigned volunteers with available data on egg counts at week 12-16 after challenge. This study is registered with ClinicalTrials.gov, NCT03702530.Findings Between Nov 8 and Dec 14, 2018, 26 volunteers were screened, of whom 23 enrolled in the trial. The first immunisation was conducted on Dec 18, 2018. 23 volunteers were randomly assigned (15 to the intervention group and eight to the placebo group). Egg load after challenge was lower in the intervention group than the placebo group (geometric mean 571 eggs per g [range 372-992] vs 873 eggs per g [268-1484]); however, this difference was not statistically significant (p=0 center dot 10). Five volunteers in the intervention group developed a severe skin rash, which was associated with 40% reduction in egg counts after challenge (geometric mean 742 eggs per g [range 268-1484] vs 441 eggs per g [range 380-520] after challenge; p=0 center dot 0025) and associated with higher peak IgG1 titres. Interpretation To our knowledge, this is the first study to describe a protective effect of short-term exposure to hookworm larvae and show an association with skin response, eosinophilic response, and IgG1. These findings could inform future hookworm vaccine development. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

BACKGROUND:After rabies pre-exposure prophylaxis (PrEP) vaccination, scarcely available rabies immunoglobulins are not required for post-exposure prophylaxis (PEP). However, PrEP is not sufficiently accessible as it is cost-intensive and time-intensive. This study investigates whether rabies PrEP schedules can be shortened to one visit, removing some of these barriers. METHODS:In a block-randomised (2:2:2:1) controlled, multicentre non-inferiority trial, healthy adult travellers (aged 18-50 years and >50 years) were randomly assigned to (A) single-visit intramuscular (1·0 mL); (B) single-visit intradermal (0·2 mL); (C) standard two-visit intramuscular (1·0 mL; day 0 and 7) PrEP; or (D) no rabies vaccination. 6 months later, participants received simulated intramuscular rabies PEP (1·0 mL; day 0 and 3). Rabies virus neutralising antibody (RVNA) concentrations were measured repeatedly. The primary outcome was the fold increase in geometric mean RVNA concentrations between day 0 and 7 after simulated PEP for all participants. The two main comparisons of this primary outcome are between the standard two-visit schedule and the one-visit intramuscular schedule, and between the standard two-visit schedule and the one-visit intradermal schedule. The non-inferiority margin was 0·67. This study is registered with EudraCT, 2017-000089-31. FINDINGS:Between May 16, 2018, and March 26, 2020, 288 healthy adult travellers were randomly assigned and 214 participants were evaluated for the primary outcome. Single-visit intramuscular rabies PrEP induced an anamnestic antibody response non-inferior compared with the two-visit intramuscular schedule; single-visit intradermal PrEP did not. The fold increases in the single-visit intramuscular and the single-visit intradermal schedule were 2·32 (95% CI [1·43-3·77]) and 1·11 (0·66-1·87) times as high as the fold increase in the standard schedule, respectively. No vaccine-related serious adverse events were observed. Adverse events related to vaccination were mostly mild. INTERPRETATION:Single intramuscular rabies vaccination can effectively prime travellers (aged 18-50 years), and potentially other populations, and could replace current standard two-visit rabies vaccination as PrEP. FUNDING:ZonMW. TRANSLATION:For the Dutch translation of the abstract see Supplementary Materials section.

Background A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome exposure. Recently, we established CHI-S model using single-sex male-only Schistosoma mansoni (Sm) cercariae in Schistosoma-naive individuals. Given important differences in antigenic profile and human immune responses to schistosomes of different sex, we pioneered a single-sex female-only CHI-S model for future use in vaccine development.Methods We exposed 13 healthy, Schistosoma-naive adult participants to 10 (n = 3) or 20 (n = 10) female cercariae and followed for 20 weeks, receiving treatment with praziquantel (PZQ) 60 mg/kg at week 8 and 12 after exposure.Findings The majority (11/13) participants reported rash and/or itch at the site of exposure, 5/13 had transient symptoms of acute schistosomiasis. Exposure to 20 cercariae led to detectable infection, defined as serum circulating anodic antigen levels >1.0 pg/mL, in 6/10 participants. Despite two rounds of PZQ treatment, 4/13 participants showed signs of persistent infection. Additional one-or three-day PZQ treatment (1 x 60 mg/kg and 3 x 60 mg/kg) or artemether did not result in cure, but over time three participants self-cured. Antibody, cellular, and cytokine responses peaked at week 4 post infection, with a mixed Th1, Th2, and regulatory profile. Cellular responses were (most) discriminative for symptoms.Interpretation Female-only infections exhibit similar clinical and immunological profiles as male-only infections but are more resistant to PZQ treatment. This limits future use of this model and may have important implications for disease control programs.

Schistosomiasis impacts African populations most strongly. Despite Uganda's leading role in the Schistosomiasis Control Initiative for mass drug administration (MDA), about half the population remains at risk and a quarter infected. Prevalence and intensity remain high, and morbidity severe, in northwest Uganda around Lake Albert and the Albert Nile. An effective vaccine could combat repeated infection following MDA, and controlled human infection (CHI) studies could enable such vaccine development. Therefore, the Uganda Schistosomiasis Multidisciplinary Research Center and CHI-in-Africa Network hosted a symposium in Uganda bringing together local and international partners to discuss research on the drivers of schistosomal morbidity and the development of CHI studies for helminth vaccine development in Africa. In this TrendsTalk, we invited 10 early-to mid-career researchers to summarise the symposium proceedings.

Schistosomiasis is a prevalent helminthiasis, affecting over 230 million people worldwide, with varied, stage specific morbidity. Whilst the Th2 and regulatory immune responses in chronic infection have been relatively well studied, we have little understanding of human immune responses during acute infection. This is despite the initial infective stages being proposed as crucial targets for much-needed vaccine development. Here, we comprehensively map immune responses in male and female single-sex controlled human Schistosoma mansoni infection. Using unbiased, high dimensional techniques we show that human immune responses to male and female single-sex infection are comparable. An early Th1-biased inflammatory response was observed at week 4 post infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. This included expansion of HLA-DR+ effector memory T cells, CD38+ monocytes and an increase in serum IFNγ. By week 8 post infection these inflammatory responses were followed by an expansion of Th2 and of regulatory cell subsets, including IL-10 producing CD4-CD8- T cells, CD11c+ atypical memory B cells and serum IL-10. This study provides immunological insight into the clinical manifestations of acute schistosomiasis, as well as critical context through which to understand the development of immune responses observed in natural infection.One sentence summary Controlled human schistosome infection reveals cellular and cytokine responses to schistosome infection, with early inflammatory responses in symptomatic individuals at week 4 and a balanced Th1, Th2 and regulatory response in all participants by week 8.### Competing Interest StatementThe authors have declared no competing interest.### Clinical TrialNCT02755324 [NCT04269915][1]### Funding StatementThis study was funded by the European Union Horizon 2020 research and innovation programme under grant agreement No 815643.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Institutional Medical Ethical Research Committee (Institutional Review Board P16.111 and P20.015) of Leiden University Medical Center gave ethical approval for this work.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04269915&atom=%2Fmedrxiv%2Fearly%2F2023%2F09%2F04%2F2023.09.01.23294933.atom

Background Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the causal chemoprophylactic activity and dose-exposure-response relationship of single oral doses of cabamiquine following the direct venous inoculation (DVI) of P falciparum sporozoites in malaria-naive, healthy volunteers.Methods This was a phase 1b, randomised, double-blind, placebo-controlled, adaptive, dose-finding, single-centre study performed in Leiden, Netherlands. Malaria-naive, healthy adults aged 18-45 years were divided into five cohorts and randomly assigned (3:1) to receive cabamiquine or placebo. Randomisation was done by an independent statistician using codes in a permuted block schedule with a block size of four. Participants, investigators, and study personnel were masked to treatment allocation. A single, oral dose regimen of cabamiquine (200, 100, 80, 60, or 30 mg) or matching placebo was administered either at 2 h (early liver-stage) or 96 h (late liver-stage) after DVI. The primary endpoints based on a per-protocol analysis set were the number of participants who developed parasitaemia within 28 days of DVI, time to parasitaemia, number of participants with documented parasite blood-stage growth, clinical symptoms of malaria, and exposure-efficacy modelling. The impact of cabamiquine on liver stages was evaluated indirectly by the appearance of parasitaemia in the blood. The Clopper-Pearson CI (nominal 95%) was used to express the protection rate. The secondary outcomes were safety and tolerability, assessed in those who had received DVI and were administered one dose of the study intervention. The trial was prospectively registered on ClinicalTrials.gov (NCT04250363).Findings Between Feb 17, 2020 and April 29, 2021, 39 healthy participants were enrolled (early liver-stage: 30 mg [n=3], 60 mg [n=6], 80 mg [n=6], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=6]; late liver-stage: 60 mg [n=3], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=3]). A dose-dependent causal chemoprophylactic effect was observed, with four (67%) of six participants in the 60 mg, five (83%) of six participants in the 80 mg, and all three participants in the 100 and 200 mg cabamiquine dose groups protected from parasitaemia up to study day 28, whereas all participants in the pooled placebo and 30 mg cabamiquine dose group developed parasitaemia. A single, oral dose of 100 mg cabamiquine or higher provided 100% protection against parasitaemia when administered during early or late liver-stage malaria. The median time to parasitaemia in those with early liver-stage malaria was prolonged to 15, 22, and 24 days for the 30, 60, and 80 mg dose of cabamiquine, respectively, compared with 10 days for the pooled placebo. All participants with positive parasitaemia showed documented blood-stage parasite growth, apart from one participant in the pooled placebo group and one participant in the 30 mg cabamiquine group. Most participants did not exhibit any malaria symptoms in both the early and late liver-stage groups, and those reported were mild in severity. A positive dose-exposure-efficacy relationship was established across exposure metrics. The median maximum concentration time was 1-6 h, with a secondary peak observed between 6 h and 12 h in all cabamiquine dose groups (early liver-stage). All cabamiquine doses were safe and well tolerated. Overall, 26 (96%) of 27 participants in the early liver-stage group and ten (833%) of 12 participants in the late liver-stage group reported at least one treatment-emergent adverse event (TEAE) with cabamiquine or placebo. Most TEAEs were of mild severity, transient, and resolved without sequelae. The most frequently reported cabamiquine-related TEAE was headache. No dose-related trends were observed in the incidence, severity, or causality of TEAEs.Interpretation The results from this study show that cabamiquine has a dose-dependent causal chemoprophylactic activity. Together with previously demonstrated activity against the blood stages combined with a half-life of more than 150 h, these results indicate that cabamiquine could be developed as a single-dose monthly regimen for malaria prevention.

Intestinal helminths are highly prevalent in low-SES children and could contribute to poor health outcomes either directly or via alteration of the gut microbiome and gut barrier function. We analysed parasitic infections and gut microbiota composition in 325 children attending high- and low-SES schools in Makassar, Indonesia before and after albendazole treatment. Lactulose/Mannitol Ratio (LMR, a marker of gut permeability); I-FABP (a surrogate marker of intestinal damage) as well as inflammatory markers (LBP) were measured. Helminth infections were highly prevalent (65.6%) in low-SES children. LMR and I-FABP levels were higher in low-SES children (geomean (95%CI): 4.03 (3.67–4.42) vs. 3.22 (2.91–3.57); p . adj < 0.001; and 1.57 (1.42–1.74) vs. 1.25 (1.13–1.38); p. adj = 0.02, respectively) while LBP levels were lower compared to the high-SES (19.39 (17.09–22.01) vs. 22.74 (20.07–26.12); p.adj = 0.01). Albendazole reduced helminth infections in low-SES and also decreased LMR with 11% reduction but only in helminth-uninfected children (estimated treatment effect: 0.89; p.adj = 0.01). Following treatment, I-FABP decreased in high- (0.91, p.adj < 0.001) but increased (1.12, p.adj = 0.004) in low-SES children. Albendazole did not alter the levels of LBP. Microbiota analysis showed no contribution from specific bacterial-taxa to the changes observed. Intestinal permeability and epithelial damage are higher while peripheral blood inflammatory marker is lower in children of low-SES in Indonesia. Furthermore, treatment decreased LMR in helminth-uninfected only.

Background: M5717 is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the chemoprophylactic activity and dose–exposure–response relationship of single oral doses of M5717 following the direct venous inoculation (DVI) of Plasmodium falciparum sporozoites in healthy volunteers.Methods: This was a phase 1b, randomised, double-blind, placebo-controlled, adaptive, dose-finding, single-centre study (NCT04250363). Eligible, malaria-naïve healthy adults aged 18–45 years were divided into five cohorts and randomised in a 3:1 ratio to receive M5717 or a placebo. A single oral dose of M5717 (200, 100, 80, 60, or 30 mg) or matching placebo was administered either at 2 hours (early liver-stage) or 96 hours (late liver-stage) after DVI. The primary outcomes were the assessments of chemoprophylactic activity and dose–exposure–response relationship. The secondary outcomes were safety and tolerability.Findings: Thirty-nine healthy participants were enrolled from 17 February 2020 to 7 June 2021. A single oral dose of ≥ 100 mg M5717 provided 100% protection against early and late liver-stage malaria. The median time to parasitaemia in early liver-stage malaria was prolonged to 15, 22, and 24 days for the 30, 60, and 80 mg dose of M5717, respectively, compared with 10 days for the pooled placebo. A positive dose–exposure–efficacy relationship was established across exposure metrics. All M5717 doses were safe and well tolerated.Interpretation: The potent, dose-dependent chemoprophylactic activity of M5717 indicates its potential as a single-dose antimalarial agent.Funding Information: This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).Declaration of Interests: MB, ÖY, AT, AS, and AK are employed by the healthcare business of Merck KGaA, Darmstadt, Germany, the study sponsor. DB is employed by Merck Pty Ltd (an affiliate of Merck KGaA, Darmstadt, Germany), Modderfontein, South Africa. CO and TS are employed by the Global Health Institute of Merck, Ares Trading S.A. (a subsidiary of Merck KGaA, Darmstadt, Germany), Eysins, Switzerland. WB is a former (retired) employee of the Merck Institute for Pharmacometrics, Merck Serono S.A. (an affiliate of Merck KGaA, Darmstadt, Germany), Lausanne, Switzerland. JW received funding for consulting with the healthcare business of Merck KGaA, Darmstadt, Germany, during the course of this study. All other authors declare no competing interests.Ethics Approval Statement: The independent medical ethics committee Stichting Beoordeling Ethiek Biomedisch Onderzoek (Assen, The Netherlands) approved the study prior to the start of any study procedure. The study was conducted in accordance with the Declaration of Helsinki, the International Council on Harmonisation guidelines for Good Clinical Practice, and applicable laws and regulations in The Netherlands.

Systemic immunosuppressive therapy (IS) renders patients with inflammatory bowel disease (IBD) vulnerable to fulminant hepatitis B virus (HBV) infection. Seroprotection against HBV through a full vaccination scheme is preferably obtained before IS is initiated, but often conflicts with the clinical need to initiate therapy rapidly. Consequently, the vast majority of patients will use IS during booster vaccinations. In this retrospective cohort study, we examined the serological response after a modified vaccination schedule which includes an initial double dose of Fendrix in patients with IBD and compared the results with the serological responses of patients with IBD who received the standard schedule. Seroprotection rates were 86.2 % and 88.9 % in the modified and standard schedule groups respectively. One-third of patients obtained seroprotection after only one double dose vaccine. A double dose may be considered in patients with IBD at high short-term risk of HBV infection when a rapid protective response is warranted.

Background: There is not much known about venom allergy in tropical regions. Here, we studied the prevalence of specific IgE (sIgE) and skin prick test (SPT) reactivity and reported sting-related symptoms, in high- and low-socioeconomic status (SES) schoolchildren living in urban city of Makassar in Indonesia. Methods: Children from high- (n = 160) and low- (n = 165) SES schools were recruited. Standardized questionnaires were used to record information on allergic disorders as well as sting-related symptoms. Parasitic infection, SPT reactivity, and sIgE to Apis mellifera (bee-venom) as well as Vespula spp. (wasp-venom) were assessed. Results: SPT reactivity to bee- and wasp-venom was 14.3 and 12.7%, while the prevalence of sIgE was 26.5 and 28.5%, respectively. When SES was considered, prevalence of SPT to bee- and wasp-venom was higher in high-SES than in low-SES schoolchildren (bee: 22.8 vs. 5.7%, p < 0.001; and wasp: 19.6 vs. 5.7%, p < 0.001). Conversely, sIgE to both venoms was lower in high-SES than in low-SES (bee: 19 vs. 34%, p = 0.016; and wasp: 19 vs. 38%, p = 0.003). Furthermore, among SPT positive subjects, considerable proportion had no detectable sIgE to bee- (65.85%) or wasp-venom (66.67%). Altogether the sensitizations were rarely translated into clinical reaction, as only 1 child reported significant local reaction after being stung. No association with parasitic infections was found. Conclusions and Clinical Relevance: Sensitization against bee- or wasp-venom is quite prevalent among schoolchildren in Indonesia. The discordance between SPT and sIgE might suggest the direct (non-IgE) effect of venoms in skin reactivity. Recorded sensitizations had poor clinical relevance as they rarely translated into clinical symptoms.