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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 Vδ2+ γδ 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.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans., Methods: In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18-55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants' serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes., Results: Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity., Conclusions: R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses., Trial Registration: The trial is registered with ClinicalTrials.gov under identifier NCT04862416., (© 2024. The Author(s).)

IgG antibodies are important mediators of vaccine-induced immunity through complement- and Fc receptor-dependent effector functions. Both are influenced by the composition of the conserved N -linked glycan located in the IgG Fc domain. Here, we compared the anti-Spike (S) IgG1 Fc glycosylation profiles in response to mRNA, adenoviral, and protein-based COVID-19 vaccines by mass spectrometry (MS). All vaccines induced a transient increase of antigen-specific IgG1 Fc galactosylation and sialylation. An initial, transient increase of afucosylated IgG was induced by membrane-encoding S protein formulations. A fucose-sensitive ELISA for antigen-specific IgG (FEASI) exploiting FcγRIIIa affinity for afucosylated IgG was used as an orthogonal method to confirm the LC-MS-based afucosylation readout. Our data suggest that vaccine-induced anti-S IgG glycosylation is dynamic, and although variation is seen between different vaccine platforms and individuals, the evolution of glycosylation patterns display marked overlaps., Competing Interests: M.L.G. and R.R. are employees of Janssen Pharmaceuticals and M.L.G. is a shareholder in Johnson & Johnson. A.S. and W.A.d.J. are employees at AdaptVac, a company commercializing virus-like particle display technology and vaccines, including several patents. A.S., A.S., T.G.T., and M.N. are founders of AdaptVac and listed as coinventors on a patent covering the AP205 CLP vaccine platform technology (WO2016112921 A1) licensed to AdaptVac. Janssen Pharmaceuticals sponsored IgG glycosylation analysis at LUMC. Sanquin provided consultancy services to Janssen Pharmaceuticals during this study. All other authors declare they have no conflicts of interests., (© 2023 The Author(s).)

Background: Capsid virus-like particles (cVLP) have proven safe and immunogenic and can be a versatile platform to counter pandemics. We aimed to clinically test a modular cVLP COVID-19 vaccine in individuals who were naive to SARS-CoV-2., Methods: In this phase 1, single-centre, dose-escalation, adjuvant-selection, open-label clinical trial, we recruited participants at the Radboud University Medical Center in Nijmegen, Netherlands, and sequentially assigned them to seven groups. Eligible participants were healthy, aged 18-55 years, and tested negative for SARS-CoV-2 and anti-SARS-CoV-2 antibodies. Participants were vaccinated intramuscularly on days 0 and 28 with 6 μg, 12 μg, 25 μg, 50 μg, or 70 μg of the cVLP-based COVID-19 vaccine (ABNCoV2). A subgroup received MF59-adjuvanted ABNCoV2. Follow-up was for 24 weeks after second vaccination. The primary objectives were to assess the safety and tolerability of ABNCoV2 and to identify a dose that optimises the tolerability-immunogenicity ratio 14 days after the first vaccination. The primary safety endpoint was the number of related grade 3 adverse events and serious adverse events in the intention-to-treat population. The primary immunogenicity endpoint was the concentration of ABNCoV2-specific antibodies. The trial is registered with ClinicalTrials.gov, NCT04839146., Findings: 45 participants (six to nine per group) were enrolled between March 15 and July 15, 2021. Participants had a total of 249 at least possibly related solicited adverse events (185 grade 1, 63 grade 2, and one grade 3) within a week after vaccination. Two serious adverse events occurred; one was classified as a possible adverse reaction. Antibody titres were dose-dependent with levels plateauing at a vaccination dose of 25-70 μg ABNCoV2. After second vaccination, live virus neutralisation activity against major SARS-CoV-2 variants was high but was lower with an omicron (BA.1) variant. Vaccine-specific IFNγ + CD4 + T cells were induced., Interpretation: Immunisation with ABNCoV2 was well tolerated, safe, and resulted in a functional immune response. The data support the need for additional clinical development of ABNCoV2 as a second-generation SARS-CoV-2 vaccine. The modular cVLP platform will accelerate vaccine development, beyond SARS-CoV-2., Funding: EU, Carlsberg Foundation, and the Novo Nordisk Foundation., Competing Interests: Declaration of interests MAN, AFS, AS, TGT, and CJ are listed as coinventors on a patent application covering the AP205 CLP vaccine platform technology (WO2016112921 A1) licensed to AdaptVac. CF, AFS, and WAdJ are employees at AdaptVac, a company commercialising virus-like particle display technology and vaccines, including several patents., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Ivermectin is safe and widely used for treating helminth infections. It also kills arthropods feeding on treated subjects, including malaria vectors. Thus, ivermectin mass drug administration as an additional tool for malaria control is being evaluated by WHO. As in vitro data, animal experiments and epidemiological observations suggest that ivermectin has a direct effect on the liver stages of the malaria parasite, this study was designed to assess the prophylactic effect of ivermectin on Plasmodium falciparum controlled human malaria infection., Methods: A total of 4 volunteers were randomised to placebo, and 8 volunteers were randomised to receive ivermectin 0.4 mg/kg, orally, once 2 h before being experimentally infected intravenously with 3200 P. falciparum sporozoites. The primary endpoint was time to parasitaemia detected by positive thick blood smear; RT-qPCR was performed in parallel., Results: All but one volunteer became thick blood smear positive between day 11 and day 12 after infection, and there was no significant effect of ivermectin on parasitaemia., Conclusion: Ivermectin - at the dose used - has no clinically relevant activity against the pre-erythrocytic stages of P. falciparum., (© 2019 This article is a U.S. Government work and is in the public domain in the USA.)

Vaccine efficacy and prophylactic treatment of infections are tested best when the vaccinated or treated individual is challenged through deliberate infection with the respective pathogen. However, this trial design calls for particular ethical caution. Awareness of the history of challenge trials is indispensable, including trials that were problematic or even connected to abuse. We briefly introduce historical aspects of experimental infections in humans and the ethical debate around them and give estimates of the numbers of volunteers participating in human experimental infection models. Challenge models can offer a great chance and benefit for the development of medical interventions to fight infectious diseases, but only when they are appropriately controlled and regulated., (© 2019 John Wiley & Sons Ltd.)

Background: Malaria transmission in most of Latin America can be considered as controlled. In such a scenario, parameters of baseline immunity to malaria antigens are of specific interest with respect to future malaria eradication efforts., Methods: A cross-sectional study was carried out in two indigenous population groups in Amazonas/Venezuela. Data from the regional malaria documentation system were extracted and participants from the ethnic groups of the Guahibo (n = 180) and Piaroa (n = 295) were investigated for the presence of Plasmodium parasites and naturally acquired antibodies to Plasmodium falciparum antigens in serum. The GMZ2 vaccine candidate proteins MSP3 and GLURP were chosen as serological markers., Results: The incidence of P. falciparum in both communities was found to be less than 2%, and none of the participants harboured P. falciparum at the time of the cross-sectional. Nearly a quarter of the participants (111/475; 23,4%) had positive antibody titres to at least one of the antigens. 53/475 participants (11.2%) were positive for MSP3, and 93/475 participants (19.6%) were positive for GLURP. High positive responses were detected in 36/475 participants (7.6%) and 61/475 participants (12.8%) for MSP3 and GLURP, respectively. Guahibo participants had significantly higher antibody titres than Piaroa participants., Conclusions: Considering the low incidence of P. falciparum, submicroscopical infections may explain the comparatively high anti-P. falciparum antibody concentrations.

Background: While the federal state of Amazonas bears the highest risk for malaria in Venezuela (2007: 68.4 cases/1000 inhabitants), little comprehensive information about the malaria situation is available from this area. The purpose of this rapid malaria appraisal (RMA) was to provide baseline data about malaria and malaria control in Amazonas., Methods: The RMA methodology corresponds to a rapid health impact assessment (HIA) as described in the 1999 Gothenburg consensus. In conjunction with the actors of the malaria surveillance system, all useful data and information, which were accessible within a limited time-frame of five visits to Amazonas, were collected, analysed and interpreted., Results: Mortality from malaria is low (< 1 in 105) and slide positivity rates have stayed at the same level for the last two decades (15% +/- 6% (SD)). Active case detection accounts for ca. 40% of slides taken. The coverage of the censured population with malaria notification points (NPs) has been achieved in recent years. The main parasite is Plasmodium vivax (84% of cases). The proportion of Plasmodium falciparum is on the decline, possibly driven by the introduction of cost-free artemisinin-based combination therapy (ACT) (1988: 33.4%; 2007: 15.4%). Monitoring and documentation is complete, systematic and consistent, but poorly digitalized. Malaria transmission displayed a visible lag behind rainfall in the capital municipality of Atures, but not in the other municipalities. In comparison to reference microscopy, quality of field microscopy and rapid diagnostic tests (RDTs) is suboptimal (kappa < 0.75). Hot spots of malaria risk were seen in some indigenous ethnic groups. Conflicting strategies in respect of training of community health workers (CHW) and the introduction of new diagnostic tools (RDTs) were observed., Conclusion: Malaria control is possible, even in tropical rain forest areas, if the health system is working adequately. Interventions have to be carefully designed and the features of the particular local Latin American context considered.

The roles of the various factors implicated in the pathogenesis of severe malaria are not well understood. Tumor necrosis factor (TNF), a cytokine produced mainly by macrophages, seems to play a crucial role in both the host's defence against the parasite and the development of severe complications. This review investigates the dual role of TNF in acute malaria, summarizing current knowledge of the beneficial and detrimental effects of this molecule. Recent work has suggested a possible explanation for this dualism, involving a complex interaction between TNF and its soluble receptors.

In the present study, we investigated 91 patients with Plasmodium falciparum malaria of different severity in a highly endemic area. Patients were examined at least twice daily until clearance of parasites and fever. Plasma cytokine concentrations without and after ex vivo PHA stimulation of whole blood were determined. On admission we found elevated plasma concentrations of TNF, IFN-gamma, and IL-10 compared to levels during and after chemotherapy. Plasma TNF levels on admission were significantly different between patients with severe and mild malaria (differentiated in schoolchildren and adults). The PHA elicited TNF production capacity of peripheral blood leucocytes was suppressed during the acute phase of malaria. High TNF production capacity was associated with faster fever clearance and parasite clearance and, in patients with severe malaria, with higher blood glucose levels. In conclusion we observed circulating TNF concentrations in malaria patients dependent on the severity of disease, which is itself dependent on age, and an association of a high TNF production capacity with parameters for accelerated cure and good prognosis.