RESUMEN
Controlled human malaria infection (CHMI) is an established model in clinical malaria research. Upon exposure to Plasmodium falciparum parasites, malaria-naive volunteers differ in dynamics and composition of their immune profiles and subsequent capacity to generate protective immunity. CHMI volunteers are either inflammatory responders who have prominent cellular IFN-γ production primarily driven by adaptive T cells, or tempered responders who skew toward antibody-mediated humoral immunity. When exposed to consecutive CHMIs under antimalarial chemoprophylaxis, individuals who can control parasitemia after a single immunization (fast responders) are more likely to be protected against a subsequent challenge infection. Fast responders tend to be inflammatory responders who can rapidly induce long-lived IFN-γ+ T cell responses. Slow responders or even non-responders can also be protected, but via a more diverse range of responses that take a longer time to reach full protective efficacy, in part due to their tempered phenotype. The latter group can be identified at baseline before CHMI by higher expression of inhibitory ligands CTLA-4 and TIM-3 on CD4+ T cells. Delineating heterogeneity in human immune responses to P. falciparum will facilitate rational design and strategy towards effective malaria vaccines.
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Interacciones Huésped-Parásitos/inmunología , Inmunidad , Malaria/inmunología , Malaria/parasitología , Plasmodium/inmunología , Animales , Variación Biológica Poblacional/inmunología , Biomarcadores , Humanos , Inmunización , Interferón gamma/metabolismo , Malaria/prevención & control , Vacunas contra la Malaria , Modelos Teóricos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Transmission-blocking interventions can play an important role in combating malaria worldwide. Recently, a highly potent Plasmodium falciparum transmission-blocking monoclonal antibody (TB31F) was demonstrated to be safe and efficacious in malaria-naive volunteers. Here we predict the potential public health impact of large-scale implementation of TB31F alongside existing interventions. We developed a pharmaco-epidemiological model, tailored to 2 settings of differing transmission intensity with already established insecticide-treated nets and seasonal malaria chemoprevention interventions. Community-wide annual administration (at 80% coverage) of TB31F over a 3-year period was predicted to reduce clinical incidence by 54% (381 cases averted per 1000 people per year) in a high-transmission seasonal setting, and 74% (157 cases averted per 1000 people per year) in a low-transmission seasonal setting. Targeting school-aged children gave the largest reduction in terms of cases averted per dose. An annual administration of the transmission-blocking monoclonal antibody TB31F may be an effective intervention against malaria in seasonal malaria settings.
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Malaria Falciparum , Malaria , Niño , Humanos , Plasmodium falciparum , Malaria Falciparum/epidemiología , Malaria Falciparum/prevención & control , Malaria Falciparum/tratamiento farmacológico , Estaciones del Año , Malaria/prevención & control , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
BACKGROUND: Whole sporozoite immunization under chemoprophylaxis (CPS regime) induces long-lasting sterile homologous protection in the controlled human malaria infection model using Plasmodium falciparum strain NF54. The relative proficiency of liver-stage parasite development may be an important factor determining immunization efficacy. Previous studies show that Plasmodium falciparum strain NF135 produces relatively high numbers of large liver-stage schizonts in vitro. Here, we evaluate this strain for use in CPS immunization regimes. METHODS: In a partially randomized, open-label study conducted at the Radboudumc, Nijmegen, the Netherlands, healthy, malaria-naïve adults were immunized by three rounds of fifteen or five NF135-infected mosquito bites under mefloquine prophylaxis (cohort A) or fifteen NF135-infected mosquito bites and presumptive treatment with artemether/lumefantrine (cohort B). Cohort A participants were exposed to a homologous challenge 19 weeks after immunization. The primary objective of the study was to evaluate the safety and tolerability of CPS immunizations with NF135. RESULTS: Relatively high liver-to-blood inocula were observed during immunization with NF135 in both cohorts. Eighteen of 30 (60%) high-dose participants and 3/10 (30%) low-dose participants experienced grade 3 adverse events 7 to 21 days following their first immunization. All cohort A participants and two participants in cohort B developed breakthrough blood-stage malaria infections during immunizations requiring rescue treatment. The resulting compromised immunizations induced modest sterile protection against homologous challenge in cohort A (5/17; 29%). CONCLUSIONS: These CPS regimes using NF135 were relatively poorly tolerated and frequently required rescue treatment, thereby compromising immunization efficiency and protective efficacy. Consequently, the full potential of NF135 sporozoites for induction of immune protection remains inconclusive. Nonetheless, the high liver-stage burden achieved by this strain highlights it as an interesting potential candidate for novel whole sporozoite immunization approaches. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under identifier NCT03813108.
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Antimaláricos , Mordeduras y Picaduras de Insectos , Vacunas contra la Malaria , Malaria , Adulto , Animales , Humanos , Antimaláricos/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Inmunización/métodos , Mordeduras y Picaduras de Insectos/tratamiento farmacológico , Malaria/prevención & control , Vacunas contra la Malaria/efectos adversos , Plasmodium falciparum , EsporozoítosRESUMEN
OBJECTIVE: The prevalence of clinical cases of pulmonary non-tuberculous mycobacteria (NTM) is increasing worldwide. The aim of this study was to determine the proportion and the NTM species isolated from presumptive tuberculosis patients in Lambaréné, Gabon. METHOD: From January 2018 to December 2020, sputum samples from presumptive TB patients were analysed at the tuberculosis reference laboratory of the Centre de Recherches Médicales de Lambaréné. Two sputum samples were collected per patient, and culture was performed using Bactec MGIT 960. The GenoType Mycobacterium CM/AS was used for NTM isolates confirmation and species differentiation. RESULTS: Among 1363 sputum samples analysed, 285 (20.9%) were Auramin acid fast bacilli (AFB) smear-positive. NTM were isolated in 137/1363 (10%) of the samples. The most prevalent NTM species was Mycobacterium intracellulare (n = 74; 54%). CONCLUSION: These results show the presence of NTM among presumptive TB patients in Gabon, which could potentially complicate TB diagnosis. This presents a new public health challenge, and emphasises the need to consider NTM in planning the prevention and management of tuberculosis control.
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Infecciones por Mycobacterium no Tuberculosas , Tuberculosis Pulmonar , Tuberculosis , Gabón/epidemiología , Humanos , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Micobacterias no Tuberculosas/genética , Esputo/microbiología , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/microbiologíaRESUMEN
The availability of an effective and appropriately implemented malaria vaccine would form a crucial cornerstone of public health efforts to fight this disease. Despite many decades of research, however, no malaria vaccine has yet shown satisfactory protective efficacy or been rolled-out. Validated immunological substitute endpoints have the potential to accelerate clinical vaccine development by reducing the required complexity, size, duration and cost of clinical trials. Besides facilitating clinical development of existing vaccine candidates, understanding immunological mechanisms of protection may drive the development of fundamentally new vaccination approaches. In this review we focus on correlates of protection in malaria vaccine development: Does immunogenicity predict malaria vaccine efficacy and why is this question particularly difficult? Have immunological correlates accelerated malaria vaccine development in the past and will they facilitate it in the future? Does Controlled Human Malaria Infection represent a valid model for identifying such immunological correlates, or a correlate of protection against naturally-acquired malaria in itself?
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Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Citocinas/sangre , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Anticuerpos Antiprotozoarios/biosíntesis , Antígenos de Protozoos/genética , Biomarcadores/sangre , Citocinas/biosíntesis , Determinación de Punto Final/métodos , Humanos , Inmunogenicidad Vacunal , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/biosíntesis , Vacunas contra la Malaria/clasificación , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/patogenicidad , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Vacunación , Potencia de la Vacuna , Vacunas de SubunidadRESUMEN
Microscopy and rapid diagnostic tests (RDTs) are the main diagnostic tools for malaria but fail to detect low-density parasitemias that are important for maintaining malaria transmission. To complement existing diagnostic methods, an isothermal reverse transcription-recombinase polymerase amplification and lateral flow assay (RT-RPA) was developed. We compared the performance with that of ultrasensitive reverse transcription-quantitative PCR (uRT-qPCR) using nucleic acid extracts from blood samples (n = 114) obtained after standardized controlled human malaria infection (CHMI) with Plasmodium falciparum sporozoites. As a preliminary investigation, we also sampled asymptomatic individuals (n = 28) in an area of malaria endemicity (Lambaréné, Gabon) to validate RT-RPA and assess its performance with unprocessed blood samples (dbRT-RPA). In 114 samples analyzed from CHMI trials, the positive percent agreement to uRT-qPCR was 90% (95% confidence interval [CI], 80 to 96). The negative percent agreement was 100% (95% CI, 92 to 100). The lower limit of detection was 64 parasites/ml. In Gabon, RT-RPA was 100% accurate with asymptomatic volunteers (n = 28), while simplified dbRT-RPA showed 89% accuracy. In a subgroup analysis, RT-RPA detected 9/10 RT-qPCR-positive samples, while loop-mediated isothermal amplification (LAMP) detected 2/10. RT-RPA is a reliable diagnostic test for asymptomatic low-density infections. It is particularly useful in settings where uRT-qPCR is difficult to implement.
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Malaria Falciparum , Malaria , Gabón , Humanos , Malaria/diagnóstico , Malaria Falciparum/diagnóstico , Técnicas de Diagnóstico Molecular , Técnicas de Amplificación de Ácido Nucleico , Plasmodium falciparum/genética , Recombinasas , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: After a controlled human malaria infection (CHMI), presentation of clinical signs and symptoms and host responses is heterogeneous. Transforming growth factor-beta (TGF-ß) is the first serum cytokine that changes in malaria-naïve volunteers after CHMI. We studied a possible relation between TGF-ß changes, pro-inflammatory cytokines, activation of haemostasis and endothelial cells and clinical symptoms. METHODS: A panel of cytokines including TGF-ß, and markers of activation of haemostasis and endothelial cells were measured in blood samples of 15 volunteers at baseline before CHMI and during CHMI at day of treatment. The change of the parameters on the day of treatment was examined for a significant alteration during infection. RESULTS: Nine of 15 volunteers showed a significant decrease in TGF-ß compared to baseline, with concomitant increased concentrations of D-dimer (pâ¯=â¯0.012), Von Willebrand factor (pâ¯=â¯0.017), IL-6 (pâ¯=â¯0.012) and IFN-γ (0.028) and a significantly decreased platelet count (pâ¯=â¯0.011). In contrast, 6 of 15 volunteers showed sustained or increased TGF-ß concentrations without change in the aforementioned parameters. The sustained responders presented with less moderate and severe clinical symptoms than the negative responders (pâ¯=â¯0.036) and had a higher baseline lymphocyte count (pâ¯=â¯0.026). TGF-ß concentrations did not correlate with the parasitaemia on day of treatment. CONCLUSION: Early decreases of serum TGF-ß might function a marker for a pro-inflammatory host response and downstream clinical symptoms and pathology during CHMI.
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Células Endoteliales/metabolismo , Hemostasis , Malaria/sangre , Parasitemia/sangre , Factor de Crecimiento Transformador beta/sangre , Adulto , Plaquetas/metabolismo , Correlación de Datos , Regulación hacia Abajo , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/parasitología , Interferón gamma/sangre , Interferones , Interleucina-6/sangre , Linfocitos/metabolismo , Malaria/parasitología , Malaria/fisiopatología , Masculino , Recuento de Plaquetas , Regulación hacia Arriba , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: Loiasis is a disease of relevance in endemic populations and there has been advocacy for its inclusion on the World Health Organization's neglected tropical diseases list. As loiasis-related healthcare-seeking behaviors and related costs are unknown, we aimed to evaluate these aspects in a population residing in an endemic region in Gabon. METHODS: Data were collected during a community-based, cross-sectional study assessing the disease burden due to loiasis. Diagnostics for microfilaremia were performed and a history of eyeworm was obtained. In addition, a standardized questionnaire about type of healthcare resources and frequency of use, as well as respective associated costs was administered to each participant. Loiasis related healthcare-seeking behaviors were evaluated, and the associated monetary burden was estimated as a secondary outcome of the study. FINDINGS: Individuals diagnosed with loiasis more frequently reported any healthcare-seeking (OR 1.52 (95%CI: 1.21-1.91)), self-medicating (OR 1.62 (1.26-2.08)), inability to work (OR 1.86 (1.47-2.35)), and consulting with traditional healers (logOdds 1.03 (0.52-1.53)), compared to loiasis negative individuals. The most frequently reported treatment for the eyeworm was traditional herbs. The estimated healthcare associated costs, per positive individual, was US-$ 58 (95% CI: 21-101) per year, which would correspond to 3.5% of the reported mean household income. Extrapolation to the rural population of Gabon (n = 204,000), resulted in an annual monetary burden estimate of US-$ 3,206,000 (1,150,000-5,577,000). INTERPRETATION: Loiasis patients have demonstrated healthcare needs, often consulted traditional healers, and used traditional treatments for disease specific symptoms. Further, loiasis seems to be associated with substantial direct and indirect costs for individuals and thus may cause a relevant economic burden for endemic populations and economies of affected countries.
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Costo de Enfermedad , Loiasis , Aceptación de la Atención de Salud , Humanos , Gabón/epidemiología , Estudios Transversales , Masculino , Femenino , Aceptación de la Atención de Salud/estadística & datos numéricos , Adulto , Loiasis/epidemiología , Loiasis/economía , Persona de Mediana Edad , Adulto Joven , Adolescente , Encuestas y Cuestionarios , Anciano , Niño , Preescolar , Costos de la Atención en Salud/estadística & datos numéricosRESUMEN
BACKGROUND: The parasitic disease loiasis is associated with significant morbidity and mortality. Individuals with hyper-microfilaremia (greater than 20,000 microfilariae per mL of blood) may suffer from serious treatment-related or spontaneous adverse events. Diagnosing loiasis remains complex and primarily relies on direct parasite detection. In this study, we analyzed the performance of various diagnostic tests and the influence of parasitological and clinical factors on test outcomes in samples from individuals living in an endemic region. METHODS: Data and samples were collected from rural Gabon. Loiasis was defined as either detectable microfilaremia, or a positive history of eyeworm as assessed by the RAPLOA questionnaire. Diagnostic testing included a quantitative PCR (qPCR) for detection of Loa loa DNA in blood samples, an in-house crude L. loa antigen IgG ELISA, and a rapid test for antibodies against the Ll-SXP-1 antigen (RDT). Sensitivity and specificity were determined for each test and factors potentially influencing outcomes were evaluated in an exploratory analysis. RESULTS: ELISA, RDT and qPCR results were available for 99.8%, 78.5%, and 100% of the 1,232 participants, respectively. The ELISA and RDT had only modest diagnostic accuracy. qPCR was specific for L. loa microfilaremia and Cycle threshold values correlated with microfilarial density. Anti-L. loa IgG levels were highest in occult loiasis, and antibody levels correlated inversely with L. loa microfilarial density as did RDT line intensities. Only 84.6% and 16.7% of hyper-microfilaremic individuals tested positive by ELISA (11/13) and RDT (2/12), respectively. CONCLUSION: None of the tests demonstrated high sensitivity and specificity for loiasis. Indirect diagnostic assays were characterized by low specificity. Additionally, hyper-microfilaremic individuals often tested negative by RDT and ELISA, indicating that these tests are not suitable for individual case management in endemic populations.
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Loiasis , Animales , Humanos , Loiasis/parasitología , Loa/genética , Microfilarias , Pruebas Serológicas , Anticuerpos Antihelmínticos , Inmunoglobulina G , Pruebas Diagnósticas de RutinaRESUMEN
BACKGROUND: Chronic infection by Loa loa remains an unsolved immunological paradox. Despite harboring subcutaneously migrating adult worms and often high densities of microfilariae, most patients experience only relatively mild symptoms, yet microfilaricidal treatment can trigger life-threatening inflammation. Here, we investigated innate cell populations hypothesized to play a role in these two faces of the disease, in an endemic population in Gabon. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed numbers and activation of eosinophils and basophils, as well as myeloid-derived suppressor cell (MDSC) subsets and associated circulating cytokine levels by flow cytometry in sex- and age-matched L. loa-uninfected (LL-), -amicrofilaraemic (MF-) and -microfilaraemic (MF+) individuals (n = 42), as well as microfilaraemic individuals treated with albendazole (n = 26). The percentage of eosinophils was lower in LL- (3.0%) than in the combined L. loa-infected population, but was similar in MF+ (13.1%) and MF- (12.3%). Upon treatment of MF+, eosinophilia increased from day 0 (17.2%) to day 14 (24.8%) and had decreased below baseline at day 168 (6.3%). Expression of the eosinophil activation marker CD123 followed the same pattern as the percentage of eosinophils, while the inverse was observed for CD193 and to some extent CD125. Circulating IL-5 levels after treatment followed the same pattern as eosinophil dynamics. Basophil numbers did not differ between infection states but increased after treatment of MF+. We did not observe differences in MDSC numbers between infection states or upon treatment. CONCLUSIONS/SIGNIFICANCE: We demonstrate that both chronic infection and treatment of L. loa microfilaraemia are associated with eosinophil circulation and distinct phenotypical activation markers that might contribute to inflammatory pathways in this setting. In this first ever investigation into MDSC in L. loa infection, we found no evidence for their increased presence in chronic loiasis, suggesting that immunomodulation by L. loa is induced through other pathways.
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Basófilos , Eosinófilos , Loa , Loiasis , Células Supresoras de Origen Mieloide , Humanos , Loiasis/tratamiento farmacológico , Loiasis/inmunología , Masculino , Femenino , Adulto , Eosinófilos/inmunología , Gabón/epidemiología , Basófilos/inmunología , Loa/fisiología , Loa/inmunología , Animales , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/inmunología , Adulto Joven , Albendazol/uso terapéutico , Enfermedad Crónica , Citometría de Flujo , Citocinas , Enfermedades Endémicas , AdolescenteRESUMEN
Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (nâ=â5) or multiple (nâ=â10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only 'adaptive' but also 'innate' lymphocyte subsets contribute to the increased IFNγ response, including αßT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αßT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO(+) CD62L(-) effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ(+)IL-2(+)) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.
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Memoria Inmunológica/fisiología , Interferón gamma/inmunología , Interleucina-2/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Linfocitos T/inmunología , Femenino , Humanos , Inmunidad Celular , Células Asesinas Naturales/inmunología , Estudios Longitudinales , Masculino , Factores de TiempoRESUMEN
INTRODUCTION: Public health measures aimed at controlling transmission of SARS-CoV-2, otherwise known as "lockdown" measures, had profound effects on circulation of non-SARS viruses, many of which decreased to very low levels. The interrupted transmission of these viruses may have lasting effects. Some of the influenza clades seem to have disappeared during this period, a phenomenon which is described as a "funnel effect". It is currently unknown if the lockdown measures had any effect on the diversity of circulating viruses, other than influenza. Enteroviruses are especially interesting in this context, as the clinical presentation of an infection with a particular enterovirus-type may be clade-dependent. METHODS AND MATERIALS: Enteroviruses were detected in clinical materials using a 5'UTR-based detection PCR, and partial VP-1 sequences were obtained, using methods described before. All samples with EV detections from a large part of the Netherlands were included in the study. The samples originated from general practitioners, general hospitals, university hospitals and public health offices. RESULTS: Five EV-genotypes circulated in significant numbers before and after the lockdown, EV-D68, E-11, CV-A6, CV-B5 and CV-A2. All five genotypes showed decreased genetic diversity after the lockdown, and four indicate a significant number of sequences clustering together with a very high sequence homology. Moreover, children with E-11 and CV-B5 detections were significantly older after the lockdown than before. CONCLUSIONS: The reduced enterovirus transmission in the Netherlands during the pandemic, seems to have led to a decrease in genetic diversity in the five most commonly detected enterovirus serotypes.
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Enterovirus Humano D , Infecciones por Enterovirus , Enterovirus , Gripe Humana , Niño , Humanos , Enterovirus/genética , Enterovirus Humano D/genética , Serogrupo , FilogeniaRESUMEN
Here we describe a complicated case of a relapsed Leishmania infantum infection after an allogeneic stem cell transplantation (allo-SCT) for primary myelofibrosis. Three years earlier the patient had been diagnosed with a hemophagocytic lymphohistiocytosis secondary to a visceral Leishmania infantum infection, for which he was effectively treated with a cumulative dose of 40 mg/kg liposomal amphotericin B. During the first disease episode he was also diagnosed with primary myelofibrosis for which he received medical follow-up. One year later ruxolitinib was started due to progressive disease. No Leishmania relapse occurred. Nevertheless, the marrow fibrosis progressed, and an allo-SCT was performed. Two months after allo-SCT prolonged fever and a persistent pancytopenia occurred, which was due to a relapse of visceral Leishmaniasis. The infection was refractory to a prolonged treatment with liposomal amphotericin B with a cumulative dose up to 100 mg/kg. Salvage treatment with miltefosine led to reduction of fever within a few days and was followed by a slow recovery of pancytopenia over the following months. The Leishmania parasite load by PCR started to decline and after 3.5 months no Leishmania DNA could be detected anymore and follow-up until ten months afterwards did not show a relapse.
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BACKGROUND: There is a lack of systematic evidence for strategies to control loiasis transmission in highly endemic regions. Here we assessed albendazole and ivermectin based treatment regimens to reduce Loa loa microfilaraemia in Gabon. METHODS: Eligible adult patients with L. loa microfilaraemia between 5,000 and 50,000 microfilariae/ml were randomized to either a control or one of three intervention groups (1:2:2:2 allocation ratio) consisting of three-week twice daily 400mg oral albendazole followed by 1) no treatment, 2) two further weeks of twice daily 400mg albendazole, or 3) a single dose of ivermectin in this open label randomized assessor blinded controlled clinical trial. The primary outcome was the proportion of participants with L. loa microfilaraemia ≤ 100 mf/ml at Day 168. RESULTS: In the efficacy-population of 42 patients 0 (0%; control group), 1 (9%; 3-week albendazole), 5 (39%; 5-weeks albendazole) and 2 (22%; 3-week albendazole plus single dose ivermectin) participants met the primary outcome of microfilaraemia below 100/ml at day 168. A 80-90% reduction of microfilaraemia was observed in the active treatment groups. CONCLUSION: The 5-week regimen of albendazole or a 3-week regimen of albendazole followed by ivermectin were most efficacious to reduce microfilaraemia. All therapeutic regimens were well tolerated and safe. TRIAL REGISTRATION: Trial registered at the Pan-African Clinical Trials Registry: PACTR201807197019027.
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Albendazol , Loiasis , Humanos , Adulto , Animales , Albendazol/efectos adversos , Ivermectina/efectos adversos , Gabón , Loiasis/tratamiento farmacológico , Protocolos Clínicos , PecesRESUMEN
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.
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COVID-19 , Vacunas Virales , Humanos , Adyuvantes Inmunológicos , Cápside , Proteínas de la Cápside , Vacunas contra la COVID-19 , SARS-CoV-2 , Vacunas Virales/efectos adversosRESUMEN
INTRODUCTION: Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. AREAS COVERED: Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving >90% efficacy against Pf infection. This review describes >30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.' EXPERT OPINION: First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers exposed to Pf in Africa, with licensure for these populations possible within 5 years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.
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Vacunas contra la Malaria , Malaria Falciparum , Malaria , Embarazo , Niño , Animales , Humanos , Femenino , Esporozoítos , Ciencia Traslacional Biomédica , Vacunas Atenuadas , Malaria/prevención & control , Malaria Falciparum/prevención & control , Plasmodium falciparum , InmunizaciónRESUMEN
BACKGROUND: We have shown that immunity to infection with Plasmodium falciparum can be induced experimentally in malaria-naive volunteers through immunisation by bites of infected mosquitoes while simultaneously preventing disease with chloroquine prophylaxis. This immunity was associated with parasite-specific production of interferon γ and interleukin 2 by pluripotent effector memory cells in vitro. We aim to explore the persistence of protection and immune responses in the same volunteers. METHODS: In an open-label study at the Radboud University Nijmegen Medical Centre (Nijmegen, Netherlands), from November to December, 2009, we rechallenged previously immune volunteers (28 months after immunisation) with the bites of five mosquitoes infected with P falciparum. Newly recruited malaria-naive volunteers served as infection controls. Our primary outcome was the detection of blood-stage parasitaemia by microscopy. We assessed the kinetics of parasitaemia with real-time quantitative PCR (rtPCR) and recorded clinical signs and symptoms. In-vitro production of interferon γ and interleukin 2 by effector memory T cells was studied after stimulation with sporozoites and red blood cells infected with P falciparum. Differences in cellular immune responses between the study groups were assessed with the Mann-Whitney test. This study is registered with ClinicalTrials.gov, number NCT00757887. FINDINGS: Four of six immune volunteers were microscopically negative after rechallenge. rtPCR-based detection of blood-stage parasites in these individuals was negative throughout follow-up. Patent parasitaemia was delayed in the remaining two immunised volunteers. In-vitro assays showed the long-term persistence of parasite-specific pluripotent effector memory T-cell responses in protected volunteers. The four protected volunteers reported several mild to moderate adverse events, of which the most commonly reported symptom was headache (one to three episodes per volunteer). The two patients with delayed patency had adverse events similar to those in the control group. INTERPRETATION: Artificially induced immunity lasts longer than generally recorded after natural exposure; providing a new avenue of research into the mechanisms of malaria immunity. FUNDING: Dioraphte Foundation.
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Inmunidad Adaptativa/inmunología , Antimaláricos/administración & dosificación , Cloroquina/administración & dosificación , Inmunización/métodos , Malaria Falciparum/inmunología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Esporozoítos/inmunología , Adulto , Especificidad de Anticuerpos/inmunología , Antimaláricos/efectos adversos , Femenino , Humanos , Inmunización/efectos adversos , Memoria Inmunológica/inmunología , Interferón gamma/sangre , Interleucina-2/sangre , Masculino , Países Bajos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunología , Adulto JovenRESUMEN
Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
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Endotoxemia/genética , Endotoxemia/inmunología , Glicoproteínas de Membrana/fisiología , Receptores de Interleucina-1/fisiología , Selección Genética , Choque Séptico/genética , Choque Séptico/inmunología , Alelos , Humanos , Inmunidad Innata/genética , Leucina/genética , Glicoproteínas de Membrana/genética , Polimorfismo Genético , Receptores de Interleucina-1/genética , Serina/genéticaRESUMEN
BACKGROUND: Chemoprophylaxis and anti-mosquito measures are key to preventing malaria in travelers. Long-term travelers are at higher risk than short-term travelers, but their adherence to preventive measures is lower. Our aim was to determine malaria exposure risks and predictors for adherence to malaria-preventive measures in long-term travelers. METHODS: Long-term travelers (>12 weeks) completed a weekly questionnaire about preventive measures, symptoms, and malaria treatment abroad. Blood samples were tested for seroconversion to Plasmodium falciparum anti-circumsporozoite (PfCSP) antibody. Adherence to preventive measures was defined as number of weeks of their usage divided by number of weeks in malaria-endemic areas. RESULTS: Of 561 travelers, the median travel time was 20 weeks (IQR 16-25). Eighteen were treated for malaria, all in sub-Saharan Africa. Sixteen PfCSP seroconversions were found, of whom only 3 had traveled to high-endemic areas. Of the 18 travelers treated for malaria, only one seroconverted. No associations were found between covariates and seroconversion. Neither treatment abroad nor seroconversion were reliable predictors for exposure. 'Full adherence' to chemoprophylaxis was reported by 52% (218/417) and was associated with travel to Africa, use of mefloquine, lack of prior travel history, shorter duration of travel, and use of DEET. CONCLUSIONS: The risk of malaria in this long-term travelers cohort was low. Our data confirm that anti-PfCSP seroconversion is not a reliable method to retrospectively identify incident infection, or probably exposure. Prevention efforts should focus on more experienced travellers and longer travel duration, for whom mefloquine should be considered as the first-choice chemoprophylaxis.