RESUMEN
Strain-transcending antibodies against virulence-associated subsets of P. falciparum-infected erythrocyte surface antigens could protect children from severe malaria. However, the evidence supporting the existence of such antibodies is incomplete and inconsistent. One subset of surface antigens associated with severe malaria, rosette-mediating Plasmodium falciparum Erythrocyte Membrane Protein one (PfEMP1) variants, cause infected erythrocytes to bind to uninfected erythrocytes to form clusters of cells (rosettes) that contribute to microvascular obstruction and pathology. Here, we tested plasma from 80 individuals living in malaria-endemic regions for IgG recognition of the surface of four P. falciparum rosetting strains using flow cytometry. Broadly reactive plasma samples were then used in antibody elution experiments in which intact IgG was eluted from the surface of infected erythrocytes and transferred to heterologous rosetting strains to look for strain-transcending antibodies. We found that seroprevalence (percentage of positive plasma samples) against allopatric rosetting strains was high in adults (63%-93%) but lower in children (13%-48%). Strain-transcending antibodies were present in nine out of eleven eluted antibody experiments, with six of these recognizing multiple heterologous rosetting parasite strains. One eluate had rosette-disrupting activity against heterologous strains, suggesting PfEMP1 as the likely target of the strain-transcending antibodies. Naturally acquired strain-transcending antibodies to rosetting P. falciparum strains in humans have not been directly demonstrated previously. Their existence suggests that such antibodies could play a role in clinical protection and raises the possibility that conserved epitopes recognized by strain-transcending antibodies could be targeted therapeutically by monoclonal antibodies or vaccines.
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Anticuerpos Antiprotozoarios , Inmunoglobulina G , Malaria Falciparum , Plasmodium falciparum , Humanos , Plasmodium falciparum/inmunología , Anticuerpos Antiprotozoarios/inmunología , Anticuerpos Antiprotozoarios/sangre , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Niño , Adulto , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Preescolar , Adolescente , Proteínas Protozoarias/inmunología , Eritrocitos/parasitología , Eritrocitos/inmunología , Antígenos de Protozoos/inmunología , Femenino , Masculino , Adulto Joven , Persona de Mediana Edad , Estudios Seroepidemiológicos , Formación de Roseta , Citometría de FlujoRESUMEN
The complement system is a key component of innate and adaptive immune responses. Complement regulation is critical for prevention and control of disease. We have determined the crystal structure of the complement regulatory enzyme human factor I (fI). FI is in a proteolytically inactive form, demonstrating that it circulates in a zymogen-like state despite being fully processed to the mature sequence. Mapping of functional data from mutants of fI onto the structure suggests that this inactive form is maintained by the noncatalytic heavy-chain allosterically modulating activity of the light chain. Once the ternary complex of fI, a cofactor and a substrate is formed, the allosteric inhibition is released, and fI is oriented for cleavage. In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors.
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Factor I de Complemento/química , Factor I de Complemento/genética , Polimorfismo Genético , Estructura Terciaria de Proteína , Regulación Alostérica , Sitios de Unión/genética , Dominio Catalítico , Complemento C3b/química , Complemento C3b/metabolismo , Complemento C4b/química , Complemento C4b/metabolismo , Factor I de Complemento/metabolismo , Cristalización , Cristalografía por Rayos X , Precursores Enzimáticos/química , Precursores Enzimáticos/genética , Precursores Enzimáticos/metabolismo , Predisposición Genética a la Enfermedad/genética , Glicosilación , Humanos , Modelos Moleculares , Mutación , Unión ProteicaRESUMEN
Outbreaks of Ebolaviruses, such as Sudanvirus (SUDV) in Uganda in 2022, demonstrate that species other than the Zaire ebolavirus (EBOV), which is currently the sole virus represented in current licensed vaccines, remain a major threat to global health. There is a pressing need to develop effective pan-species vaccines and novel monoclonal antibody-based therapeutics for Ebolavirus disease. In response to recent outbreaks, the two dose, heterologous Ad26.ZEBOV/MVA-BN-Filo vaccine regimen was developed and was tested in a large phase II clinical trial (EBL2001) as part of the EBOVAC2 consortium. Here, we perform bulk sequencing of the variable heavy chain (VH) of B cell receptors (BCR) in forty participants from the EBL2001 trial in order to characterize the BCR repertoire in response to vaccination with Ad26.ZEBOV/MVA-BN-Filo. We develop a comprehensive database, EBOV-AbDab, of publicly available Ebolavirus-specific antibody sequences. We then use our database to predict the antigen-specific component of the vaccinee repertoires. Our results show striking convergence in VH germline gene usage across participants following the MVA-BN-Filo dose, and provide further evidence of the role of IGHV3-15 and IGHV3-13 antibodies in the B cell response to Ebolavirus glycoprotein. Furthermore, we found that previously described Ebola-specific mAb sequences present in EBOV-AbDab were sufficient to describe at least one of the ten most expanded BCR clonotypes in more than two thirds of our cohort of vaccinees following the boost, providing proof of principle for the utility of computational mining of immune repertoires.
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Vacunas contra el Virus del Ébola , Ebolavirus , Fiebre Hemorrágica Ebola , Receptores de Antígenos de Linfocitos B , Vacunación , Humanos , Vacunas contra el Virus del Ébola/inmunología , Vacunas contra el Virus del Ébola/administración & dosificación , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Ebolavirus/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/genética , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Biología Computacional/métodos , Adulto , Masculino , Linfocitos B/inmunología , Femenino , Minería de DatosRESUMEN
BACKGROUND: Previously, the Vi-typhoid conjugate vaccine (Vi-TT) was found to be highly efficacious in Nepalese children under 16 years of age. We assessed the immunogenicity of Vi-TT at 9 and 12 months of age and response to a booster dose at 15 months of age. METHODS: Infants were recruited at Patan Hospital, Kathmandu and received an initial dose of Vi-TT at 9 or 12 months of age with a booster dose at 15 months of age. Blood was taken at four timepoints, and antibody titres were measured using a commercial ELISA kit. The primary study outcome was seroconversion (4-fold rise in antibody titre) of IgG one month after both the doses. FINDINGS: Fifty children were recruited to each study group.Some visits were disrupted by the COVID19 pandemic and occurred out of protocol windows.Both the study groups attained 100 % IgG seroconversion after the initial dose. IgG seroconversion in the 9-month group was significantly higher than in the 12-month group (68.42 % vs 25.8 %, p < 0.001). Among individuals who attended visits per protocol, IgG seroconversion after the first dose occurred in 100 % of individuals (n = 27/27 in 9-month and n = 32/32 in 12-month group). However, seroconversion rates after the second dose were 80 % in the 9-month and 0 % in the shorter dose-interval 12-month group (p < 0.001) (n = 16/20 and n = 0/8, respectively). INTERPRETATION: Vi-TT is highly immunogenic at both 9 and 12 months of age. Stronger response to a booster in the 9-month group is likely due to the longer interval between doses.
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Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Niño , Lactante , Humanos , Fiebre Tifoidea/prevención & control , Vacunas Conjugadas , Nepal/epidemiología , Inmunidad , Inmunoglobulina G , Anticuerpos Antibacterianos , Inmunogenicidad VacunalRESUMEN
INTRODUCTION: This is the first efficacy study of an oral live attenuated vaccine against Salmonella Paratyphi A using a human challenge model of paratyphoid infection. S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potential S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines. METHODS AND ANALYSIS: This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine against S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingest S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN15485902.
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Enfermedades Cardiovasculares , Salmonella paratyphi A , Humanos , Adulto , Vacunas Atenuadas , Voluntarios Sanos , Voluntarios , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase I como AsuntoRESUMEN
PURPOSE: To explore the perceptions of African American survivors and caregivers about participation in clinical trials. PARTICIPANTS & SETTING: 13 participants were enrolled and participated in one of the focus groups, and 11 participated in two focus groups. METHODOLOGIC APPROACH: A qualitative descriptive study using a community-based participatory research approach. Focus groups guided by Freire's dialogic model explored the perceptions of African American patients with cancer about participation in clinical trials. Focus groups were audio recorded and transcribed. FINDINGS: The analysis identified three main themes. IMPLICATIONS FOR NURSING: The under- representation of African American patients in clinical trials contributes to racial health disparity by negatively affecting health outcomes and quality of care delivered to this population. Oncology nurses are at the forefront of cancer care and in the best position to advocate for individuals with cancer, particularly those who face health inequalities. Findings from this study guided the recommendations.
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Negro o Afroamericano , Neoplasias , Participación del Paciente , Negro o Afroamericano/psicología , Supervivientes de Cáncer/psicología , Cuidadores/psicología , Ensayos Clínicos como Asunto , Grupos Focales , Humanos , Neoplasias/etnología , Neoplasias/terapia , Participación del Paciente/psicología , Investigación CualitativaRESUMEN
Complement receptor 1-related protein Y (CrrY) is an important cell-surface regulator of complement that is unique to rodent species. The structure of rat CrrY domains 1-4 has been determined in two distinct crystal forms and reveals a 70° bend between domains 3 and 4. Comparisons of this structure with those of other complement regulators suggests that rearrangement of this interface may occur on forming the regulatory complex with C3b.
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Antígenos de Superficie/química , Receptores de Superficie Celular/química , Animales , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Terciaria de Proteína , Ratas , Homología Estructural de ProteínaRESUMEN
Background: Genome assembly and annotation remain exacting tasks. As the tools available for these tasks improve, it is useful to return to data produced with earlier techniques to assess their credibility and correctness. The entomopathogenic nematode Heterorhabditis bacteriophora is widely used to control insect pests in horticulture. The genome sequence for this species was reported to encode an unusually high proportion of unique proteins and a paucity of secreted proteins compared to other related nematodes. Findings: We revisited the H. bacteriophora genome assembly and gene predictions to determine whether these unusual characteristics were biological or methodological in origin. We mapped an independent resequencing dataset to the genome and used the blobtools pipeline to identify potential contaminants. While present (0.2% of the genome span, 0.4% of predicted proteins), assembly contamination was not significant. Conclusions: Re-prediction of the gene set using BRAKER1 and published transcriptome data generated a predicted proteome that was very different from the published one. The new gene set had a much reduced complement of unique proteins, better completeness values that were in line with other related species' genomes, and an increased number of proteins predicted to be secreted. It is thus likely that methodological issues drove the apparent uniqueness of the initial H. bacteriophora genome annotation and that similar contamination and misannotation issues affect other published genome assemblies.
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Genoma , Nematodos/genética , Animales , Anotación de Secuencia MolecularRESUMEN
Scabies prevalence remains unacceptably high in many regions throughout the world. Infestation with scabies significantly impacts quality of life and is linked to pyoderma and consequently to severe long-term sequelae such as post-streptococcal glomerulonephritis. In the past, control programs using topical treatments have met with poor compliance; however, the highly effective oral agent ivermectin may offer a new paradigm in scabies management. Problems still exist with insensitive diagnostic tests, questions concerning mite reservoirs, and restrictions on who can receive ivermectin. Despite these difficulties, the elimination of scabies in communities worst affected may soon be possible.