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1.
Proc Natl Acad Sci U S A ; 119(29): e2205498119, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858344

RESUMO

HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 (G/C) and rs59097151 (A/G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed TAPBP mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.


Assuntos
Antígenos de Histocompatibilidade Classe I , Malária Falciparum , Proteínas de Membrana Transportadoras , Plasmodium falciparum , Sítios de Ligação , Variação Genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Malária Falciparum/genética , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , MicroRNAs/metabolismo , Peptídeos/imunologia , Plasmodium falciparum/imunologia , RNA Mensageiro/genética , Fator de Transcrição AP-2/metabolismo
2.
PLoS Comput Biol ; 18(2): e1009801, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35108259

RESUMO

Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene 'haplotypes' from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines.


Assuntos
Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/imunologia , Animais , Humanos
3.
Sci Rep ; 12(1): 3040, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35197516

RESUMO

The pathogenesis of malaria is associated with blood-stage infection and there is strong evidence that antibodies specific to parasite blood-stage antigens can control parasitemia. This provides a strong rational for applying blood-stage antigen components in a multivalent vaccine, as the induced antibodies in combination can enhance protection. The Plasmodium falciparum rhoptry-associated membrane antigen (PfRAMA) is a promising vaccine target, due to its fundamental role in merozoite invasion and low level of polymorphism. Polyclonal antibodies against PfRAMA are able to inhibit P. falciparum growth and interact synergistically when combined with antibodies against P. falciparum reticulocyte-binding protein 5 (PfRh5) or cysteine-rich protective antigen (PfCyRPA). In this study, we identified a novel PfRAMA-specific mAb with neutralizing activity, which in combination with PfRh5- or PfCyRPA-specific mAbs potentiated the neutralizing effect. By applying phage display technology, we mapped the protective epitope to be in the C-terminal region of PfRAMA. Our results confirmed previous finding of synergy between PfRAMA-, PfRh5- and PfCyRPA-specific antibodies, thereby paving the way of testing these antigens (or fragments of these antigens) in combination to improve the efficacy of blood-stage malaria vaccines. The results emphasize the importance of directing antibody responses towards protective epitopes, as the majority of anti-PfRAMA mAbs were unable to inhibit merozoite invasion of erythrocytes.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antiprotozoários/imunologia , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antiprotozoários/química , Antígenos de Protozoários/imunologia , Proteínas de Transporte/imunologia , Linhagem Celular , Sinergismo Farmacológico , Epitopos/química , Epitopos/imunologia , Humanos , Vacinas Antimaláricas/química , Malária Falciparum/prevenção & controle , Merozoítos/imunologia , Camundongos , Ligação Proteica , Proteínas de Protozoários/biossíntese , Proteínas de Protozoários/química , Proteínas de Protozoários/isolamento & purificação
4.
Nat Commun ; 13(1): 933, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177602

RESUMO

Understanding mechanisms of antibody synergy is important for vaccine design and antibody cocktail development. Examples of synergy between antibodies are well-documented, but the mechanisms underlying these relationships often remain poorly understood. The leading blood-stage malaria vaccine candidate, CyRPA, is essential for invasion of Plasmodium falciparum into human erythrocytes. Here we present a panel of anti-CyRPA monoclonal antibodies that strongly inhibit parasite growth in in vitro assays. Structural studies show that growth-inhibitory antibodies bind epitopes on a single face of CyRPA. We also show that pairs of non-competing inhibitory antibodies have strongly synergistic growth-inhibitory activity. These antibodies bind to neighbouring epitopes on CyRPA and form lateral, heterotypic interactions which slow antibody dissociation. We predict that such heterotypic interactions will be a feature of many immune responses. Immunogens which elicit such synergistic antibody mixtures could increase the potency of vaccine-elicited responses to provide robust and long-lived immunity against challenging disease targets.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Proteínas de Protozoários/imunologia , Animais , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/metabolismo , Anticorpos Antiprotozoários/isolamento & purificação , Anticorpos Antiprotozoários/metabolismo , Antígenos de Protozoários/genética , Antígenos de Protozoários/isolamento & purificação , Antígenos de Protozoários/metabolismo , Linhagem Celular , Drosophila melanogaster , Epitopos/imunologia , Humanos , Imunogenicidade da Vacina , Vacinas Antimaláricas/uso terapêutico , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/isolamento & purificação , Proteínas de Protozoários/metabolismo
5.
Cell Rep ; 38(7): 110367, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35172158

RESUMO

L9 is a potent human monoclonal antibody (mAb) that preferentially binds two adjacent NVDP minor repeats and cross-reacts with NANP major repeats of the Plasmodium falciparum circumsporozoite protein (PfCSP) on malaria-infective sporozoites. Understanding this mAb's ontogeny and mechanisms of binding PfCSP will facilitate vaccine development. Here, we isolate mAbs clonally related to L9 and show that this B cell lineage has baseline NVDP affinity and evolves to acquire NANP reactivity. Pairing the L9 kappa light chain (L9κ) with clonally related heavy chains results in chimeric mAbs that cross-link two NVDPs, cross-react with NANP, and more potently neutralize sporozoites in vivo compared with their original light chain. Structural analyses reveal that the chimeric mAbs bound minor repeats in a type-1 ß-turn seen in other repeat-specific antibodies. These data highlight the importance of L9κ in binding NVDP on PfCSP to neutralize sporozoites and suggest that PfCSP-based immunogens might be improved by presenting ≥2 NVDPs.


Assuntos
Anticorpos Monoclonais/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Proteínas de Protozoários/metabolismo , Sequências Repetitivas de Aminoácidos , Adolescente , Adulto , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/isolamento & purificação , Linhagem da Célula , Culicidae/parasitologia , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Moleculares , Testes de Neutralização , Peptídeos/química , Peptídeos/metabolismo , Plasmodium falciparum/imunologia , Ligação Proteica , Adulto Jovem
6.
PLoS Pathog ; 18(2): e1010282, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35108339

RESUMO

Immunization with radiation-attenuated sporozoites (RAS) can confer sterilizing protection against malaria, although the mechanisms behind this protection are incompletely understood. We performed a systems biology analysis of samples from the Immunization by Mosquito with Radiation Attenuated Sporozoites (IMRAS) trial, which comprised P. falciparum RAS-immunized (PfRAS), malaria-naive participants whose protection from malaria infection was subsequently assessed by controlled human malaria infection (CHMI). Blood samples collected after initial PfRAS immunization were analyzed to compare immune responses between protected and non-protected volunteers leveraging integrative analysis of whole blood RNA-seq, high parameter flow cytometry, and single cell CITEseq of PBMCs. This analysis revealed differences in early innate immune responses indicating divergent paths associated with protection. In particular, elevated levels of inflammatory responses early after the initial immunization were detrimental for the development of protective adaptive immunity. Specifically, non-classical monocytes and early type I interferon responses induced within 1 day of PfRAS vaccination correlated with impaired immunity. Non-protected individuals also showed an increase in Th2 polarized T cell responses whereas we observed a trend towards increased Th1 and T-bet+ CD8 T cell responses in protected individuals. Temporal differences in genes associated with natural killer cells suggest an important role in immune regulation by these cells. These findings give insight into the immune responses that confer protection against malaria and may guide further malaria vaccine development. Trial registration: ClinicalTrials.gov NCT01994525.


Assuntos
Imunidade , Inflamação , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Esporozoítos/imunologia , Adulto , Animais , Anopheles/parasitologia , Feminino , Humanos , Imunização/métodos , Mordeduras e Picadas de Insetos/imunologia , Malária Falciparum/parasitologia , Masculino , Mosquitos Vetores/parasitologia , Linfócitos T/imunologia , Vacinação/métodos , Vacinas Atenuadas/imunologia
7.
J Exp Med ; 219(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35006242

RESUMO

The induction of protective humoral immune responses against sporozoite surface proteins of the human parasite Plasmodium falciparum (Pf) is a prime goal in the development of a preerythrocytic malaria vaccine. The most promising antibody target is circumsporozoite protein (CSP). Although PfCSP induces strong humoral immune responses upon vaccination, vaccine efficacy is overall limited and not durable. Here, we review recent efforts to gain a better molecular and cellular understanding of anti-PfCSP B cell responses in humans and discuss ways to overcome limitations in the induction of stable titers of high-affinity antibodies that might help to increase vaccine efficacy and promote long-lived protection.


Assuntos
Anticorpos Antiprotozoários/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Humoral , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Especificidade de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular/imunologia , Eritrócitos/imunologia , Eritrócitos/parasitologia , Humanos , Imunogenicidade da Vacina , Memória Imunológica , Vacinas Antimaláricas/imunologia , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Sci Rep ; 12(1): 1402, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35082312

RESUMO

Burkina Faso has one of the highest malaria burdens in sub-Saharan Africa despite the mass deployment of insecticide-treated nets (ITNs) and use of seasonal malaria chemoprevention (SMC) in children aged up to 5 years. Identification of risk factors for Plasmodium falciparum infection in rural Burkina Faso could help to identify and target malaria control measures. A cross-sectional survey of 1,199 children and adults was conducted during the peak malaria transmission season in the Cascades Region of south-west Burkina Faso in 2017. Logistic regression was used to identify risk factors for microscopically confirmed P. falciparum infection. A malaria transmission dynamic model was used to determine the impact on malaria cases averted of administering SMC to children aged 5-15 year old. P. falciparum prevalence was 32.8% in the study population. Children aged 5 to < 10 years old were at 3.74 times the odds (95% CI = 2.68-5.22, P < 0.001) and children aged 10 to 15 years old at 3.14 times the odds (95% CI = 1.20-8.21, P = 0.02) of P. falciparum infection compared to children aged less than 5 years old. Administration of SMC to children aged up to 10 years is predicted to avert an additional 57 malaria cases per 1000 population per year (9.4% reduction) and administration to children aged up to 15 years would avert an additional 89 malaria cases per 1000 population per year (14.6% reduction) in the Cascades Region, assuming current coverage of pyrethroid-piperonyl butoxide ITNs. Malaria infections were high in all age strata, although highest in children aged 5 to 15 years, despite roll out of core malaria control interventions. Given the burden of infection in school-age children, extension of the eligibility criteria for SMC could help reduce the burden of malaria in Burkina Faso and other countries in the region.


Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Pirimetamina/uso terapêutico , Estações do Ano , Sulfadoxina/uso terapêutico , Adolescente , Adulto , Antígenos de Protozoários/sangue , Antígenos de Protozoários/imunologia , Burkina Faso/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Feminino , Humanos , Mosquiteiros Tratados com Inseticida , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/isolamento & purificação , Prevalência , Fatores de Risco , População Rural , Resultado do Tratamento , Adulto Jovem
10.
Malar J ; 21(1): 6, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983540

RESUMO

BACKGROUND: The GMZ2.6c malaria vaccine candidate is a multi-stage Plasmodium falciparum chimeric protein which contains a fragment of the sexual-stage Pfs48/45-6C protein genetically fused to GMZ2, a fusion protein of GLURP and MSP-3, that has been shown to be well tolerated, safe and immunogenic in clinical trials performed in a malaria-endemic area of Africa. However, there is no data available on the antigenicity or immunogenicity of GMZ2.6c in humans. Considering that circulating parasites can be genetically distinct in different malaria-endemic areas and that host genetic factors can influence the immune response to vaccine antigens, it is important to verify the antigenicity, immunogenicity and the possibility of associated protection in individuals living in malaria-endemic areas with different epidemiological scenarios. Herein, the profile of antibody response against GMZ2.6c and its components (MSP-3, GLURP and Pfs48/45) in residents of the Brazilian Amazon naturally exposed to malaria, in areas with different levels of transmission, was evaluated. METHODS: This study was performed using serum samples from 352 individuals from Cruzeiro do Sul and Mâncio Lima, in the state of Acre, and Guajará, in the state of Amazonas. Specific IgG, IgM, IgA and IgE antibodies and IgG subclasses were detected by Enzyme-Linked Immunosorbent Assay. RESULTS: The results showed that GMZ2.6c protein was widely recognized by naturally acquired antibodies from individuals of the Brazilian endemic areas with different levels of transmission. The higher prevalence of individuals with antibodies against GMZ2.6c when compared to its individual components may suggest an additive effect of GLURP, MSP-3, and Pfs48/45 when inserted in a same construct. Furthermore, naturally malaria-exposed individuals predominantly had IgG1 and IgG3 cytophilic anti-GMZ2.6c antibodies, an important fact considering that the acquisition of anti-malaria protective immunity results from a delicate balance between cytophilic/non-cytophilic antibodies. Interestingly, anti-GMZ2.6c antibodies seem to increase with exposure to malaria infection and may contribute to parasite immunity. CONCLUSIONS: The data showed that GMZ2.6c protein is widely recognized by naturally acquired antibodies from individuals living in malaria-endemic areas in Brazil and that these may contribute to parasite immunity. These data highlight the importance of GMZ2.6c as a candidate for an anti-malarial vaccine.


Assuntos
Formação de Anticorpos , Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Glicoproteínas de Membrana/imunologia , Fragmentos de Peptídeos/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Nat Commun ; 13(1): 331, 2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-35039519

RESUMO

Strengthening malaria surveillance is a key intervention needed to reduce the global disease burden. Reliable serological markers of recent malaria exposure could improve current surveillance methods by allowing for accurate estimates of infection incidence from limited data. We studied the IgG antibody response to 111 Plasmodium falciparum proteins in 65 adult travellers followed longitudinally after a natural malaria infection in complete absence of re-exposure. We identified a combination of five serological markers that detect exposure within the previous three months with >80% sensitivity and specificity. Using mathematical modelling, we examined the antibody kinetics and determined that responses informative of recent exposure display several distinct characteristics: rapid initial boosting and decay, less inter-individual variation in response kinetics, and minimal persistence over time. Such serological exposure markers could be incorporated into routine malaria surveillance to guide efforts for malaria control and elimination.


Assuntos
Anticorpos Antiprotozoários/imunologia , Biomarcadores/metabolismo , Malária/epidemiologia , Malária/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adulto , Formação de Anticorpos/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Epitopos/imunologia , Feminino , Fluorescência , Humanos , Lactente , Quênia/epidemiologia , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Curva ROC , Adulto Jovem
13.
Infect Immun ; 90(1): e0037721, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34694918

RESUMO

Plasmodium falciparum cysteine-rich protective antigen (CyRPA) is a conserved component of an essential erythrocyte invasion complex (RH5/Ripr/CyRPA) and a target of potent cross-strain parasite-neutralizing antibodies. While naturally acquired human RH5 antibodies have been functionally characterized, there are no similar reports on CyRPA. Thus, we analyzed the parasite-neutralizing activity of naturally acquired human CyRPA antibodies. In this regard, CyRPA human antibodies were measured and purified from malaria-infected plasma obtained from patients in central India and analyzed for their parasite neutralizing activity via in vitro growth inhibition assays (GIA). We report that, despite being susceptible to antibodies, CyRPA is a highly conserved antigen that does not appear to be under substantial immune selection pressure, as a very low acquisition rate for anti-CyRPA antibodies was reported in malaria-exposed Indians. We demonstrate for the first time that the small amounts of natural CyRPA antibodies exhibited functional parasite-neutralizing activity and that a CyRPA-based vaccine formulation induces highly potent antibodies in rabbits. Importantly, the vaccine-induced CyRPA antibodies exhibited a robust 50% inhibitory concentration (IC50) of 21.96 µg/ml, which is comparable to the IC50 of antibodies against the leading blood-stage vaccine candidate, reticulocyte-binding-like homologous protein 5 (RH5). Our data support CyRPA as a unique vaccine target that is highly susceptible to immune attack but is highly conserved compared to other leading candidates such as MSP-1 and AMA-1, further substantiating its promise as a leading blood-stage vaccine candidate.


Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Interações Hospedeiro-Parasita/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos/imunologia , Resistência à Doença/imunologia , Ensaio de Imunoadsorção Enzimática , Eritrócitos/imunologia , Eritrócitos/parasitologia , Humanos , Vacinas Antimaláricas/imunologia , Malária Falciparum/parasitologia , Proteínas Recombinantes/imunologia
14.
Eur J Immunol ; 52(2): 312-327, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34752634

RESUMO

Overwhelming activation of T cells in acute malaria is associated with severe outcomes. Thus, counter-regulation by anti-inflammatory mechanisms is indispensable for an optimal resolution of disease. Using Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice, we performed a comprehensive analysis of co-inhibitory molecules expressed on CD4+ and CD8+ T cells using an unbiased cluster analysis approach. We identified similar T cell clusters co-expressing several co-inhibitory molecules like programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) in the CD4+ and the CD8+ T cell compartment. Interestingly, despite expressing co-inhibitory molecules, which are associated with T cell exhaustion in chronic settings, these T cells were more functional compared to activated T cells that were negative for co-inhibitory molecules. However, T cells expressing high levels of PD-1 and LAG-3 also conferred suppressive capacity and thus resembled type I regulatory T cells. To our knowledge, this is the first description of malaria-induced CD8+ T cells with suppressive capacity. Importantly, we found an induction of T cells with a similar co-inhibitory rich phenotype in Plasmodium falciparum-infected patients. In conclusion, we demonstrate that malaria-induced T cells expressing co-inhibitory molecules are not exhausted, but acquire additional suppressive capacity, which might represent an immune regulatory pathway to prevent further activation of T cells during acute malaria.


Assuntos
Antígenos CD/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica , Malária Falciparum/imunologia , Plasmodium berghei/imunologia , Plasmodium falciparum/imunologia , Receptor de Morte Celular Programada 1/imunologia , Adolescente , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade
15.
Parasitol Int ; 87: 102525, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34896614

RESUMO

Existing control measures have significantly reduced malaria morbidity and mortality in the last two decades, although these reductions are now stalling. Significant efforts have been undertaken to develop malaria vaccines. Recently, extensive progress in malaria vaccine development has been made for Plasmodium falciparum. To date, only the RTS,S/AS01 vaccine has been tested in Phase 3 clinical trials and is now under implementation, despite modest efficacy. Therefore, the development of a malaria transmission-blocking vaccine (TBV) will be essential for malaria elimination. Only a limited number of TBVs have reached pre-clinical or clinical development with several major challenges impeding their development, including low immunogenicity in humans. TBV development efforts against P. vivax, the second major cause of malaria morbidity, lag far behind those for P. falciparum. In this review we summarize the latest progress, challenges and innovations in P. vivax TBV research and discuss how to accelerate its development.


Assuntos
Vacinas Antimaláricas , Malária Vivax/prevenção & controle , Plasmodium vivax/imunologia , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/epidemiologia , Malária Vivax/transmissão , Plasmodium falciparum/imunologia
16.
Methods Mol Biol ; 2410: 555-566, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34914067

RESUMO

Live attenuated vaccines (LAVs) are among the most critical interventions in modern medicine and have already proven their potential to save millions of lives. LAVs are always explored as potential vaccine candidates since they induce an immune response, which is as good as the wild type pathogen. For parasitic diseases, the efficacy of LAVs is still under investigation and needs extensive research to mark their presence in the field. In malaria, live attenuated sporozoites have been evaluated for a vaccine against the liver stage. This vaccine approach is limited due to the highly cumbersome technique of sporozoite isolation and related relapse issues. We have developed a novel vaccine against malaria by expressing Plasmodium falciparum antigens in Leishmania donovani promastigotes. These hybrid, recombinant L. donovani parasites mimicking P. falciparum parasite antigens were analyzed for their anti-malarial efficacy in preclinical studies. We demonstrate the potential of Leishmania spp. parasites in developing an important live vector vaccine against malaria for the induction of protective immune responses. Herein, we describe a method to express malaria parasite antigens in L. donovani promastigotes and analyze its potential for a vaccine against malaria. This methodology can be extended to live, attenuated Leishmania promastigotes parasites to develop LAV against malaria.


Assuntos
Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Animais , Antígenos de Protozoários , Leishmania donovani , Malária Falciparum/prevenção & controle , Parasitos , Plasmodium falciparum/imunologia , Esporozoítos/imunologia , Vacinas Atenuadas
17.
Methods Mol Biol ; 2410: 597-606, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34914071

RESUMO

Traditional and modern approaches have been applied to combat the malaria disease. Malaria eradication is a priority in several developing countries. Transmission-blocking vaccines are one of the suggested solutions for malaria eradication. Therefore, there is a demand for introducing the new targets and evaluation methods. Standard membrane feeding assay is the base of the evaluation process of transmission-blocking candidate molecules. Hence, this process is explained in this chapter in detail.


Assuntos
Vacinas Antimaláricas , Malária , Bioensaio , Humanos , Malária/prevenção & controle , Malária Falciparum , Membranas , Plasmodium falciparum/imunologia
18.
PLoS Pathog ; 17(12): e1010133, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34871332

RESUMO

Combinations of monoclonal antibodies (mAbs) against different epitopes on the same antigen synergistically neutralize many viruses. However, there are limited studies assessing whether combining human mAbs against distinct regions of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) enhances in vivo protection against malaria compared to each mAb alone or whether passive transfer of PfCSP mAbs would improve protection following vaccination against PfCSP. Here, we isolated a panel of human mAbs against the subdominant C-terminal domain of PfCSP (C-CSP) from a volunteer immunized with radiation-attenuated Pf sporozoites. These C-CSP-specific mAbs had limited binding to sporozoites in vitro that was increased by combination with neutralizing human "repeat" mAbs against the NPDP/NVDP/NANP tetrapeptides in the central repeat region of PfCSP. Nevertheless, passive transfer of repeat- and C-CSP-specific mAb combinations did not provide enhanced protection against in vivo sporozoite challenge compared to repeat mAbs alone. Furthermore, combining potent repeat-specific mAbs (CIS43, L9, and 317) that respectively target the three tetrapeptides (NPDP/NVDP/NANP) did not provide additional protection against in vivo sporozoite challenge. However, administration of either CIS43, L9, or 317 (but not C-CSP-specific mAbs) to mice that had been immunized with R21, a PfCSP-based virus-like particle vaccine that induces polyclonal antibodies against the repeat region and C-CSP, provided enhanced protection against sporozoite challenge when compared to vaccine or mAbs alone. Collectively, this study shows that while combining mAbs against the repeat and C-terminal regions of PfCSP provide no additional protection in vivo, repeat mAbs do provide increased protection when combined with vaccine-induced polyclonal antibodies. These data should inform the implementation of PfCSP human mAbs alone or following vaccination to prevent malaria infection.


Assuntos
Anticorpos Monoclonais/imunologia , Imunização Passiva/métodos , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Humanos , Malária Falciparum/prevenção & controle , Camundongos , Esporozoítos/imunologia
19.
Malar J ; 20(1): 452, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34856981

RESUMO

BACKGROUND: RTS,S/AS01, the leading malaria vaccine has been recommended by the WHO for widespread immunization of children at risk. RTS,S/AS01-induced anti-CSP IgG antibodies are associated with the vaccine efficacy. Here, the long-term kinetics of RTS,S/AS01-induced antibodies was investigated. METHODS: 150 participants were randomly selected from the 447 children who participated in the RTS,S/AS01 phase IIb clinical trial in 2007 from Kilifi-Kenya. Cumulatively, the retrospective follow-up period was 93 months with annual plasma samples collection. The levels of anti-CSP IgM, total IgG, IgG1, IgG2, IgG3, and IgG4 antibodies were then determined using an enzyme-linked immunosorbent assay. RESULTS: RTS,S/AS01 induced high levels of anti-CSP IgG antibodies which exhibited a rapid waning over 6.5 months post-vaccination, followed by a slower decay over the subsequent years. RTS,S/AS01-induced anti-CSP IgG antibodies remained elevated above the control group levels throughout the 7 years follow-up period. The anti-CSP IgG antibodies were mostly IgG1, IgG3, IgG2, and to a lesser extent IgG4. IgG2 predominated in later timepoints. RTS,S/AS01 also induced high levels of anti-CSP IgM antibodies which increased above the control group levels by month 3. The controls exhibited increasing levels of the anti-CSP IgM antibodies which caught up with the RTS,S/AS01 vaccinees levels by month 21. In contrast, there were no measurable anti-CSP IgG antibodies among the controls. CONCLUSION: RTS,S/AS01-induced anti-CSP IgG antibodies kinetics are consistent with long-lived but waning vaccine efficacy. Natural exposure induces anti-CSP IgM antibodies in children, which increases with age, but does not induce substantial levels of anti-CSP IgG antibodies.


Assuntos
Anticorpos Antiprotozoários/imunologia , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , /estatística & dados numéricos , Humanos , Lactente , Quênia , Cinética , Estudos Retrospectivos
20.
Microbiol Spectr ; 9(3): e0110921, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34878303

RESUMO

Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We studied the effects of coinfections on the antibody profile in a cohort of 715 Mozambican children and adults using the Luminex technology with a panel of 16 antigens from P. falciparum and 11 antigens from helminths (Ascaris lumbricoides, hookworm, Trichuris trichiura, Strongyloides stercoralis, and Schistosoma spp.) and measured antigen-specific IgG and total IgE responses. We compared the antibody profile between groups defined by P. falciparum and helminth previous exposure (based on serology) and/or current infection (determined by microscopy and/or qPCR). In multivariable regression models adjusted by demographic, socioeconomic, water, and sanitation variables, individuals exposed/infected with P. falciparum and helminths had significantly higher total IgE and antigen-specific IgG levels, magnitude (sum of all levels) and breadth of response to both types of parasites compared to individuals exposed/infected with only one type of parasite (P ≤ 0.05). There was a positive association between exposure/infection with P. falciparum and exposure/infection with helminths or the number of helminth species, and vice versa (P ≤ 0.001). In addition, children coexposed/coinfected tended (P = 0.062) to have higher P. falciparum parasitemia than those single exposed/infected. Our results suggest that an increase in the antibody responses in coexposed/coinfected individuals may reflect higher exposure and be due to a more permissive immune environment to infection in the host. IMPORTANCE Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We compared the antibody profile between groups of Mozambican individuals defined by P. falciparum and helminth previous exposure and/or current infection. Our results show a significant increase in antibody responses in individuals coexposed/coinfected with P. falciparum and helminths in comparison with individuals exposed/infected with only one of these parasites, and suggest that this increase is due to a more permissive immune environment to infection in the host. Importantly, this study takes previous exposure into account, which is particularly relevant in endemic areas where continuous infections imprint and shape the immune system. Deciphering the implications of coinfections deserves attention because accounting for the real interactions that occur in nature could improve the design of integrated disease control strategies.


Assuntos
Anticorpos Anti-Helmínticos/sangue , Anticorpos Antiprotozoários/sangue , Coinfecção/imunologia , Helmintos/imunologia , Plasmodium falciparum/imunologia , Adolescente , Adulto , Animais , Anticorpos Anti-Helmínticos/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Helmintos/imunologia , Antígenos de Protozoários/imunologia , Criança , Pré-Escolar , Feminino , Helmintíase/imunologia , Helmintíase/patologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Malária Falciparum/imunologia , Malária Falciparum/patologia , Masculino , Moçambique , Carga Parasitária , Solo/parasitologia , Adulto Jovem
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