25 research outputs found
Heterogeneity in Plasmodium falciparum whole sporozoite vaccine induced humoral immune responses and protection in African volunteers: the role of age, human pegivirus and human immunodeficiency virus co-infections.
No full textMalaria, a vector borne disease caused by Plasmodium species remains a major public health problem especially in sub-Saharan Africa. In 2018 alone, there were an estimated 228 million clinical cases and 405,000 deaths attributed to malaria. New tools such as efficacious vaccines, better drugs and diagnostics are needed to supplement the current malaria control tools that rest mainly on vector control measures. Clinical trials in malaria naïve volunteers have demonstrated high level of sterile vaccine induced protection in healthy individuals immunized with live, metabolically active, irradiation attenuated purified sporozoites (PfSPZ Vaccine) or live non-attenuated purified sporozoites given under chloroquine chemoprophylaxis (PfSPZ-CVac). Immunogenicity and protective efficacy against malaria induced by these whole sporozoite based vaccines varies widely between European/US versus African volunteers. Interestingly, variations in protection and immunogenicity of these malaria vaccines have been observed among African volunteers residing in different malaria endemic regions of East and West Africa. These different outcomes could be linked to levels of malaria pre-exposure and co-infections at the time of vaccination. Until recently safety, tolerability, immunogenicity and protective efficacy of PfSPZ Vaccine in immunocompromised populations including individuals infected with the Human Immunodeficiency Virus (HIV) was unknown. Given the high geographical overlap of HIV and malaria, an effective malaria vaccine deployed in this population could possibly support the long-term objective of regional elimination of malaria by using mass vaccination. Furthermore, the role of asymptomatic, under researched, highly prevalent viruses like Human Pegivirus (HPgV-1) circulating in Sub-Saharan Africa on malaria pathogenesis and vaccination outcomes remains elusive.
The aims of this PhD thesis include: 1) Evaluate the safety, tolerability, efficacy, and immunogenicity of the PfSPZ Vaccine in different populations and age groups residing in malaria endemic countries. 2) Compare the safety, tolerability, efficacy, and immunogenicity of two different whole sporozoite based vaccination approaches, PfSPZ Vaccine and PfSPZ-CVac in Equatorial Guinean adults. 3) The unbiased assessment of PfSPZ Vaccine induced humoral immunity using protein microarrays probed with serum samples of HIV positive and HIV negative volunteers to understand immune status before vaccination, immuno-dominance of vaccine induced antibody targets, and distinct antibody profiles that might be associated with vaccine-induced protection. 4) Investigate the interaction of chronic HPgV-1 co-infection on PfSPZ Vaccine induced humoral immunity and protection against homologous CHMI. These aims are structured around 6 manuscripts presented in this PhD thesis.
Manuscript 1-3: Safety, immunogenicity, and efficacy of radiation attenuated whole sporozoite vaccine (PfSPZ Vaccine) in African populations of different ages
In this chapter, we include the outcomes of clinical trials conducted in Bagamoyo, Tanzania. These trials for the first time i) evaluated the safety, immunogenicity and efficacy against homologous CHMI of irradiation attenuated purified Plasmodium falciparum sporozoites (PfSPZ Vaccine) in adult volunteers; ii) tested increasing dosages of PfSPZ Vaccine in different age groups including adults, adolescents, children and infants. We found PfSPZ vaccine to be safe and well tolerated and that vaccine inoculation by intravenous inoculation is well accepted even in younger age groups. Protective efficacy varied in the different trials leading to the identification of a vaccine regimen of 9x105PfSPZ per dose as suitable for further development. PfSPZ Vaccine induce immune responses, both cellular and humoral, were age dependent with infants mounting no measurable malaria specific cellular immunity in peripheral blood. Surprisingly, compared to other age groups, older children and adolescents mounted higher cellular and humoral immune responses. These findings are relevant for further optimization of PfSPZ vaccine regimen that might need to be adapted to different age groups to optimize vaccine induced protection. As an extension of these trials, we have compared PfSPZ Vaccine safety, immunogenicity and efficacy in HIV positive versus HIV negative volunteers. We observed marked differences in PfSPZ Vaccine induced efficacy between HIV positive (0%) and HIV negative individuals (80%) undergoing homologous CHMI(Manuscript in preparation).
Manuscript 4: Immunogenicity and protective efficacy of radiation-attenuated and chemo-attenuated PfSPZ vaccines in Equatoguinean adults
This work describes the outcome of a first time side-by-side comparison of two whole sporozoite based vaccine approaches (PfSPZ Vaccine and PfSPZCVac) in malaria pre-exposed individuals of Equatorial Guinea. We evaluated PfSPZ Vaccine dosages (2.7 X106) given three times at 8-week interval and PfSPZ CVac dose (1X105) given three times at 4 weeks interval. Homologous CHMI was employed for assessment of vaccine efficacy. Both approaches were safe and well tolerated in malaria pre-exposed individuals but the immunogenicity and protective efficacy differed. Vaccine efficacy was lower in the PfSPZ Vaccine group (27%) compared to the PfSPZ CVac group (55%), despite induction of about 2.9 times higher antibody titres against the circumsporozoite protein in the PfSPZ Vaccine group prior to CHMI. These results highlight the potential involvement of different protective immune mechanisms induced by each of the two whole sporozoite vaccines approaches and the effect of malaria pre-exposure on pfSPZ CVac vaccine induced efficacy in comparison to malaria naïve volunteers. We show that induction of high antibody titres against the circumsporozoite protein does not correlate with protection since no difference was observed between CHMI protected and non-protected volunteers.
Manuscript 5: HIV-1 positive and HIV-1 negative Tanzanian adults undergoing whole irradiation attenuated Plasmodium falciparum sporozoite vaccination mount antibody responses targeting the circumsporozoite protein and merozoite surface protein 5
In this manuscript, we investigated antibody profiles binding to 262 pre-selected antigens of Pf before and after vaccination as well as after homologus CHMI. We aimed to identify antibody profiles that might explain the observed poor vaccine induced protection in HIV positive individuals. We found a lower - albeit not statistically significant - antigen breadth in HIV positive volunteers at baseline before first vaccine inoculation. Immunization with PfSPZ Vaccine induced IgG and IgM isotypes specific for the Merozoite surface protein 5 (PfMSP 5) and the circumsporozoite protein (PfCSP) regardless of HIV infection status. Interestingly, volunteers displayed a highly personalized IgG and IgM immune profiles targeting Pf antigens before vaccination and these remained unchanged after PfSPZ vaccination confirming our previous results of antigenic imprinting in malaria.
Manuscript 6: Role of Pegivirus infections in whole Plasmodium falciparum sporozoite vaccine induced humoral immunity and controlled human malaria infections in African volunteers
In this study, we wanted to understand the role of human pegivirus infections in East and Western African adult volunteers and its impact on PfSPZ Vaccine induced humoral immune responses and homologous CHMI. We found HPgV-1 to be highly prevalent in our volunteers (29.2%) with circulating genotypes 1, 2 and 5 as described in other African settings. HPgV-1 infection did not alter PfSPZ vaccine induced antibody responses and parasite multiplication rates during CHMI. However, a higher proportion of individuals were protected against homologous CHMI that had ongoing, active human pegivirus infections. Significantly higher serum concentrations of IL-2 and IL-17A were measured in HPgV-1 positive volunteers likely indicating chronic activation of the immune system. CHMI was safe and well tolerated in HPgV-1 positive individuals since the viremia did not change upon acute asexual blood stage parasitemia. These results highlight the potential impact of chronic, asymptomatic viral infections on PfSPZ vaccine efficacy that needs confirmation in larger cohorts and in field studies of naturally occurring malaria infections
Symptoms of Imminent Eclampsia Among Women Attending Care at Muhimbili National Hospital: A Case Refferent Study
No full textPreeclampsia affects about 5 to 10% of all pregnancies and eclamptic seizure is one of its serious complications. In many developing countries including Tanzania, maternal and perinatal mortality due to eclampsia are high. As yet, primary prevention of eclampsia is not possible since the causes are largely unknown. Headache, visual disturbance, abdominal pain, nausea, and vomiting have been reported by various studies to precede most eclamptic seizures; thus could be used to predict and therefore prevent some cases given the availability of magnesium sulphate. These symptoms however are also common in normal pregnancy and post delivery mothers due to physiological changes of pregnancy and common disease conditions that usually affect pregnant women in our settings. The present study evaluated the characteristics of symptoms that are consistent with imminence of eclampsia This was a case referent study in which 123 eclamptic and 123 non eclamptic mothers that best matched in terms of age, parity, gestation age and delivery were enrolled, making a total of 246 women. The presence and characteristics of headache, visual disturbance, abdominal pain, nausea, and vomiting were enquired. A 4 grade scale was used to grade the severity of headache. In the rest of symptoms, common presenting features were utilized. Headache was common in both groups but was more frequent in eclamptic than in referent group of women (88% vs. 43%, p <0.001). In eclamptic mothers headache was mainly severe, frontal and most of the seizures happened within one week of the onset of headache, as compared to referent women where headache was mostly mild and either frontal or generalized. Visual problems were significantly frequent in eclamptics than in referent women, (39% vs. 3% p<0.001). Of the eclamptic mothers who presented with visual problems, 45(94%) had blurring of vision, 32(67%) had blind spots, 10(21%) had photophobia and only 7(15%) had total blindness. A total of 47(98%) of eclamptic mothers developed seizures within 12hours of the onset of visual problems. The frequency of abdominal pain was not significantly different between eclamptic and referent mothers (47% vs.38% p=0.156), however upper quadrant abdominal pain was significantly reported in eclamptic than in referent group of women (36% vs.9%, p=0.001). There was no significant difference on the type of abdominal pain presented by both groups. Nausea was common in both eclamptics and referent group of women (60% vs. 54%, p=0.303). There was no difference on presentation with vomiting among eclamptic and referent women (62% vs. 68% p=0.516) and in both groups the type of vomiting was commonly non projectile. This study has revealed that headache, abdominal pain, nausea and vomiting are common to pregnancy whether or not complicated by preeclampsia/eclampsia. The characteristics of headache, visual disturbances and abdominal pain differ between eclamptics and women without preeclampsia/eclampsia. In a pre eclamptic woman, an onset of a severe frontal headache or upper quadrant abdominal pain would suggest an occurrence of seizures within one week. Visual disturbance is the most ominous sign as seizures ensue within 12 hours of its onset. Nausea and vomiting cannot be reliably used to predict clampsia.\u
Galleguismos y/o leonesismos en el Tumbo de San Pedro de Montes
No full textThe Cartulary of the monastery of S. Pedro de Montes contains almost three
hundred documents in latin (DL) dating up to 1240, which are preceded by summaries in Romance (RR). The study of both allows us to see that, on some occasions, the phonetic and morphological characteristics coincide with those of Castillan and, on others, with those of Galician-Portuguese. Given the location of the monastery, the author refers to the Romance language used in these documents by the term "Galician-Leonese" rather than "Western-Leonese".El Tumbo del monasterio de San Pedro de Montes contiene casi trescientos documentos en latín (DL) datados hasta 1240, que están precedidos de resúmenes en romance (RR). Su estudio simultáneo permite observar que las características fonéticas y morfológicas coinciden unas veces con las del castellano y otras con las del gallego-portugués. Dada la ubicación del monasterio, el autor opta por denominar "gallego-leonés", mejor que "leonés occidental", a la lengua romance usada en dichos documentos
[Cronicones del tumbo negro de Santiago y otros documentos de historia religiosa española medieval] (Ms. 1975)
No full textManuscrito número 1975 de la Biblioteca Histórica de la USAL1 hoja guarda, 2 hojas, 75 hojas (esto es, 77), 3 hojas, 1 hoja guarda : papel ; 268 x 195 mmEn h. 2r, enmarcado en un dibujo en forma de escudo: Este libro se saco de otro escrito en pergamino y letra antigua que era del señor liçenciado Juan Diaz de Fuenmayor del consejo y camara del rey Don Phelipe 2º nro. sr. Y aunque del no se puede colegir quien es el autor pero por conjeturas y de lo que refiere Ambrosio de Morales , lib. 16, cap. 43, se entiende que el author fue Sant Pyro, cuya obra continuo Pelayo, obpo. de Oviedo, hasta los tiempos del rey don Alº el sexto que gano a Toledo en cuyo reynado se acabo esta historia.Foliación de la época; bis f. 32, 56Caja de escritura: 205 x 124 mm, línea tirada, ±30 líneas. -- Caja de escritura enmarcada en línea sencilla, en rojo. -- Rúbricas en rojoEscritura: Letra itálica. -- Hasta f. 40 abundantes correcciones marginales (probablemente de mano de Gil Ramírez de Arellano: cf. Mss. 1780, 2335, etc.), en las que se remite a dos códices, uno llamado Salmantino y otro BenedictinoProcede del Colegio de Cuenca y, probablemente, de Gil Ramírez de Arellanof. 1r-50r: [Cronicones del tumbo negro de Santiago] ---
f. 43v-45r: [Concilium Coiacense, 1050] (Decreta regis Fredenandi et Sanctiae reginae et omnium episcoporum in diebus eorum in Hispania degentium et omnium eiusdem regni obtimatum in era M Lxxx viiii...) ---
f. 45r-v: [Petrus Sancti Sepulchri canonicus, Epistola Pelagio Ovetensi episcopo] (Ut cognoscant fideles quot patriarche fuere in Iherusalem...) ---
f. 45v-48r: [Concilium Ovetense, 1125] (Sciant omnes homines presentes et futuros quoniam Deo iuvente...) ---
f. 48v-49v: [Privilegio de Alfonso II a Oviedo] (Ovetum. Incipit testamentum ecclesiae sancti Salvatoris Ovetensis sedis a rege Adefonso casto factum et confirmatum...) ---
f. 49v-50r: [Episcoporum sedes Oveti in concilio singulis designatae] ---
f. 51r-75r: [Gesta regum francorum] (Incipit prologus gentis Francorum. Explanatio vel origo gentis Francorum...
Memoria y cultura en la documentación del monasterio de Samos: la respuesta de las fórmulas "inútiles" (años 785 a 1209)
No full textThe author surveys the documentation between 785 and 1209 consierved in the rumbo of the St. Julian
Samos monastery in northeastern Spain. He perceives in its contents and in the formulas used, development of
a social consciousness and culture. These elements served in the first place to create a distinctive monastery
with spiritual content. and in the second place to consolidate its entities and establish its particularity and the
spiritual basis of its doctrines.El autor recorre la documentación recogida en el Tumbo del monasterio de San Julián Samos. en el Noroeste
de la Peninsula Ibérica. entre los años 785 y 1209, y observa. tanto en su contenido como en las fórmulas utiliza
das. elementos de desarrollo de una memoria social y de una cultura. Estos elementos de memoria y cultura
sirvieron. en una primera etapa. para crear el propio monasterio a través de donaciones enunciadas con unas
extensas arengas de contenido espiritual. y. en una segunda etapa. para consolidar su existencia y establecer el
ámbito de su particularidad. sustituyendo las razones espirituales por las doctrinales y por una progresiva sensibilidad
respecto a la memoria y a la hístoria
PfSPZ Vaccine induces focused humoral immune response in HIV positive and negative Tanzanian adults
No full textThe cartulary of San Xoán da Cova’s monastery (Vedra). Palaeographical notes and documentary abstracts
No full textA finalidade deste traballo é, dunha banda, o estudo da escritura do tombo inédito de San Xoán da Cova
(segunda metade do século XV), a través da súa consulta directa e a aplicación dunha metodoloxía paleográfica. Para unha análise máis completa, iniciamos o traballo cunha breve síntese da materialidade do
códice e dalgúns aspectos da diplomática do mesmo (certas fórmulas, as clases de notarios que interveñen
ou a tipoloxía dos documentos copiados). Tras isto, analizaremos os modelos gráficos empregados no
libro, as súas características, a posible identificación das mans ou os motivos que explican a aparición
destas grafías. Doutra banda, o segundo obxectivo é a elaboración dos rexestos dos documentos do libro,
os cales reflicten a gran diversidade documental trasladada. Observaremos, polo tanto, que os modelos
góticos, principalmente, a cortesá, foron os máis utilizados na redacción do códice, en relación coa súa
función administrativa, o carácter notarial dos documentos copiados ou o uso do galego. Estas conclusións
complétanse coa existencia dun claro multigrafismo (bastarda-latín, cortesá-galego) entre os notarios
apostólicos deste libro como consecuencia da súa formación e apreciable trala comparación deste tombo
con outras fontes notariais de Santiago.La finalidad de este trabajo es, por un lado, el estudio de la escritura del tumbo inédito de San Xoán da
Cova (segunda mitad del siglo XV), a través de su consulta directa y la aplicación de una metodología
paleográfica. Para un análisis más completo, iniciamos el trabajo con una breve síntesis de la materialidad
del códice y de algunos aspectos de la diplomática del mismo (ciertas fórmulas, las clases de notarios
que intervienen o la tipología de los documentos copiados). Tras ello, analizaremos los modelos gráficos
empleados en el libro, sus características, la posible identificación de las manos o los motivos que explican
la aparición de estas grafías. Por otro lado, el segundo objetivo es la elaboración de los regestos de los
documentos del libro, los cuales reflejan su gran diversidad tipológica. Observaremos, por lo tanto, que
los modelos góticos, principalmente, la cortesana, fueron los más utilizados en la redacción del códice, en
relación con su función administrativa, el carácter notarial de los documentos copiados o el uso del gallego.
Estas conclusiones se completan con la existencia de un claro multigrafismo (bastarda-latín, cortesanagallego) entre los notarios apostólicos de este libro como consecuencia de su formación y apreciable tras
la comparación de este tumbo con otras fuentes notariales de Santiago.The aim of this research is, on the one hand, to study the handwriting of the unpublished San Xoán da
Cova’s cartulary (second half of the 15th century), through its direct analysis and a palaeographical methodology. In order to develop a more comprehensive analysis, we present a short initial study of some
codicological issues of the codex, as well as of some other diplomatic subjects: documentary clauses, the
different kinds of scribes or the types of the copied documents. After that, we will examine the graphic
models, their features, the possible identification of their author or the reasons behind their occurrence.
On the other hand, our second goal is to elaborate the abstracts of the documents within this cartulary,
which will reflect their great range of types. Therefore, we will see that gothic scriptures, cortesana above
all, were the most commonly used in this codex. This trait is reflective of the administrative role of the
cartulary, the notarial nature of the documents or the use of Galician. These conclusions are complemented
with the existence of an evident multigraphism (bastarda-Latin, cortesana-Galicia) among the Apostolic
notaries acting in this book, as a result of their formation, and noticeable through the comparison of this
cartulary with other notarial sources from Santiago.MInisterio de Economía y Competitividad HAR2013-41378-
Red blood cell indices and\ud Prevalence of Hemoglobinopathies and Glucose 6 Phosphate Dehydrogenase Deficiencies in Male Tanzanian Residents of Dar es Salaam
No full textHemoglobinopathies, disorders of hemoglobin structure and production, are one of the most common monogenic disorders in humans. Glucose 6 phosphate dehydrogenase deficiency (G6PD) is an inherited enzymopathy resulting in increased oxygen stress susceptibility of red blood cells. The distributions of these genetic traits in populations living in tropical and subtropical regions where malaria has been or is still present are thought to result from survival advantage against severe life threatening malaria disease. 384 male Tanzanian volunteers residing in Dar es Salaam were typed for G6PD, sickle cell disease and α-thalassemia. The most prominent red blood cell polymorphism was heterozygous α+-thalassemia (37.8%), followed by the G6PD(A) deficiency (16.4%), heterozygous sickle cell trait (15.9%), G6PD(A-) deficiency (13.5%) and homozygous α+-thalassemia (5.2%). 35%, 45%, 17% and 3% of these volunteers were carriers of wild type gene loci, one, two or three of these hemoglobinopathies, respectively. We find that using a cut off value of 28.6 pg. for mean corpuscular hemoglobin (MCH), heterozygous α+-thalassemia can be predicted with a sensitivity of 84% and specificity of 72% in this male population. All subjects carrying homozygous α+-thalassemia were identified based on their MCH value < 28.6 pg
Red blood cell indices and prevalence of hemoglobinopathies and glucose 6 phosphate dehydrogenase deficiencies in male Tanzanian residents of Dar es Salaam
No full textHemoglobinopathies, disorders of hemoglobin structure and production, are one of the most common monogenic disorders in humans. Glucose 6 phosphate dehydrogenase deficiency (G6PD) is an inherited enzymopathy resulting in increased oxygen stress susceptibility of red blood cells. The distributions of these genetic traits in populations living in tropical and subtropical regions where malaria has been or is still present are thought to result from survival advantage against severe life threatening malaria disease. 384 male Tanzanian volunteers residing in Dar es Salaam were typed for G6PD, sickle cell disease and α-thalassemia. The most prominent red blood cell polymorphism was heterozygous α+-thalassemia (37.8%), followed by the G6PD(A) deficiency (16.4%), heterozygous sickle cell trait (15.9%), G6PD(A-) deficiency (13.5%) and homozygous α+-thalassemia (5.2%). 35%, 45%, 17% and 3% of these volunteers were carriers of wild type gene loci, one, two or three of these hemoglobinopathies, respectively. We find that using a cut off value of 28.6 pg. for mean corpuscular hemoglobin (MCH), heterozygous α+-thalassemia can be predicted with a sensitivity of 84% and specificity of 72% in this male population. All subjects carrying homozygous α+-thalassemia were identified based on their MCH value < 28.6 pg
Red blood cell indices and prevalence of hemoglobinopathies and glucose 6 phosphate dehydrogenase deficiencies in male Tanzanian residents of Dar es Salaam
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