Malaria, caused by Plasmodium falciparum parasites remains a huge public health problem and a major cause of morbidity and mortality in sub-Saharan Africa, especially among children and infants. The parasite and its vector – the Anopheles spp mosquito - have tremendous adaptability capacities, including the acquisition of resistance to anti-malarial drugs and insecticides, making the development of new preventive tools, such as a safe and effective vaccine, a key element to counter balance this tendency. The most advanced malaria vaccine candidate, RTS,S/AS has progressed to a Phase III trial through a research and development plan as a result of an unforeseen partnership between African, European and American research institutions together with GSK Biologicals and the PATH Malaria Vaccine Initiative (MVI). This thesis describes some critical stages of the clinical development plan of this vaccine, reporting clinical trials of the RTS/AS candidate malaria vaccine conducted in Mozambican children and infants. Here we illustrates the assessment of the RTS,S/AS02D safety, humoral and cellular mediated immune responses and the duration of protection over a one year period in infants. We also provide a detailed immunogenicity data of 4 years of follow-up of children aged 1 to 4 years by the time of immunization with RTS,S/AS02A. These studies principally show that the vaccine is safe, well tolerated and highly immunogenic, eliciting both humoral and cell-mediated antibodies. The vaccine also protects children and infants against clinical malaria. Importantly, they also describe for the first time an association between the risk of clinical malaria and Plasmodium falciparum anticircumsporozoite antibody titters. The presented results support the hypothesis that developing a safe, immunogenic and efficacious malaria vaccine is feasible and, together with other studies, they should be the basis for the registry process of what should be the first generation of vaccines against malaria. / La malaria, causada por el parásito Plasmodium falciparum sigue siendo un gran problema de salud pública y una causa importante de mortalidad y morbilidad en el África Sub-Sahariana, especialmente entre los niños y lactantes. El parásito y su vector mosquito Anofeles spp. tienen una tremenda capacidad de adaptación, incluyendo la capacidad de adquirir resistencia a los fármacos antipalúdicos e insecticidas. Es por tanto prioritario desarrollar nuevas herramientas preventivas, entre las cuales una vacuna segura y eficaz, un elemento clave para contrarrestar esta tendencia. La vacuna candidata contra la malaria más avanzada, denominada RTS,S/AS, ha progresado hasta un ensayo de Fase III siguiendo un plan de investigación y desarrollo clínico resultado de una colaboración sin precedentes entre centros de investigación Africanos, Europeos y Americanos junto con la GSK Biologicals y PATH Malaria Vaccine Initiative (MVI). Esta tesis describe algunas de las fases críticas de estos logros, reportando los ensayos clínicos de la vacuna candidata contra la malaria RTS,S/AS llevados a cabo en niños y lactantes de Mozambique. Esta tesis analiza en detalle la evaluación de la seguridad de esta estrategia, la respuesta inmunológica (tanto humoral como celular) que esta vacuna confiere, y la duración de la protección durante un período de seguimiento de un año en los lactantes. Presentamos también los datos completos de 4 años de seguimiento de la inmunogenicidad de la RTS,S/AS02A administrada a niños de 1 a 4 años de edad en el momento de su primera vacunación. Estos estudios demuestran que la vacuna es segura, bien tolerada y altamente inmunogénica, produciendo respuestas tanto humorales como celulares. La vacuna también protege a los niños y lactantes contra la malaria clínica. Además se describe por primera vez una asociación entre el riesgo de malaria clínica y los niveles de anticuerpos contra la proteína de circumsporozoito del Plasmodium falciparum. Los resultados aquí presentados apoyan la tesis de que el desarrollo de una vacuna eficaz, inmunogénica y segura contra la malaria es posible, y deberá ser la base, junto con otros estudios, del proceso de registro de la que podrá ser la primera generación de vacunas contra la malaria.

[Truncated abstract] Malaria is the most important parasitic disease of man. Of the five species known to infect humans, Plasmodium falciparum causes most deaths and illness, especially when it affects children and pregnant women living in highly endemic areas of the rural tropics. Pharmacological therapies for malaria must be optimised for these groups and must be practical for administration in critically ill patients in remote settings. The clinical studies in this thesis evaluated the clinical pharmacology of modern antimalarial treatments in a Melanesian population exposed to highly endemic malaria. The clinical studies were conducted between March 2001 and June 2007, with final data analysis completed by mid-2008. They aimed to evaluate key pharmacokinetic, parasitological, host genetic and socio-cultural determinants of treatment effectiveness in children with uncomplicated and severe malaria and in pregnant women. A multi-centre study of children with uncomplicated malaria evaluated the efficacy of four treatment regimens, including three artemisinin combination treatments. PCR corrected recrudescence rates by day 42 were 81.5%, 85.4%, 88.0% and 95.2% for chloroquine + sulphadoxine-pyrimethamine, artesunate + sulphadoxine-pyrimethamine, dihydroartemisinin-piperaquine (DHA-PQ) and artemether-lumefantrine (AL), respectively. Determinants of efficacy in the DHA-PQ group included day 7 piperaquine (PQ) levels and baseline parasitaemia. Therefore, the worse than expected efficacy in this group may have been partly due to the high parasitaemias commonly seen in this population. ... Preliminary data suggested a protective effect of the erythrocyte polymorphism caused by the glycophorin C mutation against cerebral malaria. These studies also evaluated key pharmacokinetic, host genetic and socio-cultural determinants of the likely effectiveness of a novel pharmaceutical approach using artesunate suppositories for severe malaria. These demonstrated favourable absorption characteristics, clinical efficacy, safety and patient/community acceptability. Contrary to previous data, no evidence was found to suggest that the pharmacokinetic profiles or efficacy of artemisinin derivatives are likely to be compromised by a high prevalence of thalassaemia in this population. However, their highly variable bioavailability raises questions regarding the consistency of therapeutic response. Given the favourable efficacy and socio-cultural acceptability of rectal artesunate demonstrated in these studies, the PNG Ministry of Health has decided to add artesunate suppositories to its national pharmacopoeia and incorporate them into standard treatment recommendations. A final study compared the pharmacokinetics of chloroquine, sulphadoxine and pyrimethamine in pregnant, versus non-pregnant women. This demonstrated significantly lower concentrations of all three drugs and active metabolites in the pregnant group, due to a combination of effects on either volume of distribution, clearance and elimination half-life. It suggests that significant dosage alterations are necessary to optimise therapy in pregnant women.

Diss. (sammanfattning) Umeå : Univ., 2002. / Härtill 5 uppsatser.

Thesis (Ph.D.)--Uniformed Services University of the Health Sciences, 2006 / Typescript (photocopy)

The purpose of this study was to describe the characteristics and findings of antimalarial drug efficacy studies conducted in Ethiopia and to use the findings to formulate recommendations for antimalarial drug efficacy monitoring and use of evidence to inform antimalarial treatment policy for the Ethiopian setting. This study reviewed 44 antimalarial efficacy studies conducted in Ethiopia from 1974 to 2011. The analysis of results indicated that chloroquine as the first-line antimalarial drug for the treatment of malaria due to Plasmodium falciparum had a 22% therapeutic failure in 1985. Chloroquine was replaced with sulfadoxine-pyrimethamine in 1998, more than 12 years later, when its therapeutic failure had reached 65%. Sulfadoxinepyrimethamine at the time of its introduction had a treatment failure of 7.7%; it was replaced after seven years in 2004 by artemether-lumefantrine; by then its treatment failure had reached 36%. The WHO recommends the replacement of a first-line antimalarial drug when more than 10% of treatment failure is reported. The replacement drug should have a therapeutic efficacy of more than 95%; while the change itself should be completed within two years. The prolonged delay to replace failing antimalarial drugs in Ethiopia seems to have been influenced mainly by the lack of systematic antimalarial drug efficacy data collection and pragmatic use of the data and evidence gathered.Almost eight years after its introduction, isolated studies show that the efficacy of artemether-lumefantrine has decreased from 99% in 2003 to around 96.3% in 2008. Though this decrease is not statistically significant (chi-square 1.5; P=0.22) and has not reached the threshold of 10%, it is plausible that its efficacy may drop further. This is mainly due to regulatory provisions in the country that allow marketing of oral artemisinin mono-therapies that are not recommended for malaria treatment, use of less effective antimalarial combination drugs in the neighboring countries and widespread drug quality problems. The situation calls for and this study recommends the establishment of stringent drug efficacy monitoring and early warning system and alignment of the antimalarial drug regulatory practices with recommendations of the WHO. / Health Studies / D. Litt. et Phil. (Health Studies)

Orientador: Fabio Trindade Maranhão Costa / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T23:10:56Z (GMT). No. of bitstreams: 1 Leite_JulianaAlmeida_D.pdf: 9218064 bytes, checksum: c5126692d8ce8a22660fbf8604dae7ef (MD5) Previous issue date: 2013 / Resumo: O resumo poderá ser visualizado no texto completo da tese digital / Abstract: The complete abstract is available with the full electronic document. / Doutorado / Imunologia / Doutora em Genética e Biologia Molecular

Ph.D. / Background: Most recent data have shown a slight reduction in the incidence of malaria in Nigeria. However, cases of malaria in children younger than five years of age have continued to escalate amidst ‘simple’ and ‘effective’ treatment options. The realisation of the Millennium Development Goals (MDGs) – to halve the burden of malaria by 2015 – is becoming increasingly unrealistic in Nigeria following the alarming rates of malaria in children. Apart from the ecological and environmental factors, socio-cultural and behavioural factors might be responsible for the staggering cases of malaria in children in local communities in Nigeria. It was against this background that a sociological study of health care service utilisation was conducted among caregivers of children with malaria. The study investigated the perceived threat of malaria; how the local understanding of malaria affects the recognition of signs and symptoms, perceived aetiology, treatment-seeking patterns and the use of insecticide treated nets (ITNs). The socio-generational changes in the healthcare seeking behaviour between young and older mothers as well as differences in the patterns of health care service utilisation between rural and urban subjects were also interrogated. Method: This study adopted a qualitative research design using complementary methods. A total of 40 semi-structured interviews, 20 in-depth interviews and four focus group discussions (FGDs) were conducted with caregivers and health workers. The respondents included young and older parents between the ages of 25 and 80 years whose children or wards below the age of five had manifested malaria symptoms at one time or another. A purposive sampling procedure was used to select sample for the study. The study was conducted in two selected rural areas; Okanle and Fajeromi; and one urban centre; Ilorin, Kwara State of Nigeria. Findings: The research indicated that the perceived aetiology, symptoms and treatment of malaria in children were largely influenced by the socio-cultural patterns of the communities studied. The study found that the first line of treatment for children with malaria in the communities of study was usually home treatment using traditional herbal medicines. The use of modern health care facilities is usually seen as the last resort. The traditional beliefs about causes of malaria, affordability and trust in herbal medicines, on the one hand, were found to be responsible for the widespread use of herbal medicines in the treatment of malaria in children. On the other hand, poor service delivery, lack of money, attitudes of medical personnel, mixed feelings about the efficacy of modern medicines and lack of trust in the community health centres were some factors found to be responsible for delays in seeking modern health care services when children have malaria. More importantly, the decision to seek treatment from either traditional or modern sources was largely influenced by the network of informal social interaction and social support at household and community levels. In addition, the study also found some changes in the patterns of health care seeking behaviour of young and older caregivers but generally found no differences in the patterns of health care seeking behaviour between rural and urban participants. Finally, the study found that the majority of the respondents were not aware of the effectiveness of the ITNs. Consequently, there was a high dependence on the use of traditional preventive measures which included a local leaf known as “ewe-efon” translated as “mosquito leaf”. Apart from the perceived corruption and mismanagement at the level of distribution of the ITNs, lack of appropriate knowledge about the effectiveness of the ITNs was discovered to be responsible for the widespread non-acceptance of the ITN in the prevention of malaria in children.

Magister Public Health - MPH / In Zambia, there had been a large scaling up of new interventions to control malaria since 2003, which included the distribution of rapid diagnostic tests (RDTs), used to immediately determine if someone with symptoms suggestive of malaria actually has malaria; training of health workers in the use of the RDTs; and the prescription of artemisinin-based combination therapy (ACT) to which the malaria parasite is sensitive, rather than the old treatment regime of chloroquine to which the malaria parasite had become resistant. The use of RDTs to confirm the presence of malaria before treating for it with ACT became known as the „test and treat‟ policy. Previously, since the 1960s, in malaria endemic areas such as Zambia, children presenting with fever (the commonest symptom of malaria) without any obvious other cause for the fever, were assumed to have malaria and were hence treated for it with chloroquine. This was known as "presumptive treatment" of malaria. The combination of "presumptive treatment" and the use of a single medication led to the development of high levels of resistance to chloroquine, to the extent that it is now no longer an effective treatment for malaria. Years after the introduction of the "test and treat" policy, it was still unclear to what extent it was being implemented, as there was initial reluctance by health workers to test all children presenting with fever for malaria and if they did test they may not have followed the management guidelines of treating those who test positive with ACT and further investigating those who test negative for the cause of the fever. It seemed that staff had gotten used to the "presumptive treatment" approach to malaria over almost 4 decades and hence were quite reluctant to abandon it. The conflicting guidelines for malaria treatment in children between IMCI and "test and treat‟ has promoted a paradox between presumptive treatment for malaria and "test and treat" approach as IMCI teaches health workers to treat febrile children presumptively for malaria whereas the "test and treat" approach requires them to first make a definitive diagnosis before treating. Hence although the "test and treat" approach was instituted to overcome the problems with presumptive treatment approach it now had to contend with the competing and contradictory influence of the IMCI approach. This study therefore aimed to assess what proportion of children aged five years and younger who presented with fever were managed via the "test and treat" guidelines and which factors were associated with this, in Lusaka District, Zambia. Methodology: A cross sectional analytical study design was used based on a review of medical records. A sample size of 800 medical records of children presenting with fever was selected from 10 out of the 23 health care facilities in Lusaka, using a multistage stratified random sampling technique. Four hundred records were sampled from 2008 records (five years after commencement of the "test and treat" policy) and 400 from 2011 records (eight years after commencement of the "test and treat" policy). Trained data collectors used a data extraction tool to transcribe demographic and clinical data from the medical records in a standardized manner. Data Analysis: Univariate descriptive statistics analysis was performed using measures of central tendency and measures of dispersion to analyze numerical (continuous) variables such as age, weight and body temperature; and using frequencies for categorical variables such as gender, area of residence, RDTs/microscopy malaria tests conducted, received ACT if RDT positive, presence of an ACT treatment chart on the health centre wall and availability of a weighing scale. To determine the relationship between variables, bivariate analysis via the prevalence ratio was conducted. Results: Just over half (55%) of all children with fever were tested for malaria in 2008 and this gratifyingly increased to (73%) in 2011. Overall, the proportion of children correctly and appropriately treated with ACT, which means that those who tested positive for malaria were given ACT, was 85% in 2008 but regrettably dropped to 72% in 2011. Although "presumptive treatment" decreased from 24% in 2008 to 11% in 2011, the proportion of children with fever not tested for malaria, and although not treated for malaria, but left without a definitive diagnosis of their fever being made, remained high but dropping (22% in 2008 and 16% in 2011). Similarly the proportion of children who tested negative for malaria but then did not undergo any further investigation also unfortunately remained very high and rising (57% in 2008 and 89% in 2011). A combination of the above poor clinical management practises resulted in only 38% of children with fever in 2008 and unfortunately dropping to only 33% in 2011 being correctly managed (tested for malaria via RDT or microscopy and treated with ACT if positive, while further investigated for the cause of fever if negative). On preparedness of the health facility to implement the "test and treat" policy, it was noted that only 4 out of 10 health facilities were at least minimally prepared to do so, but paradoxically on bivariate analysis those minimally prepared were less likely (PR 0.62; 95% CI 0.41-0.94) to correctly manage the patients in 2011 than those who were unprepared. A similar paradox occurred for those correctly treated with ACT after testing positive, with facilities which were minimally prepared being less likely to do so (PR 0.28; 95% CI 0.14-0.58) in 2011 than those facilities which were unprepared to implement the "test and treat" policy. However these associations were inconsistent over time, as the associations were not present in 2008. Similarly all other factors such as staff category (doctor, nurse, clinical officer) and type of presenting symptoms besides fever (anorexia, lethargy, pallor) assessed, were not consistently associated with testing for malaria in both 2008 and 2011. The same applied for the other two main outcome variables of 'treated with ACT after test positive for malaria' and 'correctly managed child with fever', in that there were no factors that showed a consistent association with them in both 2008 and 2011. Conclusion: Testing of children with fever for malaria is at a low level but rose between 2008 and 2011. Paradoxically the proportion of those diagnosed with malaria who were correctly treated with ACT dropped between 2008 and 2011, as did the proportion of children with fever who were correctly managed. No factors assessed in this study were found to be consistently associated in both 2008 and 2011 with either testing for malaria, or treating confirmed malaria cases with ACT, or managing patients with fever correctly. Recommendations: In order for health workers to correctly implement the "test and treat" policy, which involves a series of complex steps, they ought to be formally trained to do so, mentored and constructively supervised. Additionally health facilities should be adequately equipped to enable health workers to fully implement the policy. Further studies to assess factors associated with the correct management of malaria via the "test and treat" policy are warranted.

Please read the abstract in the section 00front of this document / Thesis (DPhil (Medical Immunology))--University of Pretoria, 2007. / Immunology / unrestricted

MSc (Chemistry) / Department of Chemistry / See the attached abstract below