Antimalarial Drug Evaluations: Namru-2 And Indonesian Partnership

Meningkatnya insiden malaria di beberapa daerah tertentu terutama di Indonesia Bagian Timur disebabkan antara lain : P. falciparum telah resisten terhadap beberapa obat antimalaria, ditemukannya P. vivax resisten klorokuin, dan belum tersedianya vaksin yang efektif. Sehubungan dengan hal tersebut, dilakukanlah evaluasi obat antimalaria yang perlu dipertimbangkan dalam peningkatan pelaksanaan program. Obat antimalaria meflokuin, halofantrin dan beberapa derivat qinghaosu (artesunat dan artemeter) telah diuji coba klinik di Indonesia, dan memberikan efikasi yang cukup baik walaupun perlu dipertimbangkan kemungkinan efek samping dan resistensi atau rekrudesensi yang mungkin terjadi serta harganya yang relatif masih mahal. Obat antimalaria baru yang direncanakan akan diuji coba klinik adalah azithromycin, derivat primaquine WR 238605, atovaquone dan derivat qinghaosu lain. Dasar pengembangan pengobatan malaria adalah sebagai berikut: Meningkatkan atau memperbaiki efikasi pengobatan malaria tanpa komplikasi yaitu dengan mengembangkan kombinasi atau regimen obat antimalaria yang tersedia di Indonesia (klorokuin dan tetrasiklin/doksisiklin) atau dengan mempersiapkan obat antimalaria baru (derivat qinghaosu, atovaquone, azithromycin dan WR 238605).Mencari obat antimalaria baru alternatif yang efektif sebagai obat penyelamat untuk pengobatan malaria dengan komplikasi. Dengan melakukan evaluasi obat antimalaria ini, akan didapat data efikasi dan keamanan yang dapat membantu Departemen Kesehatan untuk menentukan obat pilihan di Indonesia. Selain itu juga dapat ikut membantu menanggulangi masalah malaria di dunia

Epidemic Malaria Among Transmigrants in Irian Jaya

Malaria merupakan masalah kesehatan yang penting untuk masyarakat transmigrasi di daerah endemisitas malaria tinggi seperti Irian Jaya. Di Arso, epidemi malaria timbul setelah dua sampai enam bulan sesudah tibanya transmigran baru. Dalam tiga bulan angka parasitemia bisa mencapai 70% dan hampir 10% dari transmigran mendapat malaria berat yang membutuhkan rujukan ke rumah sakit dalam enam bulan p< rtama. Usaha penanggulangan malaria di daerah seperti Arso menghadapi berbagai tantangan dan hambatan karena tingginya derajat resistensi parasit terhadap klorokuin, fasilitas dan kemampuan untuk diagnostik yang terbatas, sulitnya pengendalian vektor (An. punctulatus group) dan tidak adanya strategi untuk menghilangkan sumber infeksi yang asimptomatik. Berbagai USAha yang dapat mengurangi risiko epidemi malaria di daerah transmigrasi Irian Jaya ialah antara lain pemberian profilaksis selama tiga bulan (selain klorokuin perlu dipertimbangkan pemberian primakuin bagi transmigran yang tidak hamil dan tidak menderita defisiensi G-6-PD), peningkatan fasilitas diagnostik dan pengobatan/termasuk rujukan untuk kasus malaria berat), pemakaian kelambu; penemuan kasus aktif untuk menghilangkan gametocytemia yang asimptomatik (selama enam bulan) serta penyuluhan dan partisipasi masyarakat dalam pemberantasan malaria (termasuk pembinaan kader kesehatan). Untuk melaksanakan kegiatan tersebut di atas perlu disediakan tenaga dan sumber dana yang khusus

Opportunities For Evaluating Malaria Vaccines In Indonesia

Di Indonesia, khususnya di Irian Jaya dan daerah malaria tinggi lainnya terdapat kesempatan yang sangat baik untuk mengevaluasi vaksin malaria. Hal ini antara lain disebabkan tersedianya data epidemiologi termasuk insidens, risiko malaria yang tinggi dan merata pada berbagai kelompok umur, jenis kelamin dan pekerjaan, adanya kelompok masyarakat yang sesuai untuk penelitian (transmigran dan angkatan bersenjata), lokasi desa yang memungkinkan randomisasi serta tersedianya fasilitas laboratorium di dekat daerah penelitian. Pemberantasan malaria dengan vaksinasi diharapkan akan menjadi fokus dari penelitian kesehatan menjelang akhir abad ke-20. Indonesia yang terdiri dari berbagai pulau memungkinkan konsolidasi pemberantasan malaria secara bertahap. Pengalaman yang diperoleh dengan pemberantasan malaria di suatu pulau akan sangat bermanfaat untuk menghadapi masalah yang lebih berat yakni malaria di daratan luas seperti Afrika atau daratan Asia Tenggara

Protection of Rhesus Monkeys by a DNA Prime/Poxvirus Boost Malaria Vaccine Depends on Optimal DNA Priming and Inclusion of Blood Stage Antigens

(Pk) malaria. This is a multi-stage vaccine that includes two pre-erythrocytic antigens, PkCSP and PkSSP2(TRAP), and two erythrocytic antigens, PkAMA-1 and PkMSP-1(42kD). The present study reports three further experiments where we investigate the effects of DNA dose, timing, and formulation. We also compare vaccines utilizing only the pre-erythrocytic antigens with the four antigen vaccine.In three experiments, rhesus monkeys were immunized with malaria vaccines using DNA plasmid injections followed by boosting with poxvirus vaccine. A variety of parameters were tested, including formulation of DNA on poly-lactic co-glycolide (PLG) particles, varying the number of DNA injections and the amount of DNA, varying the interval between the last DNA injection to the poxvirus boost from 7 to 21 weeks, and using vaccines with from one to four malaria antigens. Monkeys were challenged with Pk sporozoites given iv 2 to 4 weeks after the poxvirus injection, and parasitemia was measured by daily Giemsa stained blood films. Immune responses in venous blood samples taken after each vaccine injection were measured by ELIspot production of interferon-γ, and by ELISA.1) the number of DNA injections, the formulation of the DNA plasmids, and the interval between the last DNA injection and the poxvirus injection are critical to vaccine efficacy. However, the total dose used for DNA priming is not as important; 2) the blood stage antigens PkAMA-1 and PkMSP-1 were able to protect against high parasitemias as part of a genetic vaccine where antigen folding is not well defined; 3) immunization with PkSSP2 DNA inhibited immune responses to PkCSP DNA even when vaccinations were given into separate legs; and 4) in a counter-intuitive result, higher interferon-γ ELIspot responses to the PkCSP antigen correlated with earlier appearance of parasites in the blood, despite the fact that PkCSP vaccines had a protective effect

Clinical Laboratory Parameters Among Adult Males During a Primaquine Chemoprophylaxis Trial in Irian Jaya, Indonesia

Primakuin yang digunakan sebagai profilaksis malaria terbukti efektif dan diterima dengan baik oleh tubuh manusia yang normal terhadap aktivitas enzim 6 glukosa-6 fosfat dehidrogenase (G-6PD). Pemeriksaan laboratoris klinik adalah bagian dari uji coba secara acak dengan kontrol plasebo dalam rangka mengevaluasi penggunaan primakuin sebagai profilaksis pada penduduk transmigran yang tidak kebal di Irian Jaya. Penelitian ini dilakukan terhadap 129 pria Jawa dewasa yang normal G-6PDnya. Pemeriksaan hematologi, fungsi hati dan ginjal, dan pemeriksaan limfosit dilakukan berulang kali selama waktu penelitian profilaksis dilakukan untuk menjamin keamanan dari sukarelawan tersebut dan mengawasi Perubahan yang mungkin terjadi akibat obat profilaksis. Seperti yang diperkirakan, pengguna primakuin tidak menunjukkan gejala peningkatan methemoglobin yang kembali dalam batas normal setelah 7 hari pemberian dosis terakhir. Pada akhir penelitian (12 bulan profilaksis) nilai hematologi, fungsi hati dan ginjal, dan nilai limfosit dari kelompok primakuin sebanding dengan kelompok plasebo, dan berada dalam batas nilai normal untuk orang Indonesia.Hasil penelitian ini memberikan masukan adanya keluhan fisik yang sedikit dari sukarelawan pengguna profilaksis primakuin. Untuk membuktikan hasil penelitian ini dan mempersiapkan penggunaan secara umum primakuin untuk profilaksis malaria, perlu dilakukan uji coba lebih lanjut keamanan primakuin. Di Indonesia, primakuin tidak digunakan sebagai profilaksis dan laporan hasil penelitian ini hendaknya tidak ditafsirkan sebagai laporan keamanan dari primakuin

Identification and localization of minimal MHC-restricted CD8+ T cell epitopes within the Plasmodium falciparum AMA1 protein

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it>apical membrane antigen-1 (AMA1) is a leading malaria vaccine candidate antigen that is expressed by sporozoite, liver and blood stage parasites. Since CD8+ T cell responses have been implicated in protection against pre-erythrocytic stage malaria, this study was designed to identify MHC class I-restricted epitopes within AMA1.</p> <p>Methods</p> <p>A recombinant adenovirus serotype 5 vector expressing <it>P. falciparum </it>AMA1 was highly immunogenic when administered to healthy, malaria-naive adult volunteers as determined by IFN-γ ELISpot responses to peptide pools containing overlapping 15-mer peptides spanning full-length AMA1. Computerized algorithms (NetMHC software) were used to predict minimal MHC-restricted 8-10-mer epitope sequences within AMA1 15-mer peptides active in ELISpot. A subset of epitopes was synthesized and tested for induction of CD8+ T cell IFN-γ responses by ELISpot depletion and ICS assays. A 3-dimensional model combining Domains I + II of <it>P. falciparum </it>AMA1 and Domain III of <it>P. vivax </it>AMA1 was used to map these epitopes.</p> <p>Results</p> <p>Fourteen 8-10-mer epitopes were predicted to bind to HLA supertypes A01 (3 epitopes), A02 (4 epitopes), B08 (2 epitopes) and B44 (5 epitopes). Nine of the 14 predicted epitopes were recognized in ELISpot or ELISpot and ICS assays by one or more volunteers. Depletion of T cell subsets confirmed that these epitopes were CD8+ T cell-dependent. A mixture of the 14 minimal epitopes was capable of recalling CD8+ T cell IFN-γ responses from PBMC of immunized volunteers. Thirteen of the 14 predicted epitopes were polymorphic and the majority localized to the more conserved front surface of the AMA1 model structure.</p> <p>Conclusions</p> <p>This study predicted 14 and confirmed nine MHC class I-restricted CD8+ T cell epitopes on AMA1 recognized in the context of seven HLA alleles. These HLA alleles belong to four HLA supertypes that have a phenotypic frequency between 23% - 100% in different human populations.</p

Sterile Protection against Plasmodium knowlesi in Rhesus Monkeys from a Malaria Vaccine: Comparison of Heterologous Prime Boost Strategies

Using newer vaccine platforms which have been effective against malaria in rodent models, we tested five immunization regimens against Plasmodium knowlesi in rhesus monkeys. All vaccines included the same four P. knowlesi antigens: the pre-erythrocytic antigens CSP, SSP2, and erythrocytic antigens AMA1, MSP1. We used four vaccine platforms for prime or boost vaccinations: plasmids (DNA), alphavirus replicons (VRP), attenuated adenovirus serotype 5 (Ad), or attenuated poxvirus (Pox). These four platforms combined to produce five different prime/boost vaccine regimens: Pox alone, VRP/Pox, VRP/Ad, Ad/Pox, and DNA/Pox. Five rhesus monkeys were immunized with each regimen, and five Control monkeys received a mock vaccination. The time to complete vaccinations was 420 days. All monkeys were challenged twice with 100 P. knowlesi sporozoites given IV. The first challenge was given 12 days after the last vaccination, and the monkeys receiving the DNA/Pox vaccine were the best protected, with 3/5 monkeys sterilely protected and 1/5 monkeys that self-cured its parasitemia. There was no protection in monkeys that received Pox malaria vaccine alone without previous priming. The second sporozoite challenge was given 4 months after the first. All 4 monkeys that were protected in the first challenge developed malaria in the second challenge. DNA, VRP and Ad5 vaccines all primed monkeys for strong immune responses after the Pox boost. We discuss the high level but short duration of protection in this experiment and the possible benefits of the long interval between prime and boost

Prospective longitudinal associations between persistent sleep problems in childhood and anxiety and depression disorders in adulthood

The objective of this study was to examine the associations between persistent childhood sleep problems and adulthood anxiety and depression. Parents of 943 children (52% male) participating in the Dunedin Multidisciplinary Health and Development Study provided information on their children’s sleep and internalizing problems at ages 5, 7, and 9 years. When the participants were 21 and 26 years, adult anxiety and depression were diagnosed using a standardized diagnostic interview. After controlling for childhood internalizing problems, sex, and socioeconomic status, persistent sleep problems in childhood predicted adulthood anxiety disorders (OR (95% CI) = 1.60 (1.05– 2.45), p = .030) but not depressive disorders (OR (95% CI) = .99 (.63–1.56), p = .959). Persistent sleep problems in childhood may be an early risk indicator of anxiety in adulthood

Identification of two new protective pre-erythrocytic malaria vaccine antigen candidates

<p>Abstract</p> <p>Background</p> <p>Despite years of effort, a licensed malaria vaccine is not yet available. One of the obstacles facing the development of a malaria vaccine is the extensive heterogeneity of many of the current malaria vaccine antigens. To counteract this antigenic diversity, an effective malaria vaccine may need to elicit an immune response against multiple malaria antigens, thereby limiting the negative impact of variability in any one antigen. Since most of the malaria vaccine antigens that have been evaluated in people have not elicited a protective immune response, there is a need to identify additional protective antigens. In this study, the efficacy of three pre-erythrocytic stage malaria antigens was evaluated in a <it>Plasmodium yoelii</it>/mouse protection model.</p> <p>Methods</p> <p>Mice were immunized with plasmid DNA and vaccinia virus vectors that expressed one, two or all three <it>P. yoelii </it>vaccine antigens. The immunized mice were challenged with 300 <it>P. yoelii </it>sporozoites and evaluated for subsequent infection.</p> <p>Results</p> <p>Vaccines that expressed any one of the three antigens did not protect a high percentage of mice against a <it>P. yoelii </it>challenge. However, vaccines that expressed all three antigens protected a higher percentage of mice than a vaccine that expressed PyCSP, the most efficacious malaria vaccine antigen. Dissection of the multi-antigen vaccine indicated that protection was primarily associated with two of the three <it>P. yoelii </it>antigens. The protection elicited by a vaccine expressing these two antigens exceeded the sum of the protection elicited by the single antigen vaccines, suggesting a potential synergistic interaction.</p> <p>Conclusions</p> <p>This work identifies two promising malaria vaccine antigen candidates and suggests that a multi-antigen vaccine may be more efficacious than a single antigen vaccine.</p