Biomedical subjects

Michael P Alpers

Publications and source records attributed to Michael P Alpers.

At least 19 recordsLinked to original sources

PubMed2006

Rifampicin/Cotrimoxazole/Isoniazid versus mefloquine or quinine + sulfadoxine- pyrimethamine for malaria: a randomized trial.

OBJECTIVES: Previous studies of a fixed combination including cotrimoxazole, rifampicin, and isoniazid (Cotrifazid) showed efficacy against resistant strains of Plasmodium falciparum in animal models and in small-scale human studies. We conducted a multicentric noninferiority trial to assess the safety and efficacy of Cotrifazid against drug-resistant malaria in Papua New Guinea. DESIGN: The trial design was open-label, block-randomised, comparative, and multicentric. SETTING: The trial was conducted in four primary care health facilities, two in urban and two in rural areas of Madang and East Sepik Province, Papua New Guinea. PARTICIPANTS: Patients of all ages with recurrent uncomplicated malaria were included. INTERVENTIONS: Patients were randomly assigned to receive Cotrifazid, mefloquine, or the standard treatment of quinine with sulfadoxine-pyrimethamine (SP). OUTCOME MEASURES: Incidence of clinical and laboratory adverse events and rate of clinical and/or parasitological failure at day 14 were recorded. RESULTS: The safety analysis population included 123 patients assigned to Cotrifazid, 123 to mefloquine, and 123 to quinine + SP. The Cotrifazid group experienced lower overall incidence of adverse events than the other groups. Among the efficacy analysis population (72 Cotrifazid, 71 mefloquine, and 75 quinine + SP), clinical failure rate (symptoms and parasite load) on day 14 was equivalent for the three groups (0% for Cotrifazid and mefloquine; 1% for quinine + SP), but parasitological failure rate (P. falciparum asexual blood-stage) was higher for Cotrifazid than for mefloquine or quinine + SP (9% [PCR corrected 8%] versus 0% and 3%, respectively [p = 0.02]). CONCLUSION: Despite what appears to be short-term clinical equivalence, the notable parasitological failure at day 14 in both P. falciparum and P. vivax makes Cotrifazid in its current formulation and regimen a poor alternative combination therapy for malaria.

Journal Article↗

PubMed2006

Kuru in the 21st century--an acquired human prion disease with very long incubation periods.

BACKGROUND: Kuru provides the principal experience of epidemic human prion disease. Its incidence has steadily fallen after the abrupt cessation of its route of transmission (endocannibalism) in Papua New Guinea in the 1950s. The onset of variant Creutzfeldt-Jakob disease (vCJD), and the unknown prevalence of infection after the extensive dietary exposure to bovine spongiform encephalopathy (BSE) prions in the UK, has led to renewed interest in kuru. We investigated possible incubation periods, pathogenesis, and genetic susceptibility factors in kuru patients in Papua New Guinea. METHODS: We strengthened active kuru surveillance in 1996 with an expanded field team to investigate all suspected patients. Detailed histories of residence and exposure to mortuary feasts were obtained together with serial neurological examination, if possible. FINDINGS: We identified 11 patients with kuru from July, 1996, to June, 2004, all living in the South Fore. All patients were born before the cessation of cannibalism in the late 1950s. The minimum estimated incubation periods ranged from 34 to 41 years. However, likely incubation periods in men ranged from 39 to 56 years and could have been up to 7 years longer. PRNP analysis showed that most patients with kuru were heterozygous at polymorphic codon 129, a genotype associated with extended incubation periods and resistance to prion disease. INTERPRETATION: Incubation periods of infection with human prions can exceed 50 years. In human infection with BSE prions, species-barrier effects, which are characteristic of cross-species transmission, would be expected to further increase the mean and range of incubation periods, compared with recycling of prions within species. These data should inform attempts to model variant CJD epidemiology.

Aged↗

PubMed2006

Effect of the malaria vaccine Combination B on merozoite surface antigen 2 diversity.

Extensive genetic polymorphism is generally found in Plasmodium falciparum surface antigens. This poses a considerable obstacle to the development of a malaria vaccine. In order to assess possible effects of a polymorphic vaccine, we have analyzed the genetic diversity of parasites collected in the course of a phase 2b field trial of the blood stage vaccine Combination B in Papua New Guinea. The full-length 3D7 allele of the merozoite surface protein 2 (MSP2) was included in Combination B as one of three subunits. Vaccinees had a lower prevalence of parasites carrying a 3D7-type allele (corresponding to that in the vaccine) and selection appeared to favour the alternative FC27-type alleles resulting in a higher incidence of morbid episodes associated with FC27-type parasites. We sequenced MSP2 alleles detected in study participants after vaccination to identify breakthrough genotypes. Extensive genetic diversity of MSP2 was observed in both the repetitive and family-specific domains, but alleles occurring in vaccine recipients were no different from those found in placebo recipients. A phylogenetic analysis showed no clustering of 3D7-type breakthrough infections from vaccine recipients. The repeat unit present in the vaccine molecule occurred in a number of alleles from the trial area and was also observed in vaccinated individuals. Thus the anti-repeat immune response did not lead to elimination of parasites carrying the same repeat unit. We conclude that the conserved epitopes in the family-specific domain were the most important determinants of the vaccine effect against new 3D7-type infections and that the hypervariable domains were not subject to selective effects of the vaccine.

Animals↗

PubMed2005

The epidemiology of kuru in the period 1987 to 1995.

Kuru is an encephalopathy or neuro-degenerative disease found only in the Okapa District of the Eastern Highlands Province of Papua New Guinea. It is always fatal, with a subacute course, on average, of about 12 months from onset to death. In the 9-year period 1987 to 1995 there were 66 deaths from kuru, 17 males and 49 females. The number of deaths per year ranged from 3 to 12. All deaths occurred south of a line drawn through the centre of the kuru region perpendicular to the axis of social change. The mean age at death was 49 years, with a gradual increase in this age with time. The last patient aged in their 20s died in 1987 and the last in their 30s died in 1991. The period shows a waning epidemic, with dramatically fewer deaths than in the early years of epidemiological surveillance 30 years before. Nevertheless, the clinical features and duration of the disease were unchanged. Transmission of kuru stopped by 1960 and patients seen in the period 1987-1995 showed long incubation periods, which in 1995 would have been at least 35 years. The proportion of males was much higher than in the early years; because males were effectively exposed only in childhood their incubation periods were in many cases likely to be over 50 years. The work of the Kuru Surveillance Team in maintaining a rigorous surveillance of kuru epidemiology over this period is described.

Adult↗

PubMed2004

Benefits of routine immunizations on childhood survival in Tari, Southern Highlands Province, Papua New Guinea.

BACKGROUND: Non-specific beneficial as well as deleterious effects of childhood immunizations have been reported in areas of high mortality. This study aimed to determine the effects of diphtheria-tetanus-whole-cell-pertussis (DTP), BCG, hepatitis B, and measles vaccines on mortality in the highlands of Papua New Guinea (PNG). METHODS: Demographic events for children born in 1989-1994 who were under monthly demographic surveillance in Tari were recorded from birth until age 2 years, out-migration, death, or the end of the study period. Data on BCG, hepatitis B, DTP, measles and pneumococcal polysaccharide vaccination were collected monthly from clinic records. To allow for different characteristics of immunized and non-immunized children, analysis included conditioning on a propensity score for vaccination, adjusting for differences in children's background characteristics. RESULTS: In all, 101/3502 children (3%) who had at least one vaccine died between ages 29 days and 24 months were compared to 112/546 (21%) who had none. BCG was associated with lower mortality in the 1-5 month age group (hazard ratio [HR] = 0.17, 95% CI: 0.09, 0.34), measles vaccine with lower mortality at age 6-11 months (HR = 0.42, 95% CI: 0.17, 1.01), and pneumococcal polysaccharide vaccine with lower mortality at age 12-23 months (HR = 0.42, 95% CI: 0.19, 0.93). One or more doses of DTP was associated with lower overall mortality (HR = 0.27, 95% CI: 0.16, 0.44), particularly in the 1-5 month age group (HR = 0.19, 95% CI: 0.10, 0.34), and also in those who had had prior BCG (HR = 0.45, 95% CI: 0.22, 0.91). CONCLUSION: Routine immunizations are effective in reducing overall mortality in young children in an area of high mortality. In particular, DTP, whether considered separately or in addition to BCG, was associated with a lowering of overall mortality, in contrast to findings reported from Guinea-Bissau.

BCG Vaccine↗

PubMed2004

Disposition of artesunate and dihydroartemisinin after administration of artesunate suppositories in children from Papua New Guinea with uncomplicated malaria.

A detailed pharmacokinetic analysis was performed with 47 children from Papua New Guinea with uncomplicated falciparum or vivax malaria treated with artesunate (ARTS) suppositories (Rectocaps) given in two doses of approximately 13 mg/kg of body weight 12 h apart. Following an intensive sampling protocol, samples were assayed for ARTS and its primary active metabolite, dihydroartemisinin (DHA), by liquid chromatography-mass spectrometry. A population pharmacokinetic model was developed to describe the data. Following administration of the first dose, the mean maximal concentrations of ARTS and DHA were 1,085 nmol/liter at 0.9 h and 2,525 nmol/liter at 2.3 h, respectively. The absorption half-life for ARTS was 2.3 h, and the conversion half-life (ARTS to DHA) was 0.27 h, while the elimination half-life of DHA was 0.71 h. The mean common volumes of distribution for ARTS and DHA relative to bioavailability were 42.8 and 2.04 liters/kg, respectively, and the mean clearance values relative to bioavailability were 6 and 2.2 liters/h/kg for ARTS and DHA, respectively. Substantial interpatient variability was observed, and the bioavailability of the second dose relative to that of the first was estimated to be 0.72. The covariates age, sex, and alpha-thalassemia genotype were not influential in the pharmacokinetic model development; but the inclusion of weight as a covariate significantly improved the performance of the model. An ARTS suppositories dose of 10 of 20 mg/kg is appropriate for use in children with uncomplicated malaria.

Aging↗

PubMed2004

Strain-specific humoral response to a polymorphic malaria vaccine.

The 3D7 form of the merozoite surface protein 2 (MSP2) of Plasmodium falciparum was one of three subunits of the malaria vaccine Combination B that were tested in a phase I/IIb double-blind randomized placebo-controlled trial, which was undertaken with 120 Papua New Guinean children of 5 to 9 years of age. Because only one variant of the highly polymorphic MSP2 was used for vaccination, we examined whether the elicited response was directed against conserved or strain-specific epitopes. Postvaccination (week 12) titers of antibody against recombinantly expressed individual domains of MSP2 were measured by enzyme-linked immunosorbent assay and compared to baseline values. We found that vaccination with the 3D7 form of MSP2 induced a significant strain-specific humoral response directed against the repetitive and semiconserved family-specific part. The conserved N- and C-terminal domains were not immunogenic. Titers of antibody against the alternate FC27 family-specific domain showed a tendency to increase in vaccinated children, but there was no increase in antibodies against FC27-type 32-mer repeats. These results indicate that vaccination with one MSP2 variant mainly induced a strain-specific response, which can explain the selective effect of vaccination with combination B on the genotypes of breakthrough parasites. These findings support the inclusion of both family-specific domains (3D7 and FC27) in an improved vaccine formulation.

Amino Acid Sequence↗

PubMed2004

Polymerase chain reaction diagnosis and the changing pattern of vector ecology and malaria transmission dynamics in papua new Guinea.

The ecology and behavior of most of the 11 known members of the Anopheles punctulatus group remain unresolved and only the morphologic species An. farauti, An. koliensis, and An. punctulatus are known as vectors of malaria in Papua New Guinea. Of 1,582 mosquitoes examined morphologically, 737 were identified as An. farauti s.l., 719 as An. koliensis, and 126 as An. punctulatus. All specimens identified morphologically as An. punctulatus were shown to be An. punctulatus by polymerase chain reaction-restriction fragment length polymorphism analysis, but the An. farauti and An. koliensis morphotypes consisted of three or more species including An. farauti s.s., An. farauti No. 2, and An. farauti No. 4. The biting cycles and role in malaria transmission of some of these species are described here for the first time. We also show evidence that An. koliensis could be a sub-complex of two or more species. The epidemiologic implications of our findings are discussed.

Animals↗

PubMed2003

Safety and immunogenicity of a three-component blood-stage malaria vaccine (MSP1, MSP2, RESA) against Plasmodium falciparum in Papua New Guinean children.

Combination B is a malaria vaccine that comprises recombinant Plasmodium falciparum (P. falciparum) blood-stage proteins MSP1, MSP2 and RESA, formulated with the adjuvant Montanide ISA 720. A phase I-IIb double-blind randomised placebo-controlled trial was undertaken in 120 children aged 5-9 years. Subjects were randomised in four groups: (i) No sulphadoxine-pyrimethamine (SP)+vaccine, (ii) No SP+placebo, (iii) SP+vaccine, (iv) SP+placebo. 15 microg of each protein were given in the thigh, at both first and second injection (4 weeks apart). The placebo was adjuvant emulsified with saline. No serious or severe AEs occurred. Moderate AEs were seen in 3% of the vaccine and 3% of the placebo recipients after first injection and in 12 and 10% after second injection. The vaccine induced significant antibody responses to all three antigens but triggered an IFN-gamma response to MSP1 only. At Week 12, the IFN-gamma response to MSP1 was substantially higher in the vaccine group where No SP had been given. Combination B proved to be safe and immunogenic in children aged 5-9 years. Vaccine immunogenicity was neither impaired by circulating parasites nor increased after pre-treatment with SP and pre-treatment is not advisable in future trials of malaria vaccines, at least for those including blood-stage antigens.

Animals↗

PubMed2003

Spatial variation of Anopheles-transmitted Wuchereria bancrofti and Plasmodium falciparum infection densities in Papua New Guinea.

The spatial variation of Wuchereria bancrofti and Plasmodium falciparum infection densities was measured in a rural area of Papua New Guinea where they share anopheline vectors. The spatial correlation of W. bancrofti was found to reduce by half over an estimated distance of 1.7 km, much smaller than the 50 km grid used by the World Health Organization rapid mapping method. For P. falciparum, negligible spatial correlation was found. After mass treatment with anti-filarial drugs, there was negligible correlation between the changes in the densities of the two parasites.

Journal Article↗

PubMed2003

Studies of maternal immunisation with pneumococcal polysaccharide vaccine in Papua New Guinea.

In two studies, pneumococcal polysaccharide (Pnc PS) vaccine was given to more than 400 pregnant Papua New Guinean women. No deleterious effects were found. The vaccine prevented acute lower respiratory infection (ALRI) among offspring in utero or aged 1-17 months at the time of maternal immunisation, suggesting protection through breast feeding. Serum IgG antibody titres were higher in vaccinated than unvaccinated groups for 2-4 months after delivery and no immune suppression, evaluated by the response to subsequent Pnc PS vaccination, was detected. Breast milk IgA to four serotypes was 1.1-1.8 times higher in immunised than unimmunised women for 6 months postpartum. Given results from several developing countries, large-scale safety and efficacy trials are now justified. Postpartum maternal immunisation is another intervention under consideration.

Adult↗

PubMed2003

The malaria vaccine development program in Papua New Guinea.

Through a collaborative project led by the Papua New Guinea Institute of Medical Research (PNGIMR), Papua New Guinea has a significant role in the global effort to develop a malaria vaccine, ensuring that the malaria patterns in Asia and the Pacific region are considered in vaccine development strategies. Some of the major perspectives and achievements of the program are discussed here, one of the most successful being the trial of Combination B, a vaccine comprising three asexual blood-stage proteins [merozoite surface protein (MSP)1, MSP2 and ring-infected erythrocyte surface antigen (RESA)], which led to a considerable reduction of parasite density in the immunized children.

Animals↗

PubMed2003

The buttressing coalition of the PNGIMR: an example of international collaborative research.

Good partnerships are based on mutual benefit. This also applies to international partnerships in medical research. The Papua New Guinea Institute of Medical Research (PNGIMR) has had many successful research collaborations, from which an interactive coalition has been built that is committed to supporting the PNGIMR without jeopardizing its integrity. This coalition also involves policy-makers from the Department of Health, teachers at the Medical School of Papua New Guinea and the Medical Research Advisory Committee of PNG. The PNGIMR's Buttressing Coalition supports research and training, but also assists the process of transferring research results into policy. The concept of "buttressing" is explored and the activities of the Buttressing Coalition are briefly described here. The idea of the Buttressing Coalition is a response from the international medical research community to globalization, and could be applied elsewhere, following the model developed in PNG.

Australia↗

PubMed2003

Clinical presentation of subacute sclerosing panencephalitis in Papua New Guinea.

Eighty-three children presented at Goroka Base Hospital in the Eastern Highlands Province (EHP) of Papua New Guinea over a period of 3 years and 9 months between February 1997 and November 2000 were confirmed to have subacute sclerosing panencephalitis (SSPE). Confirmation of the diagnosis was based on the demonstration of high titres of measles antibodies in the cerebrospinal fluid and/or serum in association with clinical features supportive of SSPE, including characteristic electroencephalographic changes and amplification of measles virus genome by reverse transcriptase polymerase chain reaction in some cases. The mean cerebrospinal fluid and serum enzyme immunoassay antibody levels among the SSPE patients were 38 250 and 860 580, respectively. The mean age of onset of SSPE was 7.9 +/- 2.6 years and ranged between 2 and 14 years. The overall male to female ratio was 1.2:1 and 1.4:1 for EHP.

Adolescent↗

PubMed2003

Safety and therapeutic efficacy of artesunate suppositories for treatment of malaria in children in Papua New Guinea.

BACKGROUND: Although suppositories of artemisinin derivatives may be a valuable option for treatment of malaria in children when circumstances prevent oral and parenteral therapy, few confirmatory data have been published. METHODS: We assessed the safety and efficacy of rectal artesunate in 47 children ages 5 to 10 years with uncomplicated malaria acquired in a hyperendemic area of Papua New Guinea. Thirty were symptomatic and had Plasmodium falciparum parasitemia >2000/microl (Group 1), 12 had and either a parasitemia <2000/microl or minimal/no symptoms (Group 2) and 5 had Plasmodium vivax (Group 3). Each child received rectal artesunate 10 to 15 mg/kg at 0 and 12 h. After monitoring for 24 h, chloroquine plus sulfadoxine/pyrimethamine was given, and the patient discharged. RESULTS: Artesunate suppositories were well-tolerated. After 24 h only one child (from Group 1) had persistent parasitemia, and only one (from Group 3) had not defervesced. These two children received intramuscular quinine and recovered uneventfully. Three Group 2 children redeveloped fever and tachycardia at 24 h, but each responded to simple supportive measures and remained aparasitemic. CONCLUSIONS: Intrarectal artesunate is safe, effective initial treatment for uncomplicated malaria in children. A transient fever spike can sometimes occur after parasite clearance. We recommend that children with uncomplicated malaria receive two doses of > or =10 mg/kg rectal artesunate within the first 24 h.

Animals↗

PubMed2002

Mass treatment to eliminate filariasis in Papua New Guinea.

BACKGROUND: The global initiative to eradicate bancroftian filariasis currently relies on mass treatment with four to six annual doses of antifilarial drugs. The goal is to reduce the reservoir of microfilariae in the blood to a level that is insufficient to maintain transmission by the mosquito vector. METHODS: In nearly 2500 residents of Papua New Guinea, we prospectively assessed the effects of four annual treatments with a single dose of diethylcarbamazine plus ivermectin or diethylcarbamazine alone on the incidence of microfilariae-positive infections, the severity of lymphatic disease, and the rate of transmission of Wuchereria bancrofti by mosquitoes. Random assignment to treatment regimens was carried out according to the village of residence, and villages were categorized as having moderate or high rates of transmission. RESULTS: The four annual treatments with either drug regimen were taken by 77 to 86 percent of the members of the population who were at least five years old; treatments were well tolerated. The proportion with microfilariae-positive infections decreased by 86 to 98 percent, with a greater reduction in areas with a moderate rate of transmission than in those with a high rate. The respective aggregate frequencies of hydrocele and leg lymphedema were 15 percent and 5 percent before the trial began, and 5 percent (P<0.001) and 4 percent (P=0.04) after five years. Hydrocele and leg lymphedema were eliminated in 87 percent and 69 percent, respectively, of those who had these conditions at the outset. The rate of transmission by mosquitoes decreased substantially, and new microfilariae-positive infections in children were almost completely prevented over the five-year study period. CONCLUSIONS: Annual mass treatment with drugs such as diethylcarbamazine can virtually eliminate the reservoir of microfilariae and greatly reduce the frequency of clinical lymphatic abnormalities due to bancroftian filariasis. Eradication may be possible in areas with moderate rates of transmission, but longer periods of treatment or additional control measures may be necessary in areas with high rates of transmission.

Adolescent↗

PubMed2002

Restricted polymorphisms of the mannose-binding lectin gene in a population of Papua New Guinea.

The human mannose-binding lectin (MBL) is an important protein of the innate immune system. MBL is able to eliminate potential pathogens by activating the complement cascade or by opsonisation. We investigated the gene and promoter region of MBL in a population from Papua New Guinea infected with Plasmodium falciparum parasites and measured the appropriate serum concentrations of these individuals. Their serum levels of MBL, detected by ELISA, showed a wide range with concentrations between 632 and 7325 microg/l MBL. A known polymorphism in exon 1 at codon 54 causing an amino acid exchange from Gly to Asp occurred with a low frequency of 3%. Additional to the previously reported polymorphisms in the gene and promoter region of MBL, two novel polymorphic sites were found in the promoter region. One site was in the untranslated region of the MBL gene at position +1 (G-->A, termed R/S), and the second was located upstream of the gene at position -4 (G-->A, termed T/U).

5' Untranslated Regions↗

PubMed2002

Maternal immunization with pneumococcal polysaccharide vaccine in the highlands of Papua New Guinea.

In Tari, Southern Highlands Province (SHP), Papua New Guinea (PNG), pneumococcal polysaccharide (Pnc PS) vaccine was offered to women at 28-38 weeks gestation. Blood samples were collected for measurement of pneumococcal antibody titres prior to immunization, from mother and cord at delivery and from their children at ages 1-3 and 4-6 months; samples were also collected in a subset of children before and 1 month after Pnc PS vaccine was given at age 8-9 months. Serum was collected from unimmunized women and their children at delivery and from children of unimmunized women at the same ages in infancy. There were no differences in neonatal or post-neonatal mortality rates or congenital abnormalities in the children of 235 immunized and 202 unimmunized women. There was a significant increase in antibody titres to pneumococcal serotypes 5, 14 and 23F in immunized women but not for serotype 7F. Geometric mean titres (GMTs) of antibodies for serotypes 5 and 23F were significantly higher in children of immunized women than in the unimmunized group up to age 2 months and for serotype 14 significantly higher to age 4 months. Maternal immunization did not significantly affect the children's capacity to make antibody responses to immunization with Pnc PS vaccine in infancy. The findings of this study and those in several other developing countries provide support for the concept of Pnc PS maternal immunization and justify the planning of large-scale efficacy trials.

Adult↗