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Background In 2009, the Papua New Guinea (PNG) Department of Health adopted artemether–lumefantrine (AL) and dihydroartemisinin–piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy. Methods Between June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined. Results A total of 274 P. falciparum and 70 P. vivax cases were enrolled. The day-42 PCR-corrected ACPR for P. falciparum was 98.1% (104/106) for AL and 100% (135/135) for DHA-PPQ. The day-42 PCR-corrected ACPR for P. vivax was 79.0% (15/19) for AL and 92.3% (36/39) for DHA-PPQ. Day 3 parasite clearance of P. falciparum was 99.2% with AL and 100% with DHA-PPQ. In vitro testing of 96 samples revealed low susceptibility to chloroquine (34% of samples above IC50 threshold) but not to lumefantrine (0%). Molecular markers assessed in a sub-set of the study population indicated high rates of chloroquine resistance in P. falciparum (pfcrt SVMNT: 94.2%, n = 104) and in P. vivax (pvmdr1 Y976F: 64.8%, n = 54). Conclusions AL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG. Electronic supplementary material The online version of this article (10.1186/s12936-018-2494-z) contains supplementary material, which is available to authorized users.

BACKGROUND: Drug resistance remains a major obstacle to malaria treatment and control. It can arise and spread rapidly, and vary substantially even at sub-national level. National malaria programmes require cost-effective and timely ways of characterizing drug-resistance at multiple sites within their countries. METHODS: An improved multiplexed post-PCR ligase detection reaction-fluorescent microsphere assay (LDR-FMA) was used to simultaneously determine the presence of mutations in chloroquine resistance transporter (crt), multidrug resistance 1 (mdr1), dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes in Plasmodium falciparum (n = 727) and Plasmodium vivax (n = 574) isolates collected in 2006 from cross-sectional community population surveys in two geographically distinct regions (Madang and East Sepik) of Papua New Guinea (PNG) where strong regional differences in in vivo aminoquinoline and antifolate therapeutic efficacy had previously been observed. Data were compared to those of a follow-up survey conducted in 2010. RESULTS: Despite some very low parasite densities, the assay successfully amplified all P. falciparum and P. vivax loci in 77 and 69 % of samples, respectively. In 2006, prevalences of pfdhfr (59R-108 N) double mutation/wild type pfdhps haplotype, pfcrt SVMNT haplotype (72S-76T double mutation), and 86Y pfmdr1 mutation all exceeded 90 %. For P. vivax, 65 % carried at least two pvdhfr mutations, 97 % the 647P pvdhps mutation and 54 % the 976F pvmdr1 mutation. Prevalence of mutant haplotypes was higher in Madang than East Sepik for pfcrt SVMNT (97.4 vs 83.3 %, p = 0.001), pfdhfr (59R-108 N) (100 vs 90.6 %, p = 0.001), pvdhfr haplotypes (75.8 vs 47.6 %, p = 0.001) and pvmdr1 976F (71.2 vs 26.2 %, p < 0.001). Data from a subsequent Madang survey in 2010 showed that the prevalence of pfdhps mutations increased significantly from 30 % (p < 0.001) as did the prevalence of pvdhfr mutant haplotypes (from 75.8 to 97.4 %, p = 0.012). CONCLUSIONS: This LDR-FMA multiplex platform shows feasibility for low-cost, high-throughput, rapid characterization of a broad range of drug-resistance markers in low parasitaemia infections. Significant geographical differences in mutation prevalence correlate with previous genotyping surveys and in vivo trials and may reflect variable drug pressure and differences in health-care access in these two PNG populations.

A Phase I safety and immunogenicity study with a three-component blood-stage malaria vaccine was conducted in adult male subjects living in an endemic area of Papua New Guinea. The preparations were recombinant proteins which corresponded to parts of the two merozoite surface proteins of Plasmodium falciparum (MSP1 and 2), and of the ring-infected erythrocyte surface antigen (RESA). The three proteins were emulsified with the adjuvant Montanide ISA720. Ten subjects were injected twice (four weeks apart) with the vaccine formulation and two with the adjuvant alone. Mild pain at the site of injection was reported by about half of the subjects but no systemic reaction related to the formulation occurred. There was a sharp rise in geometric mean stimulation index after the second dose compared to baseline for MSP1 and RESA, while the rise was small for MSP2. Geometric mean antibody titres increased for MSP1 during the study, whereas they hardly changed for MSP2 and RESA. The vaccine formulation was safe when used in an already immune population. The vaccine induced good cellular responses, especially for MSP1 and RESA. Boosting of humoral responses was weak, probably because of high baseline antibody levels.

Malaria mortality and morbidity were studied in a rural population of 4000 in the Wosera area, East Sepik Province, Papua New Guinea. Malaria accounted for 4.9% of the 162 deaths investigated by verbal autopsy and for 12.2% of the 49 deaths assessed through medical records. Malaria was the first cause of death in children aged 0.5-4 years. Of the 7795 subjects interviewed and bled during six cross-sectional community-based surveys, children of 1-4 years had the highest malaria-related morbidity. In this age group, point prevalences of fever, fever associated with parasitaemia, and fever plus Plasmodium falciparum (Pf) parasitaemiaor = 10,000 parasites/microliters blood were 5%, 4.1% and 1.5%, respectively. The corresponding figures for adults were 2%, 0.9% and 0.1%, respectively. The calculation of attributable fraction (AF) using a multiple logistic regression model showed that malaria accounted for 0.44 of all fevers in children of 1-4 years and 0.08 of the fevers in adults. Prevalence data derived from the AF estimate were compared with those calculated using different accepted density thresholds. The prevalences which best approximated the results from the logistic regression model were obtained using parasitaemia cut-offs ofor = 1000 Pf parasites/microliter in children aged 1-4 years and adults older than 19 years and ofor = 10,000 parasites/microliter in those aged 5-19 years. Prevalence of fever associated with parasitaemia was highly seasonal, with a peak at the beginning of the wet season. The geographical distribution of malaria morbidity was not uniform. The measurement of malaria-related morbidity, the identification of significant seasonal and local variation as well as the assessment of different methods of defining a clinical episode of Pf malaria are crucial for the design and evaluation of intervention studies, including field trials of antimalarial vaccines.

Background. Antimalarial use is a key factor driving drug resistance and reduced treatment effectiveness in Plasmodium falciparum malaria, but there are few formal, quantitative analyses of this process. Methods. We analyzed drug usage, drug failure rates, and the frequencies of mutations and haplotypes known to be associated with drug resistance over a 12-year period (1991–2002) in a site in Papua New Guinea. This period included 2 successive treatment policies: amodiaquine (AQ) or chloroquine (CQ) from 1991 through 2000 and their subsequent replacement by sulfadoxine-pyrimethamine (SP) plus AQ or SP plus CQ. Results. Drug use approximated 1 treatment per person-year and was associated with increasing frequencies of pfcrt and pfmdr1 mutations and of treatment failure. The frequency of pfdhfr mutations also increased, especially after the change in treatment policy. Treatment failure rates multiplied by 3.5 between 1996 and 2000 but then decreased dramatically after treatment policy change. Conclusions. With high levels of resistance to CQ, AQ, and SP, the deployment of the combination of both drugs appears to increase clinical effectiveness but does not decelerate growth of resistance. Our estimates of mutation and haplotype frequencies provide estimates of selection coefficients acting in this environment, which are key parameters for understanding the dynamics of resistance.

Background In areas where malaria endemicity is high, many people harbour blood stage parasites without acute febrile illness, complicating the estimation of disease burden from infection data. For Plasmodium falciparum the density of parasitaemia that can be tolerated is low in the youngest children, but reaches a maximum in the age groups at highest risk of infection. There is little data on the age dependence of tolerance in other species of human malaria. Methods Parasite densities measured in 24,386 presumptive malaria cases at two local health centres in the Wosera area of Papua New Guinea were compared with the distributions of parasite densities recorded in community surveys in the same area. We then analyse the proportions of cases attributable to each of Plasmodium falciparum, P. vivax, and P. malariae as functions of parasite density and age using a latent class model. These attributable fractions are then used to compute the incidence of attributable disease. Results Overall 33.3%, 6.1%, and 0.1% of the presumptive cases were attributable to P. falciparum, P. vivax, and P. malariae respectively. The incidence of attributable disease and parasite density broadly follow similar age patterns. The logarithm of the incidence of acute illness is approximately proportion to the logarithm of the parasite density for all three malaria species, with little age variation in the relationship for P. vivax or P. malariae. P. falciparum shows more age variation in disease incidence at given levels of parasitaemia than the other species. Conclusion The similarities between Plasmodium species in the relationships between parasite density and risk of attributable disease are compatible with the hypothesis that pan-specific mechanisms may regulate tolerance to different human Plasmodia. A straightforward mathematical expression might be used to project disease burden from parasite density distributions assessed in community-based parasitological surveys.

Background Severe malaria (SM) is classically associated with Plasmodium falciparum infection. Little information is available on the contribution of P. vivax to severe disease. There are some epidemiological indications that P. vivax or mixed infections protect against complications and deaths. A large morbidity surveillance conducted in an area where the four species coexist allowed us to estimate rates of SM among patients infected with one or several species. Methods and Findings This was a prospective cohort study conducted within the framework of the Malaria Vaccine Epidemiology and Evaluation Project. All presumptive malaria cases presenting at two rural health facilities over an 8-y period were investigated with history taking, clinical examination, and laboratory assessment. Case definition of SM was based on the World Health Organization (WHO) criteria adapted for the setting (i.e., clinical diagnosis of malaria associated with asexual blood stage parasitaemia and recent history of fits, or coma, or respiratory distress, or anaemia [haemoglobin < 5 g/dl]). Out of 17,201 presumptive malaria cases, 9,537 (55%) had a confirmed Plasmodium parasitaemia. Among those, 6.2% (95% confidence interval [CI] 5.7%–6.8%) fulfilled the case definition of SM, most of them in children, In a study carried out in Papua New Guinea, Blaise Genton and colleagues show thatPlasmodium vivax is associated with severe malaria., Editors' Summary Background. Malaria is a parasitic infection that is transmitted to people by infected mosquitoes. Four different parasites cause malaria—Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Of these, P. vivax is the commonest and most widely distributed, whereas P. falciparum causes the most deaths. All these parasites enter their human host when an infected mosquito takes a blood meal. They then migrate to the liver where they replicate without causing any symptoms. Eight to nine days later, mature parasites are released from the liver cells and invade red blood cells. Here, they multiply rapidly before bursting out and infecting more red blood cells. The recurring flu-like symptoms of malaria are caused by this cyclical increase in parasitemia (parasites in the blood) and should be treated promptly with antimalarial drugs to prevent the development of potentially fatal complications. Infections with P. falciparum in particular can cause anemia by destroying the red blood cells and can damage vital organs (including the brain) by blocking the capillaries that supply them with blood. Why Was This Study Done? It is generally believed that P. vivax malaria is rarely fatal. There is even some evidence that infection with P. vivax alone (monoinfection) or with other malaria parasites (mixed infection) provides protection against malarial complications. Recently, however, there have been reports of severe disease and deaths associated with infection by P. vivax alone. Most of these reports do not indicate what proportion of severe malaria cases are caused by P. vivax infections, but if P. vivax is responsible for a significant proportion of malarial deaths, efforts to prevent these deaths will need to target P. vivax as well as P. falciparum. In this study, therefore, the researchers estimate the proportion of cases of severe malaria among patients infected with one or several Plasmodium species in Papua New Guinea, a country where all four species coexist. What Did the Researchers Do and Find? The researchers enrolled everyone attending two rural health facilities in the Wosera subdistrict of Papua New Guinea over an eight-year period with symptoms indicative of malaria but without symptoms of any other disease (presumptive malaria cases) into their prospective cohort study. They asked each patient about their symptoms, did a standard physical examination, looked for parasites in their blood, and measured their hemoglobin levels to see whether they were anemic. Out of 17,201 presumptive malaria cases, 483 had severe malaria (defined as parasitemia plus a recent history of fits, coma, breathing problems, or anemia). Most of the patients with severe malaria were less than five years old—children have little immunity to Plasmodium parasites. In this age group, 11.7% of patients infected with P. falciparum, 8.8% of patients infected with P. vivax, and 17.3% of patients infected with both parasites had severe malaria. Patients with severe malaria caused by P. vivax presented with breathing difficulties more often than those infected with P. falciparum, whereas anemia was more common among patients with severe malaria caused by P. falciparum than by P. vivax. What Do These Findings Mean? The researchers use these results and data on the numbers of infections with each parasite to calculate that, in this rural region of Papua New Guinea, P. vivax is responsible for one-fifth of severe malaria cases, P. falciparum is responsible for three-quarters of cases, and the rest involve mixed P. falciparum/P. vivax infections. Put another way, these findings suggest that about one in ten children under the age of five years infected with either P. vivax or P. falciparum may develop severe malaria. These findings provide no evidence, however, that mixed infections are protective. Because the diagnosis of severe malaria was not confirmed by outcome data (deaths or permanent disability), additional, more detailed studies are needed to confirm these results. Nevertheless, these findings (and those reported separately in a related article published at the same time in PLoS Medicine) suggest that a significant proportion of the illness associated with malaria may be caused by P. vivax infections. Thus, efforts to reduce or eliminate the malarial burden must target P. vivax as well as P. falciparum in regions where these species coexist. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050127. A PLoSMedicine Research in Translation article by Stephen Rogerson further discusses this study and a related paper on vivax malaria infection in patients attending a regional hospital in Papua, Indonesia The MedlinePlus encyclopedia has a page on malaria (in English and Spanish) The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish) Information is available from the Roll Back Malaria Partnership on global control of malaria and on malaria in Papua New Guinea Vivaxmalaria provides information for the malaria research community on topics related to Plasmodiumvivax The Malaria Vaccine Initiative also provides a fact sheet on Plasmodiumvivax malaria

In Papua New Guinea (PNG), complex patterns of malaria commonly include single and mixed infections of Plasmodium falciparum, P. vivax, P. malariae, and P. ovale. Here, we assess recent epidemiologic characteristics of Plasmodium blood-stage infections in the Wosera region through four cross-sectional surveys (August 2001 to June 2003). Whereas previous studies performed here have relied on blood smear/light microscopy (LM) for diagnosing Plasmodium species infections, we introduce a newly developed, post-polymerase chain reaction (PCR), semi- quantitative, ligase detection reaction-fluorescent microsphere assay (LDR-FMA). A direct comparison of the two methods for > 1,100 samples showed that diagnosis was concordant for > 80% of the analyses performed for P. falciparum (PF), P. vivax (PV), and P. malariae (PM). Greater sensitivity of the LDR-FMA accounted for 75% of the discordance between diagnoses. Based on LM, the prevalence of blood-stage PF, PV, and PM infections was found to be markedly reduced compared with an early 1990s survey. In addition, there were significant shifts in age distribution of infections, with PV becoming the most common parasite in children < 4 years of age. Consistent with previous studies, prevalence of all Plasmodium species infections increased significantly in samples analyzed by the PCR-based LDR- FMA. This increase was most pronounced for PM, PO, and mixed infections and in adolescent (10-19 years) and adult age groups, suggesting that LM may lead to under-reported prevalence of less common Plasmodium species, infection complexity, and a skewed distribution of infections towards younger age groups. This study shows that the application of LDR-FMA diagnosis in large epidemiologic studies or malaria control interventions is feasible and may contribute novel insights regarding the epidemiology of malaria.

The merozoite surface protein 2 (MSP2) is a leading asexual-stage malaria vaccine candidate that has already proven to have an effect in phase I/IIb vaccine trials, where it was tested in combination with other antigens. Alleles of msp2 fall within two major allelic families, 3D7 and FC27. We analyzed the msp2 genotype in 306 asymptomatic and 63 symptomatic infections from the Wosera region of Papua New Guinea. The multiplicity of infection and the distribution of msp2 alleles was similar to that found in previous studies in the region, but there was no association found between FC27-type or 3D7-type forms of MSP2 and clinical malaria.

The malaria vaccine Combination B comprises recombinant Plasmodium falciparum ring-infected erythrocyte surface antigen and 2 merozoite surface proteins (MSP1 and MSP2) formulated in oil-based adjuvant. A phase 1-2b double-blind, randomized, placebo-controlled trial in 120 children (5-9 years old) in Papua New Guinea demonstrated a 62% (95% confidence limits: 13%, 84%) reduction in parasite density in children not pretreated with sulfadoxine-pyrimethamine. Vaccinees had a lower prevalence of parasites carrying the MSP2-3D7 allelic form (corresponding to that in the vaccine) and a higher incidence of morbid episodes associated with FC27-type parasites. These results demonstrate functional activity of Combination B against P. falciparum in individuals with previous malaria exposure. The specific effects on parasites with particular msp2 genotypes suggest that the MSP2 component, at least in part, accounted for the activity. The vaccine-induced selection pressure exerted on the parasites and its consequences for morbidity strongly argue for developing vaccines comprising conserved antigens and/or multiple components covering all important allelic types.

Many individuals at risk of malaria also have micronutrient deficiencies that may hamper protective immunity. Vitamin A is central to normal immune function, and supplementation has been shown to lower the morbidity of some infectious diseases. We investigated the effect of vitamin A supplementation on malaria morbidity.This randomised double-blind placebo-controlled trial of vitamin A supplementation took place in a P. falciparum endemic area of Papua New Guinea. Of 520 potentially eligible children aged 6-60 months, 480 were randomly assigned high-dose vitamin A (n=239) or placebo (n=241), every 3 months for 13 months. Malaria morbidity was assessed through weekly community-based case detection and surveillance of patients who self-reported to the health centre. Cross-sectional surveys were also done at the beginning, middle, and end of the study to assess malariometric indicators. Analyses were by intention to treat.The number of P. falciparum febrile episodes (temperatureor = 37.5 degrees C with a parasite count of at least 8000/microL) was 30% lower in the vitamin A group than in the placebo group (178 vs 249 episodes; relative risk 0.70 [95% CI 0.57-0.87], p=0.0013). At the end of the study P. falciparum geometric mean density was lower in the vitamin A than the placebo group (1300 [907-1863] vs 2039 [1408-2951]) as was the proportion with spleen enlargement (125/196 [64%] vs 148/207 [71%]); neither difference was significant (p=0.093 and p=0.075). Children aged 12-36 months benefited most, having 35% fewer febrile episodes (89 vs 141; relative risk 0.65 [14-50], p=0.0023), 26% fewer enlarged spleens (46/79 [58%] vs 67/90 [74%], p=0.0045), and a 68% lower parasite density (1160 [95% CI 665-2022] vs 3569 [2080-6124], p=0.0054). Vitamin A had no consistent effect on cross-sectional indices of proportion infected or with anaemia.Vitamin A supplementation may be an effective low-cost strategy to lower morbidity due to P. falciparum in young children. The findings suggest that clinical episodes, spleen enlargement, and parasite density are influenced by different immunological mechanisms from infection and anaemia.A randomized double-blind placebo-controlled trial was conducted to assess the efficacy of vitamin A supplementation on morbidity due to Plasmodium falciparum among 520 children aged 6-60 months in a malaria-endemic area of Papua New Guinea. Malaria morbidity was assessed through weekly community-based case detection and surveillance of patients who self-reported to the health center. Cross-sectional surveys were also conducted at the beginning, middle, and end of the study to assess malariometric indicators. Laboratory tests were also analyzed for species-specific density. Findings showed that the number of episodes of falciparum malaria among young children in Papua New Guinea was 30% lower in those who received vitamin A than in the placebo recipients. The children, mostly aged 12-36 months, had fewer febrile episodes, fewer enlarged spleens and lower parasite density. No significant differences were observed for hemoglobin concentration or prevalence of anemia for any age group. The findings suggest that clinical episodes, spleen enlargement, and parasite density were influenced by immunological mechanisms that were different from infection and anemia. It also suggests that vitamin A is effective, inexpensive, and a programmatically practical tool in controlling P. falciparum malaria.

The willingness of patients in the rural tropics to seek medical care at primary health care facilities is influenced by the distance they have to travel, but few studies have tried to estimate these distance effects.Distance decay effects in attendance rates were estimated from a database of 4348 attendances at a rural health centre in Papua New Guinea, linked to demographic and house position data for the catchment population. Small-scale spatial patterns and differences between diagnoses, age groups and gender are described.Attendance decreased markedly with distance both overall (50% decrease at 3.5 km) and for patients with malaria or acute respiratory infections. This decrease was non-linear (on log scale) with distance. Although constant over time, there were big differences in this distance effect among age and gender groups: Female patients showed less distance decay in adolescents and adults, but higher in the infant group. Spatial patterns accounted for 32% of the variation in age- and gender-specific attendance rates. Of the spatial effects more than 50% were due to distance effects.Distance effects were similar in magnitude to those reported elsewhere, suggesting that distance effects may be generalizable to many parts of the rural tropics. The non-linearity of distance decay implies that a bell-shaped demand function should be used in health planning.

Nine-year follow-up (ending 1999) of survival of 3738 individuals in a malaria-endemic area of Papua New Guinea found that the use of mosquito nets was associated with a large reduction in mortality in people agedor = 40 years as well as in children aged5 years. There may be substantial benefits of malaria transmission reduction for older people, that have been overlooked in public health programmes and burden of disease calculations.

Zinc is crucial for normal immune function and can reduce morbidity from multiple infectious diseases. To determine the influence of zinc on malaria morbidity we conducted a randomized placebo-controlled trial of daily zinc supplementation in children residing in a malaria endemic region of Papua New Guinea. A total of 274 preschool children aged 6 to 60 months were given 10 mg elemental zinc (n = 136) or placebo (n = 138) for 6 days a week for 46 weeks. Slide-confirmed malaria episodes were detected by surveillance of cases self-reporting to a local health center. Cross-sectional surveys were conducted at the beginning, middle, and end of the study to assess infection rates, parasite density, spleen enlargement, and hemoglobin levels. Zinc supplementation resulted in a 38% (95% CI 3-60, P = 0.037) reduction in Plasmodium falciparum health center-based episodes, defined as parasitemia > or = 9200 parasites/microl with axial temperature > or = 37.5 degreesC or reported fever. Episodes accompanied by any parasitemia were also reduced by 38% (95% CI 5-60, P = 0.028), and episodes with parasitemia > or = 100,000/microl were reduced by 69% (95% CI 25-87, P = 0.009). There was no evidence of the effects of zinc on Plasmodium vivax morbidity or on health center attendance for causes other than P. falciparum. Zinc had no consistent effect on cross-sectional malariometric indices. Although P. falciparum prevalence tended to be lower at the end of the study in children given the placebo, such changes were absent at the mid-study survey. These results suggest that improved dietary zinc intake may reduce morbidity due to P. falciparum.