Ovalocytosis and cerebral malaria.
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Biomedical subjects
B Genton
Publications and source records attributed to B Genton.
Assessment of malaria morbidity in vaccine efficacy trials.
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Plasmodium falciparum: malaria morbidity is associated with specific merozoite surface antigen 2 genotypes.
Plasmodium falciparum merozoite surface antigen 2 (MSA2) is considered a vaccine candidate in a subunit vaccine against blood stage malaria. In order to test if a specific genotype of the highly polymorphic MSA2 is associated with disease, we conducted a case-control study in a malaria endemic area of Papua New Guinea involving 227 individuals, mostly children under the age of 10 years. All cases and controls were genotyped by polymerase chain reaction for their respective MSA2 genotypes. We report that at the time of the study parasites carrying the FC27-like genotype were twice as likely to be found in symptomatic malaria cases than in asymptomatic controls. Mixed genotype infections were significantly less frequent in symptomatic malaria infections. One individual allele (WOS10) of the FC27 family was found only in cases. This may be a form of P. falciparum infrequently encountered and may cause morbidity due to lack of immunity to it. This study provides evidence that MSA2 is involved in the morbidity of malaria and supports the inclusion of MSA2 in a subunit vaccine.
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The epidemiology of malaria in the Wosera area, East Sepik Province, Papua New Guinea, in preparation for vaccine trials. I. Malariometric indices and immunity.
The epidemiological features of malaria were studied through seven community-based surveys in a population of 4000 in the Wosera area, East Sepik Province, Papua New Guinea. Prevalence of parasitaemia (all species, all ages) was 60%. Plasmodium falciparum was the predominant species in all surveys (55%), followed by P. vivax (25%) and P. malariae (20%). The highest prevalence for asexual forms of P. falciparum occurred in the 5-9-year age group, whereas P. falciparum gametocytaemia and P. vivax parasitaemia were observed most frequently in the 1-4-year age group and P. malariae in the 10-15-year age group. Mean densities of all species decreased with age except for that of P. malariae, which was lower in children aged < 1 year than in those aged 1-4 years. The prevalence of enlarged spleen was 57% in children and 10% in adults and closely matched the corresponding age-related parasite rate. Seroprevalence of antibody to the major merozoite surface antigen 2 rapidly increased with age, with > 90% of individuals older than 5 years being positive. Malariological indices showed irregular changes over time but there was no clear-cut seasonal pattern. The geographical distribution of these indices and immune responses was not uniform within the study area. Bednet use and drug consumption were negatively correlated with malariometric indices. Identification of significant temporal and local variations in malaria endemicity is important for the design and evaluation of intervention studies, including field trials of an antimalarial vaccine.
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The epidemiology of malaria in the Wosera area, East Sepik Province, Papua New Guinea, in preparation for vaccine trials. II. Mortality and morbidity.
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) parasitaemia > or = 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 of > or = 1000 Pf parasites/microliter in children aged 1-4 years and adults older than 19 years and of > or = 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.
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Assessment of the role of the humoral response to Plasmodium falciparum MSP2 compared to RESA and SPf66 in protecting Papua New Guinean children from clinical malaria.
The prevalence and concentration of naturally acquired humoral response (IgG) to merozoite surface protein 2 (MSP2), RESA, SPf66 and crude schizont extract were measured in a population living in a malaria highly endemic area of Papua New Guinea. A prospective longitudinal study in 0.5-15 year old children was conducted for one year in order to examine the relationship between the humoral response to these antigens and subsequent susceptibility to clinical malaria using a series of clinical definitions. The prevalence and concentration of antibodies to all antigens increased with age. Such correlation with age was most marked for MSP2 recombinant proteins. When age and previous exposure were controlled for, only antibody levels to MSP2 recombinant proteins (3D7 and d3D7) and to RESA predicted a reduction in incidence rate of episodes of clinical malaria. Our results support the inclusion of the recombinant proteins of the 3D7 allelic family of merozoite surface antigen 2 and RESA into a subunit vaccine against malaria.
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Humoral and cell-mediated immunity to the Plasmodium falciparum ring-infected erythrocyte surface antigen in an adult population exposed to highly endemic malaria.
A parasitological and immunological survey was carried out in an area in Papua New Guinea highly endemic for malaria. Two hundred fourteen adult individuals were selected for studies to assess their immune responses against the malaria vaccine candidate ring-infected erythrocyte surface antigen (RESA). Total immunoglobulin G (IgG) antibodies directed against RESA as well as specific IgG1, IgG2, and IgG3 antibodies were determined. Humoral responses directed against RESA were frequent in all IgG subclasses. Only IgG3 responses were found to be age dependent. Total anti-RESA IgG antibodies were not correlated with protection against malaria as measured by parasite prevalence, parasite density, or health center attendance. In contrast, cytophilic antibodies (IgG1 and IgG3) were associated with reduced Plasmodium falciparum prevalence and reduced health center attendance. T-cell proliferation in general was low and very infrequent. No correlation between humoral and cellular immune responses could be found. Parasite density, parasite prevalence, and health center visits tended to be reduced in individuals with good humoral and cell-mediated immune responses.
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Humoral response to Plasmodium falciparum ring-infected erythrocyte surface antigen in a highly endemic area of Papua New Guinea.
The prevalence and concentration of antibodies to ring-infected erythrocyte surface antigen (RESA) were measured in blood samples collected during a cross-sectional survey conducted in Papua New Guinea. Antibodies were measured by enzyme-linked immunosorbent assay to the recombinant RESA protein in 1,398 subjects and to RESA 8 and RESA 11 synthetic peptides in a subsample of 200 adults. Overall, the seropositivity rate to recombinant RESA was 66% and the geometric mean antibody concentration was 28 micrograms/ml. There was a slow increase in antibody prevalence and concentration with age that continued to occur even after 40 years of age. In children less than 10 years of age, there was a significant positive correlation between both RESA antibody prevalence and concentration and concurrent infection with Plasmodium falciparum. The opposite was true in adults more than 20 years of age, with those having a high antibody concentration to RESA being less likely to be parasitemic at the time of the survey. This observation was consistent with the finding of a weak but significant negative correlation between log antibody concentration and log P. falciparum density, which was mainly found in adults. No consistent correlation was found between humoral immune response to RESA and morbidity indicators.
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Evidence of HLA class II association with antibody response against the malaria vaccine SPF66 in a naturally exposed population.
The antibody response against the malaria vaccine SPf66 and against circumsporozoite (CS) protein has been tested in immune adults from a malaria endemic area in Papua New Guinea. All individuals were genotyped for the HLA class II DQB1 and DRB1 loci, and the humoral response was analyzed with respect to the identified class II alleles. At each locus, only three alleles were frequent, namely DRB1*11, *15, and *16, and DQB1*0301, *0502, and *0601. Antibodies against SPf66 and CS protein were found in 84% and 79% of the individuals, respectively. A strong negative association was detected between the humoral response against SPf66 and DRB1*15 and DQB1*0601. A positive association of the response was observed with DRB1*11 and DQB1*0301. After analysis with a multiple regression model in which all alleles were included simultaneously, only DRB1*15 remained significantly associated with low antibody responses. This suggests that nonresponders may be expected after immunization with SPf66 in certain populations.
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The use of the polymerase chain reaction for more sensitive detection of Plasmodium falciparum.
The prevalence of Plasmodium falciparum in children and adults living in a malaria-endemic area in Papua New Guinea was determined by microscopy and by polymerase chain reaction (PCR). The sensitivity of detecting P. falciparum infections increased two-fold with PCR. Undetected infections by microscopy were more frequent in adults (including adolescents) than in children. Detecting this subpatent parasitaemia by PCR resulted in an equal P. falciparum prevalence in children and adults; in children the parasitaemia rate increased from 32% to 48% and in adults from 23% to 47%. In more than 50% of all blood samples positive for P. vivax and P. malariae an underlying P. falciparum infection remained undetected by microscopy. The introduction of PCR has opened up new possibilities in malaria diagnosis and research.
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Specialized Travel Consultation Part I: Travelers' Prior Knowledge.
Studies have shown that more than one third of all travelers to tropical countries experience an illness while abroad. Naiveté about diseases, such as malaria, travelers' diarrhea, cholera, and HIV infections, appears to be the most crucial factor determining travel-related morbidity rates. A study was designed both to evaluate the level of disease-related, pretravel knowledge prior to a specialized travel clinic consultation as well as to correlate the level of knowledge with demographic and travel variables and previous travel experience. Using a self-administered questionnaire, data were collected from 167 clients who attended the Hospital for Tropical Diseases Travel Clinic, London, England, in June 1991. The questionnaire evaluated clients' knowledge and attitudes of travel-related diseases, their prevention and treatment, and the scores were analyzed using the Statistical Analysis System software, Version 5. Predictors for increased knowledge scores were examined by a one-way layout model comparing disease knowledge scores with variables such as sex, age, socioeconomic class, ethnic background, previous travel experience, type and duration of travel, destination, accommodation quality, and health insurance coverage. A step-down regression model was constructed to control for the effects of the many mutually confounding factors. Travelers' diarrhea and malaria risk at destination were acknowledged by more than 85% of the respondents, and 60% of the questions on travelers' diarrhea prevention, compared to 81% of those on malaria prevention, were answered correctly. Significantly, however, only one half of the respondents indicated that they would take appropriate measures concerning diarrhea while abroad. Stepwise regression identified previous travel experience, pretravel advice, traveling for work purposes, and using backpack overland tours as significant predictors of high knowledge. This study points out the necessity of pretravel education and that it should focus not only on malaria but also on other travel-related diseases like travelers' diarrhea. As well, target groups for whom more detailed information should be provided are identified, including inexperienced travelers, those using organized tours and sleeping indoors, those planning to visit friends or relatives, and those who have not received sufficient pretravel health advice.
Journal Article↗
Specialized Travel Consultation Part II: Acquiring Knowledge.
With an increase in travel to tropical countries, the need to improve the disease-risk perceptions of travelers who are either naive or given inappropriate or ineffective advice is becoming increasingly important. More widely available, specialized centers that can provide advice on tropical or travel-related diseases have been established, but their efficacy on travelers' knowledge and health has not been verified. Therefore, this study was undertaken to evaluate the impact of the service provided by a routine travel consultation at the Hospital for Tropical Diseases Travel Clinic, London, England. Self-administered questionnaires were given to 161 preconsultation and 144 postconsultation clients. The consultation included an interview covering travel plans and immunization and medical history, and advice was given on the journey, necessary immunizations, and prophylaxis. Data were analyzed using the Statistical Analytic System software and the mean differences in knowledge between pre- and postconsultation scores were correlated using the nonparametric Mann-Whitney procedure. The control of mutually confounding factors was maintained by multiple regression using the Mantel-Haenszel summary chi-square and the General Linear Model procedures. Comparison of the entry and exit scores showed a significantly improved overall knowledge of travel-related diseases in the exit, postconsultation group. Subanalysis revealed that this difference was due to an increased knowledge of malaria and its prevention and perceived risk of cholera. Knowledge about the management of diarrhea or fever, however, was not significantly improved by a consultation. Inexperienced travelers taking packaged or organized trips, and those from socioeconomic groups I and II showed the largest increase in knowledge following consultation. Our results show that a face-to-face interview for an average of 18 minutes by trained staff is an effective way of improving travelers' knowledge on certain topics. The slight improvements overall are explained by the levels of experience of travel and previously acquired knowledge of the clients in our study. Effective advice on malaria prevention and some health risks is given during an average consultation; however, there is still a need for improvement in giving information on the management of diarrhea, fever, and other travel diseases.
Journal Article↗
Plasmodium falciparum: extensive polymorphism in merozoite surface antigen 2 alleles in an area with endemic malaria in Papua New Guinea.
Plasmodium falciparum: Extensive polymorphism in merozoite surface antigen 2 alleles in an area with endemic malaria in Papua New Guinea. Experimental Parasitology 79, 106-116. The prevalence of Plasmodium falciparum in 304 individuals from two villages in Papua New Guinea has been determined by PCR amplification of the gene encoding the merozoite surface antigen 2 (MSA2). Forty-seven percent of the blood samples were positive for P. falciparum. The MSA2 alleles of this parasite population were characterized by PCR-RFLP genotyping. In 144 P. falciparum infections 38 different MSA2 alleles were found. The most common allele (22%) was a variant of FC27. Further alleles, found in the study area, were IC1, KF1916, and MAD71. In addition to these previously described alleles, 33 novel variant forms of MSA2 were detected, most of which were represented at very low frequency in the study population. MSA2 genotyping of a local P. falciparum population revealed an unexpected amount of genetic heterogeneity. The diversity is mostly due to variation in the repeat region resulting in length polymorphism that can be easily detected by PCR-RFLP.
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Relationships between Plasmodium falciparum infection and morbidity in a highly endemic area.
A total of 736 outpatients diagnosed as having malaria using clinical criteria at a health centre in a highly endemic area of Papua New Guinea were investigated parasitologically. Plasmodium falciparum-attributable fractions were determined using a logistic regression model to compare parasite densities in cases with those of healthy individuals in community surveys. Thirty-seven percent of presumptive cases were found to have raised P. falciparum parasitaemia. This corresponds to an average reporting rate for the population of 0.53 attributable episodes per annum. Whilst the maximum prevalence of parasitaemia in the community was in children aged 5-9 years, the maximum age-specific incidence of attributable cases at the outpatient clinic was 2 cases per annum in the 2- to 4-year-old age group. The procedure for estimating attributable fractions makes it possible to compare morbidity rates between age groups, and to examine how the relationship between morbidity risk and parasite density changes with age, without diagnosing individual episodes. The average tolerance of parasites in an age group was measured by considering the level of parasitaemia associated with a given risk of malaria-attributable morbidity. In contrast to anti-parasite immunity, tolerance of parasites declines with age since at parasite isodensity the probability of being symptomatic increases with age.
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The use of untreated bednets and malaria infection, morbidity and immunity.
The effect of bednet use was investigated, without undertaking a specific intervention, in four cross-sectional community-based surveys in 10 villages of a highly endemic area of Papua New Guinea. Over half (55%) of the villagers interviewed reported that they had used a bednet on the previous night. In general and after adjustment for age, village and housing characteristics, bednet users, particularly children, had lower parasite prevalences and spleen rates and less enlarged spleens than non-users. However, users were similar to non-users in terms of fever reported for the previous week, axillary temperature, parasite density and haemoglobin level. The prevalence of antibody to the ring erythrocyte surface antigen and the major merozoite surface antigen 2 was lower in users than non-users. The association with malariometric indices and immune responses remained significant when bednet users were compared with non-users in houses without bednets. Thus, untreated bednets do not reduce malaria transmission sufficiently to decrease morbidity. They might paradoxically increase the risk of clinical malaria by lowering the development of humoral immunity.
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Assessment of the humoral and cell-mediated immunity against the Plasmodium falciparum vaccine candidates circumsporozoite protein and SPf66 in adults living in highly endemic malarious areas of Papua New Guinea.
To assess natural immunity against the circumsporozoite (CS) protein and the synthetic vaccine SPf66, immunologic studies were carried out in a highly endemic malarious area of Papua New Guinea. Antibody prevalence, antibody titers, and T cell proliferation against both antigens were measured in 214 adults. Immunologic data were analyzed with respect to longitudinal malariologic and morbidity data. Evidence of genetic traits such as glucose-6-phosphate dehydrogenase deficiency and ovalocytosis was analyzed. Antibody prevalence was high, with 79% and 84% for CS protein and SPf66, respectively, while T cell proliferation was infrequent and low, with 14% and 12% responders, respectively. Anti-CS protein antibodies increased with age but showed no association to malaria indices or morbidity. No protective value was observed with T cell responses or with humoral response to SPf66. These results provide a first description of naturally developed immunity against SPf66 and suggest further studies in to fully understand the mechanism of immunity against this antigen.
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Relationship between humoral response to Plasmodium falciparum merozoite surface antigen-2 and malaria morbidity in a highly endemic area of Papua New Guinea.
The prevalence and concentration of antibodies to merozoite surface antigen-2 (MSA-2) were measured in blood samples collected during a cross-sectional survey. Antibodies were measured by enzyme-linked immunosorbent assay using two recombinant proteins that closely approximated the full-length mature MSA-2 polypeptides expressed by the Plasmodium falciparum isolate FC27 and the cloned line 3D7 and that were representative of the dimorphic forms of MSA-2. Antibodies were also measured to a form of the 3D7 MSA-2 lacking the central repetitive sequences (d3D7). High antibody prevalence was observed to all three antigens: the overall prevalence of IgG to FC27, 3D7, and d3D7 was 91%, 90%, and 90%, respectively. The majority of individuals > or = 5 years of age had antibodies to both forms of MSA-2. The geometric mean antibody units increased with age with a plateau being reached by 15-20 years of age. There was a significant positive association of antibody prevalence with both the presence of the parasite and an enlarged spleen in children. This study provides the first evidence that antibodies against nonrepeat regions of MSA-2 are associated with fewer fever episodes and less anemia, both known to be indicators of malaria morbidity.
Adolescent↗
Malaria vaccine: the end of the tunnel?
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Clinical Trials as Topic↗