Sunetra Gupta

Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa

BACKGROUND Malaria remains a major cause of mortality and morbidity in Africa. Many approaches to malaria control involve reducing the chances of infection but little is known of the relations between parasite exposure and the development of effective clinical immunity so the long-term effect of such approaches to control on the pattern and frequency of malaria cannot be predicted. METHODS We have prospectively recorded paediatric admissions with severe malaria over three to five years from five discrete communities in The Gambia and Kenya. Demographic analysis of the communities exposed to disease risk allowed the estimation of age-specific rates for severe malaria. Within each community the exposure to Plasmodium falciparum infection was determined through repeated parasitological and serological surveys among children and infants. We used acute respiratory-tract infections (ARI) as a comparison. FINDINGS 3556 malaria admissions were recorded for the five sites. Marked differences were observed in age, clinical spectrum and rates of severe malaria between the five sites. Paradoxically, the risks of severe disease in childhood were lowest among populations with the highest transmission intensities, and the highest disease risks were observed among populations exposed to low-to-moderate intensities of transmission. For severe malaria, for example, admission rates (per 1000 per year) for children up to their 10th birthday were estimated as 3.9, 25.8, 25.9, 16.7, and 18.0 in the five communities; the forces of infection estimated for those communities (new infections per infant per month) were 0.001, 0.034, 0.050, 0.093, and 0.176, respectively. Similar trends were noted for cerebral malaria and for severe malaria anaemia but not for ARI. Mean age of disease decreased with increasing transmission intensity. INTERPRETATION We propose that a critical determinant of life-time disease risk is the ability to develop clinical immunity early in life during a period when other protective mechanisms may operate. In highly endemic areas measures which reduce parasite transmission, and thus immunity, may lead to a change in both the clinical spectrum of severe disease and the overall burden of severe malaria morbidity.

Negative epistasis between the malaria-protective effects of α + -thalassemia and the sickle cell trait

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and α+-thalassemia, a condition characterized by reduced production of the normal α-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying α+-thalassemia. Negative epistasis could explain the failure of α+-thalassemia to reach fixation in any population in sub-Saharan Africa.

Carried Meningococci in the Czech Republic: a Diverse Recombining Population

Population and evolutionary analyses of pathogenic bacteria are frequently hindered by sampling strategies that concentrate on isolates from patients with invasive disease. This is especially so for the gram-negative diplococcus Neisseria meningitidis, a cause of septicemia and meningitis worldwide. Meningococcal isolate collections almost exclusively comprise organisms originating from patients with invasive meningococcal disease, although this bacterium is a commensal inhabitant of the human nasopharynx and very rarely causes pathological effects. In the present study, molecular biology-based techniques were used to establish the genetic relationships of 156 meningococci isolated from healthy young adults in the Czech Republic during 1993. None of the individuals sampled had known links to patients with invasive disease. Multilocus sequence typing (MLST) showed that the bacterial population was highly diverse, comprising 71 different sequence types (STs) which were assigned to 34 distinct complexes or lineages. Three previously identified hyperinvasive lineages were present: 26 isolates (17%) belonged to the ST-41 complex (lineage 3); 4 (2.6%) belonged to the ST-11 (electrophoretic type [ET-37]) complex, and 1 (0.6%) belonged to the ST-32 (ET-5) complex. The data were consistent with the view that most nucleotide sequence diversity resulted from the reassortment of alleles by horizontal genetic exchange.

Risk of Severe Malaria among African Infants: Direct Evidence of Clinical Protection during Early Infancy

Little empirical evidence from field-based studies exists on the relative magnitude or duration of clinical protection from Plasmodium falciparum malaria in infancy. A prospective study was undertaken to examine the age distribution of hospital admissions in four geographically and demographically well-defined areas with differing intensities of P. falciparum transmission. Where transmission was perennial, significant clinical protection from severe morbidity was observed up to the third month of life; in the seasonal transmission area, disease rates rose after the sixth month of life. Infants exposed to the highest rates of P. falciparum exposure demonstrated significant declines in the risks of severe malaria from 6 months of age. These data provide direct evidence for the very early acquisition of clinical immunity and for the existence of a period of clinical protection, which together may explain why, in these communities, the cumulative risk of malarial disease throughout childhood appears to decline with increasing transmission intensity.

Theoretical studies of the effects of heterogeneity in the parasite population on the transmission dynamics of malaria

Periodicity in malaria transmission has generally been ascribed to seasonal fluctuations in mosquito population density or spatial heterogeneity with periodic migration. In this paper we demonstrate that simple models of strain heterogeneity can generate periodic behaviour as a consequence of the interaction between parasite strains and host immunological defences. As the degree of cross-immunity between strains increases, the system moves from a régime of independent strain transmission and coexistence, through increasingly coupled behaviour, to the displacement of the strain of lower transmissibility by the strain with a higher basic reproductive rate (R0). Cross-immunity thus serves both to bring the strains into competition, and also to couple the dynamics. We find analytical and numerical results on strain coexistence to show how the range of possible outcomes may be read as an effect of the tension between these two effects of cross-protection.

Exploring the evolution of diversity in pathogen populations.

Pathogen biodiversity is an under-exploited source of inference regarding disease processes and the evolution of pathogens and pathogenesis. In addition, the structure of pathogen populations, especially for diverse organisms such as the meningococcus, has implications for public health interventions including vaccination and antibiotic use. The predominant paradigm for interpreting bacterial diversity has been the clonal population structure, which has been modified by the incorporation of the effects of horizontal genetic exchange. Multilocus models of variable antigens, which explore the effects of immune selection, provide alternative explanations for structured diversity in pathogen populations.

Antigenic Variation in Plasmodium falciparum Malaria Involves a Highly Structured Switching Pattern

Many pathogenic bacteria, fungi, and protozoa achieve chronic infection through an immune evasion strategy known as antigenic variation. In the human malaria parasite Plasmodium falciparum, this involves transcriptional switching among members of the var gene family, causing parasites with different antigenic and phenotypic characteristics to appear at different times within a population. Here we use a genome-wide approach to explore this process in vitro within a set of cloned parasite populations. Our analyses reveal a non-random, highly structured switch pathway where an initially dominant transcript switches via a set of switch-intermediates either to a new dominant transcript, or back to the original. We show that this specific pathway can arise through an evolutionary conflict in which the pathogen has to optimise between safeguarding its limited antigenic repertoire and remaining capable of establishing infections in non-naïve individuals. Our results thus demonstrate a crucial role for structured switching during the early phases of infections and provide a unifying theory of antigenic variation in P. falciparum malaria as a balanced process of parasite-intrinsic switching and immune-mediated selection.

A strain theory of malaria transmission

Does the fact that the risk o f getting malaria is high in most endemic areas mean that it will be impossible to control through vaccination? Not if malaria is composed of several mildly transmissible strains, and what we are measuring as the high risk is the probability of being infected by any one of the several strains circulating independently within the same area. In this article, Sunetra Gupta and Karen Day discuss a strain theory of malaria transmission that fits both recent serological and molecular observations and more conventional epidemiological data on age distributions of infection and disease. Their analyses suggest that the transmissibility of malaria has been grossly overestimated, and that the control of malaria through vaccination may be far easier than previously assumed.

Acquisition of Streptococcus pneumoniae and nonspecific morbidity in infants and their families: a cohort study.

Background: Most children are believed to acquire Streptococcus pneumoniae asymptomatically, with only a few developing overt S. pneumoniae disease. This study investigates the relationship between acquisition of S. pneumoniae and mild nonspecific infection leading to general practitioner (GP) consultation. Methods: A prospective birth cohort study of 213 infants assessed at home 9 times during 24 weeks by nasopharyngeal swab and parental interview was conducted. Results: All positive S. pneumoniae swabs (including acquisition and carriage) were significantly associated with GP consultations for infection by the study infant compared with infants with negative swabs [odds ratio (OR), 1.6; 95% confidence interval (CI) 1.1–2.2; P = 0.005]. There was a stronger association with S. pneumoniae acquisition alone (OR 2.1; 95% CI 1.3–3.4; P = 0.001) than with carriage only (OR 1.4; 95% CI 0.9–2.0; P = 0.1). Multivariate analysis confirmed that S. pneumoniae acquisition by the study subject was independently associated with GP consultations: adjusted hazard ratio, 1.8 (95% CI 1.1–2.9); P = 0.02. A similar and independent association was found between S. pneumoniae acquisition by the study subject, and GP consultations for infection by the family (adjusted hazard ratio, 1.8; 95% CI 1.1–2.8; P = 0.01). Conclusion: Acquisition of S. pneumoniae by the study infant was significantly associated with GP consultations for infection by the infant or family.

Global migration and the changing distribution of sickle haemoglobin: a quantitative study of temporal trends between 1960 and 2000

Summary Background Changes in the geographical distribution of genetic disorders are often thought to happen slowly, especially when compared with infectious diseases. Whereas mutations, genetic drift, and natural selection take place over many generations, epidemics can spread through large populations within a few days or weeks. Nevertheless, population movements can interfere with these processes, and few studies have been done of their effect on genetic disorders. We aimed to investigate the effect of global migration on the distribution of the sickle-cell gene—the most common and clinically significant haemoglobin structural variant. Methods For each country, we extracted data from the World Banks Global Bilateral Migration Database about international human migrations between 1960 and 2000. We combined this information with evidence-based estimates of national HbS allele frequencies, generated within a Bayesian geostatistical framework, to analyse temporal changes in the net numbers of migrants, and classified countries with an index summarising these temporal trends. Findings The number of international migrants increased from 92·6 million in 1960, to 165·2 million in 2000. The estimated global number of migrants with HbS increased from about 1·6 million in 1960, to 3·6 million in 2000. This increase was largely due to an increase in the number of migrants from countries with HbS allele frequencies higher than 10%, from 3·1 million in 1960, to 14·2 million in 2000. Additionally, the mean number of countries of origin for each destination country increased from 70 (SE 46) in 1960, to 98 (48) in 2000, showing an increasing diversity in the network of international migrations between countries. Our index of change map shows a patchy distribution of the magnitude of temporal changes, with the highest positive and negative values scattered across all continents. Interpretation Global human population movements have had a substantial effect on the distribution of the HbS gene. Population movements can create a long-term burden on health-care systems. Our findings, which emphasise countries in which migration fluxes are changing the most, should increase awareness about the global burden of haemoglobinopathies and encourage policy makers to implement specific public health interventions, such as screening programmes and genetic counselling. Funding Wellcome Trust, European Research Council, Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases–National Institutes of Health, the Research and Policy for Infectious Disease Dynamics program, Fogarty International Center.