• The Effect of Drug Pressure and Transmission Setting on Sulfadoxine-Pyrimethamine Resistant Plasmodium falciparum Haplotype Prevalence and Selective Sweep Characteristics, in Malawi

      Artimovich, Elena M.; Takala-Harrison, Shannon (2014)
      Background: The continued expansion of resistance to anti-malarial chemotherapies is a threat to public health, and to malaria control and elimination. The reexpansion of drug sensitive parasites after the removal of drug pressure has renewed interest in epidemiological factors affecting resistance haplotype dynamics, in the hopes that previously abandoned drugs might once again find clinical utility. Objectives: Estimate the effect of changes in drug pressure and different malaria transmission settings on sulfadoxine-pyrimethamine (SP)-resistant haplotype prevalence and characteristics of selective sweeps. Methods: DNA was extracted from dried blood spots representing malaria infections from three time periods (high-SP use 1999-2001, transition-period 2007-2008, low-SP use 2012) of drug pressure in Malawi and three transmission settings (urban-low, rural-moderate, rural-high). Pyrosequencing and microsatellite genotyping were performed on all samples to determine haplotype prevalence and sweep characteristics. Changes in haplotype prevalence were assessed via Chi-squared tests and changes in sweep characteristics via permutation. Results: We observed the persistence of the DHFR 51I/59R/108N and DHPS 437G/540E haplotypes, five years after reduction in SP pressure as well as an increase in the prevalence of DHPS 437G/540E/581G haplotype. Selective sweeps indicated little to no fitness cost to the DHFR 51I/59R/108N and DHPS 437G/540E haplotypes in the absence of strong SP pressure. A decline in polyclonal infections was found across the three time periods. No significant difference in haplotype prevalence was found between transmission settings. Sweep characteristics could suggest divergent evolutionary history in the rural-moderate transmission setting. Conclusions: There is little to no fitness cost of SP-resistance in the absence of strong SP pressure in these three transmission settings within Malawi. The reexpansion of SP sensitive parasites in the region is not expected under current epidemiological conditions. Reduction in the amount of malaria in the region could further reduce the likelihood of reexpansion through the elimination of rare haplotypes due to genetic drift.
    • The Effect of Malaria During Pregnancy on Infant Susceptibility to Malaria

      Boudova, Sarah Elizabeth; Laufer, Miriam K. (2016)
      Malaria is a major cause of morbidity and mortality. Malaria during pregnancy threatens the health of both the mother and the child, with long-lasting consequences on infant health that may be attributable to the impact of maternal malaria on the fetal immune system. It is unknown what effect different manifestations of pregnancy-associated malaria have on child immunity and health. Moreover, the timing during pregnancy when malaria needs to be prevented to maximize mother-infant health is not known. In a longitudinal study in Malawi we examined the effect of maternal peripheral and placental malaria on infant risk of malaria, by following mother-infant pairs from early in pregnancy through the first two years of the child's life. We conducted active and passive surveillance for malaria infection and disease. We assessed the concentrations of serum cytokines (IFNγ, IL13, IL12p70, IL10, IL1β, IL2, IL4, IL6, TNFα, CRP and TGFβ) in cord blood, as well as peripheral blood drawn at one year of age. One in five women was infected with malaria at the first antenatal visit and this frequency decreased immediately following a universal bed net campaign. Children born to mothers with placental malaria, but not children born to mothers with peripheral malaria, were at increased risk of malaria during infancy as compared to those born to mothers with no malaria. Most cases of placental malaria were cleared by delivery. Children born to mothers with chronic placental malaria had elevated levels of TNFα, CRP and IL10 and a significantly decreased TNFα:IL10 ratio as compared to those born to mothers with peripheral malaria or no malaria. These differences in cytokine profile at birth disappeared by one year of age. We found no association between cytokine concentrations at birth and increased risk of malaria in infancy. We hypothesize that placental malaria, even early in pregnancy, causes cytokine dysregulation and induction of long-lived cellular alterations that are maintained in infancy, leading to increased risk of malaria. Our findings have direct public health significance. Interventions need to target all women of childbearing age and prevent all placental malaria in order to maximize the health of mother and child.
    • Epidemiology of Plasmodium falciparum infection and clinical malaria among infants in Malawi

      Andronescu, Liana; Laufer, Miriam K.; 0000-0003-3342-7820 (2021)
      Background: Few malaria interventions are designed to target infants under six months. The burden of malaria in infancy and its long-term health impact needs to be better characterized to inform surveillance and treatment guidelines for this age group. Objectives: The aims of this study were to (a) assess the effect of intermittent preventive treatment during pregnancy (IPTp) regimens on the risk of malaria in infancy, (b) characterize P. falciparum infection and clinical malaria in the first six months and the risk of subsequent malaria, and (c) assess effects of P. falciparum infection and clinical malaria exposure in first six months on weight and hemoglobin concentration after six months. Methods: Longitudinal cohort data collected from infants in southern Malawi between 2016 and 2019 was analyzed using Cox proportional hazards models, Poisson generalized estimating equations with a log link function, and linear mixed effects models. Results: Maternal IPTp regimen had no effect on infant incidence of clinical malaria (IRR=1.03; 95%CI: 0.58–1.86) or incidence of P. falciparum infection (IRR=1.18; 95%CI: 0.92–1.55) before two years. Maternal IPTp was not significantly associated with infant’s time to first infection (HR=1.05; 95%CI: 0.8–1.39) or clinical malaria (HR=0.92; 95%CI: 0.58–1.48). Exposure to any malaria before six months was associated with higher incidence of any malaria (IRR=1.27; 95%CI: 1.06–1.52) and clinical malaria (IRR=1.76; 95%CI: 1.42–2.19) between 6 and 24 months. Clinical malaria exposure before first six months was also associated with higher incidence of any malaria (IRR=1.64; 95%CI: 1.38–1.94) and clinical malaria (IRR=1.85, 95%CI:1.48–2.32) between 6 and 24 months. Exposure to asymptomatic P. falciparum infection before six months was associated with lower weight-for-age z-scores during follow-up (p=0.02) and exposure to clinical malaria before six months was associated with lower hemoglobin concentrations during follow-up (p=0.02). Conclusion: Prevention of malaria during pregnancy does not reduce infant risk of malaria and malaria infection before six months is associated with higher malaria incidence, lower weight-for-age Z-scores, and lower hemoglobin concentrations in early childhood. Early malaria infection may be an indication of high exposure risk and a marker for downstream health outcomes.
    • Malaria Transmission in Households in Blantyre, Malawi

      Cassin, Jessica Bailey Walters; Laufer, Miriam K. (2012)
      Although great strides have been made in the reduction of the worldwide burden of malaria disease, a better understanding of the epidemiology of malaria is needed to continue the fight against the disease. Specifically, insight into the transmission of malaria within households might offer new targets of malaria intervention, and policy changes aimed at the control of the spreading antimalarial resistance. To this end, this study examines the relationship between malaria infection and household exposure in Blantyre, Malawi. Blood samples were collected from children and their caregivers for analysis using six neutral, unlinked microsatellite markers. Parasites within infections were genotyped and the infections in children were compared to infections in their caregivers to determine the number of microsatellites shared between the two infections, a marker for the genetic relationship of the two infections. The comparison of genotype between infections, allows a specific infection to be tracked through the human-vector-human transmission cycle. The mean proportion of parasite alleles shared for individuals residing in the same house was compared to that of individuals residing in different households. Overall, children had infections that were more similar to their parents than to that of other caregiver in the population (p value =.036). This indicates that intra-household malaria infections are more similar than inter-household malaria infection and suggests that individuals in the household are a source of malaria infection within the household. For half of the occurrences of shared infections, the parasite was found in both caregiver and child at the same time, a synchronous exposure indicating a shared exposure either within the area or travel outside of the Blantyre area. The results provide encouraging indications that future research may yield new information that will be influential in reducing the burden of malaria disease worldwide through policy decisions regarding parasite control and the prevention of the spread of antimalarial resistance. Further research is needed to assess the intra-household source of infection, and validate the study in other populations.