Assessing the Relationship Between Gravidity and Placental Malaria Among Pregnant Women in a High Transmission Area in Ghana

Background Malaria infection during pregnancy can cause significant morbidity and mortality to a pregnant woman, her foetus and newborn. In areas of high endemic transmission, gravidity is an important risk factor for infection, but there is a complex relationship with other exposure-related factors, and use of protective measures. This study investigated the association between gravidity and placental malaria (PM), among pregnant women aged 14-49 in Kintampo, a high transmission area of Ghana. Methods Between 2008-2011, as part of a study investigating the association between PM and malaria in infancy, pregnant women attending antenatal care (ANC) clinics in the study area were enrolled and followed up until delivery. The outcome of PM was assessed at delivery by placental histopathology. Multivariable logistic regression analyses were used to investigate the association between gravidity and PM, identify other key risk factors, and control for potential confounders. Pre-specified effect modifiers including area of residence, socio-economic score (SES), ITN use and IPTp-SP use were explored. Results The prevalence of PM was 65.9% in primigravidae, and 26.5% in multigravidae. After adjusting for age, SES and relationship status, primigravidae were shown to have over three times the odds of PM compared to multigravidae, defined as women with 2 or more previous pregnancies (adjusted OR=3.36 (95% CI 2.39-4.71), N=1808, P<0.001). The association appeared stronger in rural areas (OR for PG vs. MG was 3.79 (95% CI: 3.61-5.51) in rural areas; 2.09 (95% CI: 1.17- 3.71) in urban areas; P for interaction =0.07), and among women with lower socio-economic scores (OR for PG vs. MG was 4.73 (95% CI 3.08-7.25) amongst women with lower SES; OR=2.14 (95% CI 1.38-3.35) among women with higher SES; P for interaction =0.008. There was also evidence of lower risk among primigravidae with better use of the current preventive measures IPTp and LLIN. Conclusions The burden of PM is most heavily focused on primigravidae of low SES living in rural areas of high transmission. Programmes should prioritize primigravidae and young women of child-bearing age for interventions such as LLIN distribution, educational initiatives and treatment to reduce the burden of malaria in first pregnancy.

Comparison of the impact of allelic polymorphisms in PfAMA1 on the induction of T Cell responses in high and low malaria endemic communities in Ghana

Background Malaria eradication requires a combined effort involving all available control tools, and these efforts would be complemented by an effective vaccine. The antigen targets of immune responses may show polymorphisms that can undermine their recognition by immune effectors and hence render vaccines based on antigens from a single parasite variant ineffective against other variants. This study compared the influence of allelic polymorphisms in Plasmodium falciparum apical membrane antigen 1 (PfAMA1) peptide sequences from three strains of P. falciparum (3D7, 7G8 and FVO) on their function as immunodominant targets of T cell responses in high and low malaria transmission communities in Ghana. Methods Peripheral blood mononuclear cells (PBMCs) from 10 subjects from a high transmission area (Obom) and 10 subjects from a low transmission area (Legon) were tested against 15 predicted CD8 + T cell minimal epitopes within the PfAMA1 antigen of multiple parasite strains using IFN-γ ELISpot assay. The peptides were also tested in similar assays against CD8 + enriched PBMC fractions from the same subjects in an effort to characterize the responding T cell subsets. Results In assays using unfractionated PBMCs, two subjects from the high transmission area, Obom, responded positively to four (26.7%) of the 15 tested peptides. None of the Legon subject PBMCs yielded positive peptide responses using unfractionated PBMCs. In assays with CD8 + enriched PBMCs, three subjects from Obom made positive recall responses to six (40%) of the 15 tested peptides, while only one subject from Legon made a positive recall response to a single peptide. Overall, 5 of the 20 study subjects who had positive peptide-specific IFN-γ recall responses were from the high transmission area, Obom. Furthermore, while subjects from Obom responded to peptides in PfAMA1 from multiple parasite strains, one subject from Legon responded to a peptide from 3D7 strain only. Conclusions The current data demonstrate the possibility of a real effect of PfAMA1 polymorphisms on the induction of T cell responses in malaria exposed subjects, and this effect may be more pronounced in communities with higher parasite exposure.

Impact of Community-Based Mass Testing and Treatment on Malaria Infection Prevalence in a High-Transmission Area of Western Kenya: A Cluster Randomized Controlled Trial

Background Global gains toward malaria elimination have been heterogeneous and have recently stalled. Interventions targeting afebrile malaria infections may be needed to address residual transmission. We studied the efficacy of repeated rounds of community-based mass testing and treatment (MTaT) on malaria infection prevalence in western Kenya. Methods Twenty clusters were randomly assigned to 3 rounds of MTaT per year for 2 years or control (standard of care for testing and treatment at public health facilities along with government-sponsored mass long-lasting insecticidal net [LLIN] distributions). During rounds, community health volunteers visited all households in intervention clusters and tested all consenting individuals with a rapid diagnostic test. Those positive were treated with dihydroartemisinin-piperaquine. Cross-sectional community infection prevalence surveys were performed in both study arms at baseline and each year after 3 rounds of MTaT. The primary outcome was the effect size of MTaT on parasite prevalence by microscopy between arms by year, adjusted for age, reported LLIN use, enhanced vegetative index, and socioeconomic status. Results Demographic and behavioral characteristics, including LLIN usage, were similar between arms at each survey. MTaT coverage across the 3 annual rounds ranged between 75.0% and 77.5% in year 1, and between 81.9% and 94.3% in year 2. The adjusted effect size of MTaT on the prevalence of parasitemia between arms was 0.93 (95% confidence interval [CI], .79–1.08) and 0.92 (95% CI, .76–1.10) after year 1 and year 2, respectively. Conclusions MTaT performed 3 times per year over 2 years did not reduce malaria parasite prevalence in this high-transmission area. Clinical Trials Registration NCT02987270.

The Role of Complement Immune Response on Artemisinin Combination Therapy in a Population from Malaria Endemic Region of Western Kenya

BACKGROUND Naturally acquired immunity which is characterized by protection against overt clinical disease and high parasitemia is acquired with age and transmission intensity. The role of naturally acquired immunity on the efficacy of antimalarial drugs including artemisinin combination therapies (ACTs), the first-line treatments for uncomplicated Plasmodium falciparum has been demonstrated. This study investigated the role of naturally acquired immunity in the response to malaria ACT drug treatment in symptomatic patients living in a malaria high-transmission area of Western Kenya. METHODS This study used samples obtained from a therapeutic efficacy study conducted in western Kenya, an areas of high transmission which assessed ACTs. Sera samples from malaria immune (n = 105) and naïve participants (n = 6) were assessed for in vitro growth inhibitory activity against 3 D7 P. falciparum using a fluorescent-based Growth Inhibition Assay (GIA). Participants’ age and parasite clearance parameters were used in the analysis. RESULTS The key observations of the study are: (1) Sera with intact complement displayed higher GIA activity at lower serum dilutions; (2) there was significant relationship between GIA activity, parasite clearance rate, and slope half-life; (3) Age was a confounding factor when comparing the GIA activity with parasite clearance kinetics. CONCLUSION Taken together, this study demonstrates for the first time there is synergy of complement, pre-existing immunity, and drug treatment in younger patients with symptomatic malaria in a high-transmission area.

The Role of Complement Immune Response on Artemisinin Combination Therapy in a Population from Malaria Endemic Region of Western Kenya

BACKGROUND: Naturally acquired immunity which is characterized by protection against overt clinical disease and high parasitemia is acquired with age and transmission intensity. The role of naturally acquired immunity on the efficacy of antimalarial drugs including artemisinin combination therapies (ACTs), the first-line treatments for uncomplicated Plasmodium falciparum has been demonstrated. This study investigated the role of naturally acquired immunity in the response to malaria ACT drug treatment in symptomatic patients living in a malaria high-transmission area of Western Kenya.METHODS: This study used samples obtained from a therapeutic efficacy study conducted in western Kenya, an areas of high transmission which assessed ACTs. Sera samples from malaria immune (n = 105) and naïve participants (n = 6) were assessed for in vitro growth inhibitory activity against 3D7 P. falciparum using a fluorescent-based Growth Inhibition Assay (GIA). Participants’ age and parasite clearance parameters were used in the analysis.RESULTS: The key observations of the study are: (1) Sera with intact complement displayed higher GIA activity at lower serum dilutions; (2) there was significant relationship between GIA activity, parasite clearance rate, and slope half-life; (3) Age was a confounding factor when comparing the GIA activity with parasite clearance kinetics.CONCLUSION: Taken together, this study demonstrates for the first time there is synergy of complement, pre-existing immunity, and drug treatment in younger patients with symptomatic malaria in a high-transmission area.