Higher platelet counts and platelet factors are associated with a reduction in Plasmodium falciparum parasite density in young Malian children.

OBJECTIVES: The association between thrombocytopenia and parasite density or disease severity is described in numerous studies. In recent years, several studies described the protective role of platelets in directly killing Plasmodium parasites, mediated by platelet factor 4 (PF4) binding to Duffy antigen. This study aimed to evaluate the protective role of platelets in young children who are Duffy antigen-negative, such as those in sub-Saharan Africa. METHODS: A zero-inflated negative binomial model was used to relate platelet count and parasite density data collected in a longitudinal birth cohort. Platelet factors were measured by enzyme-linked immunosorbent assay in samples collected from malaria-infected children who participated in a cross-sectional study. RESULTS: We described that an increase of 10,000 platelets/µl was associated with a 2.76% reduction in parasite count. Increasing levels of PF4 and CXCL7 levels were also significantly associated with a reduction in parasite count. CONCLUSIONS: Platelets play a protective role in reducing parasite burden in Duffy-negative children, possibly mediated through activation of the innate immune system.

Acquisition of antibodies that block Plasmodium falciparum adhesion to placental receptor chondroitin sulfate A with increasing gravidity in Malian women.

In malaria-endemic areas, pregnant women are more susceptible to Plasmodium falciparum infection, especially primigravidae. During pregnancy, parasites sequester in the placenta and bind to the receptor chondroitin sulfate (CSA). This unique adhesion is mediated by the parasite protein VAR2CSA expressed on the surface of infected erythrocytes (IE). Placental malaria is associated with poor pregnancy outcomes including perinatal mortality, preterm delivery, small for gestational age (SGA) and low birthweight deliveries. Over successive pregnancies, women acquire functional antibodies that inhibit IE adhesion to CSA. Here, we examine the development of anti-adhesion activity and the breadth of anti-adhesion activity as a function of number of previous pregnancies, using samples collected from pregnant women living in an area with high seasonal malaria transmission. Women reached plateau levels of anti-adhesion activity and breadth of anti-adhesion activity after 5 pregnancies. We related the level of anti-adhesion activity and reactivity with surface IE to SGA 19/232 pregnancies resulted in SGA, and report that an increase of 10% in median anti-adhesion activity reduced the odds of SGA by 13% and this relationship approached significance. Further, at an anti-adhesion activity level of 43.7%, an increase of 10% in the breadth of activity significantly reduced the odds of SGA by 21.5%. Antibodies that recognize IE surface increased over successive pregnancies, but were not associated with a reduction in SGA. These results can serve as a guideline for assessing vaccine candidates aiming to reduce poor pregnancy outcomes associated with placental malaria.

Recent malaria does not substantially impact COVID-19 antibody response or rates of symptomatic illness in communities with high malaria and COVID-19 transmission in Mali, West Africa.

Malaria has been hypothesized as a factor that may have reduced the severity of the COVID-19 pandemic in sub-Saharan Africa. To evaluate the effect of recent malaria on COVID-19 we assessed a subgroup of individuals participating in a longitudinal cohort COVID-19 serosurvey that were also undergoing intensive malaria monitoring as part of antimalarial vaccine trials during the 2020 transmission season in Mali. These communities experienced a high incidence of primarily asymptomatic or mild COVID-19 during 2020 and 2021. In 1314 individuals, 711 were parasitemic during the 2020 malaria transmission season; 442 were symptomatic with clinical malaria and 269 had asymptomatic infection. Presence of parasitemia was not associated with new COVID-19 seroconversion (29.7% (211/711) vs. 30.0% (181/603), p=0.9038) or with rates of reported symptomatic seroconversion during the malaria transmission season. In the subsequent dry season, prior parasitemia was not associated with new COVID-19 seroconversion (30.2% (133/441) vs. 31.2% (108/346), p=0.7499), with symptomatic seroconversion, or with reversion from seropositive to seronegative (prior parasitemia: 36.2% (64/177) vs. no parasitemia: 30.1% (37/119), p=0.3842). After excluding participants with asymptomatic infection, clinical malaria was also not associated with COVID-19 serostatus or symptomatic seroconversion when compared to participants with no parasitemia during the monitoring period. In communities with intense seasonal malaria and a high incidence of asymptomatic or mild COVID-19, we did not demonstrate a relationship between recent malaria and subsequent response to COVID-19. Lifetime exposure, rather than recent infection, may be responsible for any effect of malaria on COVID-19 severity.

Safety, reactogenicity and immunogenicity of 2-dose catch-up vaccination with 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Malian children in the second year of life: Results from an open study.

Pneumonia is still the leading cause of death among African children with pneumococcal serotypes 1 and 5 being dominant in the below 5 y of age group. The present study assessed the safety, reactogenicity and immunogenicity of a 2-dose catch-up vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) in Malian children. This phase III, open-label study (NCT00985465) was conducted in Ouelessebougou, Mali, between November 2009 and July 2010. The study population consisted of PHiD-CV unprimed Malian children previously enrolled in the control group of study NCT00678301 receiving a 2-dose catch-up vaccination with PHiD-CV in the second year of life. Adverse events were recorded following each PHiD-CV dose. Antibody responses and opsonophagocytic activity (OPA) were measured pre-vaccination and after the second PHiD-CV catch-up dose. Swelling and fever (axillary temperature ≥ 37.5°C) were the most frequently reported solicited symptoms following either PHiD-CV dose. Few grade 3 solicited symptoms were reported. Large swelling reactions and serious adverse events were not reported. Post-catch-up vaccination, for each vaccine pneumococcal serotype, at least 94.7% of subjects had antibody concentrations ≥ 0.2 µg/ml, except for serotypes 6B (82.5%) and 23F (87.7%). At least 94.0% of subjects had OPA titres ≥ 8, except for serotype 19F (89.4%). The geometric mean concentration for antibodies against protein D was 839.3 (95% CI: 643.5-1094.6) EL.U/ml. Two-dose PHiD-CV catch-up regimen in the second year of life was well-tolerated and immunogenic for all vaccine pneumococcal serotypes and NTHi protein D when administered to Malian children.

Safety, reactogenicity and immunogenicity of a booster dose of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Malian children.

BACKGROUND: Primary vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) was previously shown to be immunogenic and well tolerated in Malian children. Data on booster vaccination with a fourth consecutive dose of PHiD-CV are available for Europe, Asia and Latin America but are lacking for Africa. The present study evaluated further the safety, reactogenicity and immunogenicity of a fourth consecutive (booster) dose of PHiD-CV. RESULTS: Low incidences of AEs with grade 3 intensity (2.1% of subjects) were observed. There were no reports of large swelling reactions and serious adverse events. One month post-booster vaccination, for each vaccine pneumococcal serotype, at least 97.8% of subjects had antibody concentrations ≥ 0.2 µg/ml, and at least 97.1% of subjects had opsonophagocytic activity ≥ 8. From pre- to post-booster, a 12.3-fold increase in anti-protein D geometric mean concentration was observed. METHODS: This phase III, open-label study was conducted in Ouelessebougou, Mali, between November 2009 and June 2010. The study population consisted of Malian children previously primed (3 doses) with PHiD-CV in study NCT00678301 receiving a fourth consecutive (booster) dose of PHiD-CV in the second year of life. The incidences of adverse events (AEs) with grade 3 intensity (primary objective) or of any intensity (secondary objective), and the immunogenicity (secondary objective) of the PHiD-CV booster dose were assessed. CONCLUSION: A booster dose of PHiD-CV was well tolerated when administered to Malian children in the second year of life and was highly immunogenic for all 10 vaccine pneumococcal serotypes and NTHi protein D. (ClinicalTrials.gov identifier: NCT00985465).

Primary vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in infants in Mali and Nigeria: a randomized controlled trial.

BACKGROUND: Pneumonia is still the leading cause of death among children in Africa, and pneumococcal serotypes 1 and 5 are frequently isolated from African children with invasive pneumococcal disease below the age of 5 years. The immunogenicity, safety and reactogenicity of 3-dose primary vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) were evaluated in infants in Mali and Nigeria. METHODS: In an open, randomized, controlled study, 357 infants received DTPw-HBV/Hib and OPV primary vaccination with (PHiD-CV group) or without (control group) PHiD-CV co-administration at 6, 10 and 14 weeks of age. Pneumococcal antibody responses and opsonophagocytic activity (OPA) were measured and adverse events (AEs) recorded. RESULTS: One month post-dose 3, ≥ 97.2% of PHiD-CV-vaccinated infants had an antibody concentration ≥ 0.2 µg/mL for each vaccine pneumococcal serotype except for 6B (82.0%) and 23F (87.6%) versus < 10% in the control group except for serotypes 14 (35.7%) and 19F (22.5%). For each vaccine serotype, ≥ 93.3% of PHiD-CV recipients had an OPA titre ≥ 8, except for serotypes 1 (87.6%) and 6B (85.4%), compared to < 10% in the control group, except for serotypes 7F (42.9%), 9V (24.1%) and 14 (24.5%). Anti-protein D geometric mean antibody concentrations were 3791.8 and 85.4 EL.U/mL in the PHiD-CV and control groups, respectively. Overall incidences of solicited and unsolicited AEs were similar between groups. CONCLUSIONS: In sub-Saharan African infants, PHiD-CV was immunogenic for all vaccine pneumococcal serotypes and protein D. Vaccine tolerability was generally comparable between the PHiD-CV and control groups. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00678301.

Malaria morbidity in children in the year after they had received intermittent preventive treatment of malaria in Mali: a randomized control trial.

BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc) is a promising strategy for malaria control. A study conducted in Mali in 2008 showed that administration of three courses of IPTc with sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals reduced clinical malaria, severe malaria and malaria infection by >80% in children under 5 years of age. Here we report the results of a follow-on study undertaken to establish whether children who had received IPTc would be at increased risk of malaria during the subsequent malaria transmission season. METHODS: Morbidity from malaria and the prevalence of malaria parasitaemia and anaemia were measured in children who had previously received IPTc with SP and AQ using similar surveillance methods to those employed during the previous intervention period. RESULTS: 1396 of 1508 children (93%) who had previously received IPTc and 1406 of 1508 children (93%) who had previously received placebos were followed up during the high malaria transmission season of the year following the intervention. Incidence rates of clinical malaria during the post-intervention transmission season (July-November 2009) were 1.87 (95% CI 1.76-1.99) and 1.73 (95% CI; 1.62-1.85) episodes per child year in the previous intervention and placebo groups respectively; incidence rate ratio (IRR) 1.09 (95% CI 0.99-1.21) (P = 0.08). The prevalence of malaria infection was similar in the two groups, 7.4% versus 7.5%, prevalence ratio (PR) of 0.99 (95% CI 0.73-1.33) (P = 0.95). At the end of post-intervention malaria transmission season, the prevalence of anaemia, defined as a haemoglobin concentration<11g/dL, was similar in the two groups (56.2% versus 55.6%; PR = 1.01 [95% CI 0.91-1.12]) (P = 0.84). CONCLUSION: IPTc with SP+AQ was not associated with an increase in incidence of malaria episodes, prevalence of malaria infection or anaemia in the subsequent malaria transmission season. TRIAL REGISTRATION: ClinicalTrials.gov NCT00738946.

Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established. METHODS AND FINDINGS: To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3-59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76-2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29-0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%-85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%-99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%-92%) (p<0.001) during the intervention period and by 46% (95% CI 31%-68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%-67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event. CONCLUSIONS: IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT00738946. Please see later in the article for the Editors' Summary.