Age of Exposure and Immunity to Malaria in Infants

Study Overview
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Brief Summary
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The overall objective is to evaluate the effect of exposure to Plasmodium (P.) falciparum erythrocytic stage antigens during different periods of infancy on the development of naturally acquired immunity (NAI). Hypothesis: Exposure to P. falciparum prior to 5 months of age does not result in the development of NAI, while exposure to P. falciparum after 5 months of age leads to the development of NAI. The risks of clinical malaria and anaemia during the second year of life will be compared between cohorts, as well as their correlations with the type and quality of immune responses (antibodies to several P. falciparum antigens, cytokines), oxidative stress markers and host genetic factors. These results should shed light on the determinants of the development of anti-P. falciparum responses early in life and the potential constraints to early life immunisation.

Official Title
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Age of Exposure and Immunity to Malaria in Infants

Conditions
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Malaria

Intervention / Treatment
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* Drug: Sulfadoxine-pyrimethamine (SP) + Artesunate (AS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for pregnant women: Healthy HIV-negative pregnant females less than 50 years of age who attend the voluntary counseling and testing (VCT) center at the Maragra or Manhiça antenatal clinic, Permanent residents of the Manhiça area and expecting to be living in the area with their infant for at least 2 years. Inclusion criteria for newborn infants: Healthy infants, weighing >= 2 kg and having an alive mother. Exclusion Criteria: Exclusion criteria for pregnant women: Plan to leave the area in less than 2 years from the start of the study; Women not willing to get tested for HIV infection at the VCT center; Test positive for HIV; Not willing to provide informed consent; Cannot understand either Portuguese or Changana (consent forms are written in these languages). Exclusion criteria for newborn infants: Any obvious congenital malformation; Any signs of cerebral asphyxia; Any obvious neonatal infection; Same gender Twins; Low birth weight (<2 kg).

Ages Eligible for Study
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Maximum Age: 1 Week

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Late exposure group<br>Participants received monthly Sulfadoxine-Pyrimethamine (SP) plus Artesunate (AS) from 2.5-4.5 months of age and monthly placebo from 5.5-9.5 months of age. | Drug: Sulfadoxine-pyrimethamine (SP) + Artesunate (AS)<br>* Monthly chemoprophylaxis with SP (Fansidar® 500/25 mg) plus Artesunate (AS, Arsumax® 50 mg) or placebo (provided by Roche and Sanofi-Aventis) was administered according to the following age-based dosing schedule: ½ tablet of SP or placebo and ½ tablet of AS or placebo on the first day and ½ tablet of AS or placebo on the second and third days.<br>|
| Experimental: Early exposure group<br>Participants received monthly placebo from 2.5-4.5 months of age and monthly SP+AS from 5.5-9.5 months of age. | Drug: Sulfadoxine-pyrimethamine (SP) + Artesunate (AS)<br>* Monthly chemoprophylaxis with SP (Fansidar® 500/25 mg) plus Artesunate (AS, Arsumax® 50 mg) or placebo (provided by Roche and Sanofi-Aventis) was administered according to the following age-based dosing schedule: ½ tablet of SP or placebo and ½ tablet of AS or placebo on the first day and ½ tablet of AS or placebo on the second and third days.<br>|
| Placebo Comparator: Control group<br>Participants received monthly placebo from 2.5 to 9.5 months of age. | Drug: Sulfadoxine-pyrimethamine (SP) + Artesunate (AS)<br>* Monthly chemoprophylaxis with SP (Fansidar® 500/25 mg) plus Artesunate (AS, Arsumax® 50 mg) or placebo (provided by Roche and Sanofi-Aventis) was administered according to the following age-based dosing schedule: ½ tablet of SP or placebo and ½ tablet of AS or placebo on the first day and ½ tablet of AS or placebo on the second and third days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Clinical) Time to first or only episode of clinical malaria in the second year of life detected by passive case detection | Global comparison between the 3 groups of the time to first or only episode of clinical malaria (according to the primary case definition) in the second year of follow up detected by passive case detection in the According-To-Protocol cohort. In addition, pairwise comparisons of the 3 groups are also presented. | from 12 to 24 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Clinical) Time to first or only episode of malaria (using other case definitions), anaemia and other clinical endpoints. | Global comparison between the 3 study groups of the time to first or only episode of clinical malaria (according to the secondary case definitions) in the second year of follow up detected by passive case detection. Other endpoints include multiple episodes of malaria, time to first or only episode of anaemia, total hospital visits and prevalence of parasitaemia and anaemia at different time points. In addition, pairwise comparisons of the 3 groups are also presented. | 12 to 24 months of age | 
| Oxidative stress markers | Quantification of the antioxidant/pro-oxidant status over the first two years of life in relation to age of first exposure to infection. | multiple time points during the first two years of life (2.5, 5.5, 10.5, 15 and 24 months of age) | 
| Humoral and cellular immune responses | Quantification of antibody and cytokine responses to P. falciparum protein antigens and toxins over the first two years of life in relation to age of first exposure to infection | multiple time points during the first two years of life (2.5, 5.5, 10.5, 15 and 24 months of age) | 
| Host genetics | Analysis of haematological genetic factors, polymorphisms in genes involved in inflammatory or immunological responses to malaria and polymorphisms in genes involved in the Th1/Th2 immunological pathway. | 2.5 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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natural acquired immunity,, clinical malaria,, P. falciparum,, age,, exposure,, neonatal immunology,, infants