RTSS Vaccine and PBO Net Impact on Malaria Infection and Transmission in Malawi

Study Overview
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Brief Summary
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The overall goal of this study is to assess the impact of RTS,S (malaria) vaccination and PBO nets on malaria infection and transmission, independently and how they interact when they are introduced together. The specific objectives for the study are as follows: To estimate the impact of PBO nets and RTS,S vaccine on Plasmodium infection prevalence and transmission, independently and how they interact when they are introduced together in Malawi (Phase 1). To assess the feasibility of evaluating the impact of RTS,S vaccine and PBO nets independently in a larger scale future study.

Detailed Description
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Introduction: The decline in malaria incidence has stalled globally and incidence is increasing in some high transmission settings of sub-Saharan Africa, including Malawi. The situation is worsening despite the scale-up of previously effective interventions, raising concerns that the impact of current malaria control and prevention strategies maybe compromised. Problem: There is an urgent need for innovative approaches to malaria control and Malawi is currently positioned to assess two of the most promising new interventions. The Malawi Ministry of Health (MOH) is launching large scale projects to evaluate a new formulation of insecticide-treated bed nets with a chemical synergist, piperonyl butoxide (PBO), designed to enhance the insecticidal effect of pyrethroids and the new malaria vaccine RTS,S (RTS,S). In an effort to gain the most information from these, interventions Malawi's National Malaria Control Programme (NMCP) have invited the Malawi International Center for Excellence in Malaria Research (ICEMR) to evaluate the effectiveness of the two interventions (alone and in combination) on malaria prevalence and transmission. Objective: In this proposed implementation study, we propose to assess the impact of PBO nets and RTS,S vaccine on Plasmodium infection prevalence and transmission. Study type and methodology: We will enroll children in a prospective cohort study in which the follow-up will be at the 2nd, 4th, and 6th month. We are selecting two health center catchment areas: one in which both RTS,S and PBO nets are available through the government health system and one in which there is no RTS,S vaccine available and standard long-lasting insecticide-treated nets (LLINS) have been distributed through the public section. At each visit, we will collect specimens to identify malaria infection and detect gametocyte infections. We will also collect and analyze mosquitoes from 100 households in both catchment areas to provide an entomological evidence of the force of infection. Children in households that are scheduled to receive both PBO nets and RTS,S vaccine will be compared to children in households that are not scheduled to receive either of these interventions.

Official Title
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Combined Effects of RTS,S Vaccination and PBO Nets on Malaria Infection and Transmission in Malawi

Conditions
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Malaria, Malaria Vaccine, Insecticide-treated Bednets

Intervention / Treatment
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* Biological: RTS,S/AS01 malaria vaccine
* Other: PBO bed nets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 7 to 18 months of age (age-eligible for at least 3 doses of RTS,S doses) OR being one of not more than two children living in the household of an enrolled age-eligible child and being >18 mos and < 10 years of age. Not on cotrimoxazole prophylaxis for HIV infection Weight >5 kg Permanent residence of Health Centre (HC) catchment area Residence within 10 km from the HC Written informed consent from parent/guardian for the child to participate in the study Exclusion Criteria: Non-residents of the catchment area and visitors to the study area will be excluded because the study requires follow-up for at least 6 months and access to interventions such as conventional, PBO nets and malaria vaccination.

Ages Eligible for Study
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Minimum Age: 7 Months
Maximum Age: 10 Years

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Nyambi, rainy season<br>250 children of age-eligible for RTS,S vaccine (7-18 months) 500 siblings (>18 months, < 10 years of age) The duration of the cohort is six months. | Biological: RTS,S/AS01 malaria vaccine<br>* Malaria vaccine: RTS,S is a subunit vaccine that includes a portion of the circumsporozoite protein (CSP) co-expressed with Hepatitis B surface antigen combined with an adjuvant. The Phase 3 trial of three doses administered to 5-17-month-olds confirmed moderate protection, with overall efficacy estimates of 50.4% against clinical malaria and 34.8% against severe malaria after three doses. Efficacy, which waned over time, was marginally improved by boosting at 18 months. The European Medicines Agency adopted a positive scientific opinion of the vaccine for use outside of the European Union. The World Health Organization has created the Malaria Vaccine Implementation Program (MVIP) and selected Malawi as one of the sites to explore the feasibility, efficacy and safety of RTS,S vaccination in the context of routine use.<br>* Other names: RTS,S;Other: PBO bed nets<br>* PBO nets: The PBO nets represent a new formulation of insecticide-treated bed nets with a chemical synergist, piperonyl butoxide (PBO), designed to enhance the insecticidal effect of pyrethroids. They seem to be helpful in areas like Malawi where insecticide-resistance is increasing. PBO inhibits the enzyme that detoxifies the pyrethroid, allowing the pyrethroid to act on the mosquito. The impact of PBO net use was also detectable in key entomological measures including Anopheles density, sporozoite rate and entomological inoculation rates. Following these promising preliminary results in Tanzania, Malawi's National Malaria Control Program (NMCP) is piloting the use of PBO-nets iin one of our two study sites, presenting us with the opportunity to study the effectiveness of these nets in the context of real-world program setting<br>|
| Nyambi, dry season<br>250 children of age-eligible for RTS,S vaccine (7-18 months) 500 siblings (>18 months, < 10 years of age) The duration of the cohort is six months. | Biological: RTS,S/AS01 malaria vaccine<br>* Malaria vaccine: RTS,S is a subunit vaccine that includes a portion of the circumsporozoite protein (CSP) co-expressed with Hepatitis B surface antigen combined with an adjuvant. The Phase 3 trial of three doses administered to 5-17-month-olds confirmed moderate protection, with overall efficacy estimates of 50.4% against clinical malaria and 34.8% against severe malaria after three doses. Efficacy, which waned over time, was marginally improved by boosting at 18 months. The European Medicines Agency adopted a positive scientific opinion of the vaccine for use outside of the European Union. The World Health Organization has created the Malaria Vaccine Implementation Program (MVIP) and selected Malawi as one of the sites to explore the feasibility, efficacy and safety of RTS,S vaccination in the context of routine use.<br>* Other names: RTS,S;Other: PBO bed nets<br>* PBO nets: The PBO nets represent a new formulation of insecticide-treated bed nets with a chemical synergist, piperonyl butoxide (PBO), designed to enhance the insecticidal effect of pyrethroids. They seem to be helpful in areas like Malawi where insecticide-resistance is increasing. PBO inhibits the enzyme that detoxifies the pyrethroid, allowing the pyrethroid to act on the mosquito. The impact of PBO net use was also detectable in key entomological measures including Anopheles density, sporozoite rate and entomological inoculation rates. Following these promising preliminary results in Tanzania, Malawi's National Malaria Control Program (NMCP) is piloting the use of PBO-nets iin one of our two study sites, presenting us with the opportunity to study the effectiveness of these nets in the context of real-world program setting<br>|
| Kalembo, rainy season<br>250 children of age-eligible for RTS,S vaccine (7-18 months) 500 siblings (>18 months, < 10 years of age) The duration of the cohort is six months. | |
| Kalembo, dry season<br>250 children of age-eligible for RTS,S vaccine (7-18 months) 500 siblings (>18 months, < 10 years of age) The duration of the cohort is six months. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Malaria infection prevalence | Comparison of malaria infection prevalence in RTS/S cohorts compared to cohorts not exposed to RTS,S | 6 months/cohort, 4 cohorts in Phase 1 | 
| Anopheles species abundance | Comparison of Anopheles captured in households with PBO nets compared to household with conventional nets | 6 months/cohort, 4 cohorts in Phase 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gametocyte prevalence | Comparison of the prevalence of gametocytes (male and female) in cohorts exposed to RTS,S vs those not exposed | 6 months/cohort, 4 cohorts | 
| Net usage | Comparison of nightly net usage in cohorts with PBO nets compared to cohorts with conventional nets | 6 months/cohort, 4 cohorts | 
| Serological markers of immunity and exposure | Comparison of serological markers in cohorts exposed to RTS,S vs those not exposed to RTS,S | 6 months/cohort, 4 cohorts | 
| Anopheles gravidity rates | Comparison of Anopheles gravidity rates in cohorts with PBO nets compared to cohorts with conventional nets | 6 months/cohort, 4 cohorts | 
| Anopheles sporozoite rates | Comparison of Anopheles sporozoite rates in cohorts with PBO nets compared to cohorts with conventional nets | 6 months/cohort, 4 cohorts |