Malaria Vaccine Pilot Evaluation (MVPE)

• ClinicalTrials.gov Identifier: NCT03806465
• Recruitment Status: Unknown
• First Posted: January 16, 2019
• Last Update Posted: August 13, 2021
• Sponsor: World Health Organization
• Information provided by (Responsible Party): Patricia Njuguna, World Health Organization

Study Description

Brief Summary:

The RTS,S/AS01 malaria vaccine is being introduced sub-nationally in phased pilot introductions through the EPI programmes in Malawi Ghana and Kenya. Vaccine introduction is by the respective MoH in selected areas randomly assigned to receive the vaccine at the beginning of the pilots. In the context of this programmatic activity, the Malaria Vaccine Pilot Evaluation (MVPE) registered here as observational evaluations during early vaccine introduction, include a series of 3 household surveys, and sentinel hospital and community mortality surveillance, building on routine systems.

These observational evaluations will measure:

1. The programmatic feasibility of delivering a 4 dose schedule;
2. Safety in routine use, with focus on cerebral malaria and meningitis;
3. The impact of the malaria vaccine in routine use on severe malaria and all-cause mortality

Condition or disease	Intervention/treatment
Malaria,Falciparum; Feasibility; Safety; Mortality	Other: Feasibility survey; Other: Sentinel hospital surveillance; Other: Community mortality surveillance

Detailed Description:

An evaluation of the pilot implementation of RTS,S/AS01 through routine health systems in moderate to high malaria transmission settings in Ghana, Kenya and Malawi. In the context of the new vaccine introduction, the Ministries of Health in the three countries will introduce the malaria vaccine (RTS,S/AS01) in a phased fashion (with some areas introducing the malaria vaccine first and the latter half, after the evaluation period) building on the national immunization programmes which routinely deliver vaccines and expanding the schedule of their routine EPI contacts.

The evaluation of the pilot implementation will run for a total of about 46 months in each country. This will focus on the three main primary objectives of feasibility, safety and impact. The pilot implementation assumes that a total of 46-60 clusters will be identified per country, evenly split between implementation and comparison areas, with each cluster contributing approximately 4,000 children per year to the evaluation of RTS,S/AS01. Hence a total of approximately 120,000 children will receive the RTS,S vaccine in each country in each year. Evaluation data will be collected in the following ways.

COMMUNITY BASED MORTALITY SURVEILLANCE

Community based mortality surveillance will be established across the pilot evaluation areas to enable the evaluation of the impact of the malaria vaccine on all-cause mortality. This will use a network of Village Reporters (VR) to document all deaths among children aged up to 48 months in the implementation and comparison areas. Once the death is notified, a standardized, WHO-approved Verbal Autopsy (VA) will be performed, according to WHO guidelines and locally acceptable practices. The VA will focus is on confirming death, age and vaccination status. The total number of clusters per country is expected to range from 46-60. Assuming 4,000 children born per cluster per year, 30 months of vaccination and a total follow-up of 44 months, each cluster will contribute 23,134 person years at risk (pyar), allowing for 1% mortality in the first month of life, and 0.08% mortality for every month after the first month. This equates to a mortality risk of 22.2 per 1000 for children aged 5 to 36 months. A mortality risk of 21 per 1,000 equates to a rate, over 2.5 years, of 8.489455 per 1,000 pyar. Based on a minimum mortality rate of 8.5 per 1000 pyar, 23 clusters in each arm, each with an annual birth cohort of approximately 4,000 subjects, would have 80% power to detect, at the 5% significance level, a decrease of at least 10% in overall mortality in each country.

With this mortality risk, the pilot evaluation it is estimated to have approximately 80% power to detect an interaction between gender and treatment of 1.15 (i.e an increased risk of mortality in girls of 1.035), compared with the 1.9-fold increase in risk among girls receiving RTS,S/AS01 in the RTS,S Phase 3 trial.

FEASIBILITY (CROSS SECTIONAL HOUSEHOLD) SURVEYS)

Three household surveys will be conducted to evaluate the programmatic feasibility to deliver a 4 dose schedule at baseline (before vaccination starts), 18 months and 30 months after start of vaccination.

A sample size of 100 houses per cluster will estimate the cluster-specific coverage of RTS,S/AS01 to within 10% (ie 95% CI from 40 to 60%) using a conservative estimate of 50% coverage and a high response rate above 95% in each cluster. Assuming a design effect of 1.5 between clusters, the overall precision in RTS,S/AS01 and coverage estimates of other vaccines over the pilot programme's implementation and comparison areas will be 2% (ie 95%CI 48% to 52%) in each country. This will result in 15,800 (6,600 in Ghana, 4,600 each in Kenya and Malawi) households included in the surveys. The second household survey may be powered to generate coverage estimates in each arm, rather than in each cluster, to within ±2% of the true value.

SENTINEL HOSPITAL SURVEILLANCE

Four to eight sentinel hospitals will be identified in each country to collect information on a larger scale on the safety of the malaria vaccine in children aged less than 5 years admitted with a focus on cases of cerebral malaria and meningitis. The catchment area of each hospital (approximately a cluster) is expected to have an annual birth cohort of, and provide services for, approximately 4,000 children in the MVPE. Hence a total catchment area of 48,000 children in implementation areas and another 48,000 children in comparison areas will contribute to the hospital-based evaluation of safety across the programme (three countries, Ghana, Kenya and Malawi). This is expected to provide 80% power to detect a 1.7-fold increase in risk of cerebral malaria and 2.6-fold increase in risk of meningitis. Children admitted to the sentinel hospitals in this age group will be assessed for severe malaria and meningitis using a standardised surveillance approach.

Study Design

• Study Type: Observational
• Estimated Enrollment: 15800 participants
• Observational Model: Other
• Time Perspective: Prospective
• Official Title: An Evaluation of the Pilot Implementation of RTS,S/AS01 Through Routine Health Systems in Moderate to High Malaria Transmission Settings in Africa
• Actual Study Start Date: February 25, 2019
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: December 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
Feasibility survey; These will be children living in the vaccinating and in non-vaccinating areas aged less than 5 years of age. For the midline household survey, this would be restricted to children aged 12-23 months of age.	Other: Feasibility survey; A survey questionnaire will be administered at each household. At the baseline household survey, each child aged less than 5 years will be tested for malaria using a rapid malaria test.
Sentinel hospital surveillance; These will be children living in the vaccinating and in non-vaccinating areas aged less than 5 years of age who are hospitalized in the 18 sentinel hospitals.	Other: Sentinel hospital surveillance; Cerebrospinal samples will be collected from all children hospitalised and suspected of having meningitis.
Community mortality surveillance; These will be children whose deaths are reported in the vaccinating and in non-vaccinating areas aged less than 5 years of age .	Other: Community mortality surveillance; A verbal autopsy will be performed

Outcome Measures

Primary Outcome Measures :

1. The number of deaths of any cause [ Time Frame: From 0 to 46 months after vaccination starts ]
   Number of deaths of any cause in children aged 1-59 months.
2. Number of children admitted with a diagnosis of probable and confirmed meningitis cases [ Time Frame: From 0 to 30 months after vaccination starts ]
   Number of children with probable and confirmed meningitis A probable case if in a suspected case, the macroscopic aspect of the CSF is turbid, cloudy or purulent; or the CSF leukocyte count is >10 cells/mm3. A confirmed case is if a suspected or probable case is laboratory confirmed by culturing or identifying (i.e. by polymerase chain reaction, immunochromatographic dipstick or latex agglutination) bacterial, viral or other aetiology in the CSF.
3. Number of children admitted with a diagnosis of cerebral malaria [ Time Frame: From 0 to 30 months after vaccination starts ]
   Cerebral malaria is defined as Severe P. falciparum malaria with coma (Glasgow coma score < 11 in children two years of age or older [≥ 2 years] or Blantyre coma score < 3 in children less than two years of age [(< 2 years]); and If malaria with seizure: coma persisting for > 30 min after the seizure. Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, bacterial meningitis)
4. Number of children aged 12-23 months who have completed the primary series (the 3 dose regime) of the malaria vaccine [ Time Frame: At 18 months after vaccination starts ]
   Prevalence of children aged 12-23 months who had completed three doses of RTS,S/AS01 at the second household survey
5. Number of children aged 27-38 months who have completed the 4th dose of the malaria vaccine [ Time Frame: At 30 months after vaccination starts ]
   Prevalence of children aged 27-38 months who had completed four doses of RTS,S/AS01 at the third household survey

Secondary Outcome Measures :

1. Number of deaths in children by gender [ Time Frame: From 0 to 46 months after vaccination starts ]
   Number of deaths in children stratified by gender in children aged 1-59 months
2. Number of deaths in hospitalised children by gender [ Time Frame: From 0 to 46 months after vaccination starts ]
   Number of deaths in hospitalized children stratified by gender in children aged 1-59 months.
3. Number of malaria associated deaths in hospitalised children by gender [ Time Frame: From 0 to 46 months after vaccination starts ]
   Number of malaria specific deaths stratified by gender in hospitalized children aged 1-59 months.
4. Number of children with a diagnosis of severe malaria [ Time Frame: From 0 to 30 months after vaccination starts ]
   Hospital admissions with malaria which meet WHO criteria for a diagnosis of severe malaria.
5. Number of deaths excluding those attributed to trauma, poisoning and drowning [ Time Frame: From 0 to 46 months after vaccination starts ]
   Number of non traumatic deaths in children aged 1-59 months.
6. Number of children with a diagnosis of aetiology confirmed meningitis [ Time Frame: 30 months after vaccination starts ]
   Number of hospital admissions which meet WHO criteria for a diagnosis of aetiologically confirmed meningitis admitted to sentinel hospitals
7. Number of children with a diagnosis of suspected meningitis [ Time Frame: From 0 to 30 months after vaccination starts ]
   Number of hospital admissions which meet WHO criteria for a diagnosis of suspected meningitis admitted to sentinel hospitals
8. Number of children with a diagnosis of probable meningitis [ Time Frame: From 0 to 30 months after vaccination starts ]
   Number of hospital admissions which meet WHO criteria for a diagnosis of probable meningitis admitted to sentinel hospitals
9. Number of children with a diagnosis of malaria [ Time Frame: From 0 to 30 months after vaccination starts ]
   Number of hospital admissions which meet WHO criteria for a diagnosis of malaria admitted to sentinel hospitals
10. Number of children with a non-malaria diagnosis [ Time Frame: From 0 to 30 months after vaccination starts ]
    Number of hospital admissions which do not meet WHO criteria for a diagnosis of malaria admitted to sentinel hospitals
11. Number of children with a diagnosis of anaemia [ Time Frame: From 0 to 30 months after vaccination starts ]
    Number of hospital admissions which meet WHO criteria for a diagnosis of anaemia admitted to sentinel hospitals . Anaemia is haemoglobin less than 11g/dL.
12. Number of children who have received all their routine EPI vaccines as recommended by their national immunization schedule [ Time Frame: At 18 and 30 months after vaccination starts ]
    Routine EPI vaccines include all doses of OPV, pentavalent, rotavirus, pneumococcal and measles vaccines
13. Number of children who have received all the recommended malaria prevention and control measures [ Time Frame: At 18 and 30 months after vaccination starts ]
    Recommended malaria prevention and control measures include insecticide treated bed nets, IPTi and indoor residual spraying.
14. Number of children who have received all of the other key childhood interventions [ Time Frame: At 18 and 30 months after vaccination starts ]
    Other key childhood interventions include anti-helminth administration (deworming) and Vitamin A supplementation

Biospecimen Retention:   Samples Without DNA

Cerebrospinal fluid

Eligibility Criteria

• Ages Eligible for Study: 1 Month to 59 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

The study population will comprise children aged 1-59 months living in the areas geographically-defined for this evaluation of the RTS,S/AS01 Malaria Vaccine Implementation in three countries (Ghana, Kenya and Malawi) in sub-Saharan Africa.

Criteria

Inclusion Criteria:

• Children aged 1-59 months

Exclusion Criteria:

• Children aged less than 1 month or greater than 59 months

Contacts and Locations

Locations

Ghana

Kintampo Health Research Centre

Kintampo, Ghana

Kenya

CDC Kenya Malaria Programme

Kisumu, Kenya

Malawi

College of Medicine

Blantyre, Malawi

Sponsors and Collaborators

World Health Organization

Investigators

• Principal Investigator: Don Mathanga, PhD; College of Medicine, Malawi
• Principal Investigator: Kwaku Poku Asante, PhD; Kintampo Health Research Centre, Ghana
• Principal Investigator: Aaron Samuels, MD; CDC-Kenya Malaria Program

  Study Documents (Full-Text)

Documents provided by Patricia Njuguna, World Health Organization:

Study Protocol and Informed Consent Form  [PDF] April 22, 2020

Statistical Analysis Plan  [PDF] July 28, 2021

More Information

Additional Information:

Key milestones in the development of the Malaria Vaccine Implementation Programme (MVIP): from pilot recommendation to vaccine introduction 

Publications:

Malaria vaccine: WHO position paper-January 2016. Wkly Epidemiol Rec. 2016 Jan 4;91(4):33-51. No abstract available. English, French.

RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015 Jul 4;386(9988):31-45. doi: 10.1016/S0140-6736(15)60721-8. Epub 2015 Apr 23. Erratum In: Lancet. 2015 Jul 4;386(9988):30.

• Responsible Party: Patricia Njuguna, Medical Officer, World Health Organization
• ClinicalTrials.gov Identifier: NCT03806465
• Other Study ID Numbers: RTSS MVPE
• First Posted: January 16, 2019
• Last Update Posted: August 13, 2021
• Last Verified: August 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Patricia Njuguna, World Health Organization:

Vaccine; Malaria; Africa; Child

Additional relevant MeSH terms:

Malaria; Malaria, Falciparum; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases