Seasonal Malaria Vaccination (RTS,S/AS01) and Seasonal Malaria Chemoprevention (SP/AQ) (RTSS-SMC)

A Phase IIIB Comparative Trial of Seasonal Vaccination With the Malaria Vaccine RTS,S/AS01, Seasonal Malaria Chemoprevention and of the Two Interventions Combined

Malaria Research and Training Center, Bamako, Mali, Institut de Recherche en Sciences de la Sante, Burkina Faso

A double-blind, individual randomised trial will be undertaken in 6000 children under the age of five years living in areas of Burkina Faso or Mali where the transmission of malaria is intense and highly seasonal to determine whether the malaria vaccine RTS,S/AS01 is (a) as effective as SMC with SP + AQ in preventing clinical malaria (b) provides additional, useful protection when given together with SMC. The primary trial end-point will be the incidence of clinical episodes of malaria detected by passive case detection.

The RTS,S/AS01 malaria vaccine is a recombinant protein vaccine in which the fusion protein RTS (containing parts of the circumsporozoite protein (CSP) of Plasmodium falciparum fused to hepatitis B surface antigen (HBsAg)) is co-expressed in yeast together with free HBsAg (S) to form a virus like particle (RTS,S); it is given with the powerful adjuvant AS01. RTS,S/AS01 induces a strong antibody response to the P. falciparum CSP and high titres of anti-CSP antibody are associated with protection. Following a long process of development, a phase 3 study of RTS,S/AS01 conducted in 15,439 children in 7 countries in Africa showed that three doses of RTS,S/AS01 given with a one month interval between doses, followed by a fourth dose 18 months post dose 3, gave 36.5 % [95% CI 31,41%] protection against clinical attacks of malaria when given to young children aged 5-17 months who were followed for 48 months; efficacy was less when given to infants at the age of 6-12 weeks. RTS,S/AS01 provides a high level of protection during the first three months after vaccination, modelled to be about 70% in the phase 3 trial, a level of initial efficacy similar to that observed in an earlier phase 2 trial in Gambian adults. However, efficacy wanes progressively over the following months. A subsequent dose given 18 months after the primary series restores some but not all of the efficacy seen immediately after the primary series. In July 2015, the European Medicines Agency reviewed efficacy and safety data on RTS.S/AS01 and concluded that the risk benefit balance favoured the vaccine and gave a positive opinion on its use in children aged 6 weeks to 17 months. The World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) committee reviewed the vaccine's efficacy and safety in October 2015 and made a number of recommendations on its further evaluation. These included the pilot implementation of RTS,S/AS01 in children aged 5-17 months in 3-5 settings with moderate-to-high malaria transmission intensity, with a preference for areas where SMC is not being delivered, and evaluation of alternative approaches to deployment of the vaccine. Recent evidence from challenge studies conducted in American adult volunteers suggests that a higher level of protection can be obtained when the third dose of the priming schedule is reduced to one fifth of the usual amount and delayed until approximately 6 months post dose 2, and when a reduced dose is used for boosting. In these studies, a vaccine efficacy of 86% was achieved three weeks following priming and 90% efficacy following boosting with a fractional dose. This encouraging result is now being followed in further studies. SMC involves monthly administration of an antimalarial drug or drug combination in a full therapeutic course to children on three of four occasions during the period of highest risk of malaria infection. Studies undertaken in several countries in West Africa, including Burkina Faso and Mali, have shown that SMC with sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) is highly effective in areas where the transmission of malaria is markedly seasonal, reducing the incidence of severe and uncomplicated malaria by up to 80%. SMC with a combination of SP and AQ is safe, with no serious drug related adverse event being reported after administration of over 800,000 courses in Senegal. Recent studies have defined the areas where SMC would be an appropriate intervention based on the seasonality and incidence of malaria. These include most of the Sahel and sub-Sahel, population approximately 200 million, and possibly other areas in southern and eastern Africa. A Technical Expert Group of the WHO reviewed all the available evidence on the efficacy and safety of SMC in May 2011 and recommended SMC with SP+AQ in areas of the Sahel and sub-Sahel with highly seasonal transmission. This recommendation was endorsed by the WHO Malaria Policy Advisory Committee (MPAC) in February 2012. Most countries in the Sahel and sub-Sahel region have incorporated SMC, along with other malaria control interventions in their strategic malaria control plan and the implementation of SMC at scale is in progress in many countries in this region through the UNITAID supported SMC ACCESS programme and the support of other major donor organisations. Preliminary evaluation suggests that SMC is providing about 50% protection against clinical malaria when delivered through a national programme (http://www.malariaconsortium.org/pages/access-smc.htm). SMC is effective but its delivery is demanding on the recipient and provider, requiring four contacts each malaria transmission season if anti-malarials are given to mothers to administer at home and 12 contacts if directly observed treatment is employed. In addition, SMC is threatened by the emergence of resistance to SP and AQ and there are currently no other combinations of licensed antimalarials that could be used to replace them. It is likely to be 5-10 years before novel antimalarials under development could be deployed for SMC. In contrast to SMC, seasonal vaccination with RTS,S/AS01 would require only one visit each transmission season after priming. RTS,S/AS01 may be a little less effective than SMC during the malaria transmission season but this may be balanced by provision of protection during the dry season, when some malaria transmission still occurs and when SMC would provide no benefit. There is, therefore, a need for a comparative study of these two interventions. In some areas where SMC is currently being deployed, and other malaria control interventions such as long-lasting insecticide treated nets used widely, the incidence of malaria in young children remains high (0.4 episodes per year in children under the age of five years in SMC recipients in Burkina Faso). Thus, determining whether RTS,S/AS01 would provide added, useful protection to SMC in such situations is also important. It might also be able to protect some children who, because of side effects, are unable or unwilling to take SMC. Although the European Medicines Agency has given a positive opinion on RTS,S/AS01, it is not yet certain how this partially effective malaria vaccine can be used most effectively. Three, large-scale pilot implementation studies are being planned by WHO but it is unlikely that, following WHO recommendations, any of these will be conducted in a country where SMC is being delivered. The WHO recommendations on RTS,S/AS01 indicate the need for research on alternative approaches to the delivery of this vaccine. Exploration of the potential of the vaccine to prevent seasonal malaria, taking advantage of its high but rapidly waning efficacy, meets this recommendation and is, therefore, timely.

A double-blind, individually randomised trial to compare the incidence of clinical episodes of malaria across three study arms: Seasonal vaccination with the malaria vaccine RTS,S/AS01 Seasonal malaria chemoprevention with SP/AQ Combination of these two interventions

Administration of RABIPUR® in Year 1 and Hepatitis A vaccine in Year 2 and 3, followed by 4 cycles of SMC with sulphadoxine/pyrimethamine plus amodiaquine in Year 1,2 and 3.

Administration of the malaria vaccine RTS,S/AS01 followed by 4 cycles of SMC with placebo in Year 1,2 and 3.

Administration of the malaria vaccine RTS,S/AS01 followed by 4 cycles of SMC with sulphadoxine/pyrimethamine plus amodiaquine in Year 1,2 and 3.

Year 1 (2017) Three doses of rabies vaccine (April, May, June) Year 2 and 3 (2018/19) One dose of Hepatitis A vaccine (June)

Year 1 (2017) Three doses of RTSS/AS01 (April, May, June) Year 2 and 3 (2018/19) One booster dose of RTSS/AS01 (June)

Year 1, 2 and 3(2017/18/19) Four cycles of SMC (SP+AQ) during the malaria transmission season One cycle of SMC for children above one year of age consisting of sulphadoxine - pyrimethamin (SP) 500mg/25 mg, and amodiaquine (AQ) 150mg on day 1, and AQ 150mg on days 2 and 3. Infants will receive half of these doses.

Passive surveillance to detect episode of fever (temperature > 37.5 C), or a history of fever within the past 48 hours, that is severe enough to require treatment at a health centre and which is accompanied by a positive blood film with a parasite density of 5,000 per µl or more

Passive surveillance of clinical episodes of malaria within the study area starting from the date of the first dose of study vaccines (April/May 2017) until 31st March 2020- a total of 36 months.

Passive and active surveillance to detect cases with temperature > 37.5o C), or a history of fever within the past 48 hours, with a positive blood film (any level of asexual parasitaemia) or a positive rapid diagnostic test (RDT) for malaria

Passive surveillance in all health centers within the study area, active surveillance in a sub set of study children starting July 2017 till April 2020.

Hospital admissions with malaria, including cases of severe malaria which meet WHO criteria for a diagnosis of severe malaria.

Through study completion (30 months), each child admitted in a study hospital will be treated and monitored until complete cure or death (a period of 3 years). Documentation of each hospital admission according to ICH-GCP.

Active surveillance of malaria at household level to assess the prevalence of malaria infection not severe enough to warrant a clinic visit detected in a subset of randomly selected children.

Weekly home visits through study completion from July 2017 - April 2020 to screen study children for malaria.

Prevalence of Malaria Parasitaemia, Including Gametocytaemia and the Prevalence of Moderate and Severe Anemia and Malnutrition

The prevalence of malaria parasitaemia, including gametocytaemia, moderate and severe anaemia and malnutrition at the end of the malaria transmission season

Blood sample collection during 2-week cross sectional survey at the end of each malaria transmission season.

Serious adverse events (SAEs), including any deaths, occurring at any time during the study with special reference to any cases of meningitis and cerebral malaria (WHO case definition)

Through study completion (for 30 months), each SAE will be treated and documented according to ICH-GCP.

Blood sample collection prior to 1st dose of vaccine and 1 month after 3rd dose of the primary series of vaccination. In years 2 and 3 blood will be collected before the booster dose and 1 month after administration of the 4th (and 5th) vaccine dose.

Blood sample collection during the 2-week cross sectional survey conducted at the end of malaria transmission season in 2019.

The prevalence of malaria parasitaemia at the end of the malaria transmission season in school-age children resident in the study areas, to determine overall malaria transmission

Blood sample collection during the 2-week cross sectional survey at the end of the malaria transmission season in Year 2 and 3 (November 2018/19).

Children with asymptomatic malaria parasitaemia identified during the final cross-sectional survey (November 2019), treated with a full course of SP+AQ over 3 days and followed for 28 days.

The acceptability of the two interventions (separately and combined) to the health care deliverers and to the study communities (standardized questionnaires)

The feasibility of introducing two malaria control strategies simultaneously from the health system perspective (structured observations and interviews with health system officials)

Inclusion Criteria: The child is a permanent resident of the study area and likely to remain a resident for the duration of the trial The child is 5 - 17 months of age at the time of first vaccination A parent or legally recognised guardian provides informed consent for the child to join the trial Exclusion Criteria: The child is a transient resident in the study area The child is in care The age of the child is outside the stipulated range The child has a history of an adverse reaction to SP or AQ The child has a serious underlying illness, including known HIV infection, unless this is well controlled by treatment, or severe malnutrition (weight for age or mid arm circumference Z scores < 3 SD) The child is known to have an immune deficiency disease or is receiving an immunosuppressive drug The child has previously received a malaria vaccine. The child is enrolled in another malaria intervention trial The parents or guardians do not provide informed consent

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