A comparative trial of seasonal vaccination with the malaria vaccine RTS,S/AS01, seasonal malaria chemoprevention and the two interventions combined

There has been substantial progress in the control of malaria during the past decade, but it is estimated that in 2015 there were still 438 000 deaths from malaria, despite widespread deployment of insecticide treated bednets and an increase in access to diagnosis and effective treatment: new tools and approaches are needed. In the African Sahel and sub-Sahel, the risk of malaria is concentrated in the few months of the rainy season, although some transmission continues during the rest of the year. The seasonality of malaria in this part of Africa has allowed the development of a control measure called seasonal malaria chemoprevention (SMC), which involves treatment of young children, regardless of whether they have any symptoms, with the antimalarials sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals on four occasions during the malaria transmission season, a regimen which is very demanding on health care givers and recipient children.

The malaria vaccine RTS,S/AS01 has been in development for over 20 years. A recent trial conducted in 15,439 children showed that when three doses of the vaccine were given to children aged 5-17 months, followed by a fourth dose a year later, the vaccine provided 37% protection against clinical attacks of malaria over a period of 4 years, and a similar level of protection against severe malaria. The vaccine caused febrile convulsions in about 1% of children and there was a small, unexplained, increase in the incidence of meningitis in vaccine recipients. These findings were reviewed by the European Medicine Agency in July 2015 and, based on the balance of benefits and risks, the Agency gave the vaccine a positive opinion. WHO has subsequently recommended that several large pilot implementation studies should be done before the vaccine is deployed more widely and that alternative approaches to its delivery should be explored. A characteristic feature of the vaccine is that it produces high levels of protection in the first few months after vaccination but that this subsequently wanes. Vaccine efficacy of 86% (26/30 subjects protected) was obtained in a recent trial in USA military volunteers challenged shortly after three doses of vaccine had been given, the last dose at a lower concentration than usual. The aim of this study is to take advantage of the high initial efficacy of RTS,S/AS01 to investigate its potential to provide protection to children exposed to malaria for just a few months each year.

A three arm trial is proposed which will compare (a) administration of three doses of RTS,S/AS01 to young children followed by a fourth and a fifth dose at the beginning of two subsequent malaria transmission season (b) administration of SMC with SP + AQ as recommended by WHO (c) the combination of these two interventions. The main objectives of the trial will be to determine whether RTS,S/AS01 provides a similar level of protection to that of SMC and is equally cost effective as SMC but is easier to administer and whether combination of the two interventions provides an added, cost effective benefit.

The trial will be conducted in 6,000 children (2,000 in each arm) in Hounde, Burkina Faso and Bougouni, Mali where a trial of adding the antibiotic azithromycin to the anti-malaria treatment regimen used for SMC is currently under way and due to finish at the end of 2016. The study team and many of the techniques needed for the new trial are, therefore, in place. The main end-point of the new trial will be the incidence of episodes of clinical malaria severe enough to warrant treatment. Other end-points will be the incidence of severe malaria, hospital admissions with malaria and anaemia. The safety of the two interventions will be monitored, with a focus on meningitis. The costs of the two approaches and of the combination will be measured and the preference of the local populations for each intervention will be determined.

Methods for identifying children and ensuring that they receive the correct intervention, detecting clinical cases of malaria, determining the presence of anaemia and malnutrition and measuring severe adverse events have been developed during for the on-going SMC trial in the proposed study areas and appropriate standard operating procedures have been developed and are in place. The teams in Burkina Faso and Mali have each conducted successful malaria vaccine trials in the past so this component of the study should not pose any major technical issues.

Measurement of anti-circumsporozoite (CSP) antibody concentrations induced by the vaccine, in particular the response to the fourth and fifth doses and the comparison in titres between children who receive a full or fractionated dose, will be important objectives of the trial as it is possible that repeated doses could lead to a diminishing response. To allow comparison of the results obtained in the new study with those of previous trials of RTS,S/AS01 sponsored by GSK, anti-CSP antibody measurements will be undertaken by the same contractor (The University of Ghent).

The reason why the fourth dose of RTS,S/AS01 did not produce the kind of booster effect seen with many other vaccines is uncertain and, if repeated doses result in a progressive decline in antibody response, this would rule out seasonal vaccination. This study would provide the background for more detailed immunological investigation of this phenomenon, including its potential modulation, studies which might include measurement of antibody affinity, B cell function and memory and T cell immune responses. A request for support for these studies has not been included in this proposal but, if it is successful, additional funds will be sought to support more detailed immunological studies in partnership with a group with expertise in B cell immunology; one such group has already shown an interest in this proposal.

The primary beneficiaries of this research will be the communities of the Sahel and sub-Sahel where malaria transmission is highly seasonal and where SMC is currently recommended by WHO. This area has a population of approximately 300 million, including about 40 million children under the age of five years of age who are still at high risk of malaria during the rainy season. If it can be shown that a booster dose of the RTS,S/AS01 malaria vaccine given at the beginning of the malaria transmission season is as effective at preventing malaria in young children as four course of SMC, this will substantially ease the burden on the families of recipient children who currently may need to spend several hours reaching a treatment centre, and then waiting some hours for treatment to be given, on at least four occasions during the rainy season. Reducing the time required to obtain protection against malaria for their children will allow mothers or guardians to spend more time on other productive alternatives such as caring for other children in the family, farming or trading. If it can be shown that the addition of RTS,S/AS01 provides an added, cost effective benefit in the prevention of malaria this will help to reduce further the continuing burden of malaria in countries of the Sahel and sub-Sahel.

A second group of potential beneficiaries of the research are the national malaria control programmes of counties where SMC is currently recommended. Working in conjunction with national infant immunization programmes, delivery of RTS,S in early childhood and then as a seasonal booster dose may prove logistically easier, and potential cheaper, to deliver than the complex process of ordering, distributing and delivering the drugs needed for SMC.

A third potential beneficiary is WHO's Malaria Policy Advisory committee as the results of the trial will assist this committee in its deliberations on how the RTS,S/AS01 vaccine can be deployed most usefully and contribute to future discussions on whether additional malaria vaccines being developed which have high efficacy but a short duration of protection might be used in a similar way.

Finally, the trial will provide an opportunity for the academic community to undertake some more detailed immunological studies on the nature of the immune memory induced by RTS,S/AS01 and how this is affected by repeated booster doses of the vaccine. This research might lead to the development of modified formulations or immunisation schedules for RTS,S/AS01 that could improve the longer term impact of the vaccine.