Combating malaria seasonality: A conversation with Sir Brian Greenwood and Prof Paul Milligan
Prof Brian Greenwood and Prof Paul Milligan (London School of Hygiene and Tropical Medicine, LSHTM) look back on the evolution of Seasonal Malaria Chemoprevention until recommended by WHO in 2012 and discuss how the strategy can be explored to achieve further impact.
Q: Could you tell us a little bit about you and your research interests?
Brian Greenwood (BG): I first became fully aware of the seasonality of malaria in the African Sahel and sub-Sahel when, in 1970, I went to work at Ahmadu Bello University (ABU), Zaria, Nigeria where we experienced epidemic meningitis in the dry season and a big surge in cases of malaria during the rainy season. Thus, in our small research laboratory, we worked on meningococcal meningitis during the dry season and malaria during the rainy season. One of the first malaria control studies that we did at that time was a study of the impact of chemoprophylaxis with chloroquine on malaria in young children, the topic of my wife’s MD thesis.
In 1980, I moved to The Gambia where one of the earliest studies that we did in the newly established field station at Farafenni was a trial of seasonal malaria chemoprophylaxis with Maloprim (pyrimethamine + dapsone) in young children given by community health workers. This had a major impact on cases of malaria and reduced overall child deaths but the intervention was not taken up because of concerns by WHO and other organisations about the potentially harmful effects of large scale chemoprophylaxis in malaria-endemic countries and because of the development at about that time of insecticide-treated bednets, an easier control measure to implement.
Interest in seasonal prevention of malaria lapsed for nearly 20 years until the idea was revived by Dr Badara Cisse, who undertook a trial in young Senegalese children of seasonal malaria chemoprevention (SMC), then called Intermittent Preventive Treatment of malaria in children (IPTc,) with sulphadoxine-pyrimethamine and artesunate as his PhD topic. Once again, a marked reduction in the incidence of clinical episodes of malaria was seen in children who received the antimalarials throughout the malaria transmission season. This impressive result led to several larger trials of SMC, using different drug combinations and schedules, which firmly established its efficacy and led to a recommendation from WHO that SMC with sulphadoxine and amodiaquine (SP+AQ) should be deployed in children aged 3-59 months in areas of the African Sahel and sub-Sahel where malaria transmission is seasonal.
Adoption of SMC with SP+AQ as a routine malaria control measure has reduced the incidence of uncomplicated and severe malaria in many countries of the Sahel and sub-Sahel but, in many of these countries, malaria is still the most frequent cause of death and hospital admission in young children. Thus, with colleagues in Burkina Faso and Mali, I have been exploring what additional measures could be used to help reduce mortality and morbidity during the malaria transmission season in these countries. A trial of the addition of the antibiotic azithromycin to the antimalarials used for SMC showed a reduction in the incidence of respiratory, gastrointestinal and skin infections in children who received azithromycin but not in deaths or hospital admissions. Thus, a trial is now in progress to see if administration of the RTS,S/ASA01 vaccine, given with a priming series followed by annual booster doses given just prior to the malaria transmission season might provide added protection to that given by SMC alone, and might possibly be used as an alternative to SMC should marked resistance to the drugs currently used for SMC emerge without there being replacements.
Paul Milligan (PM): I am an epidemiologist, I trained initially in biology and ecology, before moving to a PhD in population biology and post-doctoral work in biomathematics and from then worked as a statistician/epidemiologist in the Liverpool School of Tropical Medicine and for eight years at the MRC laboratories in The Gambia before coming to the LSHTM, where I am now based in the faculty of Epidemiology and Population Health. I teach on our short courses and distance learning programmes, and I co-organise a distance learning MSc module in the epidemiology of infectious diseases. My research has focused on malaria and other infectious diseases, this includes field studies and I also have an interest in methodological research. One of my main partnerships has been with the researchers in Senegal, we did a series of field studies including a stepped-wedge trial to evaluate the effectiveness of SMC (then called IPTc) on a large scale, which was organised following the exciting results in the initial clinical trial done by Badara Cisse for his PhD with Prof Brian Greenwood. From 2014-17 I coordinated the evaluation of the scale-up of SMC in West and Central Africa through the ACCESS-SMC project with Malaria Consortium, and have been involved subsequently in the monitoring and evaluation of SMC programmes.
Q: Since 2012, WHO has recommended Seasonal Malaria Chemoprevention (SMC) for children aged 3 to 59 months during the high-transmission season in Africa’s Sahel sub-region. Which are the main benefits of this strategy?
BG: There was initially some scepticism whether it would be possible to deliver SMC at scale outside a trial situation but, with financial support from UNITAID and other organisations, it has been shown that high levels of coverage can be achieved by national malaria control programmes. This has been helped by the development of more palatable formulations of SP and AQ than used in the original studies. Evaluation of national SMC programmes by groups such as ACCESS-SMC has demonstrated reductions in the incidence of malaria in children in nearly all areas where SMC has been deployed and in some countries a reduction is deaths has also been shown.
PM: In areas with highly seasonal malaria, the malaria burden is concentrated in young children during and shortly after the rainy season. In these areas, chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine, given to children once a month for a few months each year, is sufficient to target a large proportion of the overall malaria burden in a region. The drugs don’t give complete protection but the benefits are clearly visible, and for this reason, and the fact that they are brought free doo- to-door, the strategy has been welcomed by communities. The door-to-door strategy has been successful in reaching the sections of the community who normally have the poorest access to health care, with high coverage. When SMC was introduced through the ACCESS-SMC project, (in populations which had in general high use of insecticide treated bednets), there were marked reductions in the number of malaria cases, severe cases, and deaths in hospital malaria due to malaria.
Q: According to the World Malaria Report 2019, in 2018 a mean total of 17 million children, out of the 26 million targeted, were treated per SMC cycle. How do you think this gap in treatment could be filled?
BG: Expansion of the delivery of SMC to epidemiologically appropriate areas where SMC is not being delivered and to children in areas where coverage is poor requires political commitment and a recognition by national malaria programmes of the value of SMC. Some of the constraints on achieving a high level of coverage are considered below.
PM: Each year the SMC Working Group, which is the network for countries involved in SMC, meets to review progress, and at the most recent meeting in Accra in February, we heard that in 2019, 85million treatments were administered in 13 countries reaching a total of about 22million children, and this year, SMC programmes are targetting 30 million children. In areas where SMC is supported by the Global Fund, complementing partner and government support, there is funding for full scale-up in 2020. The country with the largest gap was Nigeria but Malaria Consortium have expanded their programmes there. And manufacturing capacity has expanded to meet this increased demand (and although China is a major supplier this seems not to have been adversely affected by the pandemic). The challenge now is to ensure that within the areas where SMC is being implemented, it is done effectively, and all children are being reached and are receiving all their monthly treatments. We know that very high coverage is achievable thorough door to door campaigns, in areas where this is working well 90% of children consistently receive four treatments each year, this has been verified this from careful household surveys, but this is not being achieved everywhere. The reasons are different in each country and basic operational research is needed to understand the challenges and the steps needed to address them. It is important to keep the interval between cycles to strictly 28 days and in some areas, four monthly cycles are not enough to cover the high risk period and the number of cycles needs to be increased. It is important to monitor SMC programmes to generate evidence of impact to support continued investment, and this is being helped by wider use of DHIS2 and availability of more complete data on malaria incidence at health facilities.
Q: Which are the main challenges when trying to deploy SMC?
BG: There are three main challenges to enhancing and sustaining deployment of SMC which are
- Funding. Funding has, in the past, been a major constraint on the deployment of SMC. However, now that the safety and efficacy of SMC have been established clearly, countries with financial constraints can include provision for SMC in their Global Fund application and in applications to other donors. However, it is important that an increasing proportion of the funding needed to support SMC should come from internal resources.
- Logistics. Delivery of SMC four times a year is demanding and most countries have found that the most successful approach to delivery is through house to house visits. However, this is difficult in places with security risks which, unfortunately, are prevalent in several areas where SMC is an appropriate intervention. In addition COVID-19 may pose additional challenges to delivery as discussed below.
- Drug resistance. In the longer term, the emergence of a high level of resistance to SP and/or AQ, which could appear at any time in countries where SMC is deployed is a major challenge as, currently, there are no obvious alternative drug combinations that could be used. Developing novel antimalarials that could be used in combination for SMC is a priority, and this is being addressed by Medicines for Malaria Venture (MMV) which has made many important contributions to the development and deployment of SMC.
PM: SMC requires repeated contacts with the health system outside existing schedule of vaccinations and health campaigns, door to door campaigns have proved most effective but need massive human resources, for example the ACCESS-SMC project in 2016 used about 60,000 people (drug distributors, supervisors, and health workers) and to treat about 7million children. The selection, recruitment, training and supervision necessary to ensure quality of SMC delivery on this scale is a huge undertaking. A system is needed to ensure drug distributors can be paid promptly. Caregivers need to understand the purpose of the intervention and what it involves, and then need to be made aware of dates when drugs will be distributed to make sure they are at home, this needs effective channels of communication that can reach the community every month. Strategies may need to be adapted to local contexts, to deliver in areas that become difficult to access during the rains, and to reach families engaged in farming or mining or other activities that take them away from home during campaigns. Activities have to follow strict timing, to ensure treatments are received at approximately 28-day intervals. During SMC visits, children who are unwell should be assessed and treated appropriately, this will require referral to a health facility unless community case management is available locally or can be done by the SMC team. When starting SMC in new areas it can be difficult to forecast accurately the quantity of drugs that will be needed although there are improved methods of population estimation using remote sensing. There needs to be an effective pharmacovigilance (PV) system, PV protects SMC programmes by monitoring occurrence of side effects, taking steps to minimise risks, and being able to react to rumours, but maintaining effective PV this remains a challenge. Molecular markers of resistance to SMC drugs currently remain at low frequencies, and we have shown using case control studies that the effectiveness of SMC treatments delivered through national programmes is similar to the efficacy seen in the original clinical trials, but resistance will need to be carefully monitored. Much practical experience of SMC implementation has been gained by over the last 7-8 years, this is being used in preparing an updated version of WHO’s SMC field guide.
Q: In Senegal, SMC has been expanded to children up to 10 years of age. In your opinion, which are the benefits of including older children?
BG: As malaria incidence declines, the peak age of clinical cases of malaria increases and a larger proportion of the burden of malaria is seen in older children, although the majority of episodes of severe malaria still occur in younger children. Thus, in situations in which epidemiological studies have shown that malaria in older children is a significant problem, accounting for time away from school and affecting their educational progress, extension of SMC to older children is logical and this may also have an impact on the overall level of malaria transmission. WHO currently advises that the upper age of administration of SMC to older children should only take place when a high level of coverage has been achieved in the younger children who are most at risk and this is currently sound advice.
PM: In many areas where SMC is being used, there is a high burden of malaria in older children. School-age children are a neglected group often not specifically included in health programmes, including malaria programmes. Bednet surveys for example often show lowest rates of coverage in the 5-14year age group. Older children can be included in SMC programmes, when this has been done, there are economies of scope as the time and human resources needed for SMC delivery are not greatly increased, it is possible to achieve high coverage through door to door campaigns by adjusting visit times for cycles that occur in term time, and evaluations of this strategy in Senegal have shown substantial reductions in malaria cases. A further benefit is that, although indirect effects on transmission are small from SMC, they become more important when a wider age range is treated.
Q: How do you think SMC may be a helpful chemoprevention strategy in the context of the COVID-19 pandemic?
BG: COVID-19 is going to pose a major challenge to distribution of SMC during the 2020 malaria transmission season as this involves a substantial amount of person to person contract. However, the risk from denying children SMC is likely to be greater than that of spreading COVID-19, as observed during the recent West African Ebola epidemic. Thus, SMC should be continued even in the presence of a COVID outbreak but imaginative approaches will need to be taken to ensure that it can be delivered as effectively as possible whilst at the same time reducing person to person contact to the minimum.
PM: It was estimated during the ACCESS-SMC project that SMC could have averted about 0.9 deaths per 1000 monthly treatments. The risk of malaria mortality in children could be increased by the COVID-19 pandemic if access to health care is restricted because health facilities are overburdened or people avoid attending busy clinics, thus children may suffer even though the effects of COVID-19 itself may not be severe in children. Maintaining effective malaria prevention is therefore especially important. It will also reduce the burden on overstretched health facilities. Steps can be taken to deliver SMC safely, these will need to include adjusted messaging to keep the community informed, replacing training sessions with groups of people, with the use of text messages and video via phone apps, and respecting social distancing during door-to-door delivery.
Q: In your opinion, which are the next steps that the malaria community should take in order to advance towards malaria elimination?
BG: There is much more to be done in sustaining the drive to elimination in countries where this is on the near to medium horizon through maintaining the political will to achieve this elimination and the finances needed to sustain the elimination effort. However, the most important task for the malaria community at the present time is to prevent the progress that has been made towards elimination, being derailed by the COVID epidemic.
PM: The areas where SMC is being used have among the highest transmission intensity in the world and elimination is not feasible with existing tools. In central Senegal for example, scaling up of control reduced the burden but transmission then stabilised at a much lower level, and large scale trials showed that intensified control with repeated MDA combined with IRS could not achieve local elimination. Resources are better directed to reducing morbidity and mortality in the highest burden areas. More effective tools will be needed, but the experience of SMC, maintaining high levels of coverage of monthly door to door campaigns on a massive scale, does at least show that it is possible to achieve the level of community engagement that will be necessary for elimination.
Prof Brian Greenwood has spent 50 years carrying out research in Africa including some of the first trials of insecticide-treated bednets and artemisinin-based combination therapies, now widely adopted as first-line treatment for malaria. In recent years, he has contributed to several landmark studies leading to the development of Seasonal Malaria Chemoprevention.
Prof Paul Milligan is based in the faculty of Epidemiology and Population Health at the London School of Hygiene and Tropical Medicine. His research focuses on malaria and other infectious diseases, including field studies and methodological research. From 2014 to 2017 he coordinated the evaluation of the scale-up of SMC in West and Central Africa through the ACCESS-SMC project with Malaria Consortium, and has been involved subsequently in the monitoring and evaluation of SMC programmes.
