Citation: Snow RW (2016) Seasonal Malaria Chemoprevention: An Evolving Research Paradigm. PLoS Med 13(11): e1002176. https://doi.org/10.1371/journal.pmed.1002176
Published: November 22, 2016
Copyright: © 2016 Robert W. Snow. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: RWS is funded as a Principal Research Fellow by the Wellcome Trust wellcome.ac.uk (# 103602). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The author has declared that no competing interests exist.
Abbreviations: AQ, Amodiaquine; IPTi, intermittent presumptive treatment of infants; ITN, insecticide-treated net; MDA, mass drug administration; SMC, seasonal malaria chemoprevention; SP, sulphadoxine-pyrimethamine
Provenance: Commissioned; not externally peer reviewed
In this issue, Paul Milligan and colleagues  provide evidence of the dramatic impact on the incidence of malaria of seasonal malaria chemoprevention (SMC) among children aged older than five years, the current recommended upper age limit for SMC. Research on drugs to prevent malaria in Africa among nonpregnant populations has a long history with surprisingly little sustainable policy impact. The last five years of SMC research signal an important stage in drug-based policy for malaria based on evolving field science.
Antimalarial Drugs to Prevent Malaria in Africa
The use of antimalarial drugs to prevent malaria in Africa is not new [2,3]. At the turn of the last century, quininisation was widely promoted among residents of colonial administrative centres. During the “eradication” projects of the 1950s and 1960s, when indoor residual spraying failed to reach expected targets, mass drug administration (MDA) was included, resulting in huge reductions in infection incidence but never quite reaching elimination. The seasonal use of “chemoprophylaxis” was undertaken as part of pilot trials or elimination campaigns in Kenya, Burkina Faso, Senegal, Reunion, and Tunisia, again with dramatic impacts on parasite transmission and disease incidence [2,3]. Approaches to the seasonal use of drugs to prevent infection were resurrected during the 1980s with trials of fortnightly distribution by village health workers of pyrimethamine-dapsone to young children in The Gambia, resulting in an 80% reduction in clinical events and a 34% reduction in all-cause childhood mortality . Trials during the early 2000s of intermittent presumptive sulphadoxine-pyrimethamine (SP) treatment of infants (IPTi) attending routine vaccine visits showed on average a 30% protection against morbid events due to malaria . However, with the exception of the presumptive SP treatment of malaria in pregnancy, throughout the history of malaria control in Africa, drug-based interventions have received less attention compared to vector control. All commentators, since the earliest use of quinine and chloroquine prophylaxis, have highlighted concerns related to adherence, adequate coverage, sustainability, delayed acquisition of immunity, and resistance, concerns relevant to both vector- and drug-based control.
Seasonal Malaria Chemoprevention (SMC)
Trial results of SMC, between 2006 and 2011, showed dramatic impacts of the intermittent, presumptive use of combinations of antimalarial drugs on the incidence of clinical malaria in children aged between two months and five years . A meta-analysis in 2012 found strong evidence that the periodic, presumptive use of SP in combination with Amodiaquine (AQ) in areas of acute seasonal transmission could reduce malaria morbidity in young children by 75% . This evidence led to policy statements by WHO the same year  and development of regional and national plans for implementation of SMC. Donor agencies provided funding to operational plans through consortia of national malaria control programmes, nongovernmental organisations, UN agencies, and monitoring and evaluation partners. Within a year, 3.2 million children aged less than five years were protected by SMC in seven countries . This history provides an exemplary illustration of how field research evidence can lead to early policy adoption and immediate donor assistance. Importantly, previous reservations on the use of drugs for malaria control seemed less of a concern for SMC than, say, for IPTi or MDA.
Why Restrict SMC to Children Aged Less Than Five Years?
The operational costs of reaching households with children under the age of five would be similar if one aimed to reach these children’s older siblings at the same time. The only additional costs would be the increased use of comparatively cheap, well-tolerated drug combinations, while the benefits could be great if disease burdens were significant in children above five years of age. The epidemiological associations among parasite exposure, age, and clinical burden are complex, but, in broad terms, as malaria transmission intensity declines, the age at which functional clinical immunity is acquired increases (Fig 1) [9,10]. West Africa and the Sahel, where current SMC efforts, including Milligan and colleagues’ trial, are focussed, encompass a wide range of intrinsic transmission characteristics, important to predict the impact of SMC . Similarly varied has been the ability to reduce transmission potential through vector control. Countries such as Senegal, where Milligan and colleagues conducted their trial, and The Gambia have witnessed massive reductions in malaria transmission intensity over the last decade, to the extent that the phenotype of clinical malaria has transitioned from a disease concentrated in young children to one that affects an older childhood population [12,13].
Milligan and colleagues used a step-wedged design to incrementally test the effects of monthly distribution of SP+AQ to children under the age of ten years during the short malaria season in Senegal . They found a 60% reduction in malaria incidence . This empirical evidence demonstrates the benefits that can be gained by increasing the age window of targeted SMC in areas where transmission intensity is either already moderately low or brought down by vector control. Reducing the reservoir of infection will also have a wider impact on transmission. When SMC coverage is as high as 80% and insecticide-treated net (ITN) use is also high, these combined interventions will continue to change the epidemiology of parasite exposure and the clinical landscape.
Sustaining a Dynamic Research Agenda
Parasites, vectors, and humans adapt in the face of intervention. Models might be able to predict what might happen, but they do not tell you what does happen. We have become too comfortable with model predictions of impact and future predictions. After 20 years of scaling access to ITN, we still depend on models on their likely contribution to changing disease burdens. Empirical evidence is scanty, the impact of ITN on the disease phenotype and acquired immunity is poorly described, and pyrethroid resistance has emerged, but its public health impact remains unclear.
Among evidence-based policy developments, SMC is notable for incorporating the idea that different approaches may be appropriate in different settings. Maintaining careful epidemiologic surveillance alongside sustained and expanding intervention coverage should become a requirement for national malaria control programmes to redefine target populations and ensure there is no rebound . New drugs are needed, and the Medicines for Malaria Venture has already included ideal target profiles for SMC drugs in their product development portfolio . Operational research on how to access those most distant from regular health services is urgently needed. Measuring how many malaria events are prevented, without relying solely upon theoretical models, will provide the incentive for continued donor assistance. Even if a fraction of the costs of delivering SMC were dedicated to intensive surveillance and a sustained research agenda, national malaria programmes could adapt to a changing epidemiology, parasite resistance, and community acceptability. Importantly, ten years from now we won’t be left guessing whether this intervention is still working.
- Conceptualization: RWS.
- Funding acquisition: RWS.
- Project administration: RWS.
- Resources: RWS.
- Visualization: RWS.
- Writing – original draft: RWS.
- Writing – review & editing: RWS.
- 1. Cisse B, El Hadj BA, Sokhna C, Ndiaye JL, Gomis JF, Dial Y et al. Effectiveness of Seasonal Malaria Chemoprevention in children under 10 years of age in Senegal: a stepped-wedge cluster-randomized trial. PLoS Med. 2016; pmed.1002175.
- 2. von Seidlein L & Greenwood BM (2003). Mass administrations of antimalarial drugs. Trends Parasitol. 2003; 19: 452–460. pmid:14519583
- 3. Snow RW, Amratia P, Kabaria CW, Noor AM, Marsh K. The changing limits and incidence of malaria in Africa: 1939–2009. Adv Para 2012; 78: 169–262.
- 4. Greenwood BM, Greenwood AM, Bradley AK, Snow RW, Byass P et al. Comparison of two strategies for control of malaria within a primary health care programme in The Gambia, Lancet 1988; I: 1121–1127.
- 5. Aponte JJ, Schellenberg D, Egan A, Breckenridge A, Carneiro I, Critchley J et al. Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials. Lancet 2009; 374: 1533–1542. pmid:19765816
- 6. Meremikwu MM, Donegan S, Sinclair D, Esu E, Oringaje C. Intermittent preventive treatment for malaria in children living in areas with seasonal transmission (Review). Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD003756. pmid:22336792
- 7. World Health Organisation. Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa. March, 2012; http://www.who.int/malaria/publications/atoz/who_smc_policy_recommendation/en/.
- 8. UNITAID. http://www.unitaid.org/en/secondline/16-home/1592-seasonal-malaria-chemoprevention-sahel.
- 9. Snow RW, Omumbo JA, Lowe B, Molyneux SM, Obiero JO, Palmer A et al. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 1997; 349: 1650–1654. pmid:9186382
- 10. Okiro EA, Al-Taiar A, Reyburn H, Idro R, Berkley JA, Snow RW (2009). Age patterns of severe paediatric malaria and their relationship to Plasmodium falciparum transmission intensity. Mal. Jnl. 2009; 8: 4.
- 11. Noor AM, Kibuchi E, Mitto B, Coulibaly D, Doumbo OK, Snow RW. Sub-National targeting of seasonal malaria chemoprevention in the Sahelian countries of the Nouakchott initiative. PLoS ONE 2015; 10: e0136919. pmid:26322634
- 12. Ceesay SJ, Casals-Pascual C, Erskine J, Anya SE, Duah NO, Fulford AJ et al. Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis. Lancet 2008; 372: 1545–1554. pmid:18984187
- 13. Trape JF, Tall A, Sokhna C, Ly AB, Diagne N, Ndiath O et al. The rise and fall of malaria in a West African rural community, Dielmo, Senegal, from 1990 to 2012: a 22 year longitudinal study. Lancet Inf. Dis. 2014; 14: 476–488.
- 14. Snow RW. Global malaria eradication and the importance of Plasmodium falciparum epidemiology in Africa. BMC Med. 2015; 13: 23. pmid:25644195
- 15. Burrows JN, Van Huijsduijnen RH, Mohrle JJ, Oeuvray C, Wells TNC. Designing the next generation of medicines for malaria control and eradication. Malaria Journal 2013; 12: 187. pmid:23742293