SMC: still saving children, going south

In Burkina Faso, when health workers watched children under 5 swallow every dose of seasonal malaria chemoprevention (SMC), protective efficacy against clinical malaria was 57% compared with the usual programme, in which later doses are given at home ¹. SMC, a monthly course of sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) given in the rainy season, already protects tens of millions of African children. Between 2012 and 2024, the average number of children treated per SMC cycle in 20 African countries rose from about 170,000 to 54 million ⁷.

The new evidence shows three things. SMC keeps working where it started, in the Sahel. It works in new countries such as Benin. And its protection is weaker where parasites resist the drugs, which matters as SMC moves south and east.

The burden

The World Health Organization (WHO) estimates 282 million malaria cases and 610,000 malaria deaths in 2024 ⁷. The WHO African Region carried 94% of cases and 95% of deaths, and 75% of deaths in the region were in children under 5 years ⁷. WHO's fact sheet gives the African toll as 579,000 deaths ⁸. That is roughly 434,000 young children.

The countries with the most deaths include several SMC countries. Nigeria accounted for 31.9% of global malaria deaths and Niger for 6.1% ⁸. Burkina Faso, Mali, Cameroon, Ghana, Mozambique and Uganda are among the 11 African countries that together carry about two thirds of global malaria cases and deaths ⁷.

Malaria in much of the Sahel and sub-Sahel is highly seasonal. Most cases and deaths come in a few months of the rainy season. That concentration is what makes SMC possible: a short burst of protection covers most of the year's risk.

The trend is mixed. Since 2000, an estimated 14 million malaria deaths have been averted ⁷. Since 2015, the global mortality rate fell from 14.9 to 13.8 deaths per 100,000 people at risk, but the number of deaths rose from 578,000 to 610,000 because of population growth ⁷. The 2024 mortality rate was more than three times the target in WHO's Global Technical Strategy ⁷.

How it works

SMC is not a vaccine and not treatment of a sick child. It is a full treatment course of antimalarial drugs given to healthy children at regular intervals during the high-transmission season. The drugs clear any parasites already in the blood and keep a protective level of drug in the body for several weeks, so new infections cannot take hold.

WHO describes SMC as monthly doses of antimalarial drugs during the peak malaria season to children under 5, the group most vulnerable to severe malaria ⁷. In practice:

• The drugs. The standard regimen is SPAQ: sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) ¹⁵.
• The schedule. A course is given each month through the season. The Burkina trial gave four cycles ¹. Each course is a 3-day course of SPAQ, and the day 1 dose is given by a community distributor, ideally under direct observation ¹⁰. The later doses are usually given at home, and that is the weak point the Burkina trial tested ¹.
• The delivery. SMC is usually delivered door to door by community health workers or volunteers in campaigns ⁹.

Why adherence matters: if a child takes only the day 1 dose, drug levels fall faster, and protection is shorter. The Burkina trial measured drug levels in the blood to check this ¹.

Why resistance matters: SP works less well as parasites acquire mutations in two genes, dhfr and dhps. As dhps mutations accumulate, the time SP keeps a child protected shrinks ⁴. Amodiaquine resistance is linked to other markers (pfcrt and pfmdr1) ⁵. A related tool, perennial malaria chemoprevention (PMC), gives SP to infants at routine contacts through the year in places without a single sharp season ⁶⁷.

What the evidence shows

2012–2016: why seasonal prevention was adopted

A 2012 Cochrane review of seven West African trials found that seasonal preventive treatment reduced clinical malaria (rate ratio 0.26, 95% CI 0.17–0.38) and severe malaria (0.27, 0.10–0.76). The mortality estimate remained imprecise (risk ratio 0.66, 0.31–1.39) ²⁰. The review was published within this window, although the underlying trials were earlier. Disease prevention was established more firmly than a direct survival effect.

A stepped-wedge cluster trial in Senegal, published in 2016, extended delivery to children up to ten years old. SMC reduced outpatient malaria by 60%, but the primary all-cause mortality outcome did not significantly differ (rate ratio 0.90, 95% CI 0.68–1.20) ²¹. This supports the feasibility of an older age range while preserving the distinction between preventing malaria episodes and demonstrating fewer deaths.

Directly observed SMC in Burkina Faso

Who and where. Yaro, Ouedraogo and colleagues ran a trial in Saponé, Burkina Faso ¹. It is registered as NCT05878366 and funded by the Gates Foundation ¹.

Design. A three-group, open-label, cluster-randomised trial. Clusters of three family compounds were assigned to: programmatic SMC for under-5s (61 clusters); SMC for under-5s with every dose directly observed (DOTu5, 62 clusters); or directly observed SMC extended to children under 10 (DOTu10, 62 clusters) ¹. Children received four cycles of SPAQ ¹.

Size. Between 13 July and 29 August 2023, 3,467 people of all ages were enrolled, including 980 children targeted for SMC: 236 in the programmatic group, 231 in DOTu5 and 513 in DOTu10 ¹.

Primary outcome. Parasite prevalence at the end of the season. In under-5s it was 24.9% (52 of 209) with programmatic SMC and 19.7% (40 of 203) with DOTu5. The rate ratio was 0.84 (95% CI 0.55–1.30; p=0.44), which was not significant ¹.

Secondary outcomes. Clinical malaria in under-5s was lower with DOTu5 than with programmatic SMC: protective efficacy 0.57 (0.29–0.74; p=0.0009) ¹. Children scored as adherent from their blood drug levels had an incidence rate ratio of 0.21 (0.09–0.51) compared with non-adherent children after the fourth cycle ¹.

Older children. In children aged 5–9, parasite prevalence was 28.1% with DOTu10 against 47.1% with DOTu5, where they did not get SMC (RR 0.56, 0.43–0.74) ¹. Protective efficacy against clinical malaria in this age group was 0.72 (0.54–0.83) ¹.

Caveats. The primary outcome was null for under-5s. The clinical-malaria benefit is a secondary result. The authors say logistical and financial barriers to extending the age range still need study ¹.

SMC in a new country: northern Benin

Who and where. Sonounameto and colleagues evaluated Benin's SMC programme, which has run in the north since 2019 ².

Design. A quasi-experimental analysis of routine Health Management Information System data from 2019 to 2022 ². Six health zones with SMC were compared with synthetic controls built from nine eligible zones without SMC, matched on rainfall, temperature and humidity in 2017–2018 ².

Outcomes. Severe malaria in under-5s fell by 41% in SMC zones (IRR 0.59, 95% CI 0.44–0.79), while it rose by 26% in control zones (IRR 1.30, 0.97–1.63) ². Uncomplicated malaria rose in both groups, but by 2.49% in SMC zones against 16.3% in control zones ². The ratio of incidence rate ratios was 47% (30%–74%; p<0.001) for severe malaria and 78% (63%–96%; p=0.004) for uncomplicated malaria ².

Caveats. This is observational routine data, not a trial. The authors note that funding cuts threaten the programme ².

SMC in northern Mozambique

Who and where. Bonnington and colleagues, working with Malaria Consortium, nested a drug-level and parasite study in the SMC rollout in Nampula province ³.

Design and size. SPAQ was given to 460 healthy children in two large villages. Blood samples were taken before, then 7 and 28 days after the first dose ³.

Outcomes. Parasite prevalence fell from 68% to 41% ³. Preventive efficacy was 97% against Plasmodium ovale and 42% against Plasmodium falciparum ³. Protection tracked blood levels of desethylamodiaquine (from amodiaquine), but not of sulfadoxine or pyrimethamine ³.

Caveats. This is a small pharmacological study, not a mortality trial. The main finding is itself a limit, covered below.

The genotype map for SP

Who. Mousa and colleagues pooled seven SP efficacy trials with 1,639 participants at 12 sites across Africa ⁴.

Design. A Bayesian model of time to reinfection, by parasite dhps genotype ⁴.

Outcomes. SP protects for more than 42 days against sulfadoxine-susceptible parasites and 30.3 days (95% CrI 17.1–45.1) against the West African GKA genotype ⁴. Protection falls to 16.5 days (11.2–37.4) against the East African GEA genotype and 11.7 days (8.0–21.9) against the highly resistant GEG genotype ⁴. The team mapped SP protection across Africa and say the approach can use local genomic data to guide where to scale up SP chemoprevention ⁴.

2020: SMC at scale (ACCESS-SMC)

The ACCESS-SMC partnership evaluated SMC in Burkina Faso, Chad, The Gambia, Guinea, Mali, Niger and Nigeria in 2015–2016 ⁹. It delivered 25,117,480 monthly treatments in 2016 to a target of 7,551,491 children ⁹. Protective effectiveness was 88.2% (95% CI 78.7–93.4) over 28 days in case-control studies ⁹. Hospital malaria deaths in the high-transmission period fell by 42.4% in Burkina Faso and 56.6% in The Gambia ⁹. Mean monthly coverage was about 75%, but only about 53–55% of children received all four treatments ⁹.

Results at a glance

LimitsWhat didn't work (or the limits)

Protection against the main killer is moderate in the south. In the Mozambique study, preventive efficacy against Plasmodium falciparum, the parasite responsible for most malaria deaths, was only 42% ³. The authors conclude that amodiaquine had low parasitological efficacy in Nampula and that SP did not contribute significantly to chemoprevention ³. Yet all 250 P. falciparum isolates genotyped carried the pfcrt 76K marker, which signals amodiaquine susceptibility ³. So the usual marker did not predict the weak result. One third (21 of 64) of breakthrough infections seen by microscopy carried gametocytes, the form that infects mosquitoes ³.

Resistance genotype decides how long SP protects. Because SMC is given monthly, protection that lasts only 11.7 to 16.5 days against East African genotypes leaves long gaps ⁴. This gives a map of where SP-based chemoprevention still works and where it is fading.

Resistance rises slowly under long use. In Moissala, Chad, where SMC has run since 2013, Grandesso and colleagues with Epicentre/Médecins Sans Frontières ran molecular surveys in 2014, 2021 and 2023 ⁵. Quadruple-mutant parasites rose from 28.0% to 41.0% and 47.9% ⁵. Quintuple mutants, which give stronger resistance, stayed low at 7.6%, 2.8% and 5.9% ⁵. The amodiaquine-linked pfcrt K76T mutation fell from 44.6% to about 11% ⁵. The authors conclude SP and AQ remain effective, but the rise in quadruple mutants is concerning and surveillance must continue ⁵.

PMC runs against a resistant background. In Sierra Leone, three years after PMC began, Chen and colleagues found the pfdhfr triple mutant in 99.5% of samples (217/218) and dhps A437G in 92.1% ⁶. But the quintuple mutant was only 4.6% (7/151), and no sextuple mutants were seen ⁶. The authors judge that this low quintuple level justifies continued SP use for PMC and for preventive treatment in pregnancy ⁶.

Observation did not change parasite prevalence significantly. In the Burkina trial, the primary outcome was null for under-5s (24.9% vs 19.7%, RR 0.84) ¹, even though clinical malaria fell.

Full courses are the exception, not the rule. At scale, only about half of children received all four monthly treatments in ACCESS-SMC ⁹. In Mozambique, $1,726,189.63 could have been saved had ineligible children aged 60–119 months not been treated ¹⁰. Targeting and adherence are both weak points.

Perennial prevention has older trial evidence, but newer schedules need evaluation. A 2021 Cochrane review of intermittent preventive treatment in infants, the predecessor to today’s PMC approach, found that SP reduced clinical malaria (rate ratio 0.78, 95% CI 0.69–0.88), with little or no effect on all-cause mortality (risk ratio 0.93, 0.74–1.15) and weaker efficacy in later trials ²². These infant schedules do not establish the effect of every extended-age PMC programme. The newer model ¹¹ should therefore be read alongside the older trials, not as the only evidence.

Cost and scale

Cost per child. ACCESS-SMC put the weighted average economic cost of four monthly treatments at US$3.63 per child ⁹. A 2024 systematic review by Ruisch and colleagues found financial costs per child for a full course ranging from $1.71 to $12.46, and economic costs from $2.11 to $29.06 ¹². The review notes that most cost data come from pilots or new campaigns, not mature programmes ¹².

Hidden costs. Owusu and colleagues costed SMC in Mali, Burkina Faso and Senegal in 2022 ¹³. Financial cost per dose was $0.99 in Mali, $1.42 in Burkina Faso and $1.51 in Senegal ¹³. Economic costs per child for four doses were $11.85 to $12.57, and 50%–66% of economic costs were productivity losses for caregivers, volunteers and health workers ¹³.

Cost per health gain. In the review, costs per DALY averted ranged from $24.51 to $182.88, and per death averted from $688.86 to $18,418.81 ¹². In Nampula, Mozambique, Canana and colleagues estimated $93.50 per case averted, $3,286.59 per death averted and $130.16 per DALY averted, with a cost per targeted child of $6.05 ¹⁰. The authors judged SMC cost-effective ¹⁰.

Adding other services. In Bauchi State, Nigeria, Oresanya and colleagues found SMC cost $0.94 per child per cycle, and adding vitamin A supplementation raised it to $1.18 ¹⁴.

Coverage. SMC reached an average of 54 million children per cycle in 20 countries in 2024, and Kenya introduced SMC for the first time that year ⁷. At least eight countries ran PMC in 2024, including Benin, Cameroon, Côte d'Ivoire, the Democratic Republic of the Congo, Mozambique, Nigeria, Sierra Leone and Togo, and nearly 1 million children under 24 months received a first PMC dose ⁷.

Who funds and delivers. National malaria programmes deliver SMC through community distributors, often with partners such as Malaria Consortium ³¹⁰. The ACCESS-SMC scale-up was funded by Unitaid ⁹. In 2024, about 56% of all malaria funding came from international sources and 44% from endemic countries ⁷. WHO reports that partner support kept SMC campaigns largely on track despite 2025 funding cuts ⁷.

What to watch

SMC plus vaccine, delivered together. Epicentre is running a trial in Burkina Faso and Mali (NCT06860178) comparing routine R21 vaccination with an annual three-dose campaign aligned with SMC distribution for children aged 3–59 months ¹⁵. A second Epicentre trial in Moïssala and Dembo districts of Chad (NCT07038837) compares routine R21 with R21 synchronised with the SMC campaign ¹⁶. This builds on a trial in Burkina Faso and Mali in which RTS,S plus SMC cut clinical malaria by 57.7% compared with SMC alone over five years ¹⁷.

PMC effect in Nigeria. Malaria Consortium, with Nigeria's National Malaria Elimination Programme, is running a PMC effect study in Osun State (NCT06155448) in children aged 2–18 months, measuring clinical malaria and the protective effectiveness of SP ¹⁸. The registry lists it as active, not recruiting, with primary completion in 2025 ¹⁸. Results would help fill the PMC evidence gap.

PMC in the vaccine era. A Stanford University trial at Masafu General Hospital, Busia District, Uganda (NCT07322068, not yet recruiting) will test PMC with SPAQ or dihydroartemisinin-piperaquine added to R21 ¹⁹. Using a non-SP drug is one answer to the resistance problem in East Africa.

Genomic surveillance. Mousa and colleagues' method can use local genomic data to decide where SP still works ⁴. Chad's decade of surveys shows the value of repeating these measurements ⁵.

What it means

For national malaria programmes in the Sahel. SMC keeps saving children where it is delivered in full. The Burkina trial suggests the gain from making sure every dose is swallowed is large for clinical malaria ¹, and ACCESS-SMC showed only about half of children complete all four cycles ⁹. Direct observation costs more health-worker time, and caregiver time is already the largest economic cost ¹³, so programmes will need to weigh that against the protection it adds.

For countries adding SMC, such as Benin. The programme data are encouraging: severe malaria fell by 41% where SMC was delivered ².

For East and Southern Africa. The picture is mixed. SMC with SPAQ gave 42% protection against P. falciparum in Mozambique ³, and the genotype map suggests SP protection can drop below two weeks where highly resistant parasites circulate ⁴. Planners should check local resistance markers before choosing a drug regimen and a dosing interval, and follow trials of alternative drugs ¹⁹.

For funders. SMC is cheap per child ⁹¹² and cost-effective ¹⁰¹². The priorities are clear: pay for full-dose delivery, pay for molecular surveillance ⁵⁶, and fund effectiveness trials of PMC, where the evidence is still thin ¹¹.

For health workers and community distributors. Give the day 1 dose under observation, and explain to caregivers why days 2 and 3 matter. A child who takes all three days is far better protected than one who does not ¹. Children who get SMC can still get malaria: test every fever and treat promptly.