BackgroundSeasonal malaria chemoprevention (SMC) using monthly sulfadoxine-pyrimethamine-amodiaquine (SPAQ) is being deployed East Africa, where antimalarial drug resistance levels are high. Dihydroartemisinin-piperaquine (DP) is a potential alternative.MethodsA prospective 28 day pharmacometric assessment of SMC was conducted in Karamoja, Northern Uganda. In two villages children received SPAQ and in a third were randomized to DP vs. no SMC The primary outcome was malaria infection defined by capillary blood sample qPCR positivity on day 28, or presentation with fever and slide or rapid test positivity after day 2.ResultsBaseline qPCR malaria parasitemia prevalence among 1250 enrolled children was 46% (575/1250); P. falciparum 85%, other malarias (mainly P. ovale) 25%. Breakthrough parasitemias occurred in 7% (33/496) of DP, 31% (158/504) of SPAQ, and 39% (98/250) of no drug recipients. Clinical malaria (all P. falciparum) developed in 17% of no drug (42/250; 1 severe), 8% of SPAQ (38/504; 2 severe) and 2% of DP (13/496) recipients. Adjusted protective efficacies against all malaria parasitemia, P. falciparum parasitemia, and clinical malaria were SPAQ; 56% (95%CI 35-70%), 46% (11-68%), and 60% (27-78%)and for DP; 84% (77-89%), 86% (75-92%) and 86% (74-92%) respectively. Some asymptomatic P. falciparum infections were not cleared by SPAQ. All 260 P. falciparum isolates genotyped were Pfcrt K76 (haplotype CVMNK, a marker of 4-aminoquinoline susceptibility) and most were quintuple Pfdhfr/dhps mutants (i.e. relatively SP resistant). The chemoprevention drug exposure-response relationship was strong for desethylamodiaquine, but weak for sulfadoxine.ConclusionsSPAQ SMC had low clinical and parasitological chemopreventive efficacy in Northern Uganda whereas dihydroartemisinin-piperaquine was effective.