NEJM Letters respond to recent studies on malaria vaccines, treatments

The New England Journal of Medicine in its March 19 issue featured a letter to the editor written in response to a study published in its Dec. 11 issue reporting the results of the RTS,S/AS01E malaria vaccine trial. Summaries of the letter and the author's reply appear below.

• "RTS,S/AS01E Vaccine Against Malaria": The results of the vaccine trial are "impressive" but also involve "methodologic issues in the measurement of protective efficacy in sites where the transmission of malaria is falling," Roly Gosling and Daniel Chandramohan of the London School of Hygiene and Tropical Medicine write in a letter to the editor. According to Gosling and Chandramohan, although the first clinical trial found a "high protective efficacy of intermittent preventive treatment for malaria in infants," this outcome likely was "exaggerated by a fall in transmission during the trial." In addition, the "combination of decreasing transmission and protection over time could lead to an overestimate of efficacy," the authors write. They continue that the scope of the trial was "small, the risk of malaria was highly variable and transmission was falling." Gosling and Chandramohan conclude, "Testing RTS,S in high-transmission sites is a priority" in order to refine estimated trial outcomes (Gosling/Chandramohan, NEJM, 3/19).
• Author's Reply: Although malaria transmission "has indeed been falling in the study areas" involved with the RTS,S/AS01E trial, the researchers' assessment "of the survival plots is of sustained transmission throughout the period of monitoring," Philip Bejon of the Kenya Medical Research Institute, Amanda Leach of GlaxoSmithKline Biologicals and Lorenz von Seidlein of the International Vaccine Institute write in an author's reply to the letter. The authors write that they "certainly agree that estimates of efficacy during long-term follow-up are essential," adding that "estimates have been made for RTS,S/AS02A, with encouraging results." In addition, they also write that they agree with Gosling and Chandramohan "that point estimates of vaccine efficacy from phase 2b studies, such as the results we report, are surrounded by uncertainty." The authors conclude that in the future, RTS,S/AS01E "will be evaluated in a wide range of transmission sites and over longer period so follow-up in a planned Phase III multicenter efficacy trial" (Bejon et al., NEJM, 3/19).

• "Antimalarial Therapies in Children from Papua New Guinea": In their article on combination malaria treatments, the researchers "conclude that artemether-lumefantrine has more favorable efficacy than dihydroartemisinin-piperaquine, even though fat was given with the treatment only in the artemether-lumefantrine group and there was no significant difference in the primary end point," Ric Price of the Menzies School of Health Research, Grant Dorsey of the University of California-San Francisco and Francois Nosten of Shoklo Malaria Research Unit write in a letter to the editor. The authors write that they "re-analyzed data" involving 981 children younger than age five and administered dihydroartemisinin-piperaquine with milk or a biscuit. According to their analysis, the "risk of recurrent malaria was significantly reduced after treatment with dihydroartemisinin-piperaquine as compared to artemether-lumefantrine." They continue that dihydroartemisinin-piperaquine is "a highly effective treatment" for multi-drug resistant Plasmodium falciparum malaria among young children and that the drug "provides clinically significant post-treatment prophylaxis." The authors conclude that they "recommend that both dihydroartemisinin-piperaquine and artemether-lumefantrine be given with fat (milk, biscuit or other food) to increase bioavailability" (Price et al., NEJM, 3/19).
• Author's Reply: "Enhanced piperaquine bioavailability with fat co-administration was reported after" the start of the trial described in the Dec. 11 issue, Timothy Davis of the University of Western Australia, Harin Karunajeewa of Australia's Western Hospital and Ivo Mueller of the Papua New Guinea Institute of Medical Research write in an author's reply to the letter. They continue, that "no food-specific dosing recommendations for dihydroartemisinin-piperaquine" existed at the start of the trial or immediately following the trial. In addition, other studies have demonstrated "excellent efficacy when fat co-administration was not required" with dihydroartemisinin-piperaquine, according to the authors. However, they write that "determining optimal fat intake in children with falciparum malaria would be valuable." The authors conclude that the discrepancies between this study and others likely "reflect the epidemiological complexity of malaria and underscores the need for valid local efficacy trials before new treatments are deployed" (Davis et al., NEJM, 3/19).