Effect of intermittent preventive treatment for malaria during infancy on serological responses to measles and other vaccines used in the Expanded Programme on Immunization: results from five randomised controlled trials.

BACKGROUND: Intermittent preventive treatment for malaria during infancy (IPTi) is the administration of a full therapeutic course of antimalarial drugs to infants living in settings where malaria is endemic, at the time of routine vaccination in the first year of life. We investigated whether IPTi with sulfadoxine-pyrimethamine or other antimalarial drug combinations adversely affected serological responses to vaccines used in the Expanded Programme on Immunization (EPI). METHODS: The study was done in a subset of children enrolled in five randomised controlled trials in Navrongo, Ghana; Kilimanjaro, Tanzania; Manhica, Mozambique; Kisumu, Kenya; and Bungoma, Kenya. All infants presenting for the second dose of the diphtheria-tetanus-pertussis vaccination (given at 8-10 weeks of age) were eligible, and analyses included all children who had received measles vaccination (at 9 months of age) and at least one dose of IPTi or placebo. Blood samples were collected before and after vaccination, and antibody titres were measured by plaque reduction neutralisation (measles, yellow fever), microneutralisation (polio serotypes 1 and 3), and ELISA (all other EPI antigens). Laboratory personnel were unaware of the randomisation groups. We compared the proportion of infants in the IPTi and placebo groups who did not attain protective antibody titres after vaccination, using a one-sided significance non-inferiority margin of 5% for measles (the primary endpoint) and 10% for other EPI antigens. FINDINGS: Between September, 2000, and May, 2008, 8416 children were enrolled in the five studies. Paired samples from 2368 children from sites where sulfadoxine-pyrimethamine was compared with placebo were analysed for measles antibodies. 464 children with detectable measles antibody in their sample before vaccination were excluded, leaving 1904 individuals (934 placebo and 970 sulfadoxine-pyrimethamine) in the study. IPTi with sulfadoxine-pyrimethamine did not have a clinically significant effect on immune responses to measles vaccine; 61 of 970 (6·3%) children who received IPTi did not develop a protective antibody response after measles vaccination compared with 60 of 934 (6·4%) who received placebo, a difference of -0·14% (95% CI -2·3 to 2·1). When other antimalarial drugs were used for IPTi the results were much the same. Among 2396 children from whom serological response data for other EPI antigens were available, we identified no evidence of an adverse effect of IPTi with sulfadoxine-pyrimethamine or other antimalarial drugs on the proportion achieving protective antibody concentrations. INTERPRETATION: IPTi with sulfadoxine-pyrimethamine does not affect serological responses to EPI vaccines. This analysis, therefore, supports the WHO recommendation for coadministration of IPTi with sulfadoxine-pyrimethamine to infants at the time of the second and third doses of DTP and measles vaccination, in areas of sub-Saharan Africa with moderate to high malaria transmission and where malaria parasites are sensitive to these drugs. It also suggests that treatment of clinical malaria at or around the time of vaccination does not compromise vaccine responsiveness. FUNDING: Bill & Melinda Gates Foundation.