PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the burden of malaria disease in children and contribute to malaria elimination. GSK has developed a candidate vaccine called RTS,S/AS01 which helps the immune system of people vaccinated with RTS,S/AS01 prevent infection with the parasite that causes malaria. The RTS,S/AS01 vaccine has been shown to be safe in multiple studies around the world and is currently beginning a pilot implementation program in children in sub-Saharan Africa. The vaccine has been shown to be effective in adults who have never had malaria when they are challenged with malaria infection in the United States, but has been less effective when given to adults in Africa who have had malaria before. There are probably multiple reasons for this, but one possible reason that is probably very important is that prior infection with malaria or an infection with malaria for long periods, even without symptoms of the disease, can prevent the vaccine from working properly. This study is testing the question that if we treat individuals with antimalarial medications before giving the vaccine, will that make it more effective in people who have a history of malaria infection. The RTS,S/AS01 malaria vaccine will be compared to a rabies vaccine to see if this will improve the effectiveness. We will also be looking at the safety of the vaccine and the response of the immune system to this vaccine.

PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the burden of malaria disease in children and contribute to malaria elimination. GSK has developed a candidate vaccine against malaria caused by Plasmodium falciparum, RTS,S/AS01. The vaccine has been shown to be safe in multiple trials and efficacy data in pediatric populations has led to a pilot implementation program in three African countries including Kenya. The RTS,S/AS01 vaccine mechanism of action is presumed to work on the initial sporozoite and liver stages of P. falciparum infection through neutralization of the circumsporozoite (CS) antigen on parasites invading after a mosquito bite in individuals immunized with the RTS,S/AS01 vaccine. In order to inform whether a vaccine such as RTS,S/AS01 may have a future role in malaria elimination, it will be important to establish vaccine efficacy in adults in Sub-Saharan Africa who are reservoirs of parasites and who contribute to ongoing malaria transmission. However, in previous trials, the vaccine has been less effective in adults in endemic regions compared to challenge studies. While the cause of this is likely multi-factorial, there is a degree of immunologic hypo-responsiveness that occurs in endemic regions that may impede the development of a protective immune response following immunization that is presumed to be related to chronic infection. This study postulates that treatment of infection prior to immunization can reset the immune response leading to an improved vaccine efficacy. To evaluate this hypothesis, the study will recruit 5 groups. Groups 1 and 4 will have asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay (planned assay is an RNA-based PCR though the backup utilizes both RNA and DNA PCR, see protocol for details) and will be treated with antimalarial medications prior to immunization with RTS,S/AS01 or the comparator rabies vaccine, respectively, with the primary objective of evaluating the vaccine efficacy of RTS,S/AS01 relative to the rabies vaccine in this context. Groups 2 and 5 will be negative for asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay and will be treated with antimalarial medications prior to immunization with RTS,S/AS01 or the comparator rabies vaccine, respectively, with the secondary objective of evaluating the vaccine efficacy of RTS,S/AS01 relative to the rabies vaccine in this context. Group 3 will have asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay but will not be treated with antimalarial medications prior to immunization with the RTS,S/AS01 vaccine; the immunological profile (including anti-CS and cell-mediated immune responses) of this group and groups 1 and 2 will be evaluated as part of secondary and exploratory objectives. Other secondary objectives include safety assessments and other exploratory objectives defined in this protocol. A total of 619 subjects will be enrolled (164 in groups 1 and 4, 128 in groups 2 and 5, and 35 in group 3) over a period of 6 months and will participate in the study for an initial immunization period (vaccine given on 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations) followed by 6-12 months of follow-up (varying based on the number of events), with the primary and secondary efficacy endpoints of time to first malaria infection by PCR. Total duration expected to be 20.5-26.5 months. Those groups receiving antimalarial medications (1, 2, 3, 4) will receive either dihydroartemisinin-piperaquine or artemether/lumefantrine and low-dose primaquine as described in the protocol.