RTS,S/AS01E Hypo-immuno-responsiveness Study

Plasmodium Falciparum Clinical Trial

Official title: A Phase 2b Randomized, Open-label, Controlled, Single Center Study in Plasmodium Falciparum-infected and Uninfected Adults Age 18-55 Years Old in Kenya to Evaluate the Efficacy of the Delayed, Fractional Dose RTS,S/AS01E Malaria Vaccine in Subjects Treated With Artemisinin Combination Therapy Plus Primaquine

Status Completed

Clinical Trial Summary

The proposed trial design has been developed to answer several questions related to the nature of RTS,S vaccine efficacy in African adults that may be influenced by concurrent and/or past P. falciparum infection leading to a state of immunologic hypo-responsiveness. The proposed study design encompasses five groups. Three groups (Groups 1, 2, and 3) will be administered RTS,S/AS01E on a 0, 1, 7 month schedule with Dose 3 delivered as a 1/5th fractional dose. Two groups (Groups 4 and 5) will be administered a comparator vaccine on a 0, 1, 7 month schedule.

Clinical Trial Description

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/AS01E. 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/AS01E 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/AS01E vaccine. In order to inform whether a vaccine such as RTS,S/AS01E 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 polymerase chain reaction (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/AS01E or the comparator rabies vaccine, respectively, with the primary objective of evaluating the vaccine efficacy of RTS,S/AS01E 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/AS01E 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/AS01E 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. ;

Related Conditions & MeSH terms

• Malaria
• Plasmodium Falciparum

• NCT number: NCT04661579
• Study type: Interventional
• Source: PATH
• Status: Completed
• Phase: Phase 2
• Start date: November 6, 2020
• Completion date: August 17, 2022