RTS,S/AS01E Hypo-immuno-responsiveness Study
Condition: Plasmodium Falciparum
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 2

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.
    

Detailed 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.
    

Intervention name(s): RTS,S/AS01E; Abhayrab rabies vaccine
Intervention type(s): Biological; Biological
Intervention description(s): Vaccine; Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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.
Masking: None (Open Label)
Primary purpose: Other
Keywords: RTS,S/AS01E; hypo-immuno-responsiveness; open-label randomized study; Phase 2b; Kenyan adults; anti-malarials; fractional dose RTS,S/AS01E