Safety and Preliminary Protective Efficacy of Genetically Attenuated GA2 Parasites.
Condition: Plasmodium Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study will consist of two phases and be aimed at assessing the safety and tolerability
      of the new genetically attenuated GA2 malaria parasite (Phase 1) and its preliminary
      protective efficacy against controlled human malaria infection (Phase 2) in healthy Dutch
      volunteers.
    

Detailed description: 
      Malaria is one of the most common tropical diseases, accounting for 228 million infections
      and 450.000 deaths each year. It is caused by five species of protozoan parasites belonging
      to the genus of the Plasmodia. Plasmodia have a complex life cycle: they are injected into
      the human host by female Anopheles mosquitos, migrate to the liver to replicate and then
      enter red blood cells. The typical symptoms of malaria with fever episodes are caused by the
      bursting of red blood cells, as the parasites leave to infect new cells.

      The rising resistance of both parasites against anti-malarial drugs and mosquitoes against
      insecticides, make the need to eradicate malaria even more impellent. A promising approach to
      disease control is the development of an effective vaccine. Among the different approaches to
      vaccine development, live attenuated parasites stand out for their high protective efficacy
      (>90%).

      The GA2 parasite, a new genetically attenuated malaria parasite, which is derived from the
      NF45 Plasmodium falciparum strain and has been engineered to arrest development in the liver
      before entering the bloodstream, was recently created. It should therefore not be able to
      cause malaria in humans. The idea is that the GA2 parasite will prime the immune system for
      recognition of non attenuated parasites in the future without causing disease itself. In
      other words, exposure to the innocuous GA2 parasite could confer protection against
      pathogenic malaria parasites.

      Hence, this study is aimed at investigating the safety and tolerability of the GA2 parasite
      and at determining its potential protective efficacy against controlled human malaria
      infection. The former question will be investigated by exposing volunteers to sequentially
      increasing numbers of GA2-infected mosquito bites. The latter question will be investigated
      by repeatedly (3 times) exposing volunteers to the GA2 parasite and once to unattenuated
      parasites. The efficacy of the GA2 parasite will be compared to another genetically
      attenuated parasite, the GA1, which in previous studies has been shown to be safe and
      well-tolerated but only have limited protective efficacy. There will also be a placebo group.
    

Intervention name(s): GA2; GA1; Placebo
Intervention type(s): Other; Other; Other
Intervention description(s): 15 volunteers will receive 50 GA2-infected mosquito bites. The GA2 parasite is a new genetically attenuated Plasmodium falciparum parasite, which arrests development in the liver and should not be able to cause malaria in humans.; 10 volunteers will receive 50 GA1-infected mosquito bites. The GA1 parasite is a genetically attenuated Plasmodium falciparum parasite, which arrests development in the liver and is not able to cause malaria in humans.; 5 volunteers will receive 50 uninfected mosquito bites.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This trial has both a sequential as well as a parallel interventional study model.
The safety and tolerability of the GA2 parasite will be assessed in phase 1 by means of a sequential study model. There will be 2 cohorts, which will be recruited sequentially and exposed to increasing numbers of infected mosquito bites.
The preliminary protective efficacy of the GA2 parasite will be assessed in phase 2 by means of a parallel study model. There will be 3 groups of volunteers, who will be exposed to either GA2-infected, GA1-infected or uninfected mosquito bites.
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Malaria; Plasmodium falciparum; Genetically attenuated parasites