Malaria Vaccine for Children in Mali
Condition: Malaria; Malaria Infection
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will evaluate the safety and immune response of children to an experimental
      malaria vaccine called AMA1-C1/Alhydrogel® (Registered Trademark) + CPG 7909. Malaria is an
      infection of red blood cells caused by a parasite, Plasmodium falciparum, that is spread by
      certain kinds of mosquitoes. It affects at least 300 million people worldwide each year, with
      more than 1 million deaths, mostly among children less than 5 years of age in sub-Saharan
      Africa. Malaria is the leading cause of death and illness among the general population of
      Mali in West Africa. Increasing drug resistance to P. falciparum and widespread resistance of
      mosquitoes to pesticides are reducing the ability to control the disease through these
      strategies. AMA1 C1 is made from a synthetic protein similar to a P. falciparum protein. It
      is combined with Alhydrogel and CPG 7909, substances added to vaccines to make them work
      better.

      Children between 1 and 4 years of age who live in Bancoumana, Mali, and are in general good
      health may be eligible for this study. Candidates are screened with a medical history,
      physical examination, and blood and urine tests.

      Participants are randomly assigned to receive three injections (shots) of either AMA1-C1 or a
      control rabies inactivated vaccine called Imovax® (Registered Trademark). The shots are given
      in the thigh muscle on study days 0, 56 and 180. After each shot, participants are observed
      in the clinic for 30 minutes. They return to the clinic for a physical examination six or
      seven times between each shot and then four more times over a 9-month period after the last
      shot. Blood samples are drawn at several of these visits to check for side effects of the
      vaccine and to measure the response to it. The total duration of the study is 21 months.

      ...
    

Detailed description: 
      Globally, the Plasmodium falciparum parasite is responsible for at least 300 million acute
      cases of malaria each year, with more than 1 million deaths. Approximately 90 percent of
      these deaths, the majority in children under 5 years of age, occur in Africa due to infection
      with Plasmodium falciparum. Morbidity and mortality caused by malaria also has significant
      direct and indirect costs on the economic development of the endemic countries. It is
      estimated that malaria accounts for 40 percent of public health expenditures, more than 30
      percent of inpatient admissions, and approximately 50 percent of outpatient visits in some
      African countries. These factors, as well as growing drug resistance of the parasite,
      widespread resistance of mosquitoes to insecticide, and increased human travel necessitate
      the need for new approaches to malaria control and eradication. A vaccine that could reduce
      both mortality and morbidity secondary to Plasmodium falciparum infection would be a valuable
      resource in the fight against this disease.

      Over time, people living in endemic areas develop natural immunity to Plasmodium falciparum
      as a result of repeated infection. Consequently, children who survive to 7 to 10 years of age
      rarely succumb to life-threatening disease despite frequent infection. This acquired immunity
      is mediated in part by blood-stage parasite-specific antibodies. Thus, parasite proteins
      expressed during the blood-stage have been proposed to be good candidates for inclusion in a
      vaccine. The purpose of a blood-stage vaccine is to elicit immune responses that either
      destroy the parasite in the blood stream or inhibit the parasite from infecting red blood
      cells, thus reducing or preventing complications of the disease.

      A number of Plasmodium falciparum merozoite antigens have been identified as promising
      blood-stage vaccine candidates, including Apical Membrane Antigen 1 (AMA1). The precise role
      of AMA1 in the parasite is unknown; however, it is critical in the erythrocyte invasion
      process across divergent Plasmodium species and for blood-stage multiplication of the
      parasite. Recent analysis of the Plasmodium falciparum proteome detected expression of AMA1
      in the sporozoite stage and suggests an additional role for AMA1 during the liver-stage
      invasion. Therefore, an immune response against AMA1 may have an effect on liver-stage
      parasites as well as having an impact on blood-stage parasites, thus protecting the host by
      multiple immune mechanisms. Human and animal anti-AMA1 antibodies inhibit merozoite invasion
      in vitro and correlate with protection against parasite challenge in animal models. T-cells
      specific for Plasmodium falciparum AMA1 have also been demonstrated in individuals living in
      endemic areas.

      At least 68 known amino acid polymorphisms of AMA1 have been demonstrated, and animal studies
      have shown that the polymorphisms in AMA1 are not immunologically silent. The combination of
      two or more divergent AMA1 sequences within a single vaccine formulation may reduce evasion
      of the host immune response by some Plasmodium falciparum field isolates.
    

Intervention name(s): AMA1-C1/Alhydrogel plus CPG 7909
Intervention type(s): Drug
Intervention MeSH terms: Aluminum Hydroxide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Prevention
Keywords: Malaria; Reactogenicity, Safety, Immunogenicity; Maleria Endemic; Plasmodium Falciparum; Dose Escalating