This phase I, dose escalating study will evaluate the safety and immunogenicity of the experimental malaria vaccine AMA1-C1/Alhydrogel®, and the ability of the TLR-9 agonist CPG 7909 oligodeoxynucleotide (ODN) to augment antibody responses to the vaccine and alter the Th1/Th2 bias. The vaccine preparations to be studied contain an equal mixture of AMA1 from two different clones of Plasmodium falciparum (FVO and 3D7). Subjects will be randomly assigned to receive Alydrogel® formulated vaccine with or without CPG 7909 in a point of use formulation. The study will be conducted at the University of Rochester Vaccine and Treatment Evaluation Unit. Subjects for this study will be healthy adults between the ages of 18 and 45 years with no history of malaria or of recent travel to malaria-endemic areas. Subjects will be enrolled in three consecutive dose-escalation cohorts with review by a Safety Monitoring Committee between cohorts. Subjects will receive 3 vaccinations with the AMA1-C1/Alhydrogel® vaccine formulated in Alhydrogel® with or without CPG 7909 adjuvant over 2 months (0, 1, 2 months) by intramuscular (IM) injection. Subjects will have multiple blood samples obtained over the next 6 months. The primary objective of the study is to assess the safety, reactogenicity of the AMA1-C1/Alhydrogel® + CPG 7909 vaccine. The secondary objectives of the study include the following: to demonstrate that the addition of CPG 7909 improves the immune responses to AMA1-FVO and AMA1-3D7, as compared to AMA1-C1/Alhydrogel® at day 70 (14 days after 3rd vaccination; to determine the dose of AMA1-C1/Alhydrogel® + CPG 7909 that generates the highest serum antibody levels of AMA-FVO and AMA1-3D7 at day 70; to assess and compare the duration of antibody responses to AMA1-FVO and AMA1-3D7 proteins by enzyme-linked immunosorbent assay (ELISA) over an 8 month period (6 months after 3rd vaccination); and to perform exploratory studies of B and T cell populations both before and after vaccination. The safety trial endpoints include the frequency and severity of local and systemic adverse events after each dose reported on the subject diary card (solicited adverse events) or reported by subjects spontaneously (unsolicited adverse events) and the presence of abnormal clinical laboratory tests after immunization in each group. The immunogenicity endpoints include the frequency and titer of vaccine induced neutralizing and binding antibody, and the presence and quantity of antigen-specific B cells and CD4 and CD8 T cells producing specified cytokines following vaccination.