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We have previously reported that Vivax Malaria Protein 001 (VMP001), a vaccine candidate based on the circumsporozoite protein of Plasmodium vivax, is immunogenic in mice and rhesus monkeys in the presence of various adjuvants. In the present study, we evaluated the immunogenicity and efficacy of VMP001 formulated with a TLR9 agonist in a water-in-oil emulsion. Following immunization, the vaccine efficacy was assessed by challenging Aotus nancymaae monkeys with P. vivax sporozoites. Monkeys from both the low- and high-dose vaccine groups generated strong humoral immune responses to the vaccine (peak median titers of 291,622), and its subunits (peak median titers to the N-term, central repeat and C-term regions of 22,188; 66,120 and 179,947, respectively). 66.7% of vaccinated monkeys demonstrated sterile protection following challenge. Protection was associated with antibodies directed against the central repeat region. The protected monkeys had a median anti-repeat titer of 97,841 compared to 14,822 in the non-protected monkeys. This is the first report demonstrating P. vivax CSP vaccine-induced protection of Aotus monkeys challenged with P. vivax sporozoites. Author Summary: Plasmodium vivax is responsible for causing malaria in large parts of the globe, including regions with temperate climates not suited for the transmission of other Plasmodium species. In addition, P. vivax has the propensity to form dormant forms, known as hypnozoites, that can remain latent for weeks to months and reactive periodically to cause recurrent infections. Prevention of P. vivax malaria, more than any other form, will require a vaccine-based intervention due to limitations in treatment options. To this end, we tested the efficacy in non-human primates, of a vaccine based on circumsporozoite protein, a preerythrocytic stage antigen, of P. vivax. Aotus monkeys were immunized with clinical-grade antigen, combined with two immunomodulators, and then challenged with P. vivax sporozoites. Following challenge 66.7% of monkeys were protected. Analysis of serum samples indicated that protection was associated with antibodies to the central repeat region of the molecule, and that protection was lost upon waning of these antibodies. This is the first report demonstrating that active immunization with a recombinant protein can lead to complete protection in monkeys following sporozoite challenge, while also demonstrating a protective associate. Our data can help serve as a benchmark for down-selection of future vaccine formulations for P. vivax. [ABSTRACT FROM AUTHOR]