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Background  A vaccine targeting  Plasmodium vivax  will be an essential component of any comprehensive malaria elimination program, but major gaps in our understanding of  P .  vivax  biology, including the protein-protein interactions that mediate merozoite invasion of reticulocytes, hinder the search for candidate antigens. Only one ligand-receptor interaction has been identified, that between  P .  vivax  Duffy Binding Protein (PvDBP) and the erythrocyte Duffy Antigen Receptor for Chemokines (DARC), and strain-specific immune responses to PvDBP make it a complex vaccine target. To broaden the repertoire of potential  P .  vivax  merozoite-stage vaccine targets, we exploited a recent breakthrough in expressing full-length ectodomains of  Plasmodium  proteins in a functionally-active form in mammalian cells and initiated a large-scale study of  P .  vivax  merozoite proteins that are potentially involved in reticulocyte binding and invasion.    Methodology/Principal Findings  We selected 39  P .  vivax  proteins that are predicted to localize to the merozoite surface or invasive secretory organelles, some of which show homology to  P .  falciparum  vaccine candidates. Of these, we were able to express 37 full-length protein ectodomains in a mammalian expression system, which has been previously used to express  P .  falciparum  invasion ligands such as PfRH5. To establish whether the expressed proteins were correctly folded, we assessed whether they were recognized by antibodies from Cambodian patients with acute vivax malaria. IgG from these samples showed at least a two-fold change in reactivity over naïve controls in 27 of 34 antigens tested, and the majority showed heat-labile IgG immunoreactivity, suggesting the presence of conformation-sensitive epitopes and native tertiary protein structures. Using a method specifically designed to detect low-affinity, extracellular protein-protein interactions, we confirmed a predicted interaction between  P .  vivax  6-cysteine proteins P12 and P41, further suggesting that the proteins are natively folded and functional. This screen also identified two novel protein-protein interactions, between P12 and PVX_110945, and between MSP3.10 and MSP7.1, the latter of which was confirmed by surface plasmon resonance.    Conclusions/Significance  We produced a new library of recombinant full-length  P .  vivax  ectodomains, established that the majority of them contain tertiary structure, and used them to identify predicted and novel protein-protein interactions. As well as identifying new interactions for further biological studies, this library will be useful in identifying  P .  vivax  proteins with vaccine potential, and studying  P .  vivax  malaria pathogenesis and immunity.    Trial Registration  ClinicalTrials.gov  NCT00663546

A Library of Plasmodium vivax Recombinant Merozoite Proteins Reveals New Vaccine Candidates and Protein-Protein Interactions