Antibiotics have been at the forefront of combating bacterial infection for decades with great success. However, the develop-ment of new antibiotics is struggling to keep pace with the emergence of drug resistant bacterial strains, for example as in Y. pestis [6] . There has been an intense interest in developing antibody-based therapies as an alternative method of treatment [5] . Initially, antibody-based therapy was mostly limited to treating cancer or immune disorders. However, because of a better understanding of the pathogenesis of infectious agents, and the advancement in the development of protective or neutralizing antibodies, the use of antibody-based therapy against infectious agents has become more frequent [20] . In this report we described the first isolation of fully human mAbs against the Y. pestis Figure 6 . Human anti-F1and anti-V mAbs show synergistic protection when used together in the murine bubonic plague model. The human and mouse anti-F1 and anti-V mAbs were given i.p. to mice 24 hrs before parenteral challenge with Y. pestis CO92, and the number of surviving mice for each treatment group was monitored for 21 days after challenge. 6A. The following antibodies and amounts were used: normal mouse serum (NMS, 500 mg); mouse anti-F1 (F1m, 500 mg); mouse anti-V (7.3 m, 100 mg); human anti-F1 (m252, 500 mg); human anti-V (m253 and m254, 500 mg each). 6B. The following mAbs and amounts were used: NMS, 500 mg; F1m, 500 mg; m252, 500 mg; m253+ m254, 500 mg each; m252+ m253+ m254, 500 mg each. doi:10.1371/journal.pone.0013047.g006 virulence factors F1-and V-antigens. Previous studies have shown that mouse mAbs can be effective in protecting mice against Y. pestis ( [13] [14] [15] . However, because they are mouse mAbs they are not safe to use in their present form in humans [21] . Of particular concern is the immune reaction against mouse primary antibody sequences in human system. This may lead to severe adverse effects and at the same time reduce the potential benefits. It is highly desirable to have fully human antibodies for these reasons. The fully human anti-F1 (m252) reported here displayed moderate to good protection against a bubonic plague challenge with Y. pestis CO92. On the other hand, the two anti-V mAbs (m253, m254) when used separately did not show any efficacy, but when they were used together with m252, the combination of the human anti-plague mAbs resulted in better protection overall, suggesting a synergistic effect between the antibodies. A similar effect was reported in studies using mouse anti-F1 and anti-V mAbs in a mouse model of plague [15] . Further in our case with the human anti-F1 mAbs, when we gave mice the human anti-F1 mAb 1-2 days after challenge, we saw a greater protection against a plague challenge could be achieved. This suggested that the maintenance of serum concentration of the human mAbs in the mouse was possibly one critical factor for better protection. Kinetic studies revealed that indeed the serum concentration of the human antibodies dropped further than the mouse anti-plague mAbs over the course of the study. It is also plausible that the human antiplague mAbs might bind to other mouse antigens nonspecifically, thus decreasing the amount of free circulating human anti-plague antibody in the mouse. Figure 7 . A nonspecific human IgG1 antibody (Hu-IgG1) had little effect on the mean-time-to-death (MTD) and number of surviving mice that received the human anti-F1 mAb. The nonspecific human IgG1mAb, and the human and mouse anti-F1 and anti-V mAbs were given i.p. to mice 24 hrs before parenteral challenge with Y. pestis CO92, and the number of surviving mice for each treatment group was monitored for 21 days after challenge. Mouse or human mAbs and their amounts were given to the following groups of mice: nonspecific human IgG1 (Hu-IgG1, 1,500 mg); F1m (F1m, 500 mg); F1m (500 mg) + Hu-IgG1(1,000 mg); m252, 500 mg; m252 (500 mg) + Hu-IgG1 (1,000 mg). doi:10.1371/journal.pone.0013047.g007 Another important underlying factor for efficient protection by antibodies is the epitopes the antibodies recognize. Although the human anti-F1 (m252) mAb appeared to bind to the same region as the mouse antiF1, which was at the amino-terminal end of the F1antigen (Amemiya et al., unpublished), we could not demonstrate direct competition between these two antibody species. This observation may be the result of the nature of the antibody binding site or epitope, because several mouse mAbs isolated independently recognized the same region or epitope on the F1-antigen, behaved in the same manner (Amemiya et al., unpublished). It may be that once these mAbs bound to the amino-terminal end of the F1antigen, they may not readily come off the protein or may dissociate very slowly. Whether this is because the binding site involved both linear and conformational sites is not known, but both the mouse and human anti-F1 mAbs bound to the whole anti-F1 antigen very well, but only weakly -moderately to the 59-peptides. Nevertheless, the human m252 mAb was as protective as the mouse anti-F1 mAb when the human mAb was given after challenge. It has also been reported that a neutralizing epitope on the V-antigen was located in a region spanning amino acids 135 to 275, and a possible minor, secondary neutralizing epitope exists near the amino-terminal region of the V-antigen [14] . Neither of our human anti-V antibodies reported here competed with the mouse anti-V antibodies efficiently. The minor competition between the human anti-V Fab antibody and the mouse anti-V antibodies suggests that the recognition site of the human anti-V antibodies is slightly different or they may partially share conformational binding site. These differences might be one reason for their inability to protect as efficiently as the human anti-F1 m252 mAb.