The ability of the human anti-F1 and anti-V mAbs to passively protect mice against a Y. pestis infection was evaluated in a bubonic plague model. The human anti-F1 and anti-V mAbs were used either separately or together in different combinations. When mAbs m252 and m253 and m254 were given to mice separately before challenge with Y. pestis CO92, only the human anti-F1(m252) mAb showed some efficacy. The mean-time-to-death (MTD) in the m252 mAb-treated mice was shifted to 13.0 days (1/ 6 survivors) when compared with mice given normal mouse serum (NMS), which had a MTD of 7.0 days (0/6 survivors) ( Figure 6A ). Unlike m252, however, the human anti-V mAbs, m253 and m254, did not show any significant protection [mean-time-to-death (MTD) of 6.7 days (0/6 survivors) and 7.3 days (0/6 survivors), respectively] when compared to the NMS -treated mice. The mouse anti-F1 (F1m) and anti-V (7.3 m) control mAbs both passively protected all (6/6) mice under the same challenge conditions (MTD of 21 days). When both human anti-V mAbs were given to mice passively ( Figure 6B ), no improvement in protection after challenge was observed (MTD of 6.8 days, 0/6 survivors), which was similar to that seen with the NMS-treated mice (MTD of 7.3 days, 0/6 survivors). However, when the human anti-F1 m252 mAb (MTD of 11.3 days, 2/6 survivors) was given together with the two human anti-V m253 and m254 mAbs, a greater number of mice were passively protected (MTD 14.0, 5/ 6 survivors) than when the antibodies were used separately, suggesting a synergistic effect. Although we saw some protection with the human m252 mAb, and a synergistic protective effect when the human m252 mAbs was given with the human m253 and m254 mAbs in the bubonic plague model, we wondered if there was any effect (positive or negative) with a nonspecific human IgG1 mAb by itself or when combined with the human anti-F1 m252 mAb in the number of survivors in the mouse model of plague. To answer this question, we injected five groups of mice with the following mAbs: one group of mice with only a nonspecific human IgG1 mAb (Hu-IgG1, 1500 mg); another group of mice with the mouse anti-F1 mAb (F1m, 500 mg); another group of mice with the human anti-F1 mAb (m252, 500 mg). Two other groups of mice were included, that were given either F1m (500 mg) or m252 (500 mg), with the nonspecific Hu-IgG1 mAb (1000 mg) one day before challenge with Y. pestis CO92 ( Figure 7 ). All mice in the group that received only the nonspecific Hu-IgG1 mAb died by day 8, which was similar to the control antibody mouse groups in Figure 6A and 6B. The same number of survivors was obtained (6/6) whether mice were given only mouse F1m mAb or F1m combined with the nonspecific Hu-IgG1. As we have seen previously ( Figure 6A ), only 1/6 mice survived in the group that received only human m252 mAb. When the human m252 mAb was combined with the nonspecific Hu-IgG1 mAb, we obtained one more survivior (2/6) than we obtained without the nonspecific Hu-IgG1 mAb. This variation in the number of survivors was not different than we saw previously ( Figure 6B ). In addition, the MTD was not affected by the presence of the nonspecific Hu-IgG1 (15.8 days) when given with the Hu-antiF1 mAb (15.8 days). These results suggest that the nonspecific Hu-IgG1 mAb had little effect on the survival of mice given the human m252 mAb or mouse F1m mAb.