Developing an immunogen that elicits broadly neutralizing antibodies (bNAbs) is an elusive but important goal of HIV vaccine research, especially after the recent failure of the leading T cell based HIV vaccine in human efficacy trials. Even if such an immunogen can be developed, most animal model studies indicate that high serum neutralizing concentrations of bNAbs are required to provide significant benefit in typical protection experiments. One possible exception is provided by the anti-glycan bNAb 2G12, which has been reported to protect macaques against CXCR4-using SHIV challenge at relatively low serum neutralizing titers. Here, we investigated the ability of 2G12 administered intravenously (i.v.) to protect against vaginal challenge of rhesus macaques with the CCR5-using SHIVSF162P3. The results show that, at 2G12 serum neutralizing titers of the order of 1∶1 (IC90), 3/5 antibody-treated animals were protected with sterilizing immunity, i.e. no detectable virus replication following challenge; one animal showed a delayed and lowered primary viremia and the other animal showed a course of infection similar to 4 control animals. This result contrasts strongly with the typically high titers observed for protection by other neutralizing antibodies, including the bNAb b12. We compared b12 and 2G12 for characteristics that might explain the differences in protective ability relative to neutralizing activity. We found no evidence to suggest that 2G12 transudation to the vaginal surface was significantly superior to b12. We also observed that the ability of 2G12 to inhibit virus replication in target cells through antibody-mediated effector cell activity in vitro was equivalent or inferior to b12. The results raise the possibility that some epitopes on HIV may be better vaccine targets than others and support targeting the glycan shield of the envelope.Author SummaryAn effective HIV vaccine should elicit broadly neutralizing antibodies, i.e. antibodies that neutralize a wide spectrum of different HIVs in vitro. A number of human monoclonal antibodies have been isolated with broad neutralization and shown to protect macaques against vaginal HIV challenge. Protection is generally correlated with neutralization and requires relatively high antibody concentrations that may be difficult to achieve by vaccination. Here, we show that one monoclonal antibody (2G12) is unusually potent in protection relative to its neutralizing ability as hinted at by earlier data. Further studies eliminate an unusual ability of 2G12 to be transported to the vagina (site of infection) as a possible explanation for our observations. Although the precise mechanism is unclear, the studies have important implications for HIV vaccine design in general by suggesting that some vaccine targets on HIV may be better than others and, specifically, by suggesting that the sugar coat of HIV may be a particularly rewarding target if appropriate immunogens can be designed.