Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro

A major unknown in human immunodeficiency virus (HIV-1) vaccine design is t he efficacy of antibodies in preventing mucosal transmission of R5 viruses. These viruses, which use CCR5 as a coreceptor, appear to have a selective advantage in transmission of HIV-1 in humans. Hence R5 viruses predominate during primary infection and persist throughout the course of disease in mo st infected people. Vaginal challenge of macaques with chimeric simian/huma n immunodeficiency viruses (SHIV) is perhaps one of the best available anim al models for human HIV-1 infection. Passive transfer studies are widely us ed to establish the conditions for antibody protection against viral challe nge. Here we show that passive intravenous transfer of the human neutralizi ng monoclonal antibody b12 provides dose-dependent protection to macaques v aginally challenged with the R5 virus SHIV162P4. Four of four monkeys given 25 mg of b12 per kg of body weight 6 h prior to challenge showed no eviden ce of viral infection (sterile protection). Two of four monkeys given 5 mg of b12/kg were similarly protected, whereas the other two showed significan tly reduced and delayed plasma viremia compared to control animals. In cont rast, all four monkeys treated with a dose of 1 mg/kg became infected with viremia levels close to those for control animals. Antibody b12 serum conce ntrations at the time of virus challenge corresponded to approximately 400 (25 mg/kg), 80 (5 mg/kg), and 16 (1 mg/kg) times the in vitro (90%) neutral ization titers. Therefore, complete protection against mucosal challenge wi th an R5 SHIV required essentially complete neutralization of the infecting virus. This suggests that a vaccine based on antibody alone would need to sustain serum neutralizing antibody titers (90%) of the order of 1:400 to a chieve sterile protection but that lower titers, around 1:100, could provid e a significant benefit. The significance of such substerilizing neutralizi ng antibody titers in the context of a potent cellular immune response is a n important area for further study.