Application of a rapid microplaque assay for determination of human immunodeficiency virus neutralizing antibody titers.

ABSTRACT A major unknown in human immunodeficiency virus (HIV-1) vaccine design is the 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 most infected people. Vaginal challenge of macaques with chimeric simian/human immunodeficiency viruses (SHIV) is perhaps one of the best available animal models for human HIV-1 infection. Passive transfer studies are widely used to establish the conditions for antibody protection against viral challenge. Here we show that passive intravenous transfer of the human neutralizing monoclonal antibody b12 provides dose-dependent protection to macaques vaginally 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 evidence of viral infection (sterile protection). Two of four monkeys given 5 mg of b12/kg were similarly protected, whereas the other two showed significantly reduced and delayed plasma viremia compared to control animals. In contrast, 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 concentrations 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%) neutralization titers. Therefore, complete protection against mucosal challenge with 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 achieve sterile protection but that lower titers, around 1:100, could provide a significant benefit. The significance of such substerilizing neutralizing antibody titers in the context of a potent cellular immune response is an important area for further study.

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Evidence for Potent Autologous Neutralizing Antibody Titers and Compact Envelopes in Early Infection with Subtype C Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.01905-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12716-12716

Author(s):

Bing Li ◽

Julie M. Decker ◽

Roy W. Johnson ◽

Frederic Bibollet-Ruche ◽

Xiping Wei ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibody ◽

Early Infection ◽

Subtype C ◽

Immunodeficiency Virus ◽

Antibody Titers

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In Vivo Efficacy of Human Immunodeficiency Virus Neutralizing Antibodies: Estimates for Protective Titers

Journal of Virology ◽

10.1128/jvi.01792-07 ◽

2007 ◽

Vol 82 (3) ◽

pp. 1591-1599 ◽

Cited By ~ 43

Author(s):

Alexandra Trkola ◽

Herbert Kuster ◽

Peter Rusert ◽

Viktor von Wyl ◽

Christine Leemann ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Infection ◽

Chronic Infection ◽

Vaccine Development ◽

Neutralizing Antibody ◽

In Vivo Efficacy ◽

Median Difference ◽

Immunodeficiency Virus ◽

Antibody Titers

ABSTRACT The definition of plasma neutralizing antibody titers capable of controlling human immunodeficiency virus (HIV) infection in vivo is considered a critical step in vaccine development. Here we provide estimates for effective neutralization titers by assessing samples from a recent passive immunization trial with the neutralizing monoclonal antibodies (MAbs) 2G12, 2F5, and 4E10 using an analytic strategy that dissects the contributions of these MAbs to the total neutralization activity in patient plasma. Assessment of neutralization activities for six responding patients with partial or complete control of viremia during the MAb treatment and for the eight nonresponding patients revealed a significant difference between these groups: Among responders, MAb-mediated activity exceeded the autologous neutralization response by 1 to 2 log units (median difference, 43.3-fold), while in the nonresponder group, the autologous activity prevailed (median difference, 0.63-fold). In order to reach a 50% proportion of the responders in our study cohort, MAb neutralizing titers higher than 1:200 were required based on this analysis. The disease stage appears to have a significant impact on the quantities needed, since titers above 1:1,000 were needed to reach the same effect in chronic infection. Although our analysis is based on very small sample numbers and thus cannot be conclusive, our data provide a first estimate on how in vitro-measured neutralizing antibody activity can relate to in vivo efficacy in controlling HIV infection and may therefore provide valuable information for vaccine development. Interestingly, lower neutralizing antibody levels showed an effect in acute compared to chronic infection, suggesting that in early disease stages, therapeutic vaccination may show promise. Equally, this raises hopes that a preventive vaccine could become effective at comparatively lower neutralizing antibody titers.

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