Protection in Macaques Immunized with HIV-1 Candidate Vaccines Can Be Predicted Using the Kinetics of Their Neutralizing Antibodies

Abstract

BackgroundA vaccine is needed to control the spread of human immunodeficiency virus type 1 (HIV-1). An in vitro assay that can predict the protection induced by a vaccine would facilitate the development of such a vaccine. A potential candidate would be an assay to quantify neutralization of HIV-1.Methods and FindingsWe have used sera from rhesus macaques that have been immunized with HIV candidate vaccines and subsequently challenged with simian human immunodeficiency virus (SHIV). We compared neutralization assays with different formats. In experiments with the standardized and validated TZMbl assay, neutralizing antibody titers against homologous SHIVSF162P4 pseudovirus gave a variable correlation with reductions in plasma viremia levels. The target cells used in the assays are not just passive indicators of virus infection but are actively involved in the neutralization process. When replicating virus was used with GHOST cell assays, events during the absorption phase, as well as the incubation phase, determine the level of neutralization. Sera that are associated with protection have properties that are closest to the traditional concept of neutralization: the concentration of antibody present during the absorption phase has no effect on the inactivation rate. In GHOST assays, events during the absorption phase may inactivate a fixed number, rather than a proportion, of virus so that while complete neutralization can be obtained, it can only be found at low doses particularly with isolates that are relatively resistant to neutralization.ConclusionsTwo scenarios have the potential to predict protection by neutralizing antibodies at concentrations that can be induced by vaccination: antibodies that have properties close to the traditional concept of neutralization may protect against a range of challenge doses of neutralization sensitive HIV isolates; a window of opportunity also exists for protection against isolates that are more resistant to neutralization but only at low challenge doses.

Genetic Imprint of Vaccination on Simian/Human Immunodeficiency Virus Type 1 Transmitted Viral Genomes in Rhesus Macaques

“…Immunized animals received a combination of gp140 envelope proteins from subtypes A, B and C and peptides corresponding to V2, V3, CD4 binding site and membrane proximal external region (MPER) as described in methods and shown in Figure 1A. Eight weeks after the last immunization all animals were exposed to a single dose of 1,800 TCID 50 of SHIV SF162P4 virus stock via the intrarectal route [42].…”

In Vitro Neutralization of Low Dose Inocula at Physiological Concentrations of a Monoclonal Antibody Which Protects Macaques against SHIV Challenge

“…Results from in vitro neutralization assays are not a reliable guide to in vivo protection [44]: rhesus macaques with relatively high concentrations of serum neutralizing antibodies are not necessarily protected from SHIV challenge. The discrepancies may be attributed to a number of sources: the extent of inactivation when a virus forms a complex with an antibody, whether the antibody can produce an all or nothing loss in virus infectivity or only reduces the rate of a reaction associated with viral pathogenicity; the properties of the assay target cell may be different to those of the first cell to be infected in vivo ; the size and nature of the inoculum.…”

“…Various scenarios can be proposed to reconcile the conflicting observations. Where the in vitro neutralizing properties of the antibodies approximate those in the traditional concept of neutralization and the virus is relatively sensitive to neutralization there is a correlation between in vitro and in vivo results irrespective of the dose of virus [44]. Alternatively, protection may be seen if antibodies which cannot fully inactivate the virus are present in sufficient concentrations to reduce the replication of relatively resistant virus to levels below the detection limit of the laboratory assays.…”

“…Alternatively, protection may be seen if antibodies which cannot fully inactivate the virus are present in sufficient concentrations to reduce the replication of relatively resistant virus to levels below the detection limit of the laboratory assays. It is also possible that low concentrations of antibody may be able to completely inactivate neutralization resistant virus but only at low infectious doses [44]. It may be recalled that protection in rhesus macaques against a repeated low dose challenge with SIV smE660 correlated with low levels of in vitro neutralization [45].…”

“…The aim of the present study was to investigate the kinetics of neutralization with a combination of virus and antibody which is known to be protective in vivo . GHOST cell assays are used to offer greater precision in quantifying neutralization [44]. …”