Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques

Abstract

Neutralizing antibodies are thought crucial to HIV vaccine protection but a major hurdle is the high antibody concentrations likely required as suggested by studies in animal models1. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus2–4. Therefore, animal studies may have overestimated protective antibody levels in humans. To investigate the impact of virus challenge dose on antibody protection, we repeatedly exposed macaques intravaginally to low doses of a CCR5 coreceptor-using SHIV (an HIV/SIV chimera) in the presence of antibody at plasma concentrations leading to relatively modest neutralization titers of the order of 1:5 IC90 values in a PBMC assay. An effector function deficient variant of the neutralizing antibody was also included. The results show that a significantly greater number of challenges are required to infect animals treated with neutralizing antibody than control antibody-treated animals, and the notion that effector function may contribute to antibody protection is supported. Overall, the results imply that lower levels of antibody than considered hereto may provide benefit in the context of typical human exposure to HIV-1.

Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates

“…This view has been reinforced by recent studies showing that HIV-1 infection can be limited or even prevented in animals with a wide range of functional antibody titers as measured by in vitro neutralization assays when these antibodies are continuously present, as would be the case for vaccine-induced immunity (31,37,38).…”

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

“…Notwithstanding the modest efficacy of the RV144 Thai trial in humans (1) that correlated binding Abs with a lower risk of infection, much of the HIV-1 vaccine research focus has been directed toward developing strategies and immunogens that will elicit protective Abs, including broadly neutralizing Abs (bNAbs). This goal is supported by the overwhelming evidence of the capability of broadly neutralizing mAbs (bNmAbs) given prior to mucosal exposure in preventing viral infection in macaques using the chimeric simian/HIV (SHIV) bearing HIV env (2)(3)(4)(5). Neutralizing polyclonal Igs at high concentrations can block infection and have been shown to ameliorate disease pathogenesis in nonhuman primates (NHP) (6,7).…”

Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1

“…Indeed, a recent multinational study of potential PrEP users showed that route of administration was the most important attribute regarding acceptability of a PrEP program, with a monthly or bimonthly injection preferred over daily or intermittent pills (17). In addition, numerous studies in macaques have demonstrated that passive immunization with bNAbs can prevent infection by hybrid simian-human immunodeficiency viruses (18)(19)(20)(21). Until recently, however, such an approach was considered infeasible owing to the limited potency and/or breadth of the available bNAbs, such as 2F5, 4E10, and 2G12 (22,23).…”