Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys

Abstract

The holy grail for HIV vaccine development is an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the SIV model, we have taken a markedly different approach: delivery of an adeno-associated virus (AAV) gene transfer vector to muscle for the expression of antibodies or antibody-like immunoadhesins having predetermined anti-SIV specificity. With this approach, anti-SIV molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds significant promise as a novel approach to an effective HIV vaccine.

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).…”

HIV-1 vaccines

“…Long-lasting neutralizing activity in serum of macaques administered with a vector expressing SIV-specific antibodies conferred complete protection against SIV intravenous challenge. 115 The same strategy was immunogenic in humanized mice 116 and able to protect against SHIV challenge.…”

Progress in HIV-1 vaccine development

“…This technique has been shown to protect humanized mice as well as RM against high dose intravenous and repeated mucosal challenges. [87][88][89] The first human trial, IAVI A003 (clinicaltrials.gov NCT01937455) a phase I, randomized, blinded, dose-escalation study of rAAV vector coding for PG9 Ab in 24 healthy men is close to completion ( Table 2).…”