Biology Reference
In-Depth Information
efficacy trial using a gp120 monomeric vaccine demonstrated that
there was no difference in the rate of infectivity between vaccine recip-
ients and the placebo group.
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The ability of this vaccine to raise
functional antibody responses such as neutralizing Abs and ADCC has
yet to be fully evaluated, but the information gained may help to guide
further vaccine development. It will also be critical to understand the
barriers in inducing antibodies that recognize similar epitopes to those
recognized by 2F5, 4E10, Z13, F105, 2G12, and b12. Several strate-
gies are being evaluated by various investigators to develop and evalu-
ate novel Env immunogens to induce broadly neutralizing antibody
responses by vaccination, including: (A) structural optimization tar-
geting conserved neutralization epitopes, and (B) approaches to over-
come genetic diversity for vaccine development.
A.
Structural Optimization to Target Conserved
Neutralization Epitopes
The main approaches toward structural optimization of Env for
inducing broadly cross-reactive neutralizing antibodies involve the
use of: (i) native trimers, (ii) triggered-Envs, (iii) rationally designed
Env structures, and iv) mimotopes.
(i)
Native trimers as immunogen
As mentioned previously, critical neutralizing epitopes are preserved
and presented on the Env glycoprotein, but the virus has evolved
ways to minimize the immunogenicity of Env, such as by extensive
glycosylation of the molecule, to shield the conserved functional
regions. Similarly, the receptor-binding site, a likely target for immune
intervention, is buried within the molecule and is partially protected
from immune recognition. The observation that most broadly reac-
tive neutralizing antibodies isolated so far (i.e. IgG1b12, 2G12, and
2F5) have a stronger affinity for the native envelope (trimer) than for
monomeric gp120 or gp41 provides
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the impetus to evaluate
trimeric Env glycoproteins for their ability to induce broadly cross-
reactive, primary isolate neutralizing antibodies. Early immunogenicity
