Computational Design of Epitope-Scaffolds Allows Induction of Antibodies Specific for a Poorly Immunogenic HIV Vaccine Epitope

Abstract

Broadly cross-reactive monoclonal antibodies define epitopes for vaccine development against HIV and other highly mutable viruses. Crystal structures are available for several such antibody-epitope complexes, but methods are needed to translate that structural information into immunogens that re-elicit similar antibodies. We describe a general computational method to design epitope-scaffolds in which contiguous structural epitopes are transplanted to scaffold proteins for conformational stabilization and immune presentation. Epitope-scaffolds designed for the poorly immunogenic but conserved HIV epitope 4E10 exhibited high epitope structural mimicry, bound with higher affinities to monoclonal antibody (mAb) 4E10 than the cognate peptide, and inhibited HIV neutralization by HIV+ sera. Rabbit immunization with an epitope-scaffold induced antibodies with structural specificity highly similar to mAb 4E10, an important advance toward elicitation of neutralizing activity. The results demonstrate that computationally designed epitope-scaffolds are valuable as structure-specific serological reagents and as immunogens to elicit antibodies with predetermined structural specificity.

Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120

“…Nevertheless, immunization attempts to date have not been successful in eliciting strongly neutralizing Abs. For example, antigens designed to give 2G12-like (34), 4E10-like (35), or 2F5-like Abs (36) have had limited success, and although immunogens designed for greater CD4bs recognition showed an improved ability to elicit CD4bs neutralizing Abs, the potencies of these Abs were generally limited to the most neutralizationsensitive (Tier 1) viruses (37). In addition, a gp120 designed specifically to focus the immune response to the initial CD4-binding site on gp120 failed to elicit broadly potent CD4bs Abs (38), although this designed gp120 was the bait used to isolate VRC01 (20), a remarkably potent Ab that is the prototype member of the PVL Abs analyzed in our study.…”

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

“…Sera with similar overall Ab titers to a given Ag can vary significantly in neutralization or in cross-reactivity to alternate pathogen strains. Recently, there have been a number of efforts to rationally design vaccine Ags that exploit fine specificity to target highly neutralizing or highly conserved epitopes that are poorly immunogenic in natural infections, as in the case of HIV-1 (1,2) and respiratory syncytial virus (3).…”

High‐resolution structure prediction of a circular permutation loop

“…Three of the designs had T m s ranging from 48 C to 51 C (Table I) where two other variants showed no transition. The permuted variants were prone to aggregation, as many 4E10 scaffolds have been, 10 and this prevented quantitative assessment of binding affinities for the 4E10 antibody.…”

“…9 The starting molecule to be circularly permuted was an epitope-scaffold onto which the 4E10 HIV neutralization epitope had been transplanted, as previously described by Correia et al 10 The epitopescaffold, which had high affinity towards the 4E10 antibody ( Fig. 1), was used as a model system to assess the linker design and structure prediction capabilities of RosettaRemodel.…”