Based on our understanding of envelope-based mechanisms of humoral evasion, we have attempted to design envelope-based immunogens with these mechanisms disabled. Such modied immunogens with weakened defenses may elicit more broadly neutralizing antibodies. We have also devised scaffolding technologies, as a means of presenting structural mimics of the epitopes of broadly neutralizing antibodies to assist in their re-elicitation. Scaffolds can be non-homologous proteins, identified through searches of the entire protein data bank. Alternatively, scaffolds can be homologous proteins, which are structurally similar, but antigenically distinct from the HIV-1 envelope glycoproteins. An alternative to scaffolding involves "resurfacing", where the surface of a molecule, not involved in eliciting a desired response, is altered between "prime" and "boost" phases of immunization. We have also been investigating how insights from B cell ontogeny of broadly neutralizing antibodies identifies difficult steps in the elicitation process, which might be influenced by immunization. Finally, work with the fusion glycoprotein from respiratory sycytial virus (RSV) indicates that it is important to focus on a "site" versus and "epitope", and better to focus on a site that is sensitive to neutralization. Such a neutralization-sensitve site paradigm is allowing for positive vaccine results against RSV and may be useful against HIV-1.

Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2013
Total Cost
$804,553
Indirect Cost
City
State
Country
Zip Code
Liang, Bo; Ngwuta, Joan O; Herbert, Richard et al. (2016) Packaging and Prefusion Stabilization Separately and Additively Increase the Quantity and Quality of Respiratory Syncytial Virus (RSV)-Neutralizing Antibodies Induced by an RSV Fusion Protein Expressed by a Parainfluenza Virus Vector. J Virol 90:10022-10038
Li, Hui; Wang, Shuyi; Kong, Rui et al. (2016) Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A 113:E3413-22
Gorman, Jason; Soto, Cinque; Yang, Max M et al. (2016) Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design. Nat Struct Mol Biol 23:81-90
Joyce, M Gordon; Zhang, Baoshan; Ou, Li et al. (2016) Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV. Nat Struct Mol Biol 23:811-20
Boyington, Jeffrey C; Joyce, M Gordon; Sastry, Mallika et al. (2016) Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus. PLoS One 11:e0159709
Francica, Joseph R; Lynn, Geoffrey M; Laga, Richard et al. (2016) Thermo-Responsive Polymer Nanoparticles Co-Deliver RSV F Trimers with a TLR-7/8 Adjuvant. Bioconjug Chem :
Wang, Lingshu; Shi, Wei; Joyce, M Gordon et al. (2015) Evaluation of candidate vaccine approaches for MERS-CoV. Nat Commun 6:7712
Yassine, Hadi M; Boyington, Jeffrey C; McTamney, Patrick M et al. (2015) Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat Med :
Kwon, Young Do; Pancera, Marie; Acharya, Priyamvada et al. (2015) Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nat Struct Mol Biol 22:522-31
Georgiev, Ivelin S; Joyce, M Gordon; Yang, Yongping et al. (2015) Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env. J Virol 89:5318-29

Showing the most recent 10 out of 40 publications