Proof of principle for epitope-focused vaccine design

Abstract

Summary Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Multiple major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus (RSV), that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for research and development of a human RSV vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets including antigenically highly variable pathogens such as HIV and influenza.

Chimeric Pneumoviridae fusion proteins as immunogens to induce cross‐neutralizing antibody responses

“…The structure of hRSV F site II is a helix–turn–helix motif (Toiron et al , 1996) conserved in the prefusion and postfusion conformations of the F protein. Thus, hRSV F site II has been grafted onto different protein scaffolds to focus the antibody responses elicited against those unnatural antigens to a site in hRSV F, which is recognized by neutralizing antibodies (McLellan et al , 2011a; Correia et al , 2014; Luo et al , 2015). The results obtained so far have had limited success, since the antibodies induced in mice were not neutralizing despite being able to bind hRSV F. Only in one case, in which site II was grafted onto an immunoglobulin scaffold, did the resulting immunogen induce antibodies in mice that neutralized hRSV in vitro , although with relatively low efficiency (Luo et al , 2015).…”

“…The results obtained so far have had limited success, since the antibodies induced in mice were not neutralizing despite being able to bind hRSV F. Only in one case, in which site II was grafted onto an immunoglobulin scaffold, did the resulting immunogen induce antibodies in mice that neutralized hRSV in vitro , although with relatively low efficiency (Luo et al , 2015). In another case, the site II scaffold induced hRSV‐neutralizing antibodies in macaques, but not in mice, after repeated doses (Correia et al , 2014). …”

In silico analysis of Shiga toxins (Stxs) to identify new potential vaccine targets for Shiga toxin-producing Escherichia coli

“…Therefore, B-cell epitopes in conjugation with T-cell epitopes can increase the immunogenicity of the target molecule. Peptide vaccines have advantages for their chemical stability, absence of infectious potential, and ease of construction and production (Sette and Fikes 2003;Correia et al 2014). In order to find potential vaccine candidates, prediction of B-cell and T-cell epitopes was performed using bioinformatics tools.…”

Towards an anti-disease malaria vaccine

“…This could be achieved by grafting critical epitopes from PfEMP1 domains onto much smaller, weakly immunogenic scaffolds, a method that has been used successfully in viral vaccine development [49,50]. In the case of respiratory syncytial virus, the design of such immunogens, which specifically present epitopes for protective inhibitory antibodies, led to their re-elicitation [50].…”

“…This could be achieved by grafting critical epitopes from PfEMP1 domains onto much smaller, weakly immunogenic scaffolds, a method that has been used successfully in viral vaccine development [49,50]. In the case of respiratory syncytial virus, the design of such immunogens, which specifically present epitopes for protective inhibitory antibodies, led to their re-elicitation [50]. The hope is that the use of similar design tools for a diverse protein family, like the PfEMP1s, will generate antibodies that specifically target functionally important and structurally conserved surfaces, blocking processes important for pathogenesis and reducing disease.…”