Respiratory syncytial virus (RSV) is the leading viral cause of severe lower respiratory tract infections, accounting for an estimated 65 million infections and 1 million deaths annually worldwide. In the US, RSV causes approximately 100,000 hospitalizations per year in infant and elderly populations. RSV infection is also a significant cause of severe respiratory distress among the immunocompromised and those with underlying cardiopulmonary disease. Despite the significant health burden produced by RSV, there is currently no licensed RSV vaccine. This application proposes a new approach to development of an RSV vaccine candidate, and in fact a new approach to vaccine development in general, using nanotechnology. Increasingly, there is a realization that the commonality in sizes and general structural features between nanoparticles and their biological counterparts could translate into significant applications of nanoclusters to a wide variety of fields in biology and medicine. As a vaccine delivery vehicle, gold nanoclusters are very attractive candidates. A gold nanocluster of approximately 2.0-6.0 nm in diameter is stabilized by an estimated 140-150 monodentate ligands on its surface, creating the possibility for a high level of antigen presentation. Under appropriate conditions, surface-stabilizing ligands on gold nanoparticles may be exchanged, resulting in the potential for formulating a vaccine candidate incorporating both B cell and T helper cell epitopes into a single construct. Finally, colloidal gold is known to be phagocytosed by macrophages, and is safely used in human immunotherapy, establishing the plausibility of using these materials as vaccine platforms. Consequently, we hypothesize that the conformational protective B cell epitopes and T helper cell epitopes from RSV surface proteins recapitulated on the surface of a gold nanocluster will yield a vaccine candidate that induces protective efficacy through the induction of high titers of neutralizing antibodies. To test this hypothesis, we propose the following three specific aims:
Specific Aim 1. Recapitulate conformational protective B cell epitopes and T helper cell epitopes from RSV surface proteins using synthetic peptides on the surface of a gold nanocluster (BTNCs).
Specific Aim 2. Demonstrate that the magnitude and quality of the antibody response to the BTNC vaccine candidate is superior to that induced by peptide or multiple antigenic peptide (MAP) formulations.
Specific Aim 3. Test the hypothesis that the resulting RSV F BTNC-based vaccine candidate induces superior protective efficacy in vivo, compared with available delivery systems for immunizing with viral peptides. The work proposed in this application will lead to the development of new vaccine candidates for respiratory syncytial virus, the most common cause of hospitalization of infants in the U.S. Successful development of an RSV vaccine could prevent over 100,000 hospitalizations in the U.S. every year, and prevent nearly 1 million childhood deaths a year. The development of a new technology for vaccination using nanoparticles also could have wide impact, since such a vaccine technology might be useful in developing vaccines against other infections. ? ? ?
| Stone, John W; Thornburg, Natalie J; Blum, David L et al. (2013) Gold nanorod vaccine for respiratory syncytial virus. Nanotechnology 24:295102 |
