Synthetic nanoparticle vaccines for RSV

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R43AI092924-01A1
Agency Tracking Number: R43AI092924
Amount: $600,000.00
Phase: Phase I
Program: SBIR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NIAID
Solicitation Number: PA10-050
Small Business Information
5 Science Park, Suite 13, NEW HAVEN, CT, 06511
DUNS: 361522811
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (203) 772-3430
Business Contact
Phone: (203) 772-3430
Research Institution
DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract illness in infants and the elderly. There is no approved vaccine despite decades of effort. Early attempts to develop a formalin- inactivated vaccine (FI-RSV) resulted in disease enhancement following environmental exposure to RSV. Efforts to develop recombinant subunit vaccines have met with limited success due to poor immunogenicity and short-lived responses. Over the last few years, several avenues of study have suggested that the adverse inflammatory responses associated with RSV infection, and perhaps the failure of the FI-RSV vaccine, are linked to the RSV-G protein which plays a critical role in virus attachment to target cells. RSV-G contains a CX3C chemokine motif that interacts with the CX3CR1 chemokine receptor and appears to elicit an inflammatory Th2-biased immune response that contributes to disease pathogenesis. We have shown that antibody responses to the CX3C motif can reduce virus infectivity, inhibit RSV-G chemokine-modulating activity and reduce lung inflammation following infection. Vaccine designs that elicit an IFN response may also help to reduce the Th2-biased response and lung inflammation associated with RSV infection. In this Phase I project, we will use an innovative approach to produce synthetic nanoparticle vaccines carrying the RSV-G peptide coupled with RSV T-cell target antigens that favor IFN responses. Nanoparticles will be fabricated using layer-by-layer (LbL) deposition of oppositely charged polypeptides, including designed peptides (DP) carrying the antigen payload, to build ultrathin films on solid nano-sized cores. We have shown that vaccines made by this strategy improve the immunogenicityof both T-cell and antibody target epitopes without triggering adverse inflammatory reactions. The current proposal will (1) identify the optimal DP designs for increasing loading and stability of nanoparticles, (2) select LbL nanoparticle vaccine designsbased on potency and phenotype of antibody and T-cell responses induced (with particular emphasis on IFN responses that have been shown to improve protection from RSV disease), and (3) test the biological activity of antibody responses in assays measuringvirus and chemokine neutralization, inhibition of chemotaxis, and protection of mice from viral burden and lung inflammation following challenge with RSV. The RSV-G DP will include a CD4 T-cell epitope that overlaps the chemokine motif, and will be complemented by addition of T-cell target epitopes from RSV-M2 or RSV-F to provide additional IFN modulation of the Th1/Th2 balance. Thus, the novel nanoparticle vaccines produced in this study will have the capacity to elicit multiple mechanisms of protection against RSV infection and aberrant lung inflammation. The deliverable of this project is one or more LbL RSV-G vaccine candidates with demonstrated safety and efficacy in animal models; these candidates will be further developed in a subsequent Phase II project that will complete the steps necessary for Investigational New Drug application filing and eventual clinical testing. The application of this innovative approach to RSV vaccine development will also impact vaccine development for other infectious diseases. PUBLIC HEALTH RELEVANCE: This project will use an innovative nanoparticle technology to produce novel vaccine candidates for respiratory syncytial virus. Since the vaccines contain a portion of the virus responsible for both infection and hostinflammation, vaccine-induced immune responses will not only reduce the rate of RSV infectivity but will also alleviate the lung inflammation associated with RSV disease. A vaccine emerging from this effort will address a large unmet need in infants, children, elderly and immunocompromised patients.

* information listed above is at the time of submission.

Agency Micro-sites

SBA logo
Department of Agriculture logo
Department of Commerce logo
Department of Defense logo
Department of Education logo
Department of Energy logo
Department of Health and Human Services logo
Department of Homeland Security logo
Department of Transportation logo
Environmental Protection Agency logo
National Aeronautics and Space Administration logo
National Science Foundation logo
US Flag An Official Website of the United States Government