The goal of this proposal is to develop a safe and efficacious virus-like particle (VLP) based-respiratory syncytial virus (RSV) vaccine to prevent the disease caused by this pathogen. The respiratory illnesses provoked by RSV in infants, children and the elderly are of global economical and public health impact. A recent worldwide estimate [5] indicates that over 33 million children under the age of five suffer RSV associated lower respiratory infections (ALRI) and at least 3 million are hospitalized and approximately 199,000 die of the disease each year. In the US, the CDC estimates that there are over 126,000 RSV associated pediatric hospitalizations at a cost of over $900 million per year. There is no vaccine currently licensed and treatments for the disease are limited; a prophylactic intervention relies on administering a neutralizing monoclonal (Synagis) to infants at risk of infection and to supportive care. A safe and effective vaccine would be the most desirable and cost effective preventive intervention. However, to date the creation of such a vaccine has not been attained and its development hindered by the enhancement of disease provoked by a formalin-inactivated vaccine produced in the 1960's. Other approaches have not proven successful and even dangerous. Here, we propose to develop and test a virus-like particle displaying RSV antigens as a strategy to create a safe and effective RSV vaccine. VLPs are mimics of wild type virus particles but do not contain viral genetic material making them unable to replicate or cause infection. The particulate nature and redundant array of native antigen on the surface of the VLP incites a greater recognition by the immune system. We have successfully produced native RSV-VLPs that display surface spikes and resemble wild type virus. Our RSV based VLP candidate vaccines are created by co-expressing the proteins M, F and SH or M, F or M, F and G as well as additional combinations. The type and magnitude of the immune response they induce as well as the efficacy afforded by the RSV-VLP candidate vaccines will be assessed in animal models. To fulfill these goals, we have designed three specific aims: Specific aim I: Produce and characterize virus-like particles (VLPs) displaying respiratory syncytial virus surface antigens.in alternative compositions F, F+SH, F+G and F+SH+G Specific aim II: Evaluate the immunogenicity (quality and magnitude of the immune response) elicited by the RSV-VLP vaccine and establish safety profile as well as the protective efficacy afforded by alternative compositions of RSV-VLP vaccines in a mouse model of respiratory syncytial virus infection. Selected candidates will be reevaluated by escalating doses of vaccine in mice. Also, initiate development of stable cell lines for the continuous production of the preferred VLP vaccine. Specific aim III: The VLP composition demonstrating efficacy, potency and safety will be retested in the cotton rat model of respiratory syncytial virus infection seeking probe of efficacy in two model of RSV infection. These studies will support a SBIR Phase II proposal and pursue an IND application with the FDA.
Thesaurus Terms: Acute;Adult;Age;Animal Model;Animals;Antigens;Asthma;Base;Centers For Disease Control And Prevention (U.S.);Cessation Of Life;Child;Childhood;Cost;Cost Effective;Cotton Rats;Data;Design;Development;Disease;Dose;Elderly;Electron Microscopy;Equilibrium;Formalin;Genetic Materials;Goals;High Risk Infant;Hospitalization;Image;Immune Response;Immune System;Immunization;Immunogenicity;Inactivated Vaccines;Infant;Infection;Intervention;Licensing;Life;Modeling;Monoclonal Antibodies;Morbidity - Disease Rate;Mouse Model;Multiple Myeloma M Protein;Mus;Nature;Palivizumab;Particle;Particulate;Pathogen;Phase;Prevent;Prevention;Preventive Intervention;Production;Prophylactic;Protective Efficacy;Proteins;Public Health Medicine (Field);Public Health Relevance;Recurrence;Respiratory;Respiratory Syncytial Virus;Respiratory Syncytial Virus Infections;Respiratory Syncytial Virus Vaccines;Respiratory Tract Infections;Response;Risk;Risk Factors;Safety;Small Business Innovation Research Grant;Stable Cell Line;Structure;Success;Supportive Care;Surface;Surface Antigens;Testing;Vaccine Candidate;Vaccines;Viral Antigens;Virion;Virus;Virus Diseases;Virus Genetics;Virus-Like Particle;Wheezing;
