The goal of this SBIR phase I proposal is to advance the development of 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 [1,2] 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 antibody (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 has been hindered by the enhancement of disease provoked by a formalin- inactivated RSV virus (FI-RSV) vaccine produced in the 1960s. Other approaches have not proven successful and even dangerous. Here, we propose to further advance the development of a virus-like particle displaying RSV antigens as a strategy to create a safe and effective RSV vaccine. Our VLP approach displays two alternative conformation of the F protein, which is a novel and distinct strategy from other vaccine under development. Preliminary work on the immunogenicity, efficacy and safety of the RSVLP vaccine and summarized in the research strategy section showed that this vaccine is highly immunogenic and able to afford complete protection against virus challenge without the adverse reactions seen with a formalin inactivated RSV virus (FI-RSV) vaccine control [6]. 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 RSV-VLPs that display surface spikes of the F protein in its two different conformation, prefusion and postfusion. Vaccines formulated with these particles and tested in murine model of RSV demonstrated to be highly immunogenic, efficacious and safe [6]. In this application, we propose to continue the development of this vaccine performing additional preclinical testing in a second animal model, cotton rat, in order to select a candidate for further development toward clinical trials in humans. To fulfill these goals, we have designed three specific aims: Specific Aim 1- Months 1-4: Produce, purify and fully characterize RSVLP vaccine compositions containing the prefusion and postfusion F also in combination with G, SH or both. Define downstream purification strategies suitable for scale up and process validation for future cGMP manufacturing. Specific Aim 2- Months 4-11: Evaluate the magnitudes of the immune response and safety profile as well as appraise the protective efficacy afforded by alternative vaccine compositions in a cotton rat model (S. hispidus) of RSV infection. Specific Aim 3-Months 11-12: Select best RSVLP vaccine composition based on immunological profile, protective efficacy and safety for further vaccine development studies in a phase II SBIR application. Successful completion of proposed studies will generate the data necessary to warrant further development in a phase II SBIR application. An RSV vaccine is greatly needed and this project aims to advance a unique vaccine composition, which can be developed considering its lack of infectivity and safety characteristics toward several demographics such as pregnant women, young children and the elderly.
Public Health Relevance Statement: NARRATIVE Respiratory syncytial virus (RSV) causes a wide range of respiratory tract infections, particularly serious or life threatening for infants and the elderly although also a major cause of morbidity in adult and children. The respiratory illnesses provoked by RSV are of global economical and public health impact. Currently, an approved vaccine to prevent RSV is not available and the overall impact of a safe and efficacious vaccine on public health cannot be overstated. Here, we propose to advance the development of a respiratory syncytial virus-like particle (RSVLP) vaccine that is safe and highly efficacious. Our initial work showed that this vaccine is highly immunogenic, efficacious and safe. An RSV vaccine is sorely needed and this project aims to pursue this goal.
Project Terms: Adult; Advanced Development; Adverse reactions; Age; Age-Years; Animal Model; Antigens; base; Base Composition; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Child; Childhood; Clinical Trials; cost; cost effective; Cotton Rats; Cyclic GMP; Dangerousness; Data; demographics; design; Development; Disease; Disulfides; Elderly; Evaluation; experience; Formalin; Formulation; Future; Genetic Materials; Goals; Healthcare; Heart; high risk infant; Hospitalization; Human; Immune; Immune response; Immune system; immunogenic; immunogenicity; Immunologics; Infant; Infection; infection risk; Intervention; Life; Lower Respiratory Tract Infection; Lung; Minor; Modeling; Molecular Conformation; Monoclonal Antibodies; Morbidity - disease rate; mouse model; Mus; Nature; neutralizing monoclonal antibodies; novel; Palivizumab; particle; Particulate; pathogen; Phase; preclinical study; Preclinical Testing; Pregnant Women; Premature Infant; prevent; Preventive Intervention; Preventive vaccine; Process; Production; prophylactic; Prophylactic treatment; protective efficacy; Proteins; Public Health; Research; respiratory; Respiratory Signs and Symptoms; Respiratory syncytial virus; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Tract Infections; Safety; scale up; Small Business Innovation Research Grant; Supportive care; Surface; Testing; Toxicology; vaccine development; vaccine evaluation; Vaccines; Validation; Viral; Viral Antigens; Virion; Virus; virus genetics; Virus-like particle; Work
