There is currently no vaccine or standard treatment for RSV. However there is clearly an unmet medical need: RSV is responsible for approximately 100,000 hospitalizations per year in the U.S. alone, and is globally responsible for more than 150,000 deaths per year. The continued absence of vaccines and standard treatments for RSV disease represents an important and serious gap in preventive medicine. In response to RFA AI-09-016, investigators from St. Jude Children's Research Hospital, Novartis Vaccines and Diagnostics, Inc., and Le Bonheur Children's Medical Center are proposing a partnership to expedite RSV vaccine development. Recombinant murine Sendai virus (SeV) expressing RSV F glycoprotein (rSeV-RSV-F) is an extremely attractive candidate for an RSV vaccine. This xenotropic vaccine elicits rapid and durable protection against RSV in an animal model and is associated with no enhanced immunopathology upon RSV infection. Since an RSV vaccine will need to protect infants, and since maternal antibodies can reduce the efficacy of replicating and non-replicating vaccines, fundamental questions concerning vaccine-antibody interactions must be addressed prior to clinical development of rSeV-RSV-F. Our Central Hypothesis is that the rSeV-RSV-F vaccine will confer RSV protection to infants, even in the presence of maternal antibodies.
Our Specific Aims are: (1) To determine the relative functional titers of anti-SeV (PIV1) and anti-RSV antibodies in human infants, (2) To determine the influence of maternal antibodies on rSeV-RSV-F vaccine efficacy (in a cotton rat model), and (3) To optimize vaccine by formulation and regimen. When optimized vaccine doses/formulations/regimens are identified, these will be further tested: (i) to ensure the absence of enhanced immunopathology, (ii) to measure response durability, and (iii) to measure immune correlates of protection. Data from these experiments will have broad application to the pediatric vaccine field, and will be critical to the launch of clinical trials with rSeV-RSV-F.

Public Health Relevance

Despite decades of work, no successful RSV vaccine has yet been developed. The long-term objectives of our research is to develop an RSV vaccine to prevent RSV- induced morbidity and mortality in humans.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI088729-05
Application #
8637905
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Kim, Sonnie
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38105
Jones, Bart G; Sealy, Robert E; Surman, Sherri L et al. (2014) Sendai virus-based RSV vaccine protects against RSV challenge in an in vivo maternal antibody model. Vaccine 32:3264-73
Surman, Sherri L; Jones, Bart G; Rudraraju, Rajeev et al. (2014) Intranasal administration of retinyl palmitate with a respiratory virus vaccine corrects impaired mucosal IgA response in the vitamin A-deficient host. Clin Vaccine Immunol 21:598-601
Rudraraju, Rajeev; Jones, Bart G; Surman, Sherri L et al. (2014) Respiratory tract epithelial cells express retinaldehyde dehydrogenase ALDH1A and enhance IgA production by stimulated B cells in the presence of vitamin A. PLoS One 9:e86554
Surman, S L; Jones, B G; Sealy, R E et al. (2014) Oral retinyl palmitate or retinoic acid corrects mucosal IgA responses toward an intranasal influenza virus vaccine in vitamin A deficient mice. Vaccine 32:2521-4
Rudraraju, Rajeev; Jones, Bart G; Sealy, Robert et al. (2013) Respiratory syncytial virus: current progress in vaccine development. Viruses 5:577-94
Sealy, Robert; Webby, Richard J; Crumpton, Jeri C et al. (2013) Differential localization and function of antibody-forming cells responsive to inactivated or live-attenuated influenza virus vaccines. Int Immunol 25:183-95
Jones, B G; Hayden, R T; Hurwitz, J L (2013) Inhibition of primary clinical isolates of human parainfluenza virus by DAS181 in cell culture and in a cotton rat model. Antiviral Res 100:562-6
Jones, Bart G; Sealy, Robert E; Rudraraju, Rajeev et al. (2012) Sendai virus-based RSV vaccine protects African green monkeys from RSV infection. Vaccine 30:959-68
Rudraraju, Rajeev; Surman, Sherri L; Jones, Bart G et al. (2012) Reduced frequencies and heightened CD103 expression among virus-induced CD8(+) T cells in the respiratory tract airways of vitamin A-deficient mice. Clin Vaccine Immunol 19:757-65
Surman, Sherri L; Rudraraju, Rajeev; Woodland, David L et al. (2011) Clonally related CD8+ T cells responsible for rapid population of both diffuse nasal-associated lymphoid tissue and lung after respiratory virus infection. J Immunol 187:835-41

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