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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI088729-02
Application #
8050641
Study Section
Special Emphasis Panel (ZAI1-TS-M (J1))
Program Officer
Kim, Sonnie
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$617,720
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Surman, Sherri L; Jones, Bart G; Woodland, David L et al. (2017) Enhanced CD103 Expression and Reduced Frequencies of Virus-Specific CD8+ T Cells Among Airway Lymphocytes After Influenza Vaccination of Mice Deficient in Vitamins A?+?D. Viral Immunol 30:737-743
Penkert, Rhiannon R; Jones, Bart G; Häcker, Hans et al. (2017) Vitamin A differentially regulates cytokine expression in respiratory epithelial and macrophage cell lines. Cytokine 91:1-5
Penkert, Rhiannon R; Iverson, Amy; Rosch, Jason W et al. (2017) Prevnar-13 vaccine failure in a mouse model for vitamin A deficiency. Vaccine 35:6264-6268
Sealy, Robert E; Surman, Sherri L; Hurwitz, Julia L (2017) CD4+ T cells support establishment of RSV-specific IgG and IgA antibody secreting cells in the upper and lower murine respiratory tract following RSV infection. Vaccine 35:2617-2621
Russell, Charles J; Jones, Bart G; Sealy, Robert E et al. (2017) A Sendai virus recombinant vaccine expressing a gene for truncated human metapneumovirus (hMPV) fusion protein protects cotton rats from hMPV challenge. Virology 509:60-66
Jones, Bart G; Penkert, Rhiannon R; Xu, Beisi et al. (2016) Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression. Mol Immunol 77:97-102
Sealy, Robert E; Surman, Sherri L; Vogel, Peter et al. (2016) Antibody-secreting cells in respiratory tract tissues in the absence of eosinophils as supportive partners. Int Immunol 28:559-564
Hankins, Jane S; Penkert, Rhiannon R; Lavoie, Paul et al. (2016) Original Research: Parvovirus B19 infection in children with sickle cell disease in the hydroxyurea era. Exp Biol Med (Maywood) 241:749-54
Sealy, Robert E; Jones, Bart G; Surman, Sherri L et al. (2016) Murine Monoclonal Antibodies for Antigenic Discrimination of HIV-1 Envelope Proteins. Viral Immunol 29:64-70
Surman, S L; Penkert, R R; Jones, B G et al. (2016) Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D. Clin Vaccine Immunol 23:219-27

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