Respiratory syncytial virus (RSV) infection is the primary cause of respiratory infection in young children, causing >120,000 hospitalizations in the US annually. RSV vaccine development has been hampered by the history of a failed vaccine trial in the early 1960s in which vaccinated children were not protected against subsequent natural infection but rather experienced more severe disease. Subsequent experiments in animal models and human subjects suggest the occurrence of severe RSV disease correlates with the induction of virus-specific Th2 CD4+ T cells and eosinophil recruitment and degranulation. The putative attachment G glycoprotein of RSV and killed virus vaccines containing adjuvants such as alum are particularly effective in inducing such disease-enhancing immune responses. The purposes of these studies are 1) to define the precise components of RSV immunity that predispose for severe RSV disease upon subsequent exposure to the virus, 2) to determine how the structure of RSV contributes to disease, and 3) with this better understanding of RSV pathogenesis, to rationally design RSV vaccines that protect against infection without enhancing disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI005029-07
Application #
7732750
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2008
Total Cost
$625,552
Indirect Cost
City
State
Country
United States
Zip Code
Johnson, Teresa R; Rao, Srinivas; Seder, Robert A et al. (2009) TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity. Vaccine 27:3045-52
Liu, Jie; Ruckwardt, Tracy J; Chen, Man et al. (2009) Characterization of respiratory syncytial virus M- and M2-specific CD4 T cells in a murine model. J Virol 83:4934-41
Johnson, Teresa R; Rothenberg, Marc E; Graham, Barney S (2008) Pulmonary eosinophilia requires interleukin-5, eotaxin-1, and CD4+ T cells in mice immunized with respiratory syncytial virus G glycoprotein. J Leukoc Biol 84:748-59
Collins, Peter L; Graham, Barney S (2008) Viral and host factors in human respiratory syncytial virus pathogenesis. J Virol 82:2040-55
Johnson, Joyce E; Gonzales, Ricardo A; Olson, Sandy J et al. (2007) The histopathology of fatal untreated human respiratory syncytial virus infection. Mod Pathol 20:108-19
Johnson, Teresa R; Teng, Michael N; Collins, Peter L et al. (2004) Respiratory syncytial virus (RSV) G glycoprotein is not necessary for vaccine-enhanced disease induced by immunization with formalin-inactivated RSV. J Virol 78:6024-32
Johnson, Teresa R; Varga, Steven M; Braciale, Thomas J et al. (2004) Vbeta14(+) T cells mediate the vaccine-enhanced disease induced by immunization with respiratory syncytial virus (RSV) G glycoprotein but not with formalin-inactivated RSV. J Virol 78:8753-60
Johnson, Teresa R; Graham, Barney S (2004) Contribution of respiratory syncytial virus G antigenicity to vaccine-enhanced illness and the implications for severe disease during primary respiratory syncytial virus infection. Pediatr Infect Dis J 23:S46-57
Hashimoto, Koichi; Graham, Barney S; Ho, Samuel B et al. (2004) Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5. Am J Respir Crit Care Med 170:306-12
Johnson, Teresa R; Parker, Robert A; Johnson, Joyce E et al. (2003) IL-13 is sufficient for respiratory syncytial virus G glycoprotein-induced eosinophilia after respiratory syncytial virus challenge. J Immunol 170:2037-45

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