In 1967, the formalin-inactivated vaccine against respiratory syncytial virus (RSV) primed infants and children to develop an enhanced form of lower respiratory tract disease upon exposure to RSV in the community. Thirty-seven years later, the mechanism of illness of this enhanced disease remains unclear. Furthermore, why inactivated vaccines against this virus elicit non-protective antibody is not understood. No vaccine against RSV has been licensed since. We use a novel mouse model of enhanced disease to address these questions. We hypothesize that affinity maturation of RSV-specific B cells is required for development of a protective antibody response against RSV. We further hypothesize that immunization of RSV- naive mice with nonreplicating RSV vaccines activates B cells that do not undergo affinity maturation and therefore elicits a non-protective RSV-specific antibody response. This non-protective response results in immune complex formation and deposition in the lungs and enhanced disease. We propose the following Specific Aims: 1) Determine whether the method of RSV inactivation is important for vaccine-enhanced disease. 2) Determine the role of RSV F and G protective antigens in vaccine-enhanced disease. 3) Determine whether vaccine-enhanced disease is associated with the lack of affinity maturation of the B cell response to FIRSV, and therefore can be prevented by promoting affinity maturation of the B cell response to FIRSV.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VMD (01))
Program Officer
Rubin, Fran A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Caballero, Mauricio T; Serra, M Elina; Acosta, Patricio L et al. (2015) TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. J Clin Invest 125:571-82
Monsalvo, Ana Clara; Batalle, Juan P; Lopez, M Florencia et al. (2011) Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med 17:195-9
Melendi, Guillermina A; Bridget, Dowd; Monsalvo, Ana C et al. (2011) Conserved cysteine residues within the attachment G glycoprotein of respiratory syncytial virus play a critical role in the enhancement of cytotoxic T-lymphocyte responses. Virus Genes 42:46-54
Melendi, Guillermina A; Coviello, Silvina; Bhat, Niranjan et al. (2010) Breastfeeding is associated with the production of type I interferon in infants infected with influenza virus. Acta Paediatr 99:1517-21
Libster, Romina; Bugna Hortoneda, Jimena; Laham, Federico R et al. (2009) Breastfeeding prevents severe disease in full term female infants with acute respiratory infection. Pediatr Infect Dis J 28:131-4
Delgado, Maria Florencia; Coviello, Silvina; Monsalvo, A Clara et al. (2009) Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat Med 15:34-41
Guo, Jessie Yanxiang; Yamada, Ayumi; Kajino, Taisuke et al. (2008) Aven-dependent activation of ATM following DNA damage. Curr Biol 18:933-42