Project: Research project

Project Details


Respiratory syncytial virus infection (RSV) is a major cause of severe
respiratory disease in infants and young children, often requiring
intensive care hospitalization. Despite considerable effort there is no
safe and effective vaccine for RSV. A formalin-inactivated RSV vaccine
resulted in potentiation of disease in naturally infected children. Bovine
RSV (BRSV) is a closely related virus, which causes a similar disease in
young calves; clinical, immunological, and pathological features are
nearly identical. To achieve the longterm objective of development of a
safe and effective vaccine for RSV, this proposal will use a BRSV
infection model. Calves develop moderate to severe disease alter
experimental Infection with a field isolate. The model is unique in that
a chronic lung lymph fistula has been surgically created for the
monitoring of lymphocytes and lymph fluid. Specific Aims are: 1) to
determine the relationship between the type and magnitude of the immune
response to BRSV proteins and severity of experimental infection in calves
vaccinated with formalin-inactivated (FI) vaccine, 2) to compare and
contrast the effects of BRSV infection in FI-vaccinated and naive calves
on pulmonary function, cytokine production, T cell sub-populations,
eicosanoid production, immunoglobulin production, virus shedding, lung
pathology, and clinical signs, 3) to evaluate the potential for eliciting
a protective mucosal immune response by aerosol immunization of calves
with recombinant fusion protein in a liposome carrier, and 4) to compare
RSV and BRSV fusion protein with respect to their immunogenicity and
protection provided when maternal immunity is present. These specific aims
will be addressed in three experiments. In the first experiment the FI-
vaccine induced immunopotentiation will be reproduced using two different
intervals between vaccination and virus exposure to determine the effect
of early versus later viral challenge. Mock-vaccinated and mock-infected
control groups will be included. Lung lavage and pulmonary function
testing will be performed. Data gathered will include: BRSV-specific IgG,
IgA, IgE, virus neutralization, leukotriene C4, B4, and prostaglandins E2,
F2alpha, D2, and thromboxane B2, lung pathology, and lung
immunohistochemistry to evaluate antibody and complement localization. MHC
class II expression and T cell subset identification will be done in blood
and lung tissue. Lung tissue morphometry will quantitate and identify
airway-associated cellular accumulations. Cellular responses will be
evaluated by lymphocyte stimulation and cytotoxicity. Concentration of
histamine and virus recovery will be monitored in nasopharyngeal
secretions daily during infection. In experiment two lung lymph fistulas
will be created to monitor the above parameters in lymph, as well as lung
lymph cell gene expression for interleukin 4 and gamma interferon.
Experiment three will combine lymphatic cannulation with immunization of
separate groups of calves by aerosol with either recombinant BRSV F
protein or RSV F protein in liposome carrier, or a liposome control.
Results of BRSV challenge will aid in determining the potential for a
crossreactive F protein to elicit protection when maternal antibody is
present. In summary, three experiments will be performed using a calf-BRSV
infection model to evaluate vaccine protection and immunopotentiation of
Effective start/end date9/30/946/30/99


  • National Institutes of Health


  • Medicine(all)
  • Immunology and Microbiology(all)


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