Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infections. Protection against infection with RSV can be achieved by monthly administration of the humanized monoclonal antibody palivizumab. The present study analyzes if genetic delivery of a murine version of palivizumab by single administration would achieve high-level and sustained antibody expression to protect mice against pulmonary infection with RSV. A murine version of the palivizumab antibody was constructed by replacing the human sequences with sequences from the constant region of a murine IgG1 antibody, while preserving the complementarity-determining region. As a proof-of-principle to test the validity of the strategy, the coding sequence for the heavy and light chains were cloned into a replication-defective serotype 5 human adenovirus vector (AdαRSV). Antibody expression and specificity for RSV was confirmed by Western analysis. To determine if AdαRSV would mediate production of anti-RSV antibodies in vivo, 5 × 1010 particle units of AdαRSV or a control vector without transgene (AdNull), were administered intravenously to BALB/c mice. RSV neutralizing antibodies were detected in the serum after 4 days in mice receiving AdαRSV but not in AdNull-infected or naive mice (p < 0.05). The mice that had received AdαRSV had at least 5.4-fold lower RSV titers in the lung 4 days following intranasal challenge with RSV compared to the AdNull or naive group (p < 0.01). To evaluate long-term protection, the antibody construct was expressed in a non-human primate serotype rh.10 adeno-associated virus vector (AAVrh.10αRSV). RSV neutralizing antibodies were detected in serum and bronchoalveolar lavage fluid for up to 21 wk following intrapleural administration of AAVrh.10αRSV, but not with a control AAV vector expressing an unrelated transgene (AAVrh.10α1AT). Following challenge with RSV at 7 or 21 wk, 14.3-fold and 10.6-fold lower RSV titers were observed after 4 days in the lungs of mice that had received AAVrh.10αRSV compared to AAVrh.10α1AT (p < 0.05). Together these data demonstrate that a gene transfer strategy for delivery of an anti-RSV antibody can generate protective immunity in mice against RSV infection in the respiratory tract and may provide an alternative to the administration of the antibody itself.
- RSVAntibody">Gene therapy vectors
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