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"Targeted vector delivery for rapid protection from infectious diseases" Principal Investigator: Dr. Mirella Salvatore Institution: Weill Medical College of Cornell University The rapid protection of non-immune populations from the spread of infectious agents is an urgent public health issue. We propose to develop and test a novel passive immunotherapy approach using integrase-defective lentiviral vectors (ID-LV) that produce therapeutic antibodies, using influenza virus as a model. Influenza pandemic preparation is hampered by the absence of a universal influenza vaccine, and seasonal vaccines need to be constantly reformulated due to mutations of the viral hemagglutinin (HA), target of the antibodies that prevent infection. In addition, circulating influenza strains are increasingly resistant to approved drugs. Recent studies have identified monoclonal antibodies (mAbs) that are broadly neutralizing against influenza viruses of different subtypes; the administration of these mAbs has had both prophylactic and therapeutic effects. Direct administration of mAbs could be an important tool for passive immunization in cases where a rapid response is required and/or a vaccine is not available, but this approach is costly and requires multiple high dose injections to be effective, making it unsuitable for large-scale use. Genetic immunization by viral vector-mediated delivery of mAbs is an attractive alternative to direct injection. Our main objective is to address the feasibility and efficacy of using ID-LV as a novel immunotherapy to deliver broadly neutralizing antibodies against influenza virus HA. Safety features of ID-LV include their inability to integrate or replicate. Furthermore, pre-existing host immunity is absent so vectors are less likely to be cleared by the host immune response during administration. Based on previous experience with in vitro and in vivo protein expression from ID-LV that was both efficient and prolonged, we hypothesize that they will produce sufficient levels of antibodies to protect mice from influenza virus challenge. This approach can not only be applied toward a wide variety of infectious diseases, but has also the advantage that it can be combined with antigenic vaccination. In that case, the expression of broadly neutralizing anti-HA mAbs would ensure rapid protection in vivo while the endogenous antibody response to the antigen develops from the vaccine component of the vector. Our studies will advance the field of passive immunotherapy and hold excellent promise to be rapidly "translated" to patient populations. |
The above project description is supplied by the Principal Investigator |