Prior Funding

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.