Abstract
Lentiviral vectors are under intense scrutiny as unique candidate viral vector vaccines against tumor and aggressive pathogens because of their ability to initiate potent and durable specific immune responses. Strategies that alleviate safety concerns will facilitate the clinical developments involving lentiviral vectors. In this respect, the development of integration deficient lentiviral vectors circumvents the safety concerns relative to insertional mutagenesis and might pave the way for clinical applications in which gene transfer is targeted to non-dividing cells. We thus evaluated the potential use of nonintegrative lentiviral vectors as vaccination tools since the main targeted cell in vaccination procedures is the non-dividing dendritic cell (DC). In this study, we demonstrated that a single administration of nonintegrative vectors encoding a secreted form of the envelope of a virulent strain of West Nile Virus (WNV) induces a robust B cell response. Remarkably, nonintegrative lentiviral vectors fully protected mice from a challenge with a lethal dose of WNV and a single immunization was sufficient to induce early and long-lasting protective immunity. Thus, nonintegrative lentiviral vectors might represent a safe and efficacious vaccination platform for the development of prophylactic vaccines against infectious agents.
Highlights
Prevention of infectious diseases through vaccine development is one of the greatest achievements of modern medicine
Integrative lentiviral vectors elicited a higher immune response than nonintegrative vectors at doses below 30 ng, but vaccinations with 100 ng of either vector led to an equivalent intense humoral immune response. These results demonstrated that a single immunization with nonintegrative lentiviral vectors was sufficient to elicit a humoral specific immune response with a strength comparable to that obtained with integrative vectors, above a threshold dose of particles
We have demonstrated for the first time that safe nonintegrative lentiviral vectors are effective at transducing different subpopulations of dendritic cells (DC) and that a single immunization with these vectors was sufficient to afford complete protective immunity against a lethal viral challenge in mice
Summary
Prevention of infectious diseases through vaccine development is one of the greatest achievements of modern medicine. Human immunodeficiency virus (HIV)-1–derived lentiviral vectors have emerged as very promising vaccination tools These vectors elicit both specific cytotoxic and strong humoral immune responses in several animal models [1,2,3,4,5]. These properties rely in part on the ability of these vectors to mediate more efficient gene transfer into dendritic cells (DC) than other vaccinal vectors such as for instance the widely used adenoviral vectors [9] This major advantage allows a sustained expression and endogenous presentation of tumoral or viral Ags by transduced DC and subsequent activation of more potent and persistent specific immune responses [3,10,11,12,13]. Problems of vector-specific immunity are largely reduced with the use of LV because of the absence of preexisting immunity in humans
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