Recently developed viral-vectored HIV vaccine candidates, despite achieving high levels transgene expression and inducing high magnitude immune responses to HIV, have faced limitations related to anti-vector immunity. In contrast, lentiviral vectors (LV) have been shown to be less sensitive to anti-vector neutralizing activity, while displaying desirable characteristics, such as transduction of non-dividing cells, including antigen-presenting cells, and long-term transgene expression. We have developed VRX1023, an HIV-based LV expressing HIV Gag, Pol and Rev under the control of the native HIV LTR. In mice, this vector induced significant mucosal and systemic cellular and humoral responses against HIV after sub-cutaneous injection. Similarly to other viral vectors, this LV candidate can be effectively used in DNA prime, LV boost strategies, where it elicited as high as 21% HIV Gag-specific CD8 responses as measured by intracellular cytokine staining. Moreover, anti-vector immunity is not an obstacle to repeated LV administrations, as shown by improved anti-HIV responses compared to single LV immunization. In head to head comparisons with Ad5 vectors expressing the same vaccine payload, VRX1023 elicited higher and more persistent cellular and antibody responses to HIV than its adenoviral counterpart. In preparation for clinical use, manufacturing scale-up of a highly purified VRX1023 vector lot following cGMP was successfully achieved without altering the robust immunogenicity observed with the research-grade vector. VRX1023, in addition to competing favorably with existing vectors such as Ad5 for anti-HIV immune responses, demonstrates unique features likely to address some of the pitfalls of current vector-based HIV vaccine strategies.
Copyright 2009 Elsevier Ltd. All rights reserved.