NHP Core for Development of an Integrase Defective Lentiviral Vector HIV Vaccine

Duke University, Durham NC

Investigators

Linked publications, trials & patents

Abstract

An effective HIV-1 vaccine is likely to require elicitation of broadly neutralizing antibodies to block virus infection at mucosal surfaces, as well as strong T cell responses to provide help to for the antibody responses and to kill virus-infected cells at the site of transmission. The most robust cellular immune responses induced to date have been generated employing live, recombinant vaccine vectors however they are limited by anti- vector immunity and raise significant safety issues. While the pivotal RV144 trial was encouraging with 31.2% protection, the humoral correlates of protection were not sustained. Integrase-defective lentiviral vectors (IDLV) engineered to enhance antigen expression with safe guards against integration, recombination, replication or vector mobilization are a novel approach to developing an effective HIV-1 vaccine which has the distinct advantage of providing long term antigen exposure with a single immunization. In preliminary studies, this vaccine approach has elicited persistent T cell responses as well as durable Envelope-specific antibody responses in both mice and nonhuman primates (NHP). Thus, we now aim to determine the ability of the persistent antigen expression provided by this vaccine regimen to elicit highly somatically-mutated antibody responses that are likely to result in broad neutralization capacity and develop functional CD4+ and CD8+ T cell responses in NHP that are desirable in an efficacious HIV-1 vaccine candidate. IDLV engineered to express the CH505 transmitted/founder envelope and a series of subsequent variants derived from an individual that was found to be associated with broadly neutralizing antibodies will be sequentially delivered to NHP with and without protein boost with the same immunogen. The NHP core of this program project grant, will perform the NHP immunization protocols and SHIV challenge and provide samples to Projects 1 and 2 of this program to assess the safety, immunogenicity and efficacy of the IDLV Env immunogen strategy. The core will also perform in-depth analyses of the vaccine-elicited, antigen specific functional CD4+ and CD8+ T . This work will determine whether the use of IDLV vector is a viable and effective strategy for HIV-1 vaccination that should be forwarded to clinical trials.