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A NOVEL NON-INTEGRATING REPLICATION LIMITED LENTIVIRAL-BASED VECTOR FOR HIV VACCINATION

Final Report Summary - HIVNONILV (A NOVEL NON-INTEGRATING REPLICATION LIMITED LENTIVIRAL-BASED VECTOR FOR HIV VACCINATION)

There is no doubt that developing efficient prophylactic and therapeutic vaccines against the human immunodeficiency virus (HIV) is critical to end the global continuously growing epidemic in the humans. HIV continues to be a worldwide health problem with over 35 million individuals infected; over 1.5 million die and nearly 2.1 million get infected every year (WHO, 2013). Africa is the most afflicted, but infection is growing fast in Asia and in other countries in Eastern Europe. The economic impact of HIV/AIDS may be far worse than previously thought and some African countries may face complete collapse. Therefore, a prophylactic vaccine that stops this infection remains a priority.
Unlike the classical acute infectious diseases, prevention of HIV acquisition and replication requires long lasting and effective immunity. Many types of vaccine vectors and strategies have been used to induce protective immunity in the macaque model of HIV vaccine. However, the protection achieved by these vaccines remains disappointing compared to Live-attenuated vaccines. Given that the classical vectors/strategies of vaccination failed to induce protection against HIV/AIDS, innovative vectors and immunization strategies are urgently needed to generate safe and efficacious HIV vaccines. In our team, we developed a novel lentivirus-based DNA vector that does not integrate in the host genome and undergoes a single-cycle of replication. Viral proteins are constitutively expressed under the control of a Tat-independent LTR promoter from goat lentivirus. This innovative vector synergizes the properties, without the inconvenient, of both DNA and Live-attenuated vaccines. We hypothesize that these vectors will induce protective immune responses against challenge viruses, notoriously known to be difficult to control by vaccination. Our long-term goal is to develop safe and efficacious prophylactic vaccine against HIV in humans. The goal of the present project is to evaluate the safety, the immunogenicity, and the efficacy of our novel NONI-LV vector against pathogenic viruses in the macaque model of HIV vaccine. The work plan included 4 specific aims for the three years of funding. In aim 1, we focused on the safety of this type of vector by demonstrating their inability to integrate into the host genome, in vitro. In aim 2 we evaluated the increase of immunogenicity of this vector in humanized mice compared to our first generation vector. In aim 3, we immunized and characterized the immunogenicity induced in macaque model. The results demonstrate that a single dose delivery of our DNA vaccine allowed the generation of persistent vaccine-specific memory CD8+ and CD4+ T cells with immediate and recallable effector functions, in absence of persistent antigen stimulation. These types of cells have been so far mostly induced and maintained by replication competent and persistent recombinant HIV viral vectors. Importantly, our results demonstrate that a single dose immunization with DNA only (producing single cycle viral particles) does promote the development and the maintenance of such type of T cell responses. In aim 4, 6 controls macaques and 6 vaccinated macaques were challenged at 80 weeks after the single immunization with a pathogenic macaque virus. They received once a week for 10 weeks, by the intrarectal route, a low dose of a SIVmac251 (a highly heterologous virus challenge for the envelope since our vaccine contain only HIV ENV) virus stock. These applications were stopped after two consecutive positive detections of viral RNA by RT-PCR in the plasma which signs systemic infection. Most of the animals became infected after 4 to 7 applications. This absence of protection against the acquisition of infection was expected with our T cell based vaccine strategy that should mainly intervenes on infected target cells thereby at the level of control of viral replication.
Importantly however, after productive infection, 6 out of 6 (100%) vaccinated macaques had more than 1 log reduction in the peak of viremia compared to control animals and maintained lower viremia ( 1000 copies/ml in control group) during the early chronic phase (W3-14 post-infection) and late chronic phase (W18-48 post-infection). So far, these differences remain statistically significant from week 1 to week 18 but should be extended to later time-points when final results will be completed. This impressive viral control appears to be linked to the reactivation of memory (CM and EM) CD8+ T cell responses in the vaccinated group. In our ongoing study, we are trying to determine for the first time ever, whether a unique subset of memory SHIV-specific CD8+ T cell can be induced by our lentivector DNA vaccine and vaccination strategy, and these cells can be maintained/expanded following infection with the pathogenic virus and they do correlate with a long-term protection.
Vaccines have historically been the most effective biomedical interventions for controlling global infectious diseases. In the quest for an HIV-1 vaccine, our EC funded study that explores novel vector and vaccination strategy, will represent an important contribution to the HIV-1 vaccine field.

Along with our long-term goal to develop novel, safe and efficacious HIV vaccines, we filed an international patent for our DNA vaccine.
Brevet International, n0 PCT/FR2012/067863, European Patent office, number=EP12756752, Inventors: Y.Chebloune D. Aldebert, G. Arrode-Brusés. Génomes lentiviraux chimériques non-intégratifs comme vaccins innovants contre le HIV-1.