Development of a universal HIV-1 vaccine

HIV infection and AIDS continues to spread in a virtually uncontrolled manner. The best and possibly only hope to change this alarming situation is a safe, effective, accessible protective vaccine. Arguably the biggest challenge in developing such a vaccine is the enormous HIV variability, which dwarfs almost any other infection. However, all parts of the virus cannot easily change. To remain alive, HIV has to keep some smaller regions of its proteins more or less constant. We have taken an advantage of this and constructed a simple candidate vaccine designed specifically to overcome the HIV variability by focusing the body defences on the conserved viral parts. Here, we are proposing to test this approach for the first time in a small pilot study in healthy individuals in Oxford. Successful outcome of this study would strongly support further evaluation of this vaccination strategy in larger and more expensive clinical studies.

This proposal will test for the first time in humans several novel, state-of-the-art technologies combined to provide maximum benefit to vaccinated individuals. First, one of the big roadblocks in development of HIV-1/AIDS vaccines is the enormous diversity of HIV-1, which could limit the value of any HIV-1 vaccine candidate currently under test. To address the HIV-1 variation, we designed a novel T cell immunogen, designated HIVconsv, by assembling the 14 most conserved regions of the HIV-1 proteome into one chimaeric protein. Each segment is a consensus sequence from one of the four major HIV-1 clades A, B, C and D, which alternate to ensure equal clade coverage. We demonstrated that these conserved regions prime CD8+ and CD4+ T cell to highly conserved epitopes in patients during natural HIV-1 infection and that these epitopes, although usually subdominant, generate memory T cells. Here, we propose to test the immunogenicity of the HIVconsv chimearic protein in a pilot small phase I trial in healthy HIV-1-uninfected individuals in Oxford to assess the breadth, specificity and cross-clade reactivity of the vaccine induced T cells. Second, we shall deliver the HIVconsv gene in a novel vaccine vector based on adenovirus of chimpanzee origin (AdC), which matches and possibly outperforms the currently perceived most immunogenic vaccine vector, human Adenovirus serotype 5 (AdHu5). Third, we shall use the AdC.HIVconsv vaccine in a heterologous prime-boost regimen of DNA/AdC/modified vaccinia virus Ankara (MVA) to further increase the vaccination potency. The HIVconsv-induced T cell responses will be assessed in a comprehensive analysis of frequency, phenotype and functionality, which will indicate according to pre-determined stringent criteria whether or not our vaccine strategy should advance to a larger proof-of-principle trial. In summary, our vaccination approach provides an attractive and testable alternative for overcoming the HIV-1 variability, while focusing T cell responses on regions of the virus that are less likely to mutate and escape. Furthermore, it has merit in the simplicity of design and delivery, requiring only a single immunogen to provide extensive coverage of global HIV-1 population diversity.