A universal T cell vaccine for HIV-1

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 enormous HIV variability, which dwarfs that of 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 candidate vaccine designed specifically to overcome HIV variability by focusing the body defences on the conserved regions of the virus, i.e. the Achilles heel of HIV. Here, we are proposing to build on and extend our ongoing vaccine development effort and, if successful, assemble a strong case for further evaluation of this vaccination strategy in larger scale and expensive field efficacy studies.

The best solution to the HIV/AIDS epidemic is development of an effective prophylactic vaccine. T cell stimulating vaccines offer a realistic alternative, or supplement to, antibody inducing vaccines. The latter are proving extremely difficult to generate and T cell stimulating vaccines, while not preventing infection, do ameliorate disease in monkey/SIV models. However, virus variability is a major problem resulting in poor recognition of infecting virus and easy escape of virus from early T cell control. These issues could be avoided by focusing vaccine-induced T cell responses on conserved regions of HIV-1. While most patients with chronic HIV-1 infection do make some T cell responses to conserved regions, these responses are usually weak (subdominant) and, like broadly neutralizing antibody responses, develop too late in the infection to provide real benefit. We have constructed immunogen HIVconsv, which is derived from the 14 least variable HIV-1 segments and contains over 200 epitopes, and have shown that it stimulates strong T cell responses in mice and in rhesus macaques. Phase I clinical trials in Oxford evaluating safety and immunogenicity of three HIVconsv vaccines delivered as plasmid DNA, recombinant MVA and recombinant chimpanzee adenovirus have started.
Here, we shall further refine the vaccine design to improve the prototype immunogen, vaccine vectors and their formulation. We shall test different vaccination regimens to maximize T cell induction and assess surrogate efficacy in inbred and outbred mice. We shall make a second ?mosaic? immunogen complementing HIVconsv, which will improve perfect matching of amino acids to HIV-1 variants from clades A,B,C and D from 72% to 90%. We shall study in depth vaccine-induced responses in humans, looking at how well the known conserved (but often subdominant in HIV-1 infection) epitopes are presented by antigen-presenting cells exposed to these constructs. We shall examine how efficiently the HIVconsv-specific T cells recognize and kill HIV-1-infected cells. We shall employ state-of-the-art proteomics (tandem MS/nanoflow RPLC) to obtain a comprehensive picture of conserved region peptide processing and presentation on the cell surface, and comparing epitope presentation from the HIVconsv vaccines and HIV-1. This will indicate whether the HIVconsv needs further optimization.
Results generated from this programme together with our complementing, separately funded components (non-human primate and human trials) will be key in assessing the suitability of conserved region T cell vaccines for efficacy trials in high-risk human cohort(s), either alone or with an antibody-based vaccine.