HIV-Neutralising response to recombinant, cross-clade, adjuvanted, VLP-forming vaccine candidates

The development of a safe, effective and affordable HIV-1 vaccine is urgently needed especially in resource poor settings. It is widely accepted that for a vaccine to confer sterilising immunity to HIV-1 it will have to elicit broadly neutralising antibodies (nAbs) to primary isolates of HIV but this goal has remained elusive. There are two key problems to be addressed in this regard: vaccine candidates have to express the correct epitopes capable of eliciting broadly cross-reactive neutralising antibodies to HIV, and they have to provide potent stimulatory signals to the relevant B cells so that high titres ofneutralising antibodies are obtained. Plasmid DNA and recombinant poxviruses such as modified vaccinia virus Ankara (MYA) and fowlpox virus (FPV) have been safely administered to humans and offer the advantage of accommodating large amounts of additional recombinant DNA. In addition, they have provided promising cytotoxic T-Iymphocyte inducing HIV-l vaccine candidates, especially in heterologous prime-boost combinations. The hypothesis investigated here is that sequentially immunising with envelopes of different clades of HIV might lead to the antibody response being focussed on neutralising epitopes held in common. To overcome the poor immunogenicity of cross-clade neutralising epitopes, and the generally poor antibody responses elicited to priming with DNA, followed by boosting with recombinant poxviruses, B cells were stimulated by the coexpression of cholera toxin B and human complement component C3d. To further stimulate antibody production the candidate vaccines coencoded envelope and capsid components so that there would be in vivo virus-like particle formation. The candidate HIV vaccines proceeded directly to a non-human primate study of immunogenicity because this model most closely resembles the immune response in humans, and the benefits of virus-like particle formation and the adjuvant effect ofhuman C3d were most likely to be demonstrated. The work in this thesis describes the construction and characterisation of complex, adjuvanted poxviral recombinants for use as HIV vaccine candidates in a DNA primeFPV boost-MVA boost in macaques and the subsequent efficacy of macaque sera to neutralise primary isolates ofHIV-l in a validated HIV-l neutralisation assay.EThOS - Electronic Theses Online ServiceGBUnited Kingdo