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