Overcoming the obstacles of eliciting broadly neutralizing antibodies (NAb) to HIV-1 will be a major stepforward to developing a successful AIDS vaccine. The long-term objectives of project 2 are to design,evaluate and select novel HIV-1 enveloped based immunogens which are capable of inducing broadneutralizing antibodies which will have a protective effect in vaccinated individuals. The challenge andreason for this B-cell epitope focused approach is that HIV-1 has developed multiple mechanisms to shielditself and evade the antiviral effects of many antibodies. By far most host antibodies directed to the envelope(Env) of HIV-1 are ineffective in eliciting broad Nab responses. There are however several conserved B-cellepitopes which are rarely exposed, but when recognized by the host are able to elicit a broad Nab response.Here we aim to develop vaccine immunogens which together will focus the antibody response to highlyconserved Env epitopes. Specifically our aims are to:1. To improve the presentation of conformational Nab B-cell epitopes (mimotopes) for optimal presentation invivo by; a) Combinatorial Synthesis and 'Click' chemistry through direct collaboration and interaction withCore D, and, b) Engineered virus-like particles (VLPs) expressing Nab epitopes. Experience in VLPsexpressing HIV peptides will include p55 Gag as well as Hepatitis B particles (Univ Regensburg, thisproject).2. To identify the optimal vaccine platforms (protein, peptide, and/or viral vector) and regimen for eitherpriming or boosting conformationaly dependent epitope specificities. This will be facilitated by closeinteraction with the vaccine technologies core (B) as well as complementary Env structures developed inprojects 1 and 3.3. To determine how many Nab peptide epitopes can optimally be combined in a prime boost immunizationprotocol to ultimately generate robust neutralizing antibody responses in an outbred population, evaluatedfirst in rabbits and subsequently more stringently in non-human-primates models (Core C).4. To determine 'proof of principle' protective efficacy of these optimized mimotope-based vaccine regimensin the SHIV rhesus macaque vaccine challenge model. The best combination of NAb B-cell epitopepresenting structures and delivery systems will be revealed in heterologous and mucosal challenge studies.
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