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Study of the Immune Correlates of Protection in Rhesus Macaques Vaccinated against Simian Immunodeficiency Virus 10.17863/CAM.38222 Gorini, Giacomo 0000000328721531 Heeney, Jonathan After more than thirty years since the Human Immunodeficiency Virus (HIV) was identified, only the RV144 phase III vaccine clinical trial provided evidence of protection from virus infection, with 31.2% of the patients protected at three years since the end of the immunisation phase. Statistical analyses support serum IgG antibody recognition of the V2 region of viral gp120 as a mechanism of protection from acquisition. One hypothesis is that antibodies to this region might block the interaction with the integrin $\alpha4\beta7$, which protrudes from the surface of mucosal CD4+ T cells and is thought to capture the virus and facilitate infection. However, that $\alpha4\beta7$ blocking might be a protective mechanism of RV144 vaccination has yet to be definitively demonstrated. In this thesis, I aimed to describe at the molecular level the immune mechanisms of protection in a rhesus macaque (Macaca mulatta) vaccinated in an RV144-like schedule and protected from Simian Immunodeficiency Virus (SIV) infection, with a particular focus on the humoral immune response of the animal. More specifically, vaccine-induced monoclonal antibodies (mAbs) directed against the V2 region of SIV were isolated and characterised. One of them, NCI09, has been identified as a potent inhibitor of SIV gp120 interaction with human $\alpha4\beta7$. Notably, NCI09 antigen recognition is negatively affected by the presence of ITS41, a mAb targeting a distant epitope on V2. Moreover, to experimentally prove this mechanism I performed the passive immunoprophylaxis of rhesus macaques using the anti-V2 mAb ITS09. Unfortunately, this mAb proved ineffective in providing protection both alone and in combination. Finally, a vaccination protocol based on the immunisation regimen of RV144, but modified to elicit stronger immune responses was tested. Surprisingly, the protocol failed to afford protection. However, in a parallel group immunised with the standard RV144 regimen, protection was observed and correlated with the intensity of the innate immune responses. These results provide insights into possible mechanisms of protection of RV144 vaccination against HIV. Furthermore, these findings suggest that there may be a degree of structural plasticity of the V2 region that may impact its interaction with $\alpha4\beta7$ and evasion mechanisms from a potentially protective humoral immune response. University of Cambridge 2019-07-19 Thesis Doctoral Doctor of Philosophy (PhD) en https://www.repository.cam.ac.uk/handle/1810/291043 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e1523e6d-6b3b-4589-bf33-843e811b1d27/download 39fb205fcb2946ed34666ca8a25079ac https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/6ea4fdd4-72f6-4abf-a623-c783a4182586/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ This thesis contains minimal third party material that has been credited in the references. immunology antibody vaccine vaccinology hiv simian immunodeficiency virus siv monoclonal cloning innate immunity immunisation prophylaxis