IMMUNE CORRELATES OF SIV-­PROTECTION AND HIV­-CONTROL: STUDY OF AN EFFECTIVE ALVAC/SIV ¿ GP120/ALUM VACCINE AND OF HIV-­INFECTED LONG TERM NON PROGRESSORS

Background The ALVAC/HIV+ gp120/Alum RV144 vaccine trial conducted in Thailand resulted in 31% vaccine efficacy in a low-risk cohort of 16.000 volunteers. We aimed to mirror these results in an SIVmac251 model, to explore the effect of the adjuvant MF59 in a similar vaccine regimen and to investigate the immune correlates of protection. Post-hoc analysis of RV144 demonstrated that antibodies targeting the V2 region of gp120 correlated with decreased risk of infection. The same response has been detected in SIV-infected rhesus macaques that achived substained SIV control after treatment with monoclonal antibody anti-α4β7 and an intermittent period of antiretroviral therapy. To date, V2 antibody response data in HIV infected individual that naturally control HIV progression are lacking. We compared the V2 humoral response in a group of chronic HIV infected patients that never received ART and compare that to the response in HIV infected patients Long Term Non Progressors (LTNPs). Methods We immunized 54 rhesus macaques with an RV144 like vaccine regimen adjuvanted either in alum or MF59. We compared the efficacy of the vaccine to 24 simultaneous controls, as well as 23 historical controls. We challenged all the animals with repeated intra-rectal low doses of SIVmac251. We evaluated vaccine efficacy, measured humoral systemic and mucosal humoral responses by multiple antibody detection assays (with particular regard to the V2 response), we measured frequency and quality of plasma-cell precursors, Plasmablasts and Natural Killer cells by flow-citometry. We enrolled 14 HIV italian patients LTNP and 12 pre-ART chronic HIV-infected (CHI) patients and studied their systemic response to V2, with both linear and cyclic peptides. Results Our study mirrored the RV144 human trial: the ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) reduced the risk of SIV mucosal infection. Interestingly the ALVAC-SIV + gp120 MF59 vaccine did not, despite the general higher systemic and mucosal immunogenicity. Vaccine efficacy was associated with alum-induced envelope Env-dependent mucosal NK-cells that produce interleukin 17 (IL-17), as well as with mucosal IgG to the gp120 variable region 2 (V2). Notably, this latter humoral mucosal response was the only response higher in the alum group. MF59 skewed the traffic of PBs from the mucosal to the inflammatory sites. We observed similar differences, consistent with the macaque results, in α4β7 levels on circulating PBs in humans immunized in the RV135 and RV132 trials, which used the RV144 immunogens adjuvanted either with alum or MF59, respectively. The systemic antibody V2 response in LTNP was higher compared to the V2 response in pre-ART CHI patients. Conclusions Our data confirm the protection achieved in human by the immunization with a prime/boost approach with an ALVAC-HIV + gp120-Alum vaccine in a SIVmac251 model. We found novel immune features (NK-cells and PBs) that might represent immune correlated of protection. Furthermore, we confirmed in our model similar responses showed in humans vaccinated with the RV144 regimen. As already described in vaccinated humans, we now demonstrate the importance of the antibodies to V2 in prevention from SIV mucosal acquisition. The importance of antibody to V2 region of SIV/HIV has been recently corroborated by a rhesus macaque study in which substained virologic control was achived after ART suspension. We remarkably found in a group of italian LTNPs an higher antibody response to the linear and cyclic form of the V2 region of gp120 compared to a group of pre-ART CHI patients. Understanding the mechanism in which these antibody might contribute to mediate protection from HIV/SIV acqusition and HIV/SIV control will require further studies.