Dissertation Defense: James Stamos
Candidate: James Stamos
Advisor: Genoveffa Franchini, M.D.
Title: Vaccine-Induced Antibody and Cellular Correlates and Anti-Correlates of Risk of SIV/HIV Acquisition
RV144 is the only phase III HIV vaccine clinical trial that has demonstrated a statistically significant reduced risk of HIV acquisition of 31.2% and the primary correlate of reduced risk was anti-V2 IgG targeting the apex of the trimeric envelope spike protein mediating antibody-dependent cellular cytotoxicity (ADCC). The SIV mac251 macaque challenge model has served as a rigorous tool to test RV144-derived HIV vaccine candidates and study the immune correlates of risk. The first question in this thesis addressed whether passive immunization with anti-V2 monoclonal antibodies could directly reduce the risk of SIV acquisition in naïve macaques. We addressed this question mechanistically with the two monoclonal antibodies (mAb) NCI05 and NCI09, in an IgG1 format, recognizing the α-helix or the β-strand conformation of the V2 epitope respectively. NCI05 outperforms NCI09 in ADCC whereas NCI09 outperforms NCI05 in ADCP and trogocytosis. This study revealed that the mucosal level of the V2 α-helix mAb strongly correlated with delayed mucosal acquisition of SIV, suggesting that the α-helix epitope of V2 is a vulnerability site for ADCC. Thereafter, we developed a V1-deleted (ΔV1 gp120) vaccine platform to focus the antibody response to the α-helix of V2 and augment the anti-V2 ADCC. The encouraging results in macaques with the V1-deleted immunogens secured funding for a Phase I clinical trial (designated as C.L.E.A.R.) in humans with these immunogens at the NCI. The second part of this dissertation explored whether we could develop a plasmid DNA vaccine platform (omitting ALVAC) to simplify the vaccine regimen. We compared our efficacious DNA/ALVAC/ΔV1gp120/Alum 5mg vaccine platform with DNA/ΔV1gp120/Alum 0.85mg DNA/ΔV1gp120/ALFQA 0.85mg, and subsequently a double protein boosted regimen with higher alum content DNA/2xΔV1gp120/2xAlum 5mg to increase vaccine efficacy. The studies revealed that the components of the DNA vaccine platform in the absence of ALVAC elicits a protracted IFN-γ response and T-bet + CD4 + T cells indicative of a polarization of cellular immunity to inflammatory M1 macrophages and T H 1 cells correlated with increased risk of acquisition. These studies revealed that ALVAC is an essential component of our candidate HIV vaccine regimen through the elicitation of a balanced T H 1/T H 2 responses, efferocytosis, and decreased tissue recruitment of activated T-cells.