While HIV-1 broadly neutralizing antibodies (bnAbs) provide potent protection from HIV-1, to date they have been difficult to induce in the setting of vaccination. A second type of HIV-1 envelope (Env) antibodies that are easy to induce are termed non-neutralizing antibodies (NNAbs) (because they are not bnAbs), or called effector antibodies, because they mediate a myriad of potentially protective anti-HIV-1 effector mechanisms. One of the 5 Phase IIb HIV-1 vaccine efficacy trials (ALVAC/AIDSVAX in RV144) showed an estimated vaccine efficacy of 31%, with a correlate of decreased transmission risk of polyfunctional antibodies that mediate FcR-anti-HIV-1 activities including C1 and V2-targeted ADCC. Currently there are two vaccine efficacy trials ongoing to test the ability of an ALVAC-C, bivalent C/C gp120 boost (HVTN 702) and rAd26 prime, gp140 protein boost (HVTN 705) with hopes of inducing protective NNAbs. HVTN 702 has two wildtype (WT) gp120 Envs as boosts, and HVTN 705 has one WT Env as boost. However, neither trial utilitize strategies for inducing a breadth of NNAbs with boosting Env design. Thus, a key goal of current HIV-1 vaccine development is to develop the simplest and most effective vaccine that induces polyfunctional NNAbs should either of the current efficacy trials fail to improve on RV144. Our overall goals are 1) to develop an ADCC mosaic multivalent Env immunogen to follow an ALVAC-C prime; and 2) to produce ADCC mosaic Env gp120s under current good manufacturing practices (CGMP) conditions, perform toxicity studies, and prepare an investigational new drug application (IND) for testing in an HVTN Phase I clinical trial in man. Overall Specific Aim 1. Develop and produce a trivalent ADCC mosaic Env immunogen that can follow an ALVAC-C prime and test them in the Animal Core in an ADCC mediating NNAb-unmutated common ancestor (UCA) VH + VL mouse model and in a transmitted/founder (TF) tier 2, R5 SHIV rhesus macaque study (RMs) (Drew Weissman, Project Lead; Barton Haynes, Co-I) Overall Specific Aim 2. Produce CGMP trivalent ADCC mosaic mRNA gp120 immunogens. (Thomas Denny Project Lead; Maureen Maughan, Project Co-I) .
Messenger RNAs are the current most promising vaccine strategy for inducing high-titered and long-lasting antibody responses. This IPCAVD Program has the potential to change the field with a successful first in man Phase I clinical trial of trivalent ADCC mosaic mRNAs by showing the plausibility of initiation of high-titered and durable polyfunctional NNAbs that can protect from HIV-1 infection.
