Protection against and control of HIV and SHIV in natural infections and in animal models correlate with the ability of anti-Env antibodies to neutralize HIV isolates. While sophisticated binding studies using highly mutated and broadly neutralizing antibodies (bnAbs) have led to the identification of regions of vulnerability on the Env protein, Env vaccine using some of these regions have failed to elicit similarly high affinity bnAbs; instead inducing robust antibody responses but with only modest levels of mutations. Here, we propose a new approach to persistently stimulate B cell clonal lineages so as to generate highly mutated, affinity matured neutralizing antibodies and/or enhanced non-neutralizing FcR mediated functions, by harnessing the natural adjuvant properties of a particular subset of CLEC9A+ dendritic cells (DCs), known to induce very strong humoral immunity. In this application, we propose to target CLEC9A on macaque DCs using anti-CLEC9A-Env fusion proteins produced in plants to achieve antibody-mediated delivery of Env immunogens to this DC subset. This approach is highly relevant for HIV vaccines since anti-Clec9A fusion proteins have been shown in mice to efficiently generate T follicular helper cell (Tfh) responses, known to play an important role in the development of HIV/SIV specific B cell responses by facilitating somatic mutation and selecting high affinity memory and plasma B cells. This macaque study, which aims to drive B cell affinity maturation, is a collaboration between Dr. Bart Haynes, who will design the initial prime and boost Env/adjuvant vaccine regimens and PlantVax, who will produce and provide the final boost with anti-CLEC9A-Env fusion proteins.
The HIV vaccine trials to date have not been successful in producing the broadly neutralizing antibodies (bnAbs) that recognize the HIV viral envelope (Env) protein and that are required for preventing infection. In the present study, we plan to link the HIV Env protein to an antibody that binds to a receptor on a subset of dendritic cells known to induce very strong antibody responses. Using this approach, we shall deliver a final boost of this fusion molecule to macaques, that have previously been immunized several times with the HIV Env, in order to drive their antibody forming B cells to proliferate and produce mutated anti-Env antibody similar to the critical bnAbs.
