Induction of anti HIV-1 envelope protein (Env) antibodies with polyfunctional Fc-effector profiles correlates with spontaneous HIV-1 control by elite controllers and appears to be crucial for vaccine-mediated protection against HIV-1. However, the antibody responses after experimental anti-Env vaccinations seem to be biased and restrict to the T-helper type 2 (Th2) IgG subtypes with a glycosylation pattern consistent with less efficient Fc effector functions.
A common way to modulate the type of T-helper responses and the subsequent IgG subclass distribution is the addition of suitable adjuvants to the vaccine formulations. Different adjuvants were applied together with HIV-1 Env-based antigens, however, despite overall enhancement of Env-specific humoral immune responses, no significant changes in the IgG subclass distribution were observed.
Since the requirement for recognition of viral antigens differs fundamentally between T and B-cell responses, we propose to explore a novel HIV-1 vaccination strategy based on multifunctional calcium-phosphate nanoparticles (CaP). These CaPs can be selectively loaded and functionalized with different biomolecules and serve as an efficient in vivo delivery system with a large potential in biomedicine and immunology.
The work program includes design, manufacturing and evaluation of a two component vaccine, in which the first component T-CaP is optimized for induction of T-helper cell responses, while the second component B-CaP presents the Env immunogen in the correct conformation to the B-cells.
As a first step, we will analyze differences in dendritic cell activation by targeting and non-targeting T-CaP and screen potential adjuvants for the promotion of initial Th1 polarization in CD4 T-cells in vitro. After the initial in vitro screening, the most promising T-CaP formulations will be compared in vivo.
B-CaP will be designed for initial activation of naïve B-cells specific for conformationally stabilized HIV-Env-trimers. Based on the in vitro screening experiments, we will select the most potent B-CaP-nanoparticles compositions for further in vivo assays.
After individually optimizing all components, immunogenicity studies for two-component vaccines will be performed.
Thus, we aim to bypass the Env-induced bias in T-helper cell responses, and maintain the native trimeric structure of the Env immunogen required to raise antibodies to conformational epitopes. By separating the induction of T-helper cell responses and B-cell responses, we also aim to improve the understanding of the requirements for the induction of long-lived effector antibody responses against trimeric structures of HIV-Env.