Development of a structurally-defined polymer platform to boost humoral immunity against non-peptidic antigens by T cell priming

Conjugated vaccines sidestep the challenges of handling live pathogens, offering a safer and highly targeted approach to disease prevention. They represented a major breakthrough in achieving IgG antibody production against non-peptide epitopes, haptens, by invoking T cell help. Haptens random conjugation to carrier proteins can induce a T cell mediated humoral response by generating peptide-specific and hapten-specific T cells. While numerous efforts have been focused towards increasing immunogenicity of haptens, studies involving random functionalization of proteins do not tease out molecular level understanding of the criteria for hapten-specific T cell priming and impact of T cell specificity in humoral immunity. To overcome this limitation, we designed a structurally-defined polymer platform displaying position-specific haptenization of the MHCII epitope ova323-339 to study hapten-specific T cell induction and the corresponding impact on antibody production. This platform enabled a systematic study of B and T cell recognition and immune outcome and lead to the identification of the polymer pDNP-OVA2. pDNP-OVA2 outperformed a classical protein carrier platform in generating IgG titers by simultaneously priming B and T cells against a small molecule. Furthermore, it induced a signature signaling cascade that generated high titer of IgG3, an antibody subclass with superior effector function indispensable for neutralization of encapsulated bacteria like Streptococcus pneumoniae (SPn) and Haemophilus influenzae type b (Hib). This polymer vaccine platform can be leveraged to efficiently present a wide range of non-classical antigens to T cells and achieve better humoral immunity.