Mesoporous Silica Rods Scaffolds for the generation of adaptive immune responses

Abstract

The generation of T and B-cell-mediated adaptive immune responses through vaccination is a powerful tool for the prevention and treatment of disease, ranging from halting the spread of communicable infections to the treatment of cancer. Despite the exceptional potential of vaccines in improving global health, there is still a need to develop technologies that can adequately stimulate the immune system to elicit robust and persistent immune responses. In particular, immunizations that provide long-term humoral responses with a single dose would facilitate global vaccine rollout and allow faster response to pandemics. Biocompatible materials that spatiotemporally control the delivery of defined payloads offer unique opportunities to present cues to immune cells in a way that can optimally stimulate adaptive immune responses and ameliorate vaccination outcomes. In this thesis, we describe the use of Mesoporous Silicas Rods (MSR) scaffolds to this end. Upon subcutaneous injection, MSRs self-assemble into a degradable macroporous nodule that recruits millions of antigen-presenting cells through the action of the particle-loaded chemoattractant GM-CSF. Co-delivery of TLR-agonists and antigens from the particles matures antigen-presenting dendritic cells and direct them to migrate back to the draining lymph node to prime cellular responses. Moreover, the MSR scaffolds can slowly release its cargo over several weeks, exploiting the fact that prolonged presence of antigen can amplify antibody responses. Single-dose MSR vaccines directed against poorly immunogenic subunit antigens produced long-term antibody responses that surpassed that of traditional bolus and Alum vaccines, induced the generation of persistent germinal centers and significantly increased the generation of memory B-cells. Mechanistically, the presence of the scaffold was required for at least 7 days and the recruitment of cells into MSRs was necessary for maximal antibody titers to develop. MSR vaccines are easily formulated through simple mixing and adsorption of the bioactive components and can be stored lyophilized, providing a simple a path to translation and distribution. The platform enabled the development of antibodies against a variety of small molecules, peptides and proteins and could induce both cytotoxic T-cell responses and long-term neutralizing antibodies against SARS-CoV-2 with a single-dose, demonstrating utility in a wide range of applications including addiction treatment, reproductive biology, infectious diseases and cancer immunotherapy.