Engineered Ferritin Nanoparticle Vaccines Enable Rapid Screening of Antibody Functionalisation to Boost Immune Responses.

Employing monoclonal antibodies to target vaccine antigens to different immune cells within lymph nodes where adaptive immunity is initiated can provide a mechanism to fine tune the magnitude of quality of immune responses. However, studying effects of different targeting antibodies head-to-head is challenging due to the lack of a feasible method that allows rapid screening of multiple antibodies for their immunogenicity. Here we prepared self-assembling ferritin nanoparticles that co-display vaccine antigens and the Fc-binding domain of Staphylococcal protein A, which allows rapid attachment of soluble antibodies to the nanoparticle surface. Using this tunable system, we screened 10 antibodies targeting different immune cell subsets, with targeting to Clec9a associated with higher serum antibody titers after immunisation. Immune cell targeting using ferritin nanoparticles with anti-Clec9a antibodies drove concentrated deposition of antigens within germinal centres, boosting germinal centre formation and robust antibody responses. However, the capacity to augment humoral immunity was antigen-dependent, with significant boosting observed for prototypic ovalbumin immunogens but reduced effectiveness with the SARS-CoV-2 RBD. This work provides a rapid platform for screening targeting antibodies, which will accelerate mechanistic insights into optimal delivery strategies for nanoparticle-based vaccines to maximise protective immunity. This article is protected by copyright. All rights reserved.