Tu105 - A Screening Platform for Drug Effects on Vaccine Responses Using Human Tonsil Immune Organoids

The SARS-CoV-2 pandemic has reaffirmed the importance of vaccines in public health; however, efficacy is variable. Patients receiving immunosuppressive medications are at particularly high risk of poor responses, though there is no rapid mechanism to screen vaccines in the presence of drug compounds to inform patient care.

We recently developed an in vitro model of the human immune system using dissociated tonsil cells. These cultures mimic hallmarks of in vivo vaccine effects, including somatic hypermutation, class switching and secretion of high affinity antibodies. We adapted the system as a screening tool to detect adverse drug effects on vaccination efficacy.

We established immune cultures growing in 96-well plate format. Vaccination using a seasonal Live Attenuated Influenza Vaccine (LAIV) resulted in influenza-specific IgG antibody production with robust Z’ factor of 0.87 and signal to noise ratio (S/B) of 22, suitable for high-throughput screening. We tested the system using dilution series of clinically relevant but mechanistically diverse immunosuppressive medications. Methotrexate and mycophenolic acid (MPA) potently inhibited influenza-specific IgG at nanomolar concentrations, whereas hydroxychloroquine and cyclosporine A impaired responses in the micromolar range. In depth mechanistic profiling of organoids vaccinated in the presence of MPA using flow cytometry revealed impaired germinal centre B cell and plasmablast differentiation, though no changes in CD4+ T cell activation.

In summary, the system functions as a rapid and efficient method to screen how various medications impact antigen specific responses during vaccination. It provides a platform for testing novel and existing compounds to better predict clinical vaccine efficacy.