Cytokine-mediated germinal center reprogramming enhances vaccine efficacy

Abstract

Abstract Candidate vaccines against infectious agents and non-communicable diseases consist of purified proteins, proteins conjugated to synthetic peptides or haptens, and use adjuvants or novel delivery platforms. Despite pre-clinical proof of concept, vaccine clinical efficacy is often limited to a small subset of immunized subjects. Additionally, very few adjuvants meet regulatory approval. Thus, more effective immunization strategies are needed. This study tested the hypothesis that vaccine efficacy is enhanced by cytokine-based immunomodulators that guide B and T cells toward germinal center (GC) activation and generation of effective antibody (Ab) responses. To this end, a series of cytokines and monoclonal Ab against cytokines or cytokine receptors was co-administered with a candidate therapeutic vaccine for treatment of opioid abuse. Immunization with a drug-hapten conjugated to immunogenic carriers generates anti-drug Ab that block drug distribution to the brain, and reduce drug-induced behavioral effects. In this study, targeting IL-4 signaling enhanced vaccine efficacy in blocking opioid distribution to the brain in mice. Vaccine efficacy was associated with increased vaccine-specific GC B cell and GC-TFH cell differentiation, serum anti-opioid IgG Ab levels and IgG subclasses shift, and a balanced Th1/Th2 environment. No side effects were found. This strategy generalized to a model peptide-protein conjugate immunogen and an approved tetanus-diphtheria-pertussis vaccine. These data support targeting cytokine signaling to safely program vaccine-induced GC formation and achieve clinically effective Ab. This strategy provides a blueprint for rational development of more effective next-generation vaccines.