Antigen bivalency of antigen-presenting cell-targeted vaccines increases B cell responses

Antibodies are important for vaccine efficacy. Targeting antigens to antigen-presenting cells (APCs) increases antibody levels. Here, we explore the role of antigen valency in MHC class II (MHCII)-targeted vaccines delivered as DNA. We design heterodimeric proteins that carry either two identical (bivalent vaccines), or two different antigens (monovalent vaccines). Bivalent vaccines with two identical influenza hemagglutinins (HA) elicit higher amounts of anti-HA antibodies in mice than monovalent versions with two different HAs. Bivalent vaccines increase the levels of germinal center (GC) B cells and long-lived plasma cells. Only HA-bivalent vaccines completely protect mice against challenge with homologous influenza virus. Similar results are obtained with other antigens by targeting CD11c and Xcr1 on dendritic cells (DCs) or when administering the vaccine as protein with adjuvant. Bivalency probably increases B cell responses by cross-linking BCRs in readily observable DC-B cell synapses. These results are important for generating potent APC-targeted vaccines. [Display omitted] •Vaccines that target APCs including DCs enhance antibody responses•APC-targeted vaccines promote synapse formation between APCs and B cells•Antigen bivalency of targeted vaccines enhances B cell responses/antibody production•Bivalent APC-targeted protein and DNA vaccines protect against influenza Induction of antibodies is important for vaccine efficiency. Hinke et al. show that vaccines that (1) target antigen-presenting cells including dendritic cells and (2) express two identical copies of an antigen instead of only one increase antibody levels and protection against influenza virus. The principle can improve efficiency of vaccines.