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Enhancing the germinal center (GC) reaction is a prime objective in vaccine development. Targeting of antigen to MHCII on APCs has previously been shown to increase antibody responses, but the underlying mechanism has been unclear. We have here investigated the GC reaction after targeting antigen to MHCII in (i) a defined model with T and B cells of known specificity using adjuvant-free vaccine proteins, and (ii) an infectious disease model using a DNA vaccine. MHCII-targeting enhanced presentation of peptide: MHCII on APCs, and increased the numbers of GC B cells, T FH , and plasma cells. Antibodies appeared earlier and levels were increased. BCR of GC B cells and serum antibodies had increased avidity for antigen. The improved responses required cross-linking of BCR and MHCII in either cis or trans . The enhanced GC reaction induced by MHCII-targeting of antigen has clear implications for design of more efficient subunit vaccines., Competing Interests: B.B. and G.G. are inventors on (1) patents (B.B.) and (2) patent applications (G.G., B.B.) on the described vaccine molecules, filed by the TTO office of the University of Oslo and Oslo University Hospital, according to institutional rules. (1) Patent applicant: Inven2/Vaccibody AS. Inventors: Bjarne Bogen, Agnete B. Fredriksen, Inger Sandlie. Application number: European patent No. 1599504. Status of Application: granted in EU and the US. Specific aspect of manuscript covered in patent Application: Homodimeric modular constructs targeting antigens to antigen presenting cells. (2) Patent applicant: Inven2. Inventors: Bjarne Bogen, Gunnveig Grødeland, Agnete B. Fredriksen. Application number: WO2017/221072. Status of Application: National Phase from Dec 20, 2018. Specific aspect of manuscript covered in patent Application: A human version of the MHCII-specific targeting moiety. BB is head of the Scientific panel of Vaccibody AS, and holds shares in the company.