Human cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals and infants infected in utero. As such HCMV is the most frequent viral cause of congenital infection and affects 0.5–2% of all live births worldwide. It is the leading infectious cause of childhood sensorineural hearing loss and an important cause of mental retardation. In addition, HCMV infections represent a major clinical complication in transplant patients resulting in increased morbidity and mortality following transplantation. Because of the clinical relevance, the development of a vaccine has been given highest priority by governmental agencies. As with other successful vaccines, induction of protective antibodies following vaccination will be crucial. We have studied the antibody response against human (HCMV) and murine CMV (MCMV). For HCMV we have characterized the antibody response against glycoprotein B (gB), the most advanced vaccine antigen, and identified new antigenic domains on gB, which are important targets for neutralizing antibodies (Pötzsch et al., 2011; Spindler et al., 2013; Spindler et al., 2014; Wiegers et al., 2015). Using MCMV we could show that antibodies can protect from a lethal infection (Klenovsek et al., 2007), and that in vivo protection is not directly correlated to the transfer of virus-neutralizing activity (Fig. 1; Bootz et al., 2017). We propose to use MCMV as a model system to identify antigen specificity and mode of action of protective antibodies. It is planned to generate an extensive set of anti-MCMV monoclonal antibodies (mAbs). At first, the mAbs will be characterized in vitro with respect to target specificity, neutralization and inhibition of cell-to-cell spread, which is considered to be a major route of viral dissemination in vivo. Next, the mAbs will be tested for their in vivo protective capacity. Once protective mAbs have been identified, we will attempt to induce the respective antibodies following immunization. In summary, the proposed project may provide the basis for a rational vaccine design against HCMV.