Pentameric gH complex is the primary target of neutralizing antibodies generated in cytomegalovirus vaccine immunized rabbit (VAC7P.982)

Abstract

Abstract Human cytomegalovirus (HCMV) belongs to the herpesvirus family and can cause severe diseases in immune-compromised individuals and birth defects in babies from in utero infection. Understanding the protective immunity is the pre-requisite in developing an effective vaccine against HCMV. Humoral immunity can provide protection against HCMV infection and that such a protection comes from antibodies primarily targeting antigens of pentameric gH complex. To support a vaccine concept based on the pentameric gH complex, we generated and characterized 45 monoclonal antibodies (mAb) from a rabbit immunized with an experimental vaccine virus in which the expression of pentameric gH complex restored. From 45 mAbs, we identified 25 mAbs with neutralizing activities. We demonstrated that binding affinity to virions is not correlated with neutralizing activity and potent neutralizing mAbs (Elite neutralizer) preferentially bind to the pentameric gH complex. Using phylogenetic analysis, we further demonstrated that these antibodies are grouped into 26 distinct B cell lineages and the neutralizing and binding mAbs were largely segregated into different groups. In addition, neutralizing antibodies have longer complementarity-determining region (CDR) 3 than those non-neutralizing mAbs. In conclusion, the pentameric gH complex is the primary target of neutralizing antibodies by vaccination with a HCMV vaccine.