A conditionally replication-defective cytomegalovirus vaccine elicits potent and diverse functional monoclonal antibodies in a phase I clinical trial

A conditionally replication-defective human cytomegalovirus (HCMV) vaccine, V160, was shown to be safe and immunogenic in a two-part, double-blind, randomized, placebo-controlled phase I clinical trial (NCT01986010). However, the specificities and functional properties of V160-elicited antibodies remain undefined. Here, we characterized 272 monoclonal antibodies (mAbs) isolated from single memory B cells of six V160-vaccinated subjects. The mAbs bind to diverse HCMV antigens, including multiple components of the pentamer, gB, and tegument proteins. The most-potent neutralizing antibodies target the pentamer-UL subunits. The binding sites of the antibodies overlap with those of antibodies responding to natural HCMV infection. The majority of the neutralizing antibodies target the gHgL subunit. The non-neutralizing antibodies predominantly target the gB and pp65 proteins. Sequence analysis indicated that V160 induced a class of gHgL antibodies expressing the HV1-18/KV1-5 germline genes in multiple subjects. This study provides valuable insights into primary targets for anti-HCMV antibodies induced by V160 vaccination.

Lessons from studies with murine cytomegalovirus that could lead to a safe live attenuated vaccine for human cytomegalovirus

Studies with a murine cytomegalovirus mutant tsm5 suggested two possible approaches to producing a live attenuated human cytomegalovirus vaccine. One approach would be to use a combination of five to six mutants where an attenuating mutation in the gene of one mutant is compensated by the wild-type version in a second mutant, which in turn has a mutation in a different gene compensated by the wild-type version in a third mutant, etc. Important genes in this approach could include those involved in DNA replication. The importance of the carboxy terminase of the primase gene (M70/UL70) for its function suggested a second approach where some of the natural codons in this region could be substituted with synonymous non-preferred (minor) codons that would reduce the replication fitness of the mutant.