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

Abstract

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.

Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization

“…It has been suggested that Fc-mediated effector functions of antibodies are critical for the observed efficacy ( 69 ). Complement-enhanced neutralization was detected in the sera from people who received a gB vaccine, suggesting that complement may be one of the protective mechanisms ( 68 , 70 ). Notably, ORF4 has been demonstrated to be a virulence factor in the MHV-68 model during acute replication, but it is not necessary for latency establishment ( 71 ).…”

Vaccination with a disabled infectious single cycle cytomegalovirus vaccine elicits a distinct glycoprotein B-specific monoclonal antibody repertoire compared to that of naturally-infected individuals

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A novel rotavirus reverse genetics platform supports flexible insertion of exogenous genes and enables rapid development of a high-throughput neutralization assay

“…Human serum samples were reported before 21 . Rabbit, mouse, guinea pig and cotton rat serum samples were taken from animals housed in the animal facility in the research laboratories at Merck & Co., Inc., West Point, PA, USA.…”