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

Leike Li,Stuart P Adler,Xiaohua Ye,Ningyan Zhang,Zhiqiang An,Tong-Ming Fu,Richard E Rupp,Daniel C Freed,Yaping Liu,Dai Wang,Fengsheng Li,Diane F Barrett,Wei Xiong

doi:10.1038/s41541-021-00342-3

Leike Li, Stuart P Adler + Show 11 more

Open Access

https://doi.org/10.1038/s41541-021-00342-3

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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.

Highlights

Human cytomegalovirus (HCMV), a prototypical beta-herpes virus, is a major cause of morbidity and mortality in immunocompromised transplant recipients and congenitally infected fetuses[1,2].HCMV infection is widespread, with >50% of adults naturally infected worldwide[3]
Intradermally (ID) at 30 U/dose in a phase I clinical trial, which recruited 190 healthy subjects[29,30]. In this sub-study, to isolated the vaccine-induced monoclonal antibodies, and compare its pattern induced by two routes of administration, we performed the single memory B-cell culturing of three subjects in the 30 U (IM, seronegative) group, and three subjects in 30 U
An effective HCMV vaccine is urgently needed for the prevention of congenital HCMV infection

Summary

Introduction

Human cytomegalovirus (HCMV), a prototypical beta-herpes virus, is a major cause of morbidity and mortality in immunocompromised transplant recipients and congenitally infected fetuses[1,2].HCMV infection is widespread, with >50% of adults naturally infected worldwide[3]. Human cytomegalovirus (HCMV), a prototypical beta-herpes virus, is a major cause of morbidity and mortality in immunocompromised transplant recipients and congenitally infected fetuses[1,2]. The majority of primary HCMV infections lack specific clinical symptoms. HCMV infection can lead to complications for recipients of organ transplantation[2]. Both primary and secondary infections in women during pregnancy can lead to in utero HCMV infection, which can cause irreversible fetal neurodevelopmental abnormalities with severe consequences such as mental retardation, cerebral palsy, and hearing loss[4]. An estimated 0.64% of the birth cohort in the United States is born with congenital HCMV infection[5]

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