Neutralizing Monoclonal Antibodies Reduce Human Cytomegalovirus Infection and Spread in Developing Placentas.

Takako Tabata,Daniel C Freed,June Fang-Hoover,Matthew Petitt,Lenore Pereira,Zhiqiang An,Fengsheng Li,Tong-Ming Fu,Dai Wang

doi:10.3390/vaccines7040135

Abstract

Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects worldwide, yet the most effective strategies for preventing virus transmission during pregnancy are unknown. We measured the efficacy of human monoclonal antibodies (mAbs) to HCMV attachment/entry factors glycoprotein B (gB) and the pentameric complex, gH/gL-pUL128–131, in preventing infection and spread of a clinical strain in primary placental cells and explants of developing anchoring villi. A total of 109 explants from five first-trimester placentas were cultured, and infection was analyzed in over 400 cell columns containing ~120,000 cytotrophoblasts (CTBs). mAbs to gB and gH/gL, 3-25 and 3-16, respectively, neutralized infection in stromal fibroblasts and trophoblast progenitor cells. mAbs to pUL128-131 of the pentameric complex, 1-103 and 2-18, neutralized infection of amniotic epithelial cells better than mAbs 3-25 and 3-16 and hyperimmune globulin. Select mAbs neutralized infection of cell column CTBs, with mAb 2-18 most effective, followed by mAb 3-25. Treatment of anchoring villi with mAbs postinfection reduced spread in CTBs and impaired formation of virion assembly compartments, with mAb 2-18 achieving better suppression at lower concentrations. These results predict that antibodies generated by HCMV vaccines or used for passive immunization have the potential to reduce transplacental transmission and congenital disease.

Highlights

Human cytomegalovirus (HCMV) is the most common virus transmitted in utero and is an infectious cause of birth defects
We have shown that highly neutralizing monoclonal antibodies (mAbs) directed to pUL128-131 of the pentamer complex, glycoprotein B (gB) and gH/gL perform significantly better than an hyperimmune globulin (HIG) preparation in neutralization of human cytomegalovirus (HCMV)
Infection in primary placental cells and reduce infection in anchoring villus explants of first trimester placentas. These results suggest that treatment with appropriate combinations of mAbs, especially those to pUL128-131 of the pentameric complex, could be significantly more effective than current treatments with HIG to reduce HCMV transmission and congenital disease in pregnancy

Summary

Introduction

Human cytomegalovirus (HCMV) is the most common virus transmitted in utero and is an infectious cause of birth defects. Congenital infection results in permanent neurological defects, mental retardation, hearing loss, visual impairment, and pregnancy complications, including intrauterine growth restriction (IUGR), preterm delivery, and stillbirth [1,2,3]. Primary maternal HCMV infection in the first trimester of pregnancy (9000/year in the U.S.) is associated with a 40% risk of transmission and results in the most severe damage [4]. Recurrent infections are significantly more common (30,000/year) [5] and are associated with a lower risk of transmission (0.2–2%) and better outcome but can still cause hearing deficiencies [6,7]. Given the major public health impact of congenital HCMV infection, the development of a vaccine capable of preventing transmission has long been a priority [8] (reviewed in [9,10,11]). A subunit vaccine based on the envelope glycoprotein B (gB), essential for infection of all cell types [12,13,14], reduced seroconversion by 50% in seronegative women, indicating partial protection [15] and a need for formulations that include other glycoproteins that elicit neutralizing antibodies [16,17,18]

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