Abstract
Human cytomegalovirus (HCMV) is a leading cause of permanent birth defects, highlighting the need to develop an HCMV vaccine candidate. However, HCMV vaccine development is complicated by the varying capacity of neutralizing antibodies (NAb) to interfere in vitro with the HCMV entry routes mediating infection of fibroblast (FB) and epithelial cells (EC). While HCMV infection of FB and EC requires glycoprotein complexes composed of gB and gH/gL/gO, EC infection depends additionally on the envelope pentamer complex (PC) composed of gH, gL, UL128, UL130 and UL131A. Unlike NAb to gB or gH epitopes that can interfere with both FB and EC infection, NAb targeting predominantly conformational epitopes of the UL128/130/131A subunits are unable to prevent FB entry, though they are highly potent in blocking EC infection. Despite the selective requirement of the PC for EC entry, the PC is exceptionally immunogenic as vaccine antigen to stimulate both EC- and FB-specific NAb responses due to its capacity to elicit NAb that target epitopes of the UL128/130/131A subunits and gH. These findings suggest that the PC could be sufficient in a subunit vaccine formulation to induce robust FB- and EC-specific NAb responses. In this short review, we discuss NAb responses induced through natural infection and vaccination that interfere in vitro with HCMV infection of FB and EC.
Highlights
Human cytomegalovirus (HCMV) is a leading cause of severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system, such as AIDS patients and transplant recipients [1,2]
These properties of neutralizing antibodies (NAb) targeting the UL128/130/131A subunits and gH are consistent with NAb found in HCMV+ individuals and suggest that the difference in epithelial cells (EC)- and FB-specific NAb responses stimulated by the pentamer complex (PC) is primarily a result of NAb that target the
We have shown that vaccine approaches using plasmids or MVA vectors expressing either glycoprotein B (gB) or the PC of RhCMV can reduce plasma viral load in naïve
Summary
Human cytomegalovirus (HCMV) is a leading cause of severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system, such as AIDS patients and transplant recipients [1,2]. Major impediments in HCMV vaccine development include intricate immune evasion strategies, incomplete protection by natural immunity, establishment of viral latency, unknown immune correlates of protection, and lack of appropriate HCMV animal models [7,8,9,10,11] Despite these obstacles, encouraging progress in developing an HCMV vaccine candidate has been made with an approach based on envelope glycoprotein B (gB) combined with MF59 adjuvant [12,13]. Vaccines 2017, 5, 39 solid organ and hematopoetic stem cell transplant recipients, gB/MF59 remains the only vaccine that demonstrated partial efficacy to prevent primary HCMV infection in women of childbearing. Organ and hematopoetic stem cell transplant recipients, gB/MF59 remains the only vaccine that demonstrated partial efficacy to prevent primary HCMV infection in women of childbearing age
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