Current Status of Cytomegalovirus Vaccines: 2016

Abstract

A vaccine against the debilitating effects of congenital cytomegalovirus (CMV) infection is a major public health priority. Vaccines against CMV may also improve the outcome of solid organ and haematopoietic stem‐cell transplantation. In spite of the long‐recognised morbidity caused by CMV infection, progress towards a licenced vaccine has been slow, owing to uncertainties about the key immunological correlates of protective immunity and the optimal vaccine expression approaches to employ. Driven by the encouraging (albeit suboptimal) benefit conferred by a recombinant CMV glycoprotein B (gB) vaccine against CMV infection and disease in recent clinical trials, there is currently increased interest in designing and evaluating a number of candidate vaccines in both preclinical models and controlled trials. Several new CMV vaccine candidates are currently undergoing evaluation in clinical trials. Major challenges must be met before a vaccine can be licenced. Chief among these challenges are: (1) the need to define the optimal constituents of CMV vaccines; (2) the need to define the metrics of protection that would be required for licensure of a vaccine for congenital CMV infection and (3) the necessity of solving the challenge of designing successful vaccines against reinfection.

Key Concepts

  • Congenital infection with CMV is the most common congenital viral infection and is responsible for a wide range of birth defects, including sensorineural hearing loss, mental retardation and developmental delay.
  • Primary infection with CMV during pregnancy confers the greatest risk of foetal transmission, but recurrent infections are also common, and these infections can also lead to transmission of CMV with attendant disabilities.
  • Immunity to CMV is complex, and involves both cellular and humoral immune responses.
  • CMV encodes immune evasion genes that complicate the development of protective immunity, help promote reinfection and create challenges for vaccine design.
  • A vaccine for congenital CMV is a major public health priority, but no licenced vaccines exist.
  • Key targets of the humoral immune response to CMV and the cellular immune response include envelope glycoproteins, particularly gB and the PC proteins, and the pp65 and IE1 proteins, respectively.
  • Several clinical trials of both live, attenuated CMV vaccines and subunit vaccines based on recombinant and/or vectored expression of specific immunogens have been conducted.
  • Modest protection against CMV infection has been demonstrated by a recombinant, adjuvanted gB protein subunit vaccine, although the magnitude and duration of protection were suboptimal.
  • Greater public awareness of congenital CMV is required to help drive efforts to develop and licence a protective vaccine.

Keywords: cytomegalovirus vaccines; glycoprotein B; pp65; congenital cytomegalovirus infection; pentameric complex

Figure 1. CMV entry into different cell types involves distinct and unique pathways and different glycoprotein complexes. Entry into fibroblasts requires glycoproteins gH/gL (left side of figure) and occurs by fusion with the plasma membrane. In contrast, entry into endothelial and epithelial cells requires the pentameric complex (PC), a glycoprotein complex consisting of subunits encoded by gH/gL/UL128/UL130/UL131 (right‐hand side of the figure). This is mediated by endosomes. Antibody to the PC neutralises infectivity via this pathway and accordingly the PC has emerged as a novel vaccine target for CMV vaccine design. Modified from Vanarsdall and Johnson, 2012 © Elsevier.
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Schleiss, Mark R(Jun 2016) Current Status of Cytomegalovirus Vaccines: 2016. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024788]