Biology Reference
In-Depth Information
Subunit Vaccines
Subunit vaccine approaches emphasize specific immunogenic viral proteins,
expressed by a variety of techniques, and administered either singly or in combina-
tion. The candidate subunit vaccines that are in clinical or preclinical development
are described in the following sections, along with an overview of the expression
techniques being employed.
Glycoprotein B (gpUL55) Vaccine
The humoral immune response to HCMV is dominated by responses to viral glyco-
proteins, present in the outer envelope of the virus particle (see the chapters by
W. Gibson, this volume and M.K. Isaacson et al., this volume). Of these, the most
fully characterized is the glycoprotein complex I (gcI) consitisting of gB (gB;
UL55). All sera from HCMV-seropositive individuals contain antibodies to gB, and
up to 70% of the neutralizing antibody response is gB-specific (Britt et al. 1990).
Recombinant vaccines based on gB demonstrate efficacy against disease in murine
and guinea pig models of cytomegalovirus infection (Rapp et al. 1993; Schleiss
et al. 2004), providing further support for human efficacy testing. Accordingly, the
gB protein is the leading candidate for subunit vaccine development and testing and
the vaccine currently most actively studied in clinical trials.
One formulation of HCMV gB currently being explored in clinical trials is a
recombinant protein expressed in Chinese hamster ovary (CHO) cells. In contrast
to native gB, this formulation of gB is a truncated, secreted form of the protein,
modified in two ways to facilitate its expression and purification. First, the proteo-
lytic cleavage site, R-T-K-R, at which gB is normally cleaved into its amino and
carboxyl moieties, was modified to prevent cleavage of the protein; secondly, a
stop mutation was introduced prior to its hydrophobic transmembrane domain,
resulting in a truncated, soluble form of gB (Spaete 1991). The resulting secreted
protein is purified from CHO cell culture supernatants and used, with adjuvant, as
a vaccine. Purified recombinant gB vaccine has undergoing safety, immunogenicity,
and efficacy testing in several clinical trials. The first study of this vaccine was a
phase I randomized, double-blind, placebo-controlled trial, in adults, in which
recombinant gB was combined with one of two adjuvants, MF59 or alum (Pass
et al. 1999). Levels of gB-specific antibodies and total virus-neutralizing activity
after the third dose of vaccine exceeded those observed in HCMV-seropositive
controls. Antigen dose was evaluated in a phase I study of 95 HCMV-seronegative
adult volunteers (Frey et al. 1999), and the immunogenicity and safety of the vac-
cine has been studied in a limited number of toddlers (Mitchell et al. 2002). In all
studies reported to date, the safety profile of the vaccine has been favorable,
although injection-site discomfort has been observed. There is currently a double-
blinded, placebo-controlled phase II study of gB/MF59 vaccine ongoing in young
HCMV-seronegative women who are at high risk for acquisition of primary infec-
tion (Zhang et al. 2006). This study should provide insights into the potential
