Biology Reference
In-Depth Information
HCMV gB, based on the AD169 strain sequence (Wang et al. 2004). In preclinical
studies, high levels of gB-specific neutralizing antibodies, equivalent to those
induced by natural HCMV infection, were induced in immunized mice. Recombinant
MVA have similarly been generated expressing pp65 and IE1, and are capable of
inducing robust cell-mediated immune responses in preclinical studies in mice.
A trivalent MVA expressing gB, pp65, and IE1 has been developed and proposed
for clinical studies (Wang et al. 2006).
Another vectored vaccine approach that has been pursued in preclinical studies
is that of utilization of a recombinant adenovirus vector for expression of HCMV
subunit vaccine candidates. The observation that a recombinant adenovirus vaccine
expressing the related murine CMV (MCMV) gB demonstrated protection in a
mouse model of MCMV disease provides support for further studies of this strategy
in human clinical trials (Shanley and Wu 2003).
In addition, HCMV gB has been successfully expressed in transgenic plants
(Tackaberry et al. 1999), offering the possibility of a novel vaccination approach
through oral/mucosal immunization.
Potential Role of Other Viral Proteins in HCMV Vaccine Design
As noted, most efforts in clinical trials of candidate subunit HCMV vaccine devel-
opment and testing have focused on the envelope glycoprotein gB and the T cell
targets, pp65 and IE1. However, a plethora of other HCMV-encoded proteins play
key roles in the host immune response and these warrant consideration in future
clinical trials. To date, only animal model data are available to validate the potential
role of these proteins as vaccines. This information is summarized in Table 3.
HCMV Glycoproteins
In addition to gB, other envelope glycoproteins have been considered for vaccine
development, although to date no candidates have been tested in human trials.
Among the other HCMV glycoproteins, the gcII complex, consisting of gN
(UL73) and gM (UL100), is of particular interest. Proteomic analyses of the
HCMV virion have demonstrated that gcII is the most abundantly expressed glyc-
oprotein in virus particles, emphasizing its potential importance in protective
immunity (Varnum et al. 2004). HCMV infection elicits a gcII-specific antibody
response in a majority of seropositive individuals (Shimamura et al. 2006), and
DNA vaccines consisting of gcII antigens gM and gN are able to elicit neutralizing
antibody responses in rabbits and mice (Shen et al. 2007).
Constituents of the gcIII complex, consisting of glycoproteins gH (UL75), gO
(UL74), and gL (UL115), are also targets of neutralizing antibody responses, and
these proteins may also merit consideration in future vaccine studies. Recently the
Shenk and Koszinowski laboratories have shown that there are two gH/gL
