Biology Reference
In-Depth Information
DNA vaccines are currently formulated using the poloxamer adjuvant, CRL1005
and benzalkonium chloride. In a phase I trial using a bivalent vaccine consisting
of gB and pp65 (see the next section), 1-mg and 5-mg doses were studied in
HCMV-seropositive and -seronegative subjects, and appeared to be safe and
well tolerated (Evans et al. 2004; R. Moss, personal communication). There is
currently an ongoing multicenter study in HSC patients of this adjuvanted
bivalent HCMV DNA vaccine, toward the goal of reducing HCMV viremia and
disease in this high-risk patient population.
pp65 (ppUL83) Vaccines
The cellular immune response to HCMV infection includes MHC class II restricted
CD4 + and MHC class I restricted, cytotoxic CD8 + T lymphocyte responses to a number
of viral antigens, many of which are found in the viral tegument, the region of the viral
particle that lies between the envelope and nucleocapsid (see the chapter by R. Kalejta,
this volume). For vaccination strategies aimed at eliciting T cell responses, most atten-
tion has focused on the pp65 protein (ppUL83). This is in part based on the apparent
dominance of pp65 in the cellular immune response to HCMV: this protein elicits the
majority of CD8 + T lymphocyte responses following HCMV infection (McLaughlin-
Taylor et al. 1994; Wills et al. 1996). The observation that adoptive transfer of pp65-
specific CTL ameliorates HCMV disease in high-risk transplant patients provides
further support for the study of pp65-based vaccines (Walter et al. 1995).
Many of the same expression strategies described for development of candidate gB
vaccines in clinical trials have been employed for generation of pp65-based vaccines.
An ALVAC vaccine expressing pp65 was administered to HCMV seronegative adult
volunteers in a placebo-controlled trial (Berencsi et al. 2001). The ALVAC/pp65 recipi-
ents developed HCMV-specific CD8 + CTL responses at frequencies comparable to
those seen in naturally seropositive individuals. A pp65-based alphavirus/VRP vaccine
has also been developed, using the approach described above for VRP-gB (Reap et al.
2007). Support for a VRP-pp65 vaccine approach was garnered in a recent guinea pig
study, in which the guinea pig CMV (GPCMV) homolog of pp65, the GP83 gene prod-
uct, was studied as a vaccine against congenital GPCMV infection. In this study, the
VRP-GP83 vaccine improved pregnancy outcomes and reduced maternal viral load
following early third-trimester viral challenge (Schleiss et al. 2007). The VRP-pp65
vaccine has entered phase 1 trials in humans, administered in a trivalent formulation
with gB and IE1 (UL123) VRPs. As noted above, pp65 has also been expressed in a
DNA vaccine, and is currently being evaluated in a phase II study in BMT recipients,
co-administered in a bivalent formulation with gB DNA vaccine.
IE1 Vaccines
Based on the observation that the HCMV IE1 gene is an important target of the
CD8 + T cell response to HCMV infection, with IE1-specific responses being
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