Biology Reference
In-Depth Information
epitopes. This approach may ultimately prove to be most useful in the vaccine-
mediated prevention of HCMV disease in the transplant setting, where specific
peptide vaccine regimens could be tailored for donor-recipient pairs based on HLA
genetics. Nasal peptide vaccination with the immunodominant MCMV IE1 epitope,
YPHFMPTNL, in combination with cholera toxin adjuvant, protected mice against
virulent MCMV challenge (Gopal et al. 2005). In a preclinical study relevant to
HCMV vaccines, a pp65 human leukocyte antigen (HLA)-A2.1-restricted CTL
epitope corresponding to an immunodominant region spanning amino acid residues
495-503, fused to the carboxyl terminus of a pan-DR T-help epitope, was capable
of eliciting CTL responses from mice transgenic for the same human HLA mole-
cule (BenMohamed et al. 2000). Since this epitope is highly conserved in clinical
isolates, this vaccine could conceivably be broadly protective against multiple
HCMV strains. Other peptide-based vaccine studies are envisioned in future clini-
cal trials. A subset of epitopes from a group of important CTL targets has been
nominated for inclusion in a polyepitope HCMV vaccine on the basis of human
immune responsiveness and population coverage (Khanna and Diamond 2006).
Novel Vaccine Approaches
Several other vaccination approaches have been proposed for HCMV and have been
validated in varying degrees in animal models. One approach is based on exploita-
tion of viral genomes cloned in
Escherichia coli
as bacterial artificial chromosomes
(BACs). Vaccination of mice with bacteria containing the MCMV genome cloned as
a BAC conferred protective immunity against subsequent challenge (Cicin-Sain et al.
2003). In guinea pigs, a noninfectious BAC generated by transposon mutagenesis
induced immune responses that protected against congenital GPCMV infection and
disease (Schleiss et al. 2006). Given the ease of manipulation of BACs using
mutagenesis techniques available for
E. coli
, future BAC studies provide the oppor-
tunity to generate recombinant, designer vaccines with specific genomic deletions or
insertions that could modify the immune response or improve the safety profile of
the candidate vaccine. Such modified BACs are being employed as immunocontra-
ceptive vaccines for population control in mice, with insertion of heterologous pro-
teins that can serve as targets for immune responses that result in decreased fertility
in vaccinated animals (Hardy 2007).
Another novel strategy that has been validated in the MCMV model and
proposed for clinical trial evaluation is a prime-boost approach, in which priming
with DNA vaccination is followed by boosting with formalin-inactivated viral
particles. Mice were immunized with a cocktail of 13 MCMV-containing plasmids
followed by boosting with formalin-inactivated, alum-adjuvanted MCMV. This
approach elicited high levels of neutralizing antibodies as well as CD8
+
T cells
specific for the virion-associated antigen (Morello et al. 2002). Subsequent studies
examined whether similar protection levels could be achieved by priming with a
pool of plasmids encoding MCMV proteins IE1, M84, and gB. This approach was
