Biology Reference
In-Depth Information
Live, Attenuated HCMV Vaccines
HCMV has been the target of live, attenuated vaccine development efforts since the
1970s (reviewed in Schleiss and Heineman 2005). The first live, attenuated HCMV
vaccine candidate tested in humans was based on the laboratory-adapted AD169
strain. Subsequent trials with another laboratory-adapted clinical isolate, the Towne
strain, confirmed that live attenuated vaccines could elicit neutralizing antibodies,
as well as CD4
+
and CD8
+
T lymphocyte responses. The efficacy of Towne vaccine
was tested in a series of studies in renal transplant recipients. Although Towne
failed to prevent HCMV infection after transplantation, vaccination did provide a
protective impact on HCMV disease (Plotkin et al. 1994). Towne vaccine was also
evaluated in a placebo-controlled study in seronegative mothers who had children
attending group daycare. This study indicated that immunization with Towne failed
to protect these women from acquiring HCMV infection from their children. The
apparent failure of Towne vaccine was in contrast to the protection against reinfec-
tion observed in women with preexisting immunity, who were protected against
acquiring a new strain of HCMV from their children (Adler et al. 1995). One inter-
pretation of this study is that a HCMV vaccine that induced immune responses
comparable to natural infection could provide protection of a high-risk patient pop-
ulation, but that the Towne vaccine may be overattenuated for this purpose. The
molecular basis for the apparent overattenuation of the Towne vaccine remains
unknown. Recent evidence suggests that the relative defect in Towne vaccine may
be related to inadequate antigen-specific interferon gamma responses by CD4
+
and
CD8
+
cells following vaccination (Jacobsen et al. 2006a). An approach to improve
the immunogenicity of the Towne vaccine is currently being explored, in which
recombinant interleukin-12 (rhIL-12) is co-administered with Towne vaccine. The
adjuvant effect of rhIL-12 was associated with increases in antibody titer to glyco-
protein B and improved CD4
+
T cell proliferation responses in this recently reported
phase I study(Jacobsen et al. 2006b).
Another approach to improve the immunogenicity of the Towne vaccine has
recently been reported, in which a series of genetic recombinant vaccines were
generated containing regions from the genome of the unattenuated Toledo strain of
HCMV, substituted for the corresponding regions of the Towne genome (see the
chapter by E. Murphy and T. Shenk, this volume). These Towne/Toledo chimeras
retain some, but not all, of the mutations that apparently contribute to Towne
vaccine attenuation and were hypothesized to be less attenuated, and hence
presumably more immunogenic, than the Towne vaccine. Four independent
chimeric vaccines were produced and tested in a double-blinded, placebo-controlled
study (Heineman et al. 2006). All of the vaccines were well tolerated, and none
were shed by vaccinees, as assessed by viral culture and PCR analyses of blood and
body fluids. Thus, these vaccines are sufficiently attenuated to warrant future stud-
ies in seronegative individuals. Concerns about the potential risk of establishing a
latent HCMV infection have hindered the progress of live, attenuated vaccine stud-
ies, although to date there has been no evidence that any of these approaches have
resulted in latent or persistent infections in any subject.
