Project Details
Description
ABSTRACT
Development of an effective preventative vaccine against human cytomegalovirus (HCMV) for women of
childbearing age is a major public health priority. Subunit vaccines are in clinical trials, but uncertainty exists
about optimal platforms and correlates of protection. Live, attenuated vaccines may induce a broader
repertoire of immune responses, but striking the balance between safety and immunogenicity is challenging.
The long-term goal of this ongoing collaboration is to use the guinea pig cytomegalovirus (GPCMV) model to
test hypotheses about optimal design of safe and effective vaccines against congenital infection. We recently
discovered that inclusion of a pentameric complex (PC), consisting of the GPCMV gH, gL and GP129, 131 and
133 (homologs of the HCMV PC), enabled generation of a live, attenuated vaccine that was protective against
congenital GPCMV transmission, but the vaccine was unacceptably virulent. In parallel studies we observed
that viral challenge of pregnant dams with preconception immunity to the prototypical GPCMV strain 22122
with a heterologous `clinical isolate', the CIDMTR strain, resulted in both maternal re-infection and congenital
transmission of the new challenge strain. These findings, as well as clinical observations in HCMV-infected
women, suggest that a vaccine may need to perform better than `natural immunity' in order to protect against
reinfection. We hypothesize that a rationally designed, PC-intact, but disabled infectious single cycle (DISC)
vaccine will provide superior protective immunity, including against re-infection, compared to subunit gB and to
`natural' immunity. In Aim 1, we test this hypothesis by comparing a PC-positive vaccine, attenuated by
deletions of GPCMV-encoded MHC I homologs and a viral protein kinase R (PKR) evasin, versus MF59-
adjuvanted recombinant gB. We will examine the magnitude of protection after both primary maternal infection
and re-infection of dams with preconception immunity following challenge with a heterologous strain during
pregnancy. We will further optimize CMV vaccines in Aim 2 by developing DISC vaccines, using a PC-intact
virus with destabilizing domains fused to essential viral proteins. In contrast to HCMV vaccines in clinical trials,
we hypothesize that DISC vaccines in which viral replication is blocked downstream of DNA replication will
progress to late gene expression and produce a broader array of immunogenic proteins. Aim 3 will evaluate
whether deletion of viral antagonists of host cell defenses such as protein kinase R (PKR) can aid in vaccine
design. We will test the hypothesis that GPCMV encodes a second PKR antagonist, elimination of which would
be expected to generate a safe and effective vaccine. In addition, we will overexpress dsRNA in the vaccine
construct with the aim of improving safety and immunogenicity. Vaccines will be evaluated for attenuation and
immunogenicity and optimized vaccines will be used to identify immune correlates of protection, including non-
neutralizing functions of IgG. Our studies will explore the overarching hypothesis that immunity conferred by a
CMV vaccine can be superior to `natural' preconception immunity, a highly relevant issue for HCMV vaccines.
Status | Active |
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Effective start/end date | 9/1/19 → 5/31/24 |
Funding
- National Institute of Child Health and Human Development: $629,164.00
- National Institute of Child Health and Human Development: $689,044.00
- National Institute of Child Health and Human Development: $635,993.00
- National Institute of Child Health and Human Development: $655,748.00
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