An Attenuated CMV Vaccine with a Deletion in Tegument Protein GP83 (pp65 Homolog) Protects against Placental Infection and Improves Pregnancy Outcome in a Guinea Pig Challenge Model.
OBJECTIVE
Congenital human cytomegalovirus (HCMV) infection can lead to long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Preconception vaccine strategies relevant to prevention of HCMV-mediated injury to the newborn can be studied in the guinea pig cytomegalovirus (GPCMV) model. The objectives of this study were: 1) to assess in guinea pigs the protective efficacy against congenital infection and disease of a recombinant live, attenuated vaccine with a targeted deletion of the GPCMV homolog of the HCMV pUL83 tegument protein, GP83; and, 2) to compare the extent of placental infection in vaccine and control groups, using anin situhybridization (ISH) assay.


METHODS
Outbred Hartley guinea pigs were vaccinated prior to pregnancy with a two-dose series of 5×104pfu of vAM409, a GP83 deletion virus. Deletion of the GP83 gene resulted in an attenuated virus, and vAM409 vaccinated animals did not demonstrate evidence of DNAemia following vaccination, although ELISA antibody responses were comparable to those observed in natural infection. After mating, pregnant animals were challenged with salivary gland-adapted (SG) GPCMV (1×106pfu) in the second trimester, and pregnancy outcomes were compared to controls.


RESULTS
Compared to placebo-immunized controls, vaccination resulted in significantly reduced maternal DNAemia following SG challenge, and there was significantly decreased pup mortality in litters born to vaccinated dams (3/29; 10%), compared to control (35/50; 70%; p<0.001). Byin situhybridization study, recovered placentas in the vAM409 vaccine group demonstrated reduced infection and fewer infectious foci compared to the control group.


CONCLUSIONS
In summary, preconception immunization with a GP83 deletion vaccine reduced maternal DNAemia and results in protection against congenital GPCMV-associated pup mortality compared to unvaccinated controls. Vaccination resulted in reduced placental infection, probably related to the reduction in maternal DNAemia. Although the pp65 homolog in GPCMV, GP83, is a known target of protective T cell immune responses, it is nevertheless dispensable for effective vaccination against maternal and fetal CMV disease in this model.
University of Minnesota Medical School, Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, 2001 6 Street SE, Minneapolis, MN 55455-3007.
Mark R
MR
Schleiss
University of Minnesota Medical School, Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, 2001 6 Street SE, Minneapolis, MN 55455-3007.
Ryan
R
Buus
University of Minnesota Medical School, Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, 2001 6 Street SE, Minneapolis, MN 55455-3007.
K Yeon
KY
Choi
University of Minnesota Medical School, Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, 2001 6 Street SE, Minneapolis, MN 55455-3007.
Alistair
A
McGregor
CMV UL83; CMV pp65; Cytomegalovirus; Cytomegalovirus vaccine; GPCMV GP83; Guinea pig challenge model; Guinea pig cytomegalovirus; Live; Vaccine efficacy; attenuated CMV vaccine; cytomegalovirus immune evasion