2022 Early Hearing Detection & Intervention Virtual Conference
March 13 - 15, 2022
9/25/2018 | 12:00 PM - 12:30 PM | The Pentameric Complex (PC) is Not Required for Successful Vaccination Against Congenital CMV Infection in a Guinea Pig Model: Lessons and Perspectives for Human Clinical Trials | Emerald Ballroom I/II
The Pentameric Complex (PC) is Not Required for Successful Vaccination Against Congenital CMV Infection in a Guinea Pig Model: Lessons and Perspectives for Human Clinical Trials
A vaccine against congenital CMV (cCMV) infection is a major public health priority. The live, attenuated Towne vaccine demonstrated suboptimal efficacy in clinical trials, possibly based on loss of expression of the pentameric complex (PC) made up of proteins gH-gL-UL128-130-131A. To clarify the importance of the homologous PC encoded by guinea pig cytomegalovirus (GPCMV) in a cCMV vaccine, PC-intact and PC-deficient live, attenuated vaccines were analyzed for immunogenicity and protective efficacy in a vertical transmission study. A point mutation in GP129 (UL128 homolog), generated by galK mutagenesis in a GPCMV BAC, abrogated PC expression. PC/null and wild-type, PC/intact BAC-derived viruses were compared in a two-dose preconception vaccine regimen, via subcutaneous inoculation of 24 GPCMV-seronegative Hartley guinea pigs (n=12/group). Controls were sham-immunized. ELISA titers in the PC/intact group (GMT 13,669) were significantly higher than the PC/null group (GMT 8,127, p<0.01). Dams were challenged with virulent salivary-gland GPCMV in the second trimester, and pregnancy outcomes compared. Remarkably, both vaccines conferred near-complete sterilizing immunity against maternal viremia. Newborn weights were significantly lower in control pups (84±2.5g) compared to PC/intact (98.6±2g) or PC/null (96±2.3g) pups (both p<0.01). Pup mortality in controls was 26/40 (65%), reduced to 1/44 (2%) and 2/46 (4%) in PC/intact and PC/null groups (p<0.001). Congenital GPCMV transmission occurred in 5/44 (11%) and 16/46 (35%) pups in PC/intact and PC/null groups, versus 36/40 (90%) in controls (p<0.0001). Strikingly, parallel study of a three-dose series of MVA-vectored gB vaccine also demonstrated reduced pup mortality, but was associated with significantly higher cCMV transmission (17/31; 55%). We conclude that in the GPCMV model, sterilizing immunity against cCMV is more effectively conferred by live-attenuated virus vaccination than by gB-based vaccine. Moreover, protection against cCMV does not require a functional PC. Recommendations regarding how GPMCV studies can help inform and direct cCMV vaccine trials will be discussed.
- Understand how guinea pigs, as well as other animal models, can serve as valuable tools for validating vaccine approaches for prevention of maternal viremia and subsequent fetal CMV infection.
- Compare the relative efficacy and protectiveness of vectored glycoprotein vaccines with live, attenuated vaccines - generated by mutagenesis of the viral genome in bacterial artificial chromosome (BAC) systems - in the guinea pig model of congenital CMV infection.
- Discuss how these data can be put into a broader perspective of various preclinical studies and active clinical trials of human CMV vaccines currently in development.
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Presenters/Authors
Mark R. Schleiss
(), schleiss@umn.edu ;
Dr. Schleiss is a Professor of Pediatrics and holds the American Legion and Auxiliary Endowed Research Chair at the University of Minnesota Medical School. His laboratory is supported by the NIH and March of Dimes Birth Defects Foundation. He conducts research in small animal models testing vaccine strategies against congenital CMV infection. His laboratory is also engaged in the study of the epidemiology, pathogenesis and management of congenital and neonatal CMV infections.
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Michael McVoy
(), michael.mcvoy@vcuhealth.org;
Dr. McVoy is a Professor of Pediatrics at Virginia Commonwealth University School of Medicine in the Division of Pediatric Infectious Diseases. His laboratory is supported by the NIH and his research program focuses on CMV vaccines, molecular and cellular correlates of protection against CMV, and vaccine and antiviral strategies to protect against congenital CMV infection.
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