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Characterization of CMV Reinfection by Different Strains Using Ultra High-Dimensional Serology

Abstract Summary

Background: Congenital CMV infection (cCMV) has been associated with maternal reinfection during pregnancy, as defined by the acquisition of new CMV strain-specific antibody responses using an assay that distinguishes 16 different serotypes (4 epitopes: one from glycoprotein (g)B and another from gH, from 2 CMV strains). However, CMV exhibits high variability, and the true frequency of reinfection is unclear. Methods: We developed a phage-display immunoprecipitation sequencing (PhIP-Seq) assay, called "CMV-Scan", which consists of a library of ~400,000 CMV peptide sequences representing all reported genomic variants. We tested samples from eight pregnant women, comparing CMV-Scan responses between the 1st and 3rd trimesters: three women displaying evidence of reinfection by conventional strain-specific-ELISA, and five who did not but who presented with detectable CMV viremia during pregnancy and/or gave birth to an infant with cCMV. Positive CMV-Scan responses were defined as >50-fold enrichment of a given peptide compared to control (mock) immunoprecipitation. Results: As expected, the majority of CMV-Scan responses targeted surface and tegument proteins, but a wide spectrum of patterns was found among participants with respect to the proteins targeted and the strength of responses. Strain-specific gB and gH responses detected by ELISA were corroborated by CMV-Scan in all samples. In addition, CMV-Scan identified the acquisition of numerous responses during pregnancy in other regions of gB and gH, and in other CMV proteins. Among the five women without reinfection detected by strain-specific-ELISA, four (80%) acquired new antibody responses during pregnancy to at least one variant CMV antigen. Conclusion: CMV-Scan is a sensitive and comprehensive method to characterize CMV-specific antibody responses and identify the antigenic variants responsible for past (re)infections. Our findings suggest that CMV reinfection during pregnancy is more common than previously acknowledged, providing crucial insights into the pathogenesis of CMV reinfection and cCMV. These insights may inform CMV vaccine development strategies.

Learning Objectives

• Estimate the rate of maternal reinfection during pregnancy
• Characterise the scope and magnitude of the CMV-specific antibody response
• Compare the results between HIV-positive and HIV-negative mothers

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