Immunological profile of pregnant women with preconception immunity with or without vertical transmission of human cytomegalovirus to the fetus: a retrospective observational study

Background: Vertical transmission of human cytomegalovirus (CMV) to the fetus (congenital CMV infection) can occur in pregnant women with preconception immunity. Maternal immunological features associated with congenital CMV infection have been poorly investigated. We aimed to characterise the immunological features of pregnant women with preconception immunity in cases with and without vertical transmission of human CMV to the fetus. Methods: In this retrospective cohort study, we included pregnant women (aged >18 years) with preconception immunity enrolled between Sept 1, 2017, and Oct 15, 2020, in the Congenital Human Cytomegalovirus Infection in Lombardy (CHILd) study (Italy) with (congenital CMV group) and without (no-congenital CMV group) intrauterine human CMV transmission. Blood was collected at 13 weeks of gestation and at delivery. The following immune parameters were measured and compared between groups: serum neutralising titres, antibody-dependent cell cytotoxicity, human CMV-specific long-term memory T cells (interleukin [IL]-7R+ and IL-2+), and effector memory CD45RA+ (TEMRA) cells. Immune parameters were also compared with those of two groups of pregnant women with human CMV primary infection enrolled at Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) in two previous studies: primary infection group 1 for antibody response (followed up for 12 months; enrolled between Feb 23, 2011, and Sept 1, 2015,) and primary infection group 2 for T-cell response (followed up for 24 months; enrolled between July 10, 2016, and March 18, 2020). Findings: 128 women were included in this study: 56 women from the CHILd study (16 women in the congenital CMV group and 40 women in the no-congenital CMV group) and 72 pregnant women with primary infection (40 in primary infection group 1 [15 with and 25 without vertical transmission] and 32 in primary infection group 2 [11 with and 21 without vertical transmission]). Higher neutralising activity (p≤0·022) but lower antibody-dependent cell cytotoxicity (p=0·0004) was observed in the congenital CMV group versus the no-congenital CMV group. Additionally, the congenital CMV group had a lower percentage of long-term memory T cells than the no-congenital CMV group (p≤0·022). No significant difference was found for TEMRA cells between congenital CMV and no-congenital CMV groups. Immunological parameters of the congenital CMV group were similar to those observed in primary infection groups 1 and 2 within 12–24 months after infection. Interpretation: Immune women with intrauterine human CMV transmission have distinct immunological parameters (different from immune women without CMV transmission, but similar to women with primary infection) and might be those who had a primary human CMV infection within a few years earlier before maternal immunity development was completed. A vaccine able to elicit a fully developed maternal immunity to human CMV is likely to be protective for the fetus.