Pregnant Women Develop a Specific Immunological Long-Lived Memory Against SARS-COV-2

Abstract

It is well established that pregnancy induces deep changes in the immune system. This is part of the physiological adaptation of the female organism to the pregnancy and the immunological tolerance toward the fetus. Indeed, over the three trimesters, the suppressive T regulatory lymphocytes are progressively more represented, while the expression of co-stimulatory molecules decreases overtime. Such adaptations relate to an increased risk of infections and progression to severe disease in pregnant women, potentially resulting in an altered generation of long-lived specific immunological memory of infection contracted during pregnancy. How potent is the immune response against SARS-CoV-2 in infected pregnant women and how long the specific SARS-CoV-2 immunity might last need to be urgently addressed, especially considering the current vaccinal campaign. To address these questions, we analyzed the long-term immunological response upon SARS-CoV-2 infection in pregnant women from delivery to a six-months follow-up. In particular, we investigated the specific antibody production, T cell memory subsets, and inflammation profile. Results show that 80% developed an anti-SARS-CoV-2-specific IgG response, comparable with the general population. While IgG were present only in 50% of the asymptomatic subjects, the antibody production was elicited by infection in all the mild-to-critical patients. The specific T-cell memory subsets rebalanced over-time, and the pro-inflammatory profile triggered by specific SARS-CoV-2 stimulation faded away. These results shed light on SARS-CoV-2-specific immunity in pregnant women; understanding the immunological dynamics of the immune system in response to SARS-CoV-2 is essential for defining proper obstetric management of pregnant women and fine tune gender-specific vaccinal plans.

Keywords: SARS-CoV-2; antibody; immunological memory; long term; pregnancy.

Figure 1

SARS-CoV-2-specific IgM and IgG measured in plasma collected at T0, T2, T4 and T24. The percentage of the positive subjects for IgM (grey) and IgG (black) is depicted throughout the timepoints in (A). The antibody titer expressed in AU/ml for IgM (grey) and IgG (black) is depicted throughout the timepoints in (B). The percentage of the positive subjects for IgG at T4 stratified by disease severity is depicted in (C). The antibody titer expressed in AU/ml for IgG at T4 stratified by disease severity is depicted in (D). The neutralization titer related to the IgG titer expressed in AU/ml is expressed in (E).

Figure 2

Flow cytometric analyses of memory subsets at T0, T2, T4 and T24 upon SARS-CoV-2 specific in-vitro stimulation of PBMCs. Percentages of naïve, central memory (T_CM), effector memory (T_EM) and effector memory re-expressing CD45RA (T_EMRA) T helper CD4+ and T cytotoxic CD8+ are depicted in (A, B), respectively. Mixed-effects model (REML) analysis showed a statistical significance of p=0.006 for the time effect on CD4+ cells, and p=0.058 for CD8+. Statistical significance obtained by multiple t Test analyses is reported in (C). p≤0.05 values are highlighted in bold.

Figure 3

mRNA expression of 74 genes involved in the inflammatory response at T0, T2, T4 and T24 upon SARS-CoV-2 specific in-vitro stimulation of PBMCs (A). Gene expression (nfold) is shown as a Colour scale from light to dark blue. Only the most relevant targets are shown in the table. Statistical significance obtained by multiple t Test analyses is reported in (B). p≤0.05 values are highlighted in bold.

Figure 4

A 27 cytokine/chemokine multiplex array was performed on a maternal plasma at T0, T2, T4 and T24 (A). Protein concentration is shown as pg/ml. Statistical significance obtained by multiple t Test analyses is reported in (B). p≤0.05 values are highlighted in bold. * p≤0.05.