Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women

Abstract

Importance: Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in these populations are therefore limited.

Objective: To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern.

Design, setting, and participants: An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection.

Main outcomes and measures: SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine-staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants.

Results: This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants.

Conclusion and relevance: In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.

Figure 1.. SARS-CoV-2 Binding and Functional Antibody Responses in Serum From Vaccinated and Unvaccinated, Infected Pregnant, Lactating, and Nonpregnant Women

This figure presents serum binding and functional antibody responses following COVID-19 vaccination and SARS-CoV-2 infection among women 45 years or younger. A and B, Each panel compares vaccine antibody responses at 2 through 8 weeks after the second dose to nonpregnant and pregnant women who were unvaccinated and infected. Thirteen women (7 nonpregnant, 4 pregnant, and 2 lactating) who had baseline samples collected within 7 days of their first vaccine dose were selected based on the earliest sample availability and were analyzed as a negative assay control. C, D, and E, Systems serology was used to quantify spike-specific antibody–dependent neutrophil phagocytosis (ADNP), antibody–dependent complement deposition (ADCD), and antibody–dependent monocyte cellular phagocytosis (ADCP). For an explanation of antibody binding, neutralizing, and systems serology assays see Table 2. The red bars indicate the median; the dotted lines in panels A and B, the limit of detection; C3, complement component 3; NT50, neutralizing antibody titer serum dilution.

Figure 2.. SARS-CoV-2 Binding and Neutralizing Antibody Responses in Infant Cord Blood and Breast Milk From Women Following Vaccination or Infection

A and B, The paired sera samples from maternal blood and cord blood at delivery were used to measure transplacental transfers of the SARS-CoV-2 receptor binding domain (RBD) and binding neutralizing antibody levels after 2 doses of vaccines compared with levels in women who were not vaccinated but were infected with SARS-CoV-2. C, D, and E, Paired sera samples and breast milk from lactating participants were used to assess IgG and IgA RBD binding antibody and neutralizing antibody levels and compare them between women who were vaccinated and women who were not vaccinated but were infected with SARS-CoV-2. Three participants (green data points) were vaccinated during pregnancy and provided breast milk in the immediate postpartum period. These 3 participants are included as vaccinated in the figure and are included in Table 1 with the pregnant group. An explanation of binding and neutralizing assays can be found in Table 2. The red bars indicate the median and the dotted lines, the limit of detection.

Figure 3.. SARS-CoV-2 Spike–Specific Cellular Immune Responses in Vaccinated Pregnant, Lactating, and Nonpregnant Women

Peripheral blood mononuclear cells (PBMCs) following 2 doses of vaccines were stimulated with SARS-CoV-2 USA-WA1/2020 spike peptides. The T-cell responses were measured using IFN-γ enzyme-linked immunospot (ELISPOT) assays and multiparameter intracellular cytokine staining assays to assess IFN-γ total CD4 T cells, CD45RA⁻ CD27⁺ central memory CD4 T cells, total CD8 T cells, and CD45RA⁻ CD27⁺ central memory CD8 T cells. The red bars indicate the median and the dotted lines, the limit of detection. See Table 2 for an explanation of ELISPOT and ICS assays.

Figure 4.. Vaccine-Elicited Humoral and Cellular Immune Responses Against SARS-CoV-2 Variants of Concern

Serum receptor binding domain (RBD) IgG binding antibody titers and neutralizing antibody titers (NT50) were compared with SARS-CoV-2 wild-type USA-WA1/2020 and variants of concern B.1.1.7 and B.1.351 following 2 doses of vaccines, as well as in cord blood and in breast milk. Peripheral blood mononuclear cells (PBMCs) were stimulated with SARS-CoV-2 wild-type USA-WA1/2020, B.1.1.7, and B.1.351 spike peptides. IFN-γ T-cell responses were measured using enzyme-linked immunospot (ELISPOT) assays and multiparameter intracellular cytokine staining assays gated on total CD4 T cells, CD45RA⁻CD27⁺ central memory CD4 T cells, total CD8 T cells, and CD45RA⁻ CD27⁺ central memory CD8 T cells. The red bars indicate the median and the dotted lines, the limit of detection. See Table 2 for an explanation of antibody binding and neutralizing assays and ELISPOT and ICS assays.