Reduced control of SARS-CoV-2 infection associates with lower mucosal antibody responses in pregnancy

Abstract

Pregnant patients are at greater risk of hospitalization with severe COVID-19 than non-pregnant people. This was a retrospective observational cohort study of remnant clinical specimens from patients who visited acute care hospitals within the Johns Hopkins Health System in the Baltimore, MD-Washington DC, area between October 2020 and May 2022. Participants included confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant people and matched non-pregnant people (the matching criteria included age, race/ethnicity, area deprivation index, insurance status, and vaccination status to ensure matched demographics). The primary dependent measures were clinical COVID-19 outcomes, infectious virus recovery, viral RNA levels, and mucosal anti-spike (S) IgG titers from upper respiratory tract samples. A total of 452 individuals (117 pregnant and 335 non-pregnant) were included in the study, with both vaccinated and unvaccinated individuals represented. Pregnant patients were at increased risk of hospitalization (odds ratio [OR] = 4.2; confidence interval [CI] = 2.0-8.6), intensive care unit admittance (OR = 4.5; CI = 1.2-14.2), and being placed on supplemental oxygen therapy (OR = 3.1; CI = 1.3-6.9). Individuals infected during their third trimester had higher mucosal anti-S IgG titers and lower viral RNA levels (P < 0.05) than those infected during their first or second trimesters. Pregnant individuals experiencing breakthrough infections due to the Omicron variant had reduced anti-S IgG compared to non-pregnant patients (P < 0.05). The observed increased severity of COVID-19 and reduced mucosal antibody responses particularly among pregnant participants infected with the Omicron variant suggest that maintaining high levels of SARS-CoV-2 immunity through booster vaccines may be important for the protection of this at-risk population.IMPORTANCEIn this retrospective observational cohort study, we analyzed remnant clinical samples from non-pregnant and pregnant individuals with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who visited the Johns Hopkins Hospital System between October 2020 and May 2022. Disease severity, including intensive care unit admission, was greater among pregnant than non-pregnant patients. Vaccination reduced recovery of infectious virus and viral RNA levels in non-pregnant patients, but not in pregnant patients. In pregnant patients, increased nasopharyngeal viral RNA levels and recovery of infectious virus were associated with reduced mucosal IgG antibody responses, especially among women in their first trimester of pregnancy or experiencing breakthrough infections from Omicron variants. Taken together, this study provides insights into how pregnant patients are at greater risk of severe COVID-19. The novelty of this study is that it focuses on the relationship between the mucosal antibody response and its association with virus load and disease outcomes in pregnant people, whereas previous studies have focused on serological immunity. Vaccination status, gestational age, and SARS-CoV-2 omicron variant impact mucosal antibody responses and recovery of infectious virus from pregnant patients.

Keywords: COVID-19; Delta variant; Omicron variant; breakthrough infection; gestation.

Fig 1

SARS-CoV-2 viral RNA levels and antibody responses stratified by pregnancy and vaccination status. Remnant clinical upper respiratory tract specimens were used to determine rates of infectious virus recovery (A), viral RNA level (B), and anti-S (ancestral) IgG titers calculated as AUC (C) from mucosal swab samples. In panel A, a positive CPE in tissue culture was indicative of the presence of infectious virus. The dashed line in panel B represents the cutoff value (Ct ≤ 20) between high viral RNA and low viral levels, and the red text indicates the percentage of participants with Ct values > 20 (low viral RNA levels). The dashed line in panel C represents the limit of detection, and the red text indicates the percentage of non-responders (results below the limit of detection). Multivariable logistic regression was used to analyze the association between anti-spike IgG AUC and infectious virus-positive cultures (D) or viral RNA levels (E). Variables were continuous, and comparisons by vaccination and pregnancy status are shown. Analysis included Fisher’s exact test (A), two-way ANOVAs with Tukey’s multiple comparisons test (B and C), and multivariable logistic regression (E). ^*P < 0.05. anti-S IgG, anti-ancestral strain spike immunoglobulin G.

Fig 2

The effects of gestational age on mucosal viral RNA levels and antibody responses. Study participants were divided into unvaccinated and vaccinated pregnant patients according to the trimester of pregnancy and analyzed to assess differences in viral RNA levels (A) and anti-S IgG AUC (B). The red text indicates the percentage of individuals with recoverable infectious virus (A) or the percentage of IgG non-responders (i.e., those with anti-S IgG AUC below the limit of detection; B). Two-way ANOVA with Tukey’s multiple comparisons test. ^*P < 0.05.

Fig 3

Analysis of mucosal viral RNA levels and antibody responses to Delta and Omicron breakthrough infections during pregnancy. Samples were classified according to infecting strain (Delta or Omicron), pregnancy status, and vaccination status and reanalyzed to assess differences in viral RNA level (A) and anti-S (ancestral/vaccine strain) IgG AUC (B). Two-way ANOVA with Tukey’s multiple comparisons tests (A and B). ^*P < 0.05.