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[Preprint]. 2023 Mar 20:2023.03.19.23287456.

doi: 10.1101/2023.03.19.23287456.

Reduced control of SARS-CoV-2 infection is associated with lower mucosal antibody responses in pregnant women

Laura A St Clair¹, Raghda E Eldesouki^{2

3}, Jaiprasath Sachithanandham¹, Anna Yin¹, Amary Fall², C Paul Morris^{2

4}, Julie M Norton², Michael Forman², Omar Abdullah², Santosh Dhakal¹, Caelan Barranta¹, Hana Golding⁵, Susan J Bersoff-Matcha⁶, Catherine Pilgrim-Grayson⁷, Leah Berhane⁷, Andrea L Cox^{1

8

9}, Irina Burd¹⁰, Andrew Pekosz^{1

8

11}, Heba H Mostafa², Eili Y Klein^{11

12}, Sabra L Klein^{1

8}

Affiliations

¹ W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
² Department of Pathology, Division of Medical Microbiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Medical Genetics Unit, Histology Department, School of Medicine, Suez Canal University, Egypt.
⁴ National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
⁵ Division of Viral Products, Center of Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁶ Office of Women's Health, U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁷ Division of Urology, Obstetrics, and Gynecology; Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine; Office of New Drugs; Center for Drug Evaluation and Research; U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁸ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹ Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Center for Disease Dynamics, Economics, and Policy, Washington DC, USA.

PMID: 36993216
PMCID: PMC10055594
DOI: 10.1101/2023.03.19.23287456

Reduced control of SARS-CoV-2 infection is associated with lower mucosal antibody responses in pregnant women

Laura A St Clair et al. medRxiv. 2023.

[Preprint]. 2023 Mar 20:2023.03.19.23287456.

doi: 10.1101/2023.03.19.23287456.

Authors

Affiliations

¹ W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
² Department of Pathology, Division of Medical Microbiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Medical Genetics Unit, Histology Department, School of Medicine, Suez Canal University, Egypt.
⁴ National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
⁵ Division of Viral Products, Center of Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁶ Office of Women's Health, U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁷ Division of Urology, Obstetrics, and Gynecology; Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine; Office of New Drugs; Center for Drug Evaluation and Research; U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁸ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹ Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Center for Disease Dynamics, Economics, and Policy, Washington DC, USA.

PMID: 36993216
PMCID: PMC10055594
DOI: 10.1101/2023.03.19.23287456

Update in

Reduced control of SARS-CoV-2 infection associates with lower mucosal antibody responses in pregnancy.
St Clair LA, Eldesouki RE, Sachithanandham J, Yin A, Fall A, Morris CP, Norton JM, Abdullah O, Dhakal S, Barranta C, Golding H, Bersoff-Matcha SJ, Pilgrim-Grayson C, Berhane L, Cox AL, Burd I, Pekosz A, Mostafa HH, Klein EY, Klein SL. St Clair LA, et al. mSphere. 2024 Mar 26;9(3):e0081223. doi: 10.1128/msphere.00812-23. Epub 2024 Mar 1. mSphere. 2024. PMID: 38426787 Free PMC article.

Abstract

Importance: Pregnant women are at increased risk of severe COVID-19, but the contribution of viral RNA load, the presence of infectious virus, and mucosal antibody responses remain understudied.

Objective: To evaluate the association of COVID-19 outcomes following confirmed infection with vaccination status, mucosal antibody responses, infectious virus recovery and viral RNA levels in pregnant compared with non-pregnant women.

Design: A retrospective observational cohort study of remnant clinical specimens from SARS-CoV-2 infected patients between October 2020-May 2022.

Setting: Five acute care hospitals within the Johns Hopkins Health System (JHHS) in the Baltimore, MD-Washington, DC area.

Participants: Participants included confirmed SARS-CoV-2 infected pregnant women and matched non-pregnant women (matching criteria included age, race/ethnicity, and vaccination status).

Exposure: SARS-CoV-2 infection, with documentation of SARS-CoV-2 mRNA vaccination.

Main outcomes: 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. Clinical outcomes were compared using odds ratios (OR), and measures of virus and antibody were compared using either Fisher's exact test, two-way ANOVA, or regression analyses. Results were stratified according to pregnancy, vaccination status, maternal age, trimester of pregnancy, and infecting SARS-CoV-2 variant.

Resultss: A total of 452 individuals (117 pregnant and 335 non-pregnant) were included in the study, with both vaccinated and unvaccinated individuals represented. Pregnant women were at increased risk of hospitalization (OR = 4.2; CI = 2.0-8.6), ICU admittance, (OR = 4.5; CI = 1.2-14.2), and of being placed on supplemental oxygen therapy (OR = 3.1; CI =13-6.9). An age-associated decrease in anti-S IgG titer and corresponding increase in viral RNA levels (P< 0.001) was observed in vaccinated pregnant, but not non-pregnant, women. Individuals in their 3^rd trimester had higher anti-S IgG titers and lower viral RNA levels (P< 0.05) than those in their 1^st or 2^nd trimesters. Pregnant individuals experiencing breakthrough infections due to the omicron variant had reduced anti-S IgG compared to non-pregnant women (P< 0.05).

Conclusions and relevance: In this cohort study, vaccination status, maternal age, trimester of pregnancy, and infecting SARS-CoV-2 variant were each identified as drivers of differences in mucosal anti-S IgG responses in pregnant compared with non-pregnant women. 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 may be important for protection of this at-risk population.

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

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Conflict of interest statement

Conflict of Interest Disclosures: The authors have no conflicts of interest to disclose.

Figures

**Figure 1 –. SARS-CoV-2 viral RNA levels and antibody responses stratified by pregnancy and vaccination status.**
Remnant clinical upper respiratory tract specimens were used determine rates of infectious virus recovery (A), viral RNA level (B), and anti-spike (ancestral spike) IgG titers (C) from mucosal swab samples. In (A), a positive cytopathic effect (CPE) in tissue culture was indicative of the presence of infectious virus. The *dashed line* in (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 (C) represents the limit of detection, and the red text indicates the percentage of non-responders (results below the limit of detection). Multivariate logistic regression was used to assess the correlation between anti-spike IgG titer and the probability of recovery of infectious virus (D). Analysis included Fisher’s exact test (A) and) and two-way ANOVAs with Tukey’s multiple comparisons test (B-C). *P < 0.05, *** P < 0.001, **** P < 0.0001. *anti-S IgG*, anti-ancestral strain spike immunoglobulin G; *AUC*, area under the curve; Ct, cycle threshold; *SARS-CoV-2*, severe acute respiratory syndrome coronavirus 2.

**Figure 2 –. The effects of maternal and gestational age on mucosal viral RNA levels and antibody responses**
(A-B) Study participants were divided into three maternal age groups: ages 18-24, ages 25-34, and ages 35-44, and samples were re-analyzed to assess differences in viral RNA levels (A) and anti-S IgG (B). (C-D) Results from unvaccinated and vaccinated pregnant women were stratified according to trimester of pregnancy and re-analyzed to assess differences in viral RNA levels (C) and anti-S IgG (D). The red text in (A,C) indicates the percentage of individuals with recoverable infectious virus, and the red text in (B,D) indicates the percentage of non-responders (i.e. those with anti-S IgG below the limit of detection). (A-D): Two-way ANOVA with Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01, ***P < 0.001, ****p < 0.0001.

**Figure 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 re-analyzed to assess differences in viral RNA level (A) and anti-S (ancestral/vaccine strain) IgG (B). Two-way ANOVA with Tukey’s multiple comparisons tests (A-B) *P < 0.05, **P <0.01, ***P < 0.001, ****P <0.0001.

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References

1. World Health Organization. WHO Coronavirus (COVID-19) Dashboard. 2022; Available from https://covid19.who.int/.
1. Vermillion M.S. and Klein S.L., Pregnancy and infection: using disease pathogenesis to inform vaccine strategy. NPJ Vaccines, 2018. 3: p. 6. - PMC - PubMed
1. Allotey J., et al. , Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. Bmj, 2020. 370: p. m3320. - PMC - PubMed
1. Yang Z., et al. , Coronavirus disease 2019 (COVID-19) and pregnancy: a systematic review. J Matern Fetal Neonatal Med, 2022. 35(8): p. 1619–1622. - PubMed
1. Strid P., et al. , Coronavirus Disease 2019 (COVID-19) Severity Among Women of Reproductive Age With Symptomatic Laboratory-Confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection by Pregnancy Status-United States, 1 January 2020-25 December 2021. Clin Infect Dis, 2022. 75(Supplement_2): p. S317–s325. - PMC - PubMed

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This is a preprint.

Reduced control of SARS-CoV-2 infection is associated with lower mucosal antibody responses in pregnant women

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Reduced control of SARS-CoV-2 infection is associated with lower mucosal antibody responses in pregnant women

Authors

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Abstract

Conflict of interest statement

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