Waning of the Humoral Response to SARS-CoV-2 in Pregnancy is Variant-Dependent

  1. Romina Plitman Mayo
  2. Tal Raz
  3. Bar Ben David
  4. Gila Meir
  5. Haim Barr
  6. Leonardo J. Solmesky
  7. Rony Chen
  8. Ana Idelson
  9. Lucilla Zorzetti
  10. Rinat Gabbay-Benziv
  11. Yuval Jaffe Moshkovich
  12. Tal Biron-Shental
  13. Gil Shechter-Maor
  14. Hen Yitzhak Sela
  15. Itamar Glick
  16. Hedi Benyamini Raischer
  17. Raed Salim
  18. Yariv Yogev
  19. Ofer Beharier
  20. Debra Goldman-Wohl
  21. Ariel Many
  22. Michal Kovo
  23. Simcha Yagel
  24. Michal Neeman

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Abstract

Importance

The SARS-CoV-2 alpha variant posed increased risk for COVID-19 complications in pregnant women. However, its impact on the maternal humoral response and placental IgG transport remains unclear.

Objective

To characterize the maternal humoral waning and neonate immunity acquired during the 3 rd COVID-19 wave in Israel, dominated by the Alpha variant, as compared to earlier Wildtype infections and humoral response to vaccination across gestation.

Design

Maternal and fetal blood serum were collected at delivery since April 2020 from parturients. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel supplemented with additional HA-coupled microspheres.

Setting

A nationwide multicenter cohort study on SARS-CoV-2 infections and vaccination during pregnancy.

Participants

Expectant women presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 primary groups: SARS-CoV-2 positive ( n = 157) and fully vaccinated during pregnancy ( n = 125), and unvaccinated noninfected controls matched to the infected group by BMI, maternal age, comorbidities and gestational age ( n = 212). Eligibility criteria included pregnant women without active COVID-19 disease, age ≥18 years and willingness to provide informed consent.

Main Outcome(s) and Measure(s)

Pregnant women’s humoral response is dependent on the SARS-CoV-2 strain.

Results

The humoral response to infection as detected at birth, showed a gradual and significant decline as the interval between infection/vaccination and delivery increased. Significantly faster decay of antibody titers was found for infections occurring during the 3 rd wave compared to earlier infections/vaccination. Cord blood IgG antigens levels correlated with maternal IgG. However, cord IgG-HA variance significantly differed in SARS-CoV2 infections as compared to the other groups. No sexual dimorphism in IgG transfer was observed. Lastly, high fetal IgM response to SARS-CoV-2 was detected in 17 neonates, all showing elevated IgM to N suggesting exposure to SARS-Cov-2 antigens.

Conclusions and Relevance

Infections occurring during the 3 rd wave induced a faster decline in humoral response when compared to Wildtype infections or mRNA BNT162b2 vaccination during pregnancy, consistent with a shift in disease etiology and severity induced by the Alpha variant. Vaccination policies in previously infected pregnant women should consider the timing of exposure along pregnancy as well as the risk of infection to specific variants of concern.

Key Points

Question

What is the difference in the maternal-fetal humoral response between Alpha variant and SARS-CoV-2 Wildtype infections?

Findings

In this nationwide multicenter study including 494 pregnant women, the maternal humoral response to Alpha variant infection was weaker and shorter when compared to Wildtype infections. Placental transport compensated for the maternal waning of immunity. Fetal sex did not affect humoral response.

Meaning

Vaccination policies should be adjusted to account for the timing of infection and the SARS-CoV-2 variant.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.11.03.21265478: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Eligibility criteria included maternal age ≥18 years and willing to provide informed consent.
    Sex as a biological variableStudy Design: Pregnant women admitted for delivery at eight medical centers in Israel (Hadassah Mount-Scopus, Wolfson, HaEmek, Hillel Yafe, Rabin, Shaare Zedek, Meir, and Sourasky Medical Centers) were approached for enrollment in the Israel Covid-19 in Pregnancy study, starting in April 2020.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    IgG and IgM antibody (S1, S2, RBD, N) MFI were log10-transformed for the analyses.
    S1
    suggested: None
    Additionally, when relevant, the effects of wave (either the 2nd or 3rd wave), trimester (1st, 2nd, 3rd), and the wave by trimester interaction on IgG and IgM antibody concentrations or their transfer ratios were analyzed in a General Analysis of Variance Test (ANOVA), followed by Tukey HSD All-Pairwise Comparisons test.
    IgM
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical Analyses: Statistical analyses were performed using Statistix 8 software (Analytical Software, Tallahassee, FL USA) and Prism 5.01 (GraphPad Software; San-Diego, CA, USA).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The present work possesses several limitations, including bias in sample collection due to daytime recruitment of participants, thereby excluding most emergency cases. The period of sample collection differed among groups, as the Israeli vaccination campaign started after the commencement of the study. Additionally, antibody levels were quantified using antigens of the original virus, and may thus show reduced affinity to antibodies induced by the alpha variant. Pregnancy induces particular changes in a women’s immune system placing them at a vulnerable position when it comes to infections. Therefore, general population immunity dynamics are not always applicable to pregnant women. This is the first study to compare the evolution and dynamics of the maternal-fetal humoral response between Alpha variant and Wildtype SARS-CoV-2 infections, demonstrating that pregnant women response is variant dependent. Additionally, this work enhances the important role of active transport and placental regulation for fetal immunity supporting vaccination during pregnancy.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.11.03.21265478v1 on medRxiv