No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination

  1. Alice Lu-Culligan
  2. Alexandra Tabachnikova
  3. Maria Tokuyama
  4. Hannah J. Lee
  5. Carolina Lucas
  6. Valter Silva Monteiro
  7. M. Catherine Muenker
  8. Subhasis Mohanty
  9. Jiefang Huang
  10. Insoo Kang
  11. Charles Dela Cruz
  12. Shelli Farhadian
  13. Melissa Campbell
  14. Inci Yildirim
  15. Albert C. Shaw
  16. Albert I. Ko
  17. Saad B. Omer
  18. Akiko Iwasaki

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Abstract

The impact of coronavirus disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated two of the most widely propagated claims to determine 1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities, and 2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from vaccinated murine pregnancies exhibit high circulating levels of anti-Spike and anti-RBD antibodies to SARS-CoV-2 consistent with maternal antibody status, indicating transplacental transfer. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.

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  1. ScreenIT

    SciScore for 10.1101/2021.12.07.471539: (What is this?)

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

    Table 1: Rigor

    EthicsField Sample Permit: Human plasma collection and cohort selection: Plasma was collected from healthcare worker (HCW) volunteers who received the mRNA vaccine (Moderna mRNA-1273 or Pfizer-BioNTech BNT162B2) between November 2020 and January 2021 as approved by the Yale Human Research Protection Program Institutional Review Board (IRB Protocol ID 2000028924).
    IRB: Human plasma collection and cohort selection: Plasma was collected from healthcare worker (HCW) volunteers who received the mRNA vaccine (Moderna mRNA-1273 or Pfizer-BioNTech BNT162B2) between November 2020 and January 2021 as approved by the Yale Human Research Protection Program Institutional Review Board (IRB Protocol ID 2000028924).
    Consent: After obtaining informed consent, peripheral blood was collected in EDTA tubes from human subjects, and plasma was extracted upon centrifugation.
    Sex as a biological variableTimed mating and injections: C57BL/6J mice were mated overnight and females were checked for the presence of seminal plugs each morning, designated E0.5.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti-HERV-W/Syncytin-1 antibody and ELISAs: 96-well MaxiSorp plates (Thermo Scientific #442404
    Anti-HERV-W/Syncytin-1
    suggested: None
    Mouse Anti-HERV-W monoclonal antibody (Abnova #H00030816-M06) was serially diluted to generate a standard curve.
    Anti-HERV-W
    suggested: None
    Plates were washed three times with PBS-T (PBS with 0.1% Tween-20) and 50 μl of HRP anti-Human IgG Antibody (GenScript #A00166) diluted 1:5000 in dilution solution were added to each well.
    anti-Human IgG
    suggested: None
    50 ul of HRP anti-Mouse IgG1 Antibody (Southern Biotech #1070-05) diluted 1:3000 in dilution solution were added to each standard well.
    HRP anti-Mouse IgG1 Antibody
    suggested: None
    anti-Mouse IgG1
    suggested: (SouthernBiotech Cat# 1070-05, RRID:AB_2650509)
    Experimental Models: Organisms/Strains
    SentencesResources
    Timed mating and injections: C57BL/6J mice were mated overnight and females were checked for the presence of seminal plugs each morning, designated E0.5.
    C57BL/6J
    suggested: RRID:IMSR_JAX:000664)
    Software and Algorithms
    SentencesResources
    All statistical analyses comparing fetal viability and growth measurements were performed with GraphPad Prism 8.4.3 software.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Human plasma collection and cohort selection: Plasma was collected from healthcare worker (HCW) volunteers who received the mRNA vaccine (Moderna mRNA-1273 or Pfizer-BioNTech BNT162B2) between November 2020 and January 2021 as approved by the Yale Human Research Protection Program Institutional Review Board (IRB Protocol ID 2000028924).
    Yale Human Research Protection Program
    suggested: None

    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:
    Limitations of our mouse model of vaccination include the use of a single dose of mRNA-1273 during pregnancy whereas the full vaccine schedule in humans is two doses approximately 28 days apart, longer than the murine gestation period. While this study provides the first step in establishing safety for early vaccine approaches in pregnancy, we surveyed litters only for overt birth defects and size at E18.5. Findings of this work await validation with results from the ongoing human studies of vaccination during the first trimester. Our study does not capture potential effects of mRNA vaccination timing during late gestation. Finally, using human data we demonstrated that circulating anti-syncytin-1 antibodies do not rise following COVID-19 mRNA vaccination with either mRNA-1273 or BNT162B2. These findings support the mounting evidence that a syncytin-1-based mechanism of infertility is not supported by scientific observations [19,21]. This study is limited as we only interrogated the presence of anti-syncytin-1 in a total of 51 subjects. Larger studies are warranted to further assess anti-syncytin-1 antibody status in women who receive the mRNA vaccines. Millions of women and pregnancies continue to be impacted by the ongoing COVID-19 pandemic and by vaccine hesitancy. In the absence of complete clinical trial data, many women are choosing to vaccinate during pregnancy after weighing the risks and benefits of their situation. Thus, filling in gaps in knowledge, particularly su...

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.12.07.471539 on bioRxiv