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

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.

[1]  P. MacAry,et al.  No crossreactivity of anti-SARS-CoV-2 spike protein antibodies with Syncytin-1 , 2021, Cellular & Molecular Immunology.

[2]  S. Grisaru-Granovsky,et al.  Covid‐19 vaccination during the third trimester of pregnancy: rate of vaccination and maternal and neonatal outcomes, a multicentre retrospective cohort study , 2021, BJOG : an international journal of obstetrics and gynaecology.

[3]  K. Vesco,et al.  Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy. , 2021, JAMA.

[4]  B. Zikmund‐Fisher,et al.  COVID-19 vaccine hesitancy among reproductive-aged female tier 1A healthcare workers in a United States Medical Center , 2021, Journal of Perinatology.

[5]  A. Wilcox,et al.  Receipt of mRNA COVID-19 vaccines preconception and during pregnancy and risk of self-reported spontaneous abortions, CDC v-safe COVID-19 Vaccine Pregnancy Registry 2020–21 , 2021, Research square.

[6]  M. C. Muenker,et al.  Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity , 2021, Nature.

[7]  H. Seung,et al.  Increased Risk of Severe COVID-19 Disease in Pregnancy in a Multicenter Propensity Score-Matched Study. , 2021, medRxiv.

[8]  R. Morris SARS-CoV-2 spike protein seropositivity from vaccination or infection does not cause sterility , 2021, F&S Reports.

[9]  M. Krajewska,et al.  Immune Response to Vaccination against COVID-19 in Breastfeeding Health Workers , 2021, Vaccines.

[10]  Z. Williams,et al.  COVID-19 vaccine acceptance among pregnant, breastfeeding, and nonpregnant reproductive-aged women , 2021, American Journal of Obstetrics & Gynecology MFM.

[11]  M. Choolani,et al.  Addressing anti-syncytin antibody levels, and fertility and breastfeeding concerns, following BNT162B2 COVID-19 mRNA vaccination , 2021, medRxiv.

[12]  A. Iwasaki,et al.  Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus , 2021, The Journal of experimental medicine.

[13]  M. Neeman,et al.  Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine. , 2021, The Journal of clinical investigation.

[14]  M. Wick,et al.  Pregnancy and birth outcomes after SARS-CoV-2 vaccination in pregnancy , 2021, American Journal of Obstetrics & Gynecology MFM.

[15]  R. Nahum,et al.  Does mRNA SARS-CoV-2 vaccine influence patients' performance during IVF-ET cycle? , 2021, Reproductive Biology and Endocrinology.

[16]  M. C. Muenker,et al.  Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface , 2021, Med.

[17]  L. Riley,et al.  Antibody Response to Coronavirus Disease 2019 (COVID-19) Messenger RNA Vaccination in Pregnant Women and Transplacental Passage Into Cord Blood , 2021, Obstetrics and gynecology.

[18]  C. Olson,et al.  Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons , 2021, The New England journal of medicine.

[19]  Dilek Şahin,et al.  COVID‐19 vaccine acceptance in pregnant women , 2021, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[20]  D. Wolf,et al.  Ovarian follicular function is not altered by SARS–CoV-2 infection or BNT162b2 mRNA COVID-19 vaccination , 2021, medRxiv.

[21]  I. Youngster,et al.  SARS-CoV-2-Specific Antibodies in Breast Milk After COVID-19 Vaccination of Breastfeeding Women. , 2021, JAMA.

[22]  J. Goldstein,et al.  Cord blood antibodies following maternal coronavirus disease 2019 vaccination during pregnancy , 2021, American Journal of Obstetrics and Gynecology.

[23]  M. Good,et al.  Anti–severe acute respiratory syndrome coronavirus 2 antibodies induced in breast milk after Pfizer-BioNTech/BNT162b2 vaccination , 2021, American Journal of Obstetrics and Gynecology.

[24]  M. Good,et al.  Anti–severe acute respiratory syndrome coronavirus 2 antibodies induced in breast milk after Pfizer-BioNTech/BNT162b2 vaccination , 2021, American Journal of Obstetrics and Gynecology.

[25]  G. Alter,et al.  Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study , 2021, American Journal of Obstetrics and Gynecology.

[26]  S. Porat,et al.  Efficient maternofetal transplacental transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination , 2021, medRxiv.

[27]  V. Male Are COVID-19 vaccines safe in pregnancy? , 2021, Nature Reviews Immunology.

[28]  Jasmine Rah,et al.  Higher SARS-CoV-2 Infection Rate in Pregnant Patients , 2021, American Journal of Obstetrics and Gynecology.

[29]  C. Spong,et al.  COVID-19 Vaccination in Pregnant and Lactating Women. , 2021, JAMA.

[30]  S. Klein,et al.  COVID-19 vaccine testing in pregnant females is necessary. , 2021, The Journal of clinical investigation.

[31]  P. Hyland,et al.  Psychological characteristics associated with COVID-19 vaccine hesitancy and resistance in Ireland and the United Kingdom , 2021, Nature Communications.

[32]  J. Mascola,et al.  Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine , 2020, The New England journal of medicine.

[33]  D. Lauffenburger,et al.  Compromised SARS-CoV-2-specific placental antibody transfer , 2020, Cell.

[34]  P. Dormitzer,et al.  Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine , 2020, The New England journal of medicine.

[35]  Jesse M. Fajnzylber,et al.  Assessment of Maternal and Neonatal SARS-CoV-2 Viral Load, Transplacental Antibody Transfer, and Placental Pathology in Pregnancies During the COVID-19 Pandemic , 2020, JAMA network open.

[36]  J. Overbey,et al.  Pregnant women with severe or critical coronavirus disease 2019 have increased composite morbidity compared with nonpregnant matched controls , 2020, American Journal of Obstetrics and Gynecology.

[37]  E. Olsen,et al.  Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–October 3, 2020 , 2020, MMWR. Morbidity and mortality weekly report.

[38]  E. Olsen,et al.  Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy — SET-NET, 16 Jurisdictions, March 29–October 14, 2020 , 2020, MMWR. Morbidity and mortality weekly report.

[39]  S. Farhadian,et al.  Newborn Dried Blood Spots for Serologic Surveys of COVID-19 , 2020, The Pediatric infectious disease journal.

[40]  M. Suchard,et al.  Clinical characteristics, symptoms, management and health outcomes in 8,598 pregnant women diagnosed with COVID-19 compared to 27,510 with seasonal influenza in France, Spain and the US: a network cohort analysis , 2020, medRxiv.

[41]  L. Mofenson,et al.  Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis , 2020, BMJ.

[42]  Eric Song,et al.  Longitudinal analyses reveal immunological misfiring in severe COVID-19 , 2020, Nature.

[43]  Philip L. Felgner,et al.  A serological assay to detect SARS-CoV-2 seroconversion in humans , 2020, medRxiv.

[44]  J. Neill,et al.  Evolution of a maternal immune activation (mIA) model in rats: Early developmental effects , 2019, Brain, Behavior, and Immunity.

[45]  H. Sangi-Haghpeykar,et al.  Association Between Third-Trimester Tdap Immunization and Neonatal Pertussis Antibody Concentration , 2018, JAMA.

[46]  A. Iwasaki,et al.  Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development. , 2018, Immunity.

[47]  C. Combescure,et al.  Pertussis Antibody Transfer to Preterm Neonates After Second- Versus Third-Trimester Maternal Immunization , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[48]  M. Davies-Tuck,et al.  The optimal gestation for pertussis vaccination during pregnancy: a prospective cohort study. , 2016, American journal of obstetrics and gynecology.

[49]  C. Combescure,et al.  Maternal Immunization Earlier in Pregnancy Maximizes Antibody Transfer and Expected Infant Seropositivity Against Pertussis , 2016, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[50]  R. Weiss,et al.  N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[51]  R. Gonen,et al.  The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels - a prospective study. , 2014, Vaccine.

[52]  A. Borghesi,et al.  IUGR and infections. , 2014, Early human development.

[53]  K. A. Adams Waldorf,et al.  Influence of infection during pregnancy on fetal development. , 2013, Reproduction.

[54]  K. Karimi,et al.  Interleukin‐15 is required for maximal lipopolysaccharide‐induced abortion , 2013, Journal of leukocyte biology.

[55]  S. Saito,et al.  NKG2D Blockade Inhibits Poly(I:C)-Triggered Fetal Loss in Wild Type but Not in IL-10−/− Mice , 2013, The Journal of Immunology.

[56]  V. Abrahams,et al.  Syncytin 1 in the human placenta. , 2012, Placenta.

[57]  R. Romero,et al.  TLR9 Activation Coupled to IL-10 Deficiency Induces Adverse Pregnancy Outcomes1 , 2009, The Journal of Immunology.

[58]  C. Zhang,et al.  Reactive oxygen species contribute to lipopolysaccharide-induced teratogenesis in mice. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[59]  P. Coyle,et al.  Dietary Zinc Supplementation Ameliorates LPS-Induced Teratogenicity in Mice , 2006, Pediatric Research.

[60]  M. Hochberg,et al.  Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. , 1997, Arthritis and rheumatism.

[61]  G. Daston,et al.  Tumor necrosis factor-alpha alters maternal and embryonic zinc metabolism and is developmentally toxic in mice. , 1995, The Journal of nutrition.

[62]  J F Fries,et al.  The 1982 revised criteria for the classification of systemic lupus erythematosus. , 1982, Arthritis and rheumatism.