M. Blake Evans, D.O.1, Carolyn Alexander, M.D.2, Emily Barnard, D.O.3, M. Max Ezzati, M.D.4, Micah J. Hill, D.O.5, Luis R. Hoyos, M.D.6, Eduardo Hariton, M.D.7Sasha Mikhael, M.D.8, Alan Penzias, M.D.9
1Division of Reproductive Endocrinology and Infertility, University of Oklahoma College of Medicine, Oklahoma City, OK.
2Southern California Reproductive Center, Los Angeles, CA.
3Shady Grove Fertility Center, Rockville, MD.
4Palo Alto Medical Foundation, Palo Alto, CA.
5Program in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
6 IVF Florida Reproductive Associates, Margate, FL.
7Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA.
8Division of Reproductive Endocrinology, Infertility and Genetics, Augusta University, Augusta, GA.
9Boston IVF; Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for causing coronavirus disease 2019 (COVID-19), has resulted in a pandemic of global proportions which has relentlessly crippled economies and healthcare systems throughout the world. However, after a year of absolute devastation with society at the mercy of this disease, a light at the end of the tunnel formed when two vaccine developers, first Pfizer-BioNtech and then Moderna, published the results of their respective clinical trials [1, 2]. In the United States, this led to emergency use authorization of both vaccines by The Food and Drug Administration (FDA) in December of 2020. These two vaccines, although made by two different companies, are both messenger ribonucleic acid (mRNA)-based vaccines and therefore, do not contain any live viral particles. In terms of vaccine development, the implementation of this novel technology is completely innovative by borrowing the cell’s transcription machinery to produce the desired particle set to generate an immunogenic response.
Despite being novel, the technology appears to have a reassuring safety profile [1, 2] Additionally, it is important to highlight that mRNA, as a molecule, is widely present in our cells where it has been generated by transcription from our DNA. Therefore, it lacks the ability to modify our own DNA in any way. In regards to COVID-19, the mRNA from the vaccine is able to enter our cells and become translated into spike proteins, also known as SARS-CoV-2 glycoprotein (the same protein that SARS-CoV-2 uses to enter cells). These newly formed SARS-CoV-2 glycoproteins elicit an immune response by activating helper T cells and B-cells. Antibodies to the newly formed SARS-CoV-2 glycoproteins are then induced by B cells, and ultimately help build immunity against SARS-CoV-2 [1, 3].
Shortly after the FDA approved the Pfizer vaccine, there was widespread excitement about the safety and efficacy of these vaccines from the government and medical community. Despite this reassuring news, social media platforms were plagued with baseless claims that the vaccine could lead to “female sterilization.” The origin of this rather ridiculous claim appeared to be a post from a blog called “Health and Money News”, which is no longer available . In this post, without any scientific proof, two European doctors (one of them a pulmonary specialist, and the other a former Pfizer respiratory research employee) claim that the vaccine could lead to infertility. The argument was that the vaccine “contains a spike protein called syncytin-1, vital for the formation of human placenta in women”. Syncytin-1 is an envelope protein from a human endogenous retrovirus shown to mediate cell fusion. Indeed, it is critical in the formation of the syncytriotrophoblast layer of the human placenta, and is responsible for establishing blood circulation from mother to embryo and delivery of nutrients to the fetus [5, 6]. Furthermore, it was claimed that “if the vaccine works so that we form an immune response AGAINST the spike protein, we are also training the female body to attack syncytin-1, which could lead to infertility in women of an unspecified duration”.
The basis for their argument was that the spike protein and syncyntin-1 share similar amino acid sequences, or in their own words: “spike proteins contain syncytin-homologous proteins”[4, 7]. However, it is important to note that the vaccine contains neither syncyntin-1 nor the mRNA sequence for syncyntin-1 . Additionally, the American Society for Reproductive Medicine (ASRM) has stated that “because COVID-19 mRNA vaccines are not composed of live virus, they are not thought to cause an increased risk of infertility, first or second trimester loss stillbirth, or congenital anomalies” . Nevertheless, as an independent group of reproductive medicine specialists, we would like to provide this document to serve as a source of scientific scrutiny to the claims regarding a potential relationship between COVID-19 mRNA vaccines and infertility.
In order to show that the SARS-CoV-2 surface glycoprotein (spike protein) antibodies produced by the vaccine would also bind to syncytin-1, one would first need to:
- a)Demonstrate a significant (almost identical) homology between antigenic epitopes of the SARS-CoV-2 surface glycoprotein and those on Syncytin-1
- b)Demonstrate that this potential cross-reactivity and binding of induced antibodies to Syncytin-1 (if it binds to it at all) actually impairs placental function leading to said “sterilization”.
Even if the SARS-CoV-2 surface glycoprotein and syncytin-1 share similar amino acid sequences, which they do not, they are not coding for the same protein that the COVID-19 vaccine forms antibodies to. When referring to the National Center for Biotechnology and Informatics (NCBI) for the Homo Sapiens (human) amino acid sequence of syncytin-1 (accession number NP_001124397.1), aligning this sequence with the SARS-CoV2 surface glycoprotein using a tool called BLAST, (https://blast.ncbi.nlm.nih.gov) no significant similarities are found. This indicates little homology between the two proteins, and further invalidates any claims of cross-reactivity of the SARS-CoV2 surface glycoprotein antibody to Syncytin-1.
Additionally, due to the process of clonal deletion, T-cells that can recognize the epitopes expressed on endogenous proteins (such as Syncytin-1) are usually eliminated by apoptosis in the thymus gland during embryonic development, and hence we observe the self- tolerance of our immune system . In other words, even if the immune system was indeed able to mount a response against Syncytin-1, it would have been noted in prior pregnancies, and no vaccine is actually able to bring back the "deleted clones" of T-cells (which would be required even for B-cell antibody response).
PREGNANCY AND COVID-19/COVID-19 VACCINE
Furthermore, since our bodies naturally make antibodies to SARS-CoV-2 surface glycoproteins after exposure to SARS-CoV-2, one would presume to see an increased risk of miscarriage from pregnant women diagnosed with COVID-19. Although data is limited and constantly evolving, a recent publication in American Journal of Obstetrics and Gynecology does not note an increased miscarriage rate in patients diagnosed with COVID-19 compared to pregnant patients without the virus . Additionally, twenty-three women became pregnant after participating in Pfizer's mRNA vaccine clinical trial . Of these, Pfizer reported one adverse event (spontaneous abortion and retained products of conception) in someone in the control/placebo group – meaning they had not received the vaccine. No adverse events were reported in the participants who were administered the vaccine.
Although pregnant and lactating women were excluded from both Pfizer-BioNTech and Moderna trials [1, 14], a recent statement by ASRM points out that since mRNA vaccines do not actually contain live viral components, there is no reason to suspect that the mechanism of action would lead to an increased risk of infertility or miscarriage . While the safety data in pregnant patients or those actively trying to conceive are not yet available, there are plans to include these patients in future studies. In light of this, the ASRM, the Advisory Committee for Immunization Practices (ACIP) of the U.S. Centers for Disease Prevention and Control (CDC), the Society for Maternal-Fetal Medicine (SMFM), and the American College of Obstetricians and Gynecologists (ACOG) all agree that the vaccine should not be withheld from patients “who are planning to conceive, who are currently pregnant, or who are lactating” [9, 15-17]. This recommendation is based on a risk-benefit analysis, and largely driven by the known increased risk posed by COVID-19 to pregnant individuals such as ICU admission, mechanical ventilation, and death . There are a number of vaccinations recommended to patients surrounding/during pregnancy to avoid comorbid sequelae , and the COVID-19 vaccination should be no exception.
In regards to men, although prior studies indicate that COVID-19 infection may adversely affect sperm parameters , current ongoing studies are evaluating whether or not the COVID-19 vaccine will also male fertility. Having said that, diminished sperm parameters does not necessarily imply male infertility.
In a world in which social media is largely a part of our daily routine, patients are particularly susceptible to misinformation derived from unreliable sources. Without having a medical background, a social media post regarding the COVID-19 vaccine leading to infertility can lead to unnecessary worry and vaccination reluctance. Nevertheless, the COVID-19 mRNA vaccines have now been administered to hundreds of thousands of people to date, and there has yet to be any reported issues for men or women with regard to infertility. To make such a baseless claim without any scientific evidence to support this theory elicits unfounded fear in our patient population, and creates an unnecessary sense of hesitancy to receive the COVID-19 vaccine.
Furthermore, our country is already unnecessarily divided regarding the legitimacy of the vaccine to help control the COVID-19 pandemic. Baseless claims such as the one at hand can lead to vulnerable patients not obtaining the vaccine and remaining unnecessarily susceptible to contracting COVID-19. Although women that were trying to conceive, pregnant, or lactating were not enrolled in the Pfizer or Moderna clinical trials, there is enough information provided in this document to counsel patients that claiming the vaccine results in female infertility is not only completely baseless, but also dangerous. Contrasting the low biologic plausibility for harm from the vaccine with the real risk of contracting COVID-19 should be seriously considered when making the decision to become immunized. It is important to note that as other false claims arise on social media, there are reliable repositories of truth that can be referenced, as recently stated by the ASRM Task Force .
- Polack, F.P., et al., Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 2020. 383(27): p. 2603-2615.
- Baden, L.R., et al., Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine, 2020.
- Sahin, U., et al., COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature, 2020. 586(7830): p. 594-599.
- News, H.a.M. Head of Pfizer Research: Covid Vaccine is Female Sterilization. 2020 January 6, 2020]; Available from: https://archive.is/9EULk.
- Chen, C.P., et al., Functional characterization of the human placental fusogenic membrane protein syncytin 2. Biol Reprod, 2008. 79(5): p. 815-23.
- Frendo, J.L., et al., Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cell Biol, 2003. 23(10): p. 3566-74.
- Sandhu, P. FACT CHECK: Did Pharma Research Head Say Pfizer Covid-19 Vaccine Causes Female Sterilization? 2020 [cited 2021 January 3]; Available from: https://www.ibtimes.sg/fact-check-did-pharma-research-head-say-pfizer-covid-19-vaccine-causes-female-sterilization-53921#slideshow/44752.
- FACT SHEET FOR RECIPIENTS AND CAREGIVERS. EMERGENCY USE AUTHORIZATION (EUA) OF THE PFIZER-BIONTECH COVID-19 VACCINE TO PREVENT CORONAVIRUS DISEASE 2019 (COVID-19) IN INDIVIDUALS 16 YEARS OF AGE AND OLDER. 2020; Available from: https://www.fda.gov/media/144414/download.
- AMERICAN SOCIETY FOR REPRODUCTIVE MEDICINE (ASRM) PATIENT MANAGEMENT AND CLINICAL RECOMMENDATIONS DURING THE CORONAVIRUS (COVID-19) PANDEMIC: UPDATE No. 11 – COVID-19 Vaccination December 16, 2020; Available from: https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate11.pdf.
- Rose, N.R., Negative selection, epitope mimicry and autoimmunity. Curr Opin Immunol, 2017. 49: p. 51-55.
- Nemazee, D., Mechanisms of central tolerance for B cells. Nat Rev Immunol, 2017. 17(5): p. 281-294.
- Cosma, S., et al., Coronavirus disease 2019 and first-trimester spontaneous abortion: a case-control study of 225 pregnant patients. Am J Obstet Gynecol, 2020.
- Vaccines and Related Biological Products Advisory Committee Meeting. 2020 December 10, 2020; Available from: https://www.fda.gov/media/144245/download.
- A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older. 2020 July 27, 2020; Available from: https://clinicaltrials.gov/ct2/show/NCT04470427.
- American College of Obstetrics and Gynecology. Vaccinating Pregnant and Lactating Patients Against COVID-19. Dec. 13, 2020.
- Society for Maternal-Fetal Medicine (SMFM) Statement: SARS-CoV-2 Vaccination in Pregnancy. December 1, 2020 Available from: https://s3.amazonaws.com/cdn.smfm.org/media/2591/SMFM_Vaccine_Statement_12-1- 20_(final).pdf.
- S, M. ACIP COVID-19 Vaccines Work Group. Use of Pfizer-BioNTech COVID-19 Vaccine: Clinical Considerations. Dec. 12, 2020 Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides2020-12/slides-12-12/COVID-03-Mbaeyi.pdf.
- ACOG Committee Opinion No. 741: Maternal Immunization. Obstet Gynecol, 2018. 131(6): p. e214-e217.
- Li, H., et al., Impaired spermatogenesis in COVID-19 patients. EClinicalMedicine, 2020. 28: p. 100604.
- AMERICAN SOCIETY FOR REPRODUCTIVE MEDICINE (ASRM) PATIENT MANAGEMENT AND CLINICAL RECOMMENDATIONS DURING THE CORONAVIRUS (COVID-19) PANDEMIC: UPDATE No. 9. Table 2. Resources on addressing rumors and misinformation 2020 November 9, 2020; Available from: https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate9.pdf.