Detection of Messenger RNA COVID-19 Vaccines in Human Breast Milk

Authors: Nazeeh Hanna, MD1Ari Heffes-Doon, MD1Xinhua Lin, PhD2et alClaudia Manzano DeMejia, MD2Bishoy Botros, BS2;  Ellen Gurzenda, BS2Amrita Nayak, MD1 JAMA Pediatric Published online September 26, 2022. doi:10.1001/jamapediatrics.2022.3581

Vaccination is a cornerstone in fighting the COVID-19 pandemic. However, the initial messenger RNA (mRNA) vaccine clinical trials excluded several vulnerable groups, including young children and lactating individuals.1 The US Food and Drug Administration deferred the decision to authorize COVID-19 mRNA vaccines for infants younger than 6 months until more data are available because of the potential priming of the children’s immune responses that may alter their immunity.2 The Centers for Disease Control and Prevention recommends offering the COVID-19 mRNA vaccines to breastfeeding individuals,3 although the possible passage of vaccine mRNAs in breast milk resulting in infants’ exposure at younger than 6 months was not investigated. This study investigated whether the COVID-19 vaccine mRNA can be detected in the expressed breast milk (EBM) of lactating individuals receiving the vaccination within 6 months after delivery.

Methods

This cohort study included 11 healthy lactating individuals who received either the Moderna mRNA-1273 vaccine (n = 5) or the Pfizer BNT162b2 vaccine (n = 6) within 6 months after delivery (Table 1). Participants were asked to collect and immediately freeze EBM samples at home until transported to the laboratory. Samples of EBM were collected before vaccination (control) and for 5 days postvaccination. A total of 131 EBM samples were collected 1 hour to 5 days after vaccine administration. Extracellular vesicles (EVs) were isolated in EBM using sequential centrifugation, and the EV concentrations were determined by ZetaView (Analytik) (eMethods in the Supplement). The presence of COVID-19 vaccine mRNA in different milk fractions (whole EBM, fat, cells, and supernatant EVs) was assayed using 2-step quantitative reverse transcriptase–polymerase chain reaction. The vaccine detection limit was 1 pg/mL of EBM (eMethods in the Supplement).

Results

Of 11 lactating individuals enrolled, trace amounts of BNT162b2 and mRNA-1273 COVID-19 mRNA vaccines were detected in 7 samples from 5 different participants at various times up to 45 hours postvaccination (Table 2). The mean (SD) yield of EVs isolated from EBM was 9.110 (5.010) particles/mL, and the mean (SD) particle size was 110.0 (3.0) nm. The vaccine mRNA appears in higher concentrations in the EVs than in whole milk (Table 2). No vaccine mRNA was detected in prevaccination or postvaccination EBM samples beyond 48 hours of collection. Also, no COVID-19 vaccine mRNA was detected in the EBM fat fraction or the EBM cell pellets.

Discussion

The sporadic presence and trace quantities of COVID-19 vaccine mRNA detected in EBM suggest that breastfeeding after COVID-19 mRNA vaccination is safe, particularly beyond 48 hours after vaccination. These data demonstrate for the first time to our knowledge the biodistribution of COVID-19 vaccine mRNA to mammary cells and the potential ability of tissue EVs to package the vaccine mRNA that can be transported to distant cells. Little has been reported on lipid nanoparticle biodistribution and localization in human tissues after COVID-19 mRNA vaccination. In rats, up to 3 days following intramuscular administration, low vaccine mRNA levels were detected in the heart, lung, testis, and brain tissues, indicating tissue biodistribution.4 We speculate that, following the vaccine administration, lipid nanoparticles containing the vaccine mRNA are carried to mammary glands via hematogenous and/or lymphatic routes.5,6 Furthermore, we speculate that vaccine mRNA released into mammary cell cytosol can be recruited into developing EVs that are later secreted in EBM.

The limitations of this study include the relatively small sample size and the lack of functional studies demonstrating whether detected vaccine mRNA is translationally active. Also, we did not test the possible cumulative vaccine mRNA exposure after frequent breastfeeding in infants. We believe it is safe to breastfeed after maternal COVID-19 vaccination. However, caution is warranted about breastfeeding children younger than 6 months in the first 48 hours after maternal vaccination until more safety studies are conducted. In addition, the potential interference of COVID-19 vaccine mRNA with the immune response to multiple routine vaccines given to infants during the first 6 months of age needs to be considered. It is critical that lactating individuals be included in future vaccination trials to better evaluate the effect of mRNA vaccines on lactation outcomes.

References

1.Van Spall  HGC.  Exclusion of pregnant and lactating women from COVID-19 vaccine trials: a missed opportunity.   Eur Heart J. 2021;42(28):2724-2726. doi:10.1093/eurheartj/ehab103PubMedGoogle ScholarCrossref

2.US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes Moderna and Pfizer-BioNTech COVID-19 vaccines for children down to 6 months of age. Released June 17, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-moderna-and-pfizer-biontech-covid-19-vaccines-children

3.Centers for Disease Control and Prevention. COVID-19 vaccines while pregnant or breastfeeding. Accessed March 8, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html.

4.European Medicines Agency. Assessment report: COVID-19 vaccine Moderna. Published March 11, 2021. http://www.ema.europa.eu/en/documents/assessment-report/spikevax-previously-covid-19-vaccine-moderna-epar-public-assessment-report_en.pdf.

5.Pardi  N, Tuyishime  S, Muramatsu  H,  et al.  Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes.   J Control Release. 2015;217:345-351. doi:10.1016/j.jconrel.2015.08.007PubMedGoogle ScholarCrossref

6.Bansal  S, Perincheri  S, Fleming  T,  et al.  Cutting edge: circulating exosomes with COVID spike protein are induced by BNT162b2 (Pfizer-BioNTech) vaccination prior to development of antibodies: a novel mechanism for immune activation by mRNA vaccines.   J Immunol. 2021;207(10):2405-2410. doi:10.4049/jimmunol.2100637PubMedGoogle ScholarCrossref

Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs

Authors: Stephanie Seneff 1Greg Nigh 2Anthony M Kyriakopoulos 3Peter A McCullough 4

PMID: 35436552 PMCID: PMC9012513 DOI: 10.1016/j.fct.2022.113008

Abstract

The mRNA SARS-CoV-2 vaccines were brought to market in response to the public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious disease has no precedent. The many alterations in the vaccine mRNA hide the mRNA from cellular defenses and promote a longer biological half-life and high production of spike protein. However, the immune response to the vaccine is very different from that to a SARS-CoV-2 infection. In this paper, we present evidence that vaccination induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health. Immune cells that have taken up the vaccine nanoparticles release into circulation large numbers of exosomes containing spike protein along with critical microRNAs that induce a signaling response in recipient cells at distant sites. We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances potentially have a causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell’s palsy, liver disease, impaired adaptive immunity, impaired DNA damage response and tumorigenesis. We show evidence from the VAERS database supporting our hypothesis. We believe a comprehensive risk/benefit assessment of the mRNA vaccines questions them as positive contributors to public health.

References

  1. Abe M., Bonini N.M. MicroRNAs and neurodegeneration: role and impact. Trends Cell Biol. 2013;23(1):30–36. doi: 10.1016/j.tcb.2012.08.013. – DOI – PMC – PubMed
  2. Agashe D., Martinez-Gomez N.C., Drummond D.A., Marx C.J. Good codons, bad transcript: large reductions in gene expression and fitness arising from synonymous mutations in a key enzyme. Mol. Biol. Evol. 2013;30:549–560. doi: 10.1093/molbev/mss273. – DOI – PMC – PubMed
  3. Akiyama H., Kakiuchi S., Rikitake J., Matsuba H., Sekinada D., Kozuki Y., Iwata N. Immune thrombocytopenia associated with Pfizer-BioNTech’s BNT162b2 mRNA COVID-19 vaccine. IDCases. 2021;25 doi: 10.1016/j.idcr.2021.e01245. – DOI – PMC – PubMed
  4. Al-Khalaf H.H., Aboussekhra A. p16 controls p53 protein expression through miR-dependent destabilization of MDM2. Mol. Cancer Res. 2018;16(8):1299–1308. doi: 10.1158/1541-7786.MCR-18-0017. – DOI – PubMed
  5. Alsamman K., El-Masry O.S. Interferon regulatory factor 1 inactivation in human cancer. Biosci. Rep. 2018;38(3) doi: 10.1042/BSR20171672. 2018. – DOI – PMC – PubMed

Detection of Messenger RNA COVID-19 Vaccines in Human Breast Milk

Authors: Nazeeh Hanna, MD1Ari Heffes-Doon, MD1Xinhua Lin, PhD2et al JAMA Pediatr. Published online September 26, 2022. doi:10.1001/jamapediatrics.2022.3581

Vaccination is a cornerstone in fighting the COVID-19 pandemic. However, the initial messenger RNA (mRNA) vaccine clinical trials excluded several vulnerable groups, including young children and lactating individuals.1 The US Food and Drug Administration deferred the decision to authorize COVID-19 mRNA vaccines for infants younger than 6 months until more data are available because of the potential priming of the children’s immune responses that may alter their immunity.2 The Centers for Disease Control and Prevention recommends offering the COVID-19 mRNA vaccines to breastfeeding individuals,3 although the possible passage of vaccine mRNAs in breast milk resulting in infants’ exposure at younger than 6 months was not investigated. This study investigated whether the COVID-19 vaccine mRNA can be detected in the expressed breast milk (EBM) of lactating individuals receiving the vaccination within 6 months after delivery.

Methods

This cohort study included 11 healthy lactating individuals who received either the Moderna mRNA-1273 vaccine (n = 5) or the Pfizer BNT162b2 vaccine (n = 6) within 6 months after delivery (Table 1). Participants were asked to collect and immediately freeze EBM samples at home until transported to the laboratory. Samples of EBM were collected before vaccination (control) and for 5 days postvaccination. A total of 131 EBM samples were collected 1 hour to 5 days after vaccine administration. Extracellular vesicles (EVs) were isolated in EBM using sequential centrifugation, and the EV concentrations were determined by ZetaView (Analytik) (eMethods in the Supplement). The presence of COVID-19 vaccine mRNA in different milk fractions (whole EBM, fat, cells, and supernatant EVs) was assayed using 2-step quantitative reverse transcriptase–polymerase chain reaction. The vaccine detection limit was 1 pg/mL of EBM (eMethods in the Supplement).

Results

Of 11 lactating individuals enrolled, trace amounts of BNT162b2 and mRNA-1273 COVID-19 mRNA vaccines were detected in 7 samples from 5 different participants at various times up to 45 hours postvaccination (Table 2). The mean (SD) yield of EVs isolated from EBM was 9.110 (5.010) particles/mL, and the mean (SD) particle size was 110.0 (3.0) nm. The vaccine mRNA appears in higher concentrations in the EVs than in whole milk (Table 2). No vaccine mRNA was detected in prevaccination or postvaccination EBM samples beyond 48 hours of collection. Also, no COVID-19 vaccine mRNA was detected in the EBM fat fraction or the EBM cell pellets.

Discussion

The sporadic presence and trace quantities of COVID-19 vaccine mRNA detected in EBM suggest that breastfeeding after COVID-19 mRNA vaccination is safe, particularly beyond 48 hours after vaccination. These data demonstrate for the first time to our knowledge the biodistribution of COVID-19 vaccine mRNA to mammary cells and the potential ability of tissue EVs to package the vaccine mRNA that can be transported to distant cells. Little has been reported on lipid nanoparticle biodistribution and localization in human tissues after COVID-19 mRNA vaccination. In rats, up to 3 days following intramuscular administration, low vaccine mRNA levels were detected in the heart, lung, testis, and brain tissues, indicating tissue biodistribution.4 We speculate that, following the vaccine administration, lipid nanoparticles containing the vaccine mRNA are carried to mammary glands via hematogenous and/or lymphatic routes.5,6 Furthermore, we speculate that vaccine mRNA released into mammary cell cytosol can be recruited into developing EVs that are later secreted in EBM.

The limitations of this study include the relatively small sample size and the lack of functional studies demonstrating whether detected vaccine mRNA is translationally active. Also, we did not test the possible cumulative vaccine mRNA exposure after frequent breastfeeding in infants. We believe it is safe to breastfeed after maternal COVID-19 vaccination. However, caution is warranted about breastfeeding children younger than 6 months in the first 48 hours after maternal vaccination until more safety studies are conducted. In addition, the potential interference of COVID-19 vaccine mRNA with the immune response to multiple routine vaccines given to infants during the first 6 months of age needs to be considered. It is critical that lactating individuals be included in future vaccination trials to better evaluate the effect of mRNA vaccines on lactation outcomes.

References

1. Van Spall  HGC.  Exclusion of pregnant and lactating women from COVID-19 vaccine trials: a missed opportunity.   Eur Heart J. 2021;42(28):2724-2726. doi:10.1093/eurheartj/ehab103PubMedGoogle ScholarCrossref

2. US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes Moderna and Pfizer-BioNTech COVID-19 vaccines for children down to 6 months of age. Released June 17, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-moderna-and-pfizer-biontech-covid-19-vaccines-children

3. Centers for Disease Control and Prevention. COVID-19 vaccines while pregnant or breastfeeding. Accessed March 8, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html.

4. European Medicines Agency. Assessment report: COVID-19 vaccine Moderna. Published March 11, 2021. http://www.ema.europa.eu/en/documents/assessment-report/spikevax-previously-covid-19-vaccine-moderna-epar-public-assessment-report_en.pdf.

5. Pardi  N, Tuyishime  S, Muramatsu  H,  et al.  Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes.   J Control Release. 2015;217:345-351. doi:10.1016/j.jconrel.2015.08.007PubMedGoogle ScholarCrossref

6. Bansal  S, Perincheri  S, Fleming  T,  et al.  Cutting edge: circulating exosomes with COVID spike protein are induced by BNT162b2 (Pfizer-BioNTech) vaccination prior to development of antibodies: a novel mechanism for immune activation by mRNA vaccines.   J Immunol. 2021;207(10):2405-2410. doi:10.4049/jimmunol.2100637PubMedGoogle ScholarCrossref

Italy: Peer-Reviewed Study Finds ‘Metal-Like Objects’ in 94% of Individuals With Reported mRNA Vaccine Side Effects

Authors:  Jim Hoft September 7, 2022 The Gateway Pundit

A peer-reviewed study in Italy found that 94% of people who experienced side effects after receiving mRNA vaccines had abnormal blood and contained foreign matter one month after vaccination, Epoch Times reported.

This new study was published in August 2022 in the open access peer-reviewed journal, International Journal of Vaccine Theory, Practice, and Research (IJVTPR).

Starting in March 2021, three Italian surgeons analyzed peripheral blood, using a single drop from each of 1,006 symptomatic participants who had had at least one mRNA injection (from Pfizer or Moderna.)

According to the study, “there were 948 subjects (94% of the total sample) whose blood showed aggregation of erythrocytes and the presence of particles of various shapes and sizes of unclear origin one month after the mRNA inoculation.”

Erythrocytes also known as red blood cells contain a protein called hemoglobin, which carries oxygen from the lungs to all parts of the body.

“In 12 subjects, blood was examined with the same method before vaccination, showing a perfectly normal hematological distribution. The alterations found after the inoculation of the mRNA injections further reinforce the suspicion that the modifications were due to the so-called “vaccines” themselves. We report 4 clinical cases, chosen as representative of the entire case series. Further studies are needed to define the exact nature of the particles found in the blood and to identify possible solutions to the problems they are evidently causing,” it added.

“Of the 1,006 subjects, 426 were males and 580 were females and 141 of them received only a single dose of the mRNA experimental injection, 453 got a second dose, and 412 received a third dose. The average age of the 1,006 subjects was 49 years and their age ranged from 15-85. On the average, 5.77% of the 1,006 individuals had normal blood samples in spite of their COVID-19 symptoms,” according to the study.

“The remaining 94.23% had abnormal blood samples as illustrated in the 4 cases we selected out of the 12 who were normal before receiving any mRNA injections but were no longer normal afterward. For each case, a drop of blood was drawn by pricking a finger and was analyzed under a ZEISS Primostar orLEITZ Laborlux 12 dark-field microscope. The observation of the blood under an optical microscope in a dark-field took place an average of thirty days after the last inoculation,” the study added.

The three surgeons behind the study—Franco Giovannini, Riccardo Benzi Cipelli, and Gianpaolo Pisano—claim that their findings are similar to those of a study by Young Mi Lee, Sunyoung Park, and Ki-Yeob Jeon from South Korea, titled “Foreign Materials in Blood Samples of Recipients of COVID-19 Vaccines,” but the Italian study has “much larger sample.”

“Our findings, however, are bolstered by their parallel analysis of the fluids in vials of the mRNA concoctions alongside centrifuged plasma samples from the cases they studied intensively. What seems plain enough is that metallic particles resembling graphene oxide and possibly other metallic compounds, like those discovered by Gatti and Montanari, have been included in the cocktail of whatever the manufacturers have seen fit to put in the so-called mRNA “vaccines.”

The surgeons believed that the vaccine makers should provide an explanation as to what is within the shots and why those components are present.

“In our experience as clinicians, these mRNA injections are very unlike traditional “vaccines” and their manufacturers need, in our opinions, to come clean about what is in the injections and why it is there,” they said.

Below are the results of the study:

These photos are at 40x magnification. At the left side, (a) shows the blood condition of the patient before the inoculation. The right side image, (b) shows the same person’s blood one month after the first dose of Pfizer mRNA “vaccine”. Particles can be seen among the red blood cells which are strongly conglobated around the exogenous particles; the agglomeration is believed to reflect a reduction in zeta potential adversely affecting the normal colloidal distribution of erythrocytes as see at the left. The red blood cells at the right (b) are no longer spherical and are clumping as in coagulation and clotting. (Source: IJVTPR)

The image at 120x magnification shows two exogenous particles and clusters of fibrin 2 months after vaccination. (Source: IJVTPR)

This image at 120x magnification (3x magnification digitally produced)highlights a typical self-aggregating structuring in fibro/tubular mode.Figure 2. In this case the assembly of particles takes on crystalline features; furthermore, there is an area of close influence, butterfly wings, in the context of which a crystalline type organization occurs.Figure 3. The image at 120x magnification shows two exogenous particles and clusters of fibrin 2 months after vaccination. (Source: IJVTPR)

Case No. 1:

“This individual is a male of 33 years, who formerly was an athlete, apparently healthy before inoculation with an mRNA Pfizer injection. One month after receiving the first dose of the Pfizer “vaccine”, he showed marked asthenia, a constant gravitational headache (i.e., one sensitive to the position and movements of his head and body such that the pain was increased by movement of the head up or down). The headaches were unresponsive to common painkillers. Diffuse rheumatic arthralgia with dyspnea on exertion were noted.” See illustration below:

(a) The photo on the left at 40x magnification shows the blood condition of the patient before the inoculation. (b)The image on the right, also at 40x magnification, shows the deformation of the erythrocyte cell profile, and the strong tendency for the deformed erythrocytes to aggregate. (Source: IJTPVR)

Case No. 2:

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“This case was a woman 54 years old whose symptoms included the drug-resistant severe headache, profound worsening asthenia, sleep/wake rhythm disorders, generalized paresthesia and dysesthesia, psychic manifestations with depressive mood after the second dose of the Pfizer vaccine.” Her blood story is captured below:

(a) Deformation and erythrocyte aggregation with signs of hemolysis at 40x magnification. (b) A foreign crystallized tubular structure at 120x magnification. (Source: IJTPVR)

(a) Aggregated/conglobated erythrocytes, with hemolysis, and clustered fibrinat 40x magnification. (b) A blowup of a foreign complex crystalline structureat 120x magnification.Figure 8. (a) Deformation and erythrocyte aggregation with signs of hemolysis at 40x magnification. (b) A foreign crystallized tubular structure at 120x magnification. (Source: IJTPVR)

CDC Quietly Removes Statement that Says “mRNA and the Spike Protein Do Not Last Long in the Body” from Their Website

Authors: Jim Hoft Published August 14, 2022 

The US Center for Disease Control and Prevention (CDC) has taken down from its website the statement that states “mRNA and the spike protein do not last long in the body.”

On July 15, the CDC quietly modified its website, removing the section that suggested mRNA and spike protein do not last in human bodies.

Under this topic, it stated that “our cells break down mRNA from these vaccines and get rid of it within a few days after vaccination.”

“Scientists estimate that the spike protein, like other proteins our bodies create, may stay in the body up to a few weeks,” it continued.

The CDC’s decision to remove this information about mRNA and spike proteins from the public is still an open question.

Below is the updated information on the CDC website:

Source: CDC

Research conducted by a third party and linked to the CDC at the bottom of this page reveals the following:

How long mRNA lasts in the body

The Pfizer and Moderna vaccines work by introducing mRNA (messenger RNA) into your muscle cells. The cells make copies of the spike protein and the mRNA is quickly degraded (within a few days). The cell breaks the mRNA up into small harmless pieces. mRNA is very fragile; that’s one reason why mRNA vaccines must be so carefully preserved at very low temperatures.

How long spike proteins last in the body

The Infectious Disease Society of America (IDSA) estimates that the spike proteins that were generated by COVID-19 vaccines last up to a few weeks, like other proteins made by the body. The immune system quickly identifies, attacks and destroys the spike proteins because it recognizes them as not part of you. This “learning the enemy” process is how the immune system figures out how to defeat the real coronavirus. It remembers what it saw and when you are exposed to coronavirus in the future it can rapidly mount an effective immune response.

When you click on the link, a popup notification will appear that says, “CDC cannot attest to the accuracy of a non-federal website.”

“However, a peer-reviewed study by researchers at Stanford University finds that the spike protein created by the COVID vaccines remains in the body much longer than believed and at levels higher than those of severely ill COVID-19 patients,” Clark County Today reported.

“Dr. Robert Malone, the key developer of the mRNA technology in the Pfizer-BioNTech and Moderna vaccines, said the findings were “buried” in the study, which was published by the journal Cell. He described the results as a potential “health public policy nightmare” in an analysis on his Substack page,” the outlet added.

It should be clear by now that Americans were lied to about the vaccine and its effectiveness.

A study published in the New England Journal of Medicine and conducted in Israel found that the immunity against the delta variant of SARS-CoV-2 waned in all age groups a few months after receipt of the second dose of vaccine, as reported by The Gateway Pundit.

“These findings indicate that immunity against the delta variant of SARS-CoV-2 waned in all age groups a few months after receipt of the second dose of vaccine,” the study concluded.

And according to a study published by CDC in February this year, the Covid booster mRNA vaccine effectiveness wanes after 4 months during the omicron period.

“During the Omicron-predominant period, VE against COVID-19–associated ED/UC visits and hospitalizations was 87% and 91%, respectively, during the 2 months after a third dose and decreased to 66% and 78% by the fourth month after a third dose. Protection against hospitalizations exceeded that against ED/UC visits.” the CDC said.

The Centers for Disease Control and Prevention also quietly released new guidelines on the COVID vaccination last week, as reported by TGP.

In a news briefing on Thursday, Greta Massetti, chief of the CDC’s Field Epidemiology and Prevention Branch, said, “The current conditions of this pandemic are extremely different from those of the prior two years.”

How the Pfizer-BioNTech COVID-19 vaccine affects human liver cells

Authors: Lund University MARCH 10, 2022 Medical Xpress

A recent study from Lund University in Sweden on how the Pfizer-BioNTech COVID-19 vaccine affects human liver cells under experimental conditions, has been viewed more than 800,000 times in just over a week. The results have been widely discussed across social media—but the results have in many cases been misinterpreted. Two of the authors, Associate Professor Yang de Marinis (YDM) and Professor Magnus Rasmussen (MR), share their views.

How did this study come about?

YDM: A previous study from MIT has indicated that the SARS-CoV-2 virus mRNA can be converted to DNA and integrated into the human genome. Indeed, about 8 percent of human DNA comes from viruses inserted into our genomes during evolution. Does the Pfizer-BioNTech mRNA vaccine get converted to DNA or not? This has been the question our study aims to answer.

What did your study conclude?

YDM: This study does not investigate whether the Pfizer vaccine alters our genome. Our publication is the first in vitro study on the conversion of mRNA vaccine into DNA, inside cells of human origin. We show that the vaccine enters liver cells as early as six hours after the vaccine has been administered. We saw that there was DNA converted from the vaccine’s mRNA in the host cells we studied.

MR: These findings were observed in petri dishes under experimental conditions, but we do not yet know if the converted DNA is integrated into the cells’ DNA in the genome—and if so, if it has any consequences.

Why liver cells and why the specific dose?

YDM: About 18 percent of the vaccine accumulates in the liver just 30 minutes after the vaccine is injected in mice as reported by Pfizer in EMA assessment report, and therefore we chose to study liver cells. This also explains the choice of vaccine concentrations in our study, something we specifically address in the paper, which are 0.5–2% of the injection site concentration.

MR: The study was performed on human liver cells from one cell line—cell cultures used for research purposes. It is a good tool when studying molecular and cellular processes, they are easy to research, and since the cell lines are easily accessible, studies often start with various cell lines.

What are key limitations of the study?

MR: One should consider that cell lines differ from cells in living organisms, and therefore it is important that similar investigations are also studied in humans.

It is important to bear in mind that the liver cells in this study are more genetically unstable than our own liver cells.

YDM: One of the limitations of our study is that we don’t know if what we observed in this cell line could also happen in cells of other tissue types, and this needs to be addressed in follow-up studies.

The study has received a lot of media attention, what are your thoughts on that?

MR: We understood that the study would attract attention, but we think it is self-evident that this type of research should be pursued. We have a new vaccine, and it needs to be tested in cell and animal models and also in humans, in various ways. The result might be surprising, but it is also a bit surprising that such studies do not seem to have been carried out before.

YDM: The attention of the media and the general public reflects a concern among some regarding new vaccine technologies. This in itself motivates the need for further studies.

Based on this study, is there any reason to not get vaccinated?

MR: There is no reason for anyone to change their decision to take the vaccine based on this study.

What are the next steps in this research?

YDM: More research is needed. Data, especially data from vaccinated humans, will hopefully sort out the question marks. Whether our results are true for other cell types in humans, or if they are specific to mRNA vaccines, are among many questions for further research.

About the study:

In a lab environment, i.e., in petri dishes, the researchers added Pfizer BioNTech’s vaccine to a cell line that originally came from a human liver tumor.

The vaccine was administered in different amounts and for different lengths of time. Cells that received no vaccine at all were used for control purposes. The researchers then investigated how different gene expressions in the cells changed over time. A gene that the researchers studied produces the protein LINE-1.

“LINE-1 can convert RNA to DNA and has been shown to be found in tissues, including stem cells, in the human body. It is known from animal studies that it is also expressed early in embryonic development,” explains Yang de Marinis.

Nonintegrating Direct Conversion Using mRNA into Hepatocyte-Like Cells

Authors:: angtae Yoon, 1 , 2 Kyojin Kang, 1 , 2 Young-duck Cho, 3 Yohan Kim, 1 , 2 Elina Maria Buisson, 1 , 2 Ji-Hye Yim, 1 , 2 Seung Bum Lee, 4 Ki-Young Ryu, 5 Jaemin Jeong, 1 , 2 and Dongho Choi 1 , 2 Biomed Res Int. 2018; 2018: 8240567.Published online 2018 Sep 20.doi:  10.1155/2018/8240567 PMCID: PMC6171260PMID: 30327781

Abstract

Recently, several researchers have reported that direct reprogramming techniques can be used to differentiate fibroblasts into hepatocyte-like cells without a pluripotent intermediate step. However, the use of viral vectors for conversion continues to pose important challenges in terms of genome integration. Herein, we propose a new method of direct conversion without genome integration with potential clinical applications. To generate hepatocyte-like cells, mRNA coding for the hepatic transcription factors Foxa3 and HNF4α was transfected into mouse embryonic fibroblasts. After 10-12 days, the fibroblasts converted to an epithelial morphology and generated colonies of hepatocyte-like cells (R-iHeps). The generated R-iHeps expressed hepatocyte-specific marker genes and proteins, including albumin, alpha-fetoprotein, HNF4α, CK18, and CYP1A2. To evaluate hepatic function, indocyanine green uptake, periodic acid-Schiff staining, and albumin secretion were assessed. Furthermore, mCherry-positive R-iHeps were engrafted in the liver of Alb-TRECK/SCID mice, and we confirmed FAH enzyme expression in Fah1RTyrc/RJ models. In conclusion, our data suggest that the nonintegrating method using mRNA has potential for cell therapy.

1. Introduction

Liver disease is a serious public health issue worldwide because of its high prevalence and poor long-term prognosis including cirrhosis, hepatocellular carcinoma, and premature death from liver failure [12]. Furthermore, injuries with acquired, traumatic, or genetic etiologies can prevent the liver from performing a number of functions such as storing, detoxifying, and producing bile fluid and clotting factors and metabolic activities resulting in end-stage liver disease which ultimately requires liver transplantation [35]. Therefore, generating large quantities of hepatocytes is of paramount importance for scientists and clinicians. The ability of stem cells to be used in cell therapy has enormous potential [6]. Pluripotent stem cells have been used to generate hepatocyte-like cells [710]. Despite the usefulness of pluripotent stem cells, the risk of tumor formation [1112], long-term differentiation failure [13], and low differentiation efficiency [14] have emerged as points of controversy. The direct conversion of fibroblasts into target cells became feasible through lineage-specific transcription factors (TFs), and the direct conversion process is simpler and faster than induced pluripotent stem cell (iPSC) generation [1516]. Direct conversion of one cell type into another without using a pluripotent intermediate is a promising practical source for invaluable cells such as hepatocytes [17].

Compared to pluripotent stem cell differentiation, direct reprogramming has a number of advantages, including the lack of tumorigenic risk [18], a fast conversion rate [19], and the promise of injured tissue repair using in vivo reprogramming [2021]. Recently, a number of studies have investigated the results of direct conversion by RNA in cells such as neurons and cardiomyocyte-like cells [2223]; however, insufficient studies have been carried out in hepatocytes. We propose a method of functional hepatocyte generation suitable for engrafting in a damaged liver animal model, in which modified mRNA is used to overexpress reprogramming factors without genomic modification.

2. Materials and Methods

2.1. mRNA Synthesis by In Vitro Transcription (IVT)

To make mRNAs, template DNAs were obtained from Foxa3 and HNF4α plasmid. mRNAs were transcribed in vitro from 1.5 ug of each DNA template and synthesized using the MEGAscript T7 kit (Ambion, Austin, TX, USA), per each 40 ul of reaction buffer. IVT reactions were mixed with 2 ul of each NTP and incubated between 2 and 4 hrs at 37°C. To remove the template DNAs, 1ul of TURBO DNase was used after IVT reaction and incubated for 15 min at 37°C and purified with 70% EtOH for 5 min. Reacted mRNAs were capped during m7G capping and 2′-O-Methylation (ScriptCap m7G capping system and 2′-O-Methyltransferase kit, CELLSCRIPT, Madison, WI, USA), subsequently tailed (A-Plus Poly (A) Polymerase Tailing kit; CELLSCRIPT), and repurified as previously described. mRNA length was confirmed using 1% LE Agarose Gels (GenomicsOne Co. Ltd., Seoul, Korea). RNA concentrations were calculated with the use of Nanodrop and were adjusted to 200-300 ng/ul by adding Nuclease-free water (Ambion). As a control, eGFP mRNA was used and the expression of eGFP was observed and compared with Foxa3 and HNF4α.

2.2. Modified mRNA Transfection

To generate R-iHeps, mouse embryonic fibroblasts (MEFs) were cultured in Dulbecco’s Modified Eagle’s Medium (Life Technologies, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum, 3.14 uM β-mercaptoethanol (Sigma-Aldrich, St. Louis, MO, USA), and 1% penicillin/streptomycin (Life Technologies) at 37°C in a CO2 incubator. Lipofectamine 2000 (Life Technologies) was used for mRNA transfection.  On day 0 and 3, 1.5 ug of Foxa3 and HNF4α mRNA each and 3 ul of lipofectamine 2000 were diluted in a mixture of 125 ul of Opti-MEM reduced serum media (Life Technologies) in separate tubes. They were then mixed together into one tube and were incubated at room temperature for 5 minutes. In a culture dish, 250 ul of the incubated mixture was added in 1ml of cell growth media and was incubated at 37°C for 4 hours. After 24 hours, the medium was changed with DMEM/F-12 (Life Technologies) supplemented with 10% fetal bovine serum (Life Technologies), 10mM Nicotinamide (Sigma-Aldrich), 0.1 uM dexamethasone (Sigma-Aldrich), 1% Insulin-Transferrin-Selenium-X Supplement (Life Technologies), 1% penicillin/streptomycin (Life Technologies), 20 ng/ml hepatocyte growth factor (Peprotech, Rocky Hill, NJ, USA), and 20 ng/ml epidermal growth factor (Peprotech). The medium was changed every two days.

2.3. Quantitative Real-Time PCR

One ug of mRNA isolated with Trizol reagent (Life Technologies) was reverse transcribed with the Transcriptor First Strand cDNA Synthesis Kit (Roche, Basel, Switzerland). Then, quantitative real-time PCR was performed using 10 ul of qPCR PreMix (Dyne Bio, Seongnam-si, Gyeonggi-do, Korea), 1 ul cDNA, and oligonucleotide primers on a CFX Connect Real-Time PCR Detection System (Bio-Rad, Hercules, CA, USA). Reactions were analyzed in triplicate for each gene. A total of 40 PCR cycles were performed, each cycle at 95°C for 20 sec, then 60°C for 40 sec. Melting curves and melting peak data were obtained to characterize PCR products. All primers are shown in Supplementary Table 1.

2.4. Immunostaining

The cells were fixed in 4% paraformaldehyde in phosphate buffered saline (PBS, pH 7.4) for 20 min at room temperature. The fixed cells were washed twice with a staining solution of PBS containing 1% fetal bovine serum for 5 min and then permeabilized with 0.25% Triton X-100 for 30 min at room temperature. Thereafter, the cells were incubated overnight at 4°C with the following primary antibodies: anti-albumin, E-cadherin, CK18, HNF4a, CYP1A2, ASGR1, Hep par-1, AFP, and vimentin (Table S2). The next day, cells were washed three times with a staining solution, and the appropriate fluorescence labeled Alexa-Fluor secondary antibody was added and incubated for 2 hours, in the dark, at room temperature. The nucleus was counterstained with Hoechst 33342 (Invitrogen, Carlsbad, CA, United States).

2.5. ICG Uptake and PAS Staining

For the indocyanine green (ICG) uptake assay, the cells were incubated for 15 min at room temperature with 1mg/ml DID Indocyanine Green Inj. (Dongindang Pharmaceutical, Siheung-si, Gyeonggi-do, Korea) and washed three times with PBS. For periodic acid-Schiff (PAS) staining, Periodic Acid-Schiff staining kit (Abcam, Cambridge, UK) was used. First, the cells were fixed with 4% paraformaldehyde in PBS for 20 min at room temperature. These fixed cells were rinsed in slow running tap water and then exposed to periodic acid solution for 5 min at room temperature. After being washed four times with distilled water, the cells were treated with Schiff’s reagent for 15 min at room temperature and washed three times with distilled water. Thereafter, the cells were stained with hematoxylin (Modified Mayer’s) for 2 min and washed three times with distilled water. A bluing reagent was applied for 30 sec to clearly identify the stained cells.

2.6. Albumin Secretion

To assess the function of these R-iHeps, we measured the secretion of the most well-known hepatic marker, albumin. Albumin secretion in R-iHeps was done according to the manufacturer’s protocol using the Mouse Albumin ELISA kit (Bethyl Laboratories, Montgomery, TX, USA). Media was collected every two days and were stored at -80°C. The undiluted samples were measured in duplicate following the protocol’s suggestion.

2.7. In Vivo Experiment

To determine whether R-iHeps can engraft and differentiate into functional hepatocytes in vivo, we used a liver injury mouse model, Alb-TRECK/SCID (kind gift from Taniguchi Hideki, Yokohama City University, Japan) and Fah1RTyrc/RJ (kind gift from Hyongbum (Henry) Kim, Yonsei University). The animal experiments were performed in accordance with the Center for Laboratory Animal Sciences, the Medical Research Coordinating Center, and the HYU Industry-University Coordinating Foundation regulations (2016-0212A, 2017-0055A). To induce liver injury, Alb-TRECK/SCID mice were intraperitoneally injected with 2 ug/kg of diphtheria toxin (Sigma-Aldrich) 2 days before transplantation. Liver damage was also induced in Fah1RTyrc/RJ mice by withdrawing NTBC ((2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)) 24 hrs before transplantation. mCherry-positive R-iHeps were obtained via FACS sorting and were transplanted through the spleen of the mouse (5×105 cells/mice). Alb-TRECK/SCID and Fah1RTyrc/RJ mice were sacrificed at 48 hrs and three weeks after transplantation, respectively.

3. Results

3.1. In Vitro Transcription and Expression of mRNA

To synthesize mRNA of Foxa3 and HNF4α, we cloned cDNA into pcDNA/UTR120A (Figure 1(a)). We conducted in vitro transcription using T7 polymerase and then modified synthesized mRNA. Synthesized mRNA is loaded in 1.5% agarose gels to confirm mRNA degradation. Foxa3 and HNF4α mRNA are synthesized to full length and not degraded (Figure 1(b)). mRNA stability and expression are evaluated for GFP mRNA transfection into MEFs (Figure 1(c)). After GFP mRNA transfection, GFP fluorescence was detected on day 1 and 3 under fluorescence microscope. However it almost disappeared on day 7.  The transfection efficiency of GFP mRNA was 18.53% onday 1 (Figure 1(d)). Therefore we decided transfection time of Foxa3 and HNF4α mRNA on day 0 and 3 to convert them into hepatocyte-like cells.Open in a separate windowFigure 1

Transcription and expression of modified mRNA of HNF4α and Foxa3. (a) Scheme of in vitro transcription and modification of mRNA. (b) Gel loading of HNF4α and Foxa3 mRNA. (c) One time transfection and protein expression of green fluorescence protein mRNA into MEFs for 7 days. Green fluorescence was detected under fluorescence microscope. Scale bars: 100 um. (d) Analysis of transfection efficiency of GFP mRNA by Flow Cytometry.

3.2. Generation of R-iHeps from MEFs and Morphogenesis of Hepatocyte-Like Cells

In order to generate hepatocyte-like cells, Foxa3 and HNF4α mRNA were transfected into mouse embryonic fibroblasts (MEFs) for 4 hours at temperature of 37°C (Figure 2(a)) on day 0 and 3. Two days after transfection, we switched media to direct conversion media for effective conversion into hepatic lineage. On day 6, MEFs started moving and switching morphology steadily (Figure 2(b)). Finally we found epithelial colonies similar with hepatocyte which are plentiful cytosol, small nuclei, and forming bile canaliculi after 12 days after transfection. These results suggest that directly converted R-iHeps are effective for generating hepatocyte-like cells from MEFs using mRNA.Open in a separate windowFigure 2

Generation of R-iHeps using mRNA from MEFs. (a) Scheme of generation of R-iHeps. mRNAs of modified HNF4α and Foxa3 were transfected with lipofectamine on day 0 and 3. MEFs: mouse embryonic fibroblasts; R-iHeps: RNA induced hepatocyte-like cells. (b) The morphology of directly converted R-iHeps by mRNA. On day 12, R-iHeps were shown and grown. Insets: higher magnification of the boxed areas. Scale bars: 100 um.

3.3. Acquisition of Hepatic Characteristics of R-iHeps

To gain a better understanding of R-iHeps characteristics, we performed quantitative real-time PCR (qPCR) of hepatocyte-specific genes. Albumin, alpha-fetoprotein (AFP), HNF4α, CK18, and CYP1A2 expressions were markedly increased in R-iHeps as compared to MEFs (Figure 3(a)). Also, these genes’ expressions were similar to miHeps which were generated using Foxa3 and HNF4α retrovirus [2425] and were correlated with protein expression (Figure 3(b)). Albumin, E-cadherin, CK18, HNF4α, CYP1A2, ASGR1, Hep par-1, and AFP were expressed in R-iHeps but not MEFs. Vimentin which is a fibroblast marker was only stained in MEFs. To evaluate hepatic function of R-iHeps in vitro, glycogen storage was revealed through Periodic Acid-Schiff (PAS) staining by more than 70% of the glycogen storage in R-iHeps and increased uptake of Indocyanine green (ICG) uptake compared to MEFs. This proved the xenobiotic metabolic activities in more than 50% of the R-iHeps which showed effective hepatic function (Figure 3(c)). In addition, the albumin secretion rate of R-iHeps was measured by Enzyme-Linked Immunosorbent Assay (ELISA) in the culture media (Figure 3(d)). Albumin secretion of R-iHeps (1×105 cells) rapidly increased six days after seeding. This indicates that R-iHeps secrete albumin abundantly after stabilization period. These findings demonstrate that R-iHeps generated by the mRNA of Foxa3 and HNF4α could be another cell source of hepatocyte-like cells representing hepatic marker gene, protein expression, and a gain of hepatic function.Open in a separate windowFigure 3

Analysis of hepatic characteristics of R-iHeps. (a, b) Comparison of hepatic gene and protein marker expression of R-iHeps and MEFs. (a) Expression levels of hepatic marker genes in R-iHeps (red bar) as determined by qPCR. Albumin, AFP, HNF4α, CK18, and CYP1A2 expression were increased in R-iHeps. MEFs: mouse embryonic fibroblasts; R-iHeps: RNA induced hepatocyte-like cells; miHeps: directly converted hepatocyte-like cells using retrovirus; mPHs: mouse primary hepatocytes. , p<.05; , p<.01; , p<.001. (b) Albumin (green)/E-cadherin (red), CK18 (green)/HNF4α (red), CYP1A2 (green)/ASGR1 (red), and Hep par-1 (green)/AFP (red) protein expression were detected in R-iHeps. Vimentin which is a fibroblast marker was detected not in R-iHeps but MEFs. Hoechst (blue) labels all nuclei. The images were captured using confocal microscopy. Scale bars: 50 um. (c) Confirmation of hepatic transporter function and presence of glycoprotein in R-iHeps by indocyanine green (ICG) uptake and Periodic Acid-Schiff (PAS) staining, respectively. (d) Measurement of secreted albumin in the culture media in vitro by ELISA. , p<.001.

3.4. In Vivo Transplantation of R-iHeps

Finally, we implanted R-iHeps into two fulminant hepatic failure models to test whether engraftment and differentiation into functional hepatocytes in damaged liver could occur. First, we used Alb-TRECK/SCID model mice which were injured by diphtheria toxin (DT) [26]. mCherry tagged R-iHeps (5X105 cells/mice), labeled for easy tracing in vivo, were administrated into the spleen 48 hrs after DT injection (2 ug/kg). At two days after transplantation, livers were harvested and sectioned. Histologically damaged liver (PBS injection group) showed disrupted cell junctions, necrotic cells were also found in H&E staining, and albumin expression was significantly decreased as seen through many unstained hepatocytes observed under confocal microscopy as compared to normal and R-iHeps injection groups (Figure 4(a)). On the other hand, in R-iHeps injection group, albumin positive hepatocytes costained with mCherry were found around blood vessels. In addition, liver structure was recovered by R-iHeps injection as shown in H&E staining. To prove the above data, R-iHeps were transplanted into Fah1RTyrc/RJ mice model which was damaged by the withdrawal of NTBC ((2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)) [27]. Being transplanted after three weeks, R-iHeps and mouse primary hepatocytes (mPHs) were detected through fumarylacetoacetate hydrolase (FAH) enzyme (Figure 4(b)). Fah1RTyrc/RJ mice model did not express FAH, but R-iHeps or mPHs transplanted mice liver produced FAH enzyme. Taken together, these results suggest that mRNA induced hepatocyte-like cells (R-iHeps) not only are transplantable in fulminant damaged liver, but also express the hepatic specific enzyme in vivo. Therefore, R-iHeps might be another cell source for liver regeneration.Open in a separate windowFigure 4

In vivo transplantation of R-iHeps. (a) mCherry labeled R-iHeps (5X105 cells/100 ul) transplanted into Alb-TRECK/SCID mice via intrasplenic injection. Alb-TRECK/SCID mice were liver damaged by diphtheria toxin (DT, 2 ug/kg) 48 hrs before cell transplantation. All histological data were shown at 48 hrs after cell transplantation. Normal group: no DT administered; PBS group: PBS injection only after DT injury; R-iHeps group: R-iHeps injection after DT injury. Hoechst 33342 (blue) labels all nuclei. Scale bars in H&E staining picture: 100 um; scale bars in fluorescence pictures: 50 um. (b) R-iHeps (5X105 cells/100 ul) transplanted into Fah1RTyrc/RJ mice via intrasplenic injection. Fah1RTyrc/RJ mice were liver damaged by NTBC ((2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)) withdrawal 24 hrs before cell injection. PBS group: PBS injection only; R-iHeps group: R-iHeps injection; mPHs group: mouse primary hepatocytes (5X105 cells/100 ul) injection. Detection of FAH enzyme expression by immunoperoxidase staining at 3 weeks after transplantation. Scale bars: 100 um.

4. Discussion

Patients with end-stage chronic liver disease generally require liver transplantation as the sole definitive method of treatment [2829]. Potential liver transplant recipients are outstripping possible donors [30]. Numerous studies have investigated ways to surmount this shortage [3]. The introduction of lineage-specific TFs into somatic cells enabled distinct cellular identities to be introduced, while bypassing a pluripotent stem cell state [3134]. However, viral transduction systems have the potential risk of insertional mutations and integration-associated genotoxicity [3538]. We propose a simple method of forming hepatocyte-like cells without relying on retroviral vectors. Our method successfully induced direct reprogramming of mouse embryonic fibroblasts into R-iHeps by mRNA transfection. Our data proved that R-iHeps, functionally similar to hepatocytes, were produced through direct reprogramming with mRNA. The R-iHeps showed a markedly increased expression of albumin and AFP, which are widely known as hepatocyte-specific proteins, while the expression of fibroblast-specific proteins such as vimentin decreased. In addition, PAS staining showed an increase in glycogen storage capacity, and ICG uptake confirmed that the cells effectively performed hepatic functions. Increases in albumin secretion and urea synthesis were confirmed by ELISA.

5. Conclusion

This study showed that mRNA can be utilized for direct hepatocyte reprogramming and that this technique is beneficial because it allows accurate control of reprogramming factors. As it has a number of advantages over traditional methods using retroviral vectors, our model has revealed a new paradigm with exciting potential for cell therapy with clinical applications.

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Autoimmune Hepatitis Following Vaccination for SARS-CoV-2 in Korea: Coincidence or Autoimmunity?

Authors: Seong Hee Kang 1 2Moon Young Kim 1 3Mee Yon Cho 4Soon Koo Baik 1 5Affiliations expandPMID: 35437965PMCID: PMC9015903DOI: 10.3346/jkms.2022.37.e116

J Korean Med Sci 2022 Apr 18;37(15):e116. doi: 10.3346/jkms.2022.37.e116.

Abstract

Autoimmune hepatitis (AIH) is a chronic, autoimmune disease of the liver that occurs when the body’s immune system attacks liver cells, causing the liver to be inflamed. AIH is one of the manifestations of a coronavirus disease 2019 (COVID-19), as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few cases of AIH have been described after vaccination with two messenger RNA (mRNA)-based vaccines—BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)—against SARS-CoV-2. Herein, we report a case of AIH occurring after Pfizer-BioNTech COVID-19 vaccine. A 27-year-old female presented with jaundice and hepatomegaly, appearing 14 days after receiving the second dose of Pfizer-BioNTech vaccine. Her laboratory results showed abnormal liver function with high total immunoglobulin G level. She was diagnosed with AIH with histologic finding and successfully treated with oral prednisolone. We report an AIH case after COVID-19 vaccination in Korea.
Go to:Graphical Abstract

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic, putatively caused by the widespread transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in 257,469,528 laboratory-confirmed cases of infection and 5,158,211 deaths globally as of November 28, 2021.1 Rapid vaccine development, however, has significantly mitigated severe COVID-19 illness. Two messenger RNA (mRNA) COVID-19 vaccines, BNT162b2 (Pfizer-BioNTech, New York, NY, USA/Mainz, Germany) and mRNA-1273 (Moderna, Cambridge, MA, USA), were granted emergency use authorization by the United States Food and Drug Administration in December 2020. SARS-CoV-2 infection has been associated with the development of autoimmune processes.2 Because SARS-CoV-2 harbors the same protein motif the mRNA vaccine codes for, it is plausible that these vaccines could trigger autoimmune diseases in predisposed patients.34 Autoimmune hepatitis (AIH) is a polygenic multifactorial disease that may be triggered by specific environmental factors, such as viral infections, resulting in the loss of self-tolerance to autoantigens in genetically susceptible individuals.5

Go to:CASE DESCRIPTION

We treated a 27-year-old female nurse who developed AIH after COVID-19 vaccination. She had no known history of liver disease and did not use herbal remedies or alcohol. She received a second dose of the Pfizer-BioNTech COVID-19 vaccine on March 30, 2021, and, since April 6, 2021, symptoms of nausea, vomiting, headache, fever, and dark urine continued. Accordingly, she was hospitalized via the emergency room 14 days after COVID-19 vaccination. A COVID-19 polymerase chain reaction test, performed at the local hospital on April 7 and 12, 2021, was negative. The physical examination was unremarkable, except for scleral icterus, jaundice, and palpable hepatomegaly. In the emergency room, laboratory investigations were significant for the following: bilirubin, 8.6 mg/dL; aspartate aminotransferase (AST), 1,004 U/L; alanine aminotransferase (ALT), 1,478 U/L; alkaline phosphatase, 182 U/L, white blood cell count, 6,720/μL (neutrophils, 46.8%); hemoglobin, 13.0 g/dL; platelet count 373,000/μL; blood urea nitrogen/creatinine, < 5.0/0.54 mg/dL (estimated glomerular filtration rate, 145.0 mL/min/1.73 m2); and prothrombin international normalized ratio, 1.1. Laboratory results were negative for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus types 1 and 2, and human immunodeficiency virus. Antinuclear antibody (ANA) was positive (1:80; mixed pattern). Other antibodies (including anti-mitochondrial, anti-smooth muscle, liver-kidney microsomal, and antineutrophil cytoplasmic antibodies) were negative. Total immunoglobulin G (IgG) level was 1,641 mg/dL (normal range, 549–1,584 mg/dL). Ceruloplasmin, transferrin saturation, thyroid function test, and serum protein electrophoresis were all normal. Abdominal ultrasound revealed splenomegaly (12.5 cm) without cirrhosis and gallbladder wall thickening.

Liver dynamic computed tomography revealed no evidence of biliary lithiasis or biliary dilation, and ultrasound-guided transabdominal liver biopsies were obtained. In microscopic examination, 17 portal tracts were identified. Although there was a focal bridging, the overall lobular architecture was preserved in the low magnification. Some portal tracts were widened by moderate inflammation with periportal fibrosis (Fig. 1). The portal inflammation was composed of mainly lymphocytes, clusters of plasma cells and few eosinophils, extending into proto-lobular interface (interface hepatitis) (Fig. 2A). The immunohistochemical staining for plasma cell markers, MUM1 and CD138 confirmed significant plasma cell infiltration in portal tracts as well as in lobules (Fig. 2B). Diffuse moderate necroinflammatory damage in lobules, associated with perivenular hepatocytes degeneration, mild cholestasis with hepatocytic rosettes (Fig. 2C) and sinusoidal inflammation were found. Other than COVID-19 vaccination, no other drug, herbal supplement, or toxin use were reported by the patient. The revised original score for AIH pretreatment was 18 (results > 15 suggest definite AIH). Treatment with oral prednisolone (40 mg daily) was initiated. Plasma ALT, AST, and total bilirubin levels over time, and before and after treatment, are summarized in Fig. 3. After three weeks of treatment, diarrhea and fever developed, and she was transferred to the hospital’s emergency room. Treatment with prednisolone (20 mg daily) was discontinued with the diagnosis of enteritis. Four days after admission, symptoms were relieved, and she was discharged from hospital with steroid discontinuation. Two weeks after stopping therapy, there were biochemical signs of an AIH relapse; therefore, treatment with oral prednisolone (10 mg daily) was restarted. Liver enzyme levels were completely normalized and the patient’s symptoms significantly improved.


Fig. 1
The microphotograph of low magnification of liver biopsy shows portal widening with periportal fibrosis (A) hematoxylin and eosin ×100, (B) Masson trichrome ×100.Click for larger imageDownload as PowerPoint slide

Fig. 2
Histological finding. (A) The porto-lobular interface shows severe inflammation composed of lymphocytes, clausters of plasma cells (circle) and a few eosinophils. Bile ducts (closed arrow) are not damaged (H&E, ×400). (B) The photomicrography of MUM1 immunohistochemical stain demonstrates numerous plasma cell infiltration (×400). (C) The lobules show diffuse degeneration of hepatocytes, mild cholestasis in hepatocytic rosettes (opened arrow) and sinusoidal lymphoplasma cells infiltration (H&E ×400).
H&E = hematoxylin and eosin.Click for larger imageDownload as PowerPoint slide

Fig. 3
Trends of serum ALT, AST and total bilirubin over time.
ALT = alanine aminotransferase, AST = aspartate aminotransferase.Click for larger imageDownload as PowerPoint slide

We described a case of AIH that developed in a patient after vaccination with the Pfizer-BioNTech COVID-19 vaccine, which was resolved with steroid treatment. To date, four cases of AIH have been reported after Pfizer-BioNTech COVID-19 vaccination in the literature (Table 1)678, the first of which was reported by Bril et al.3 The patient was a 35-year-old woman in her third month postpartum who developed AIH after COVID-19 vaccination. In this case, AIH exhibited some atypical features: autoantibodies other than ANA were negative and eosinophils were present on liver histology. Similarly, Lodato et al.6 reported a case of AIH occurring after vaccination, with no development of autoantibodies and eosinophil infiltrate in liver histology. Thereafter, two patients had a history of Hashimoto’s disease, high IgG levels, and typical findings on biopsy, unlike the above cases.78 Although our patient had no autoimmune disease, autoantibodies were positive, and IgG level was high. In addition, our case had typical findings on biopsy and responded well to steroid therapy. It is thought to be a new-onset AIH triggered by COVID-19 vaccination, but periportal fibrosis was observed in histological examination. However, in case with acute onset, there may be minimal fibrosis. Moreover, symptoms developed after the second vaccination in this patient, but there is a possibility that inflammation may have occurred even though there were no symptoms after the first vaccination.


Table 1
Characteristics of patients with autoimmune hepatitis after Pfizer-BioNTech COVID-19 vaccineClick for larger imageClick for full tableDownload as Excel file

Because causality cannot be definitively confirmed, it is possible that this association was coincidental. However, severe cases of SARS-CoV-2 infection are characterized by autoinflammatory dysregulation.9 Because the viral spike protein appears to be responsible, it is plausible that spike-directed antibodies induced by vaccination may also trigger autoimmune conditions in predisposed individuals.10 In support of this, several cases of immune thrombocytopenia have been reported days after COVID-19 vaccination. Vaccines protect the host from the virus by inducing antibody generation against viral peptides.11 Autoimmunity can develop due to cross-reactivity to the generated antibodies. The epitopes used for induction of the host immune system may mimic the structure of self-peptides, and antibodies that develop after vaccination may cause cross-reactivity directed to the self.12

Given the close temporal relationship between vaccination and onset of symptoms, we hypothesized that vaccination against COVID-19 could have triggered the development of AIH in our patient. To the best of our knowledge, this is the first reported episode of AIH that developed post-COVID-19 vaccination in Korea. Whether a causal relationship exists between COVID-19 vaccination and the development of AIH remains to be determined. Nevertheless, it is necessary to raise awareness about potential side effects that will likely emerge as more individuals are vaccinated.

1. World Health Organization. Global surveillance for COVID-19 caused by human infection with COVID-19 virus: interim guidance 2020. [Updated 2020]. [Accessed November 28, 2021].https://apps.who.int/iris/handle/10665/331506.2. Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol 2021;33(2):155–162.

3. Bril F, Al Diffalha S, Dean M, Fettig DM. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty? J Hepatol 2021;75(1):222–224.

4. Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD, et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol 2021;96(5):534–537.

5. Czaja AJ. Autoimmune liver disease. Curr Opin Gastroenterol 2004;20(3):231–240.

6. Lodato F, Larocca A, D’Errico A, Cennamo V. An unusual case of acute cholestatic hepatitis after m-RNABNT162b2 (Comirnaty) SARS-CoV-2 vaccine: coincidence, autoimmunity or drug-related liver injury. J Hepatol 2021;75(5):1254–1256.

7. Rocco A, Sgamato C, Compare D, Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casuality. J Hepatol 2021;75(3):728–729.

8. Avci E, Abasiyanik F. Autoimmune hepatitis after SARS-CoV-2 vaccine: new-onset or flare-up? J Autoimmun 2021;125:102745

9. Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, et al. COVID-19 and autoimmunity. Autoimmun Rev 2020;19(8):102597

10. Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol 2020;217:108480

11. Sadarangani M, Marchant A, Kollmann TR. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans. Nat Rev Immunol 2021;21(8):475–484.

12. Malonis RJ, Lai JR, Vergnolle O. Peptide-based vaccines: current progress and future challenges. Chem Rev 2020;120(6):3210–3229.

Study into mRNA vaccine death rates sends ‘danger signals’

A new Danish study reveals disparities in all-cause mortality between mRNA and adenovirus vaccines

Do the covid vaccines save lives? That is the question on many people’s minds, that has led to heated discussions across the world.

A bombshell new study by a distinguished team of Danish researchers led by Prof. Christine Stabell-Benn suggests a surprisingly nuanced answer. In the randomized trials of the covid vaccines, the adenovector-based vaccines, including the AstraZeneca and Johnson & Johnson vaccines, reduced all-cause mortality of study participants relative to people randomly assigned a placebo. Indeed, the reduction in mortality is larger than expected from the Covid effect and may suggest additional beneficial “non-specific effects” from those vaccines against other health threats.

On the other hand, Stabell-Benn and her colleagues found no statistically meaningful evidence in the trial data that the mRNA vaccines reduced all-cause mortality. The numbers of deaths from other causes including cardiovascular deaths appear to be increased in this group, compensating for the beneficial effect of the vaccines on Covid. Stabell-Benn is keen to stress that the sample is relatively small and is calling for further investigation, and also that the study took place during very low levels of Covid, so the relative advantage of protection against Covid would have been smaller at that time compared to at other points in the pandemic.

However, these preliminary results stand in sharp contrast to the unambiguous message from public health agencies and governments worldwide, which granted emergency authorization to the vaccines based on evidence from the trials that the vaccines reduce the likelihood of getting symptomatic covid. From a purely scientific perspective, preventing symptomatic covid is an interesting outcome to study. From a public health perspective, prevention of covid symptoms is not as important as prevention of death or disease transmission, which the randomized trials did not study. Dr. Stabell Benn and her colleagues have now looked at overall mortality for the first time.

At the very least, the plain implication (since both sets of vaccines are available) is that public health authorities should have recommended the cheaper adenovector vaccines over the mRNA vaccines all along for most patients.

In other words, the international move to de-authorise the AstraZeneca vaccine across Europe and elsewhere looks like it may have been a mistake, and that AZ was actually a better option than the Pfizer or Moderna vaccines.

It offers a potential contributory explanation for the better overall mortality outcomes in the UK (which overwhelmingly used the AZ vaccine) than much of continental Europe (which phased out the AZ vaccine) after the vaccine programme in the second half of 2021. 

Since its publication in pre-print, the Stabell-Benn study has received very little coverage in the media. As Dr Stabell-Benn told Freddie Sayers in her UnHerd interview, she has become used to this reticence: I have been in this game for now almost thirty years, studying vaccines and finding these non-specific effects which have been very controversial. There are strong powers out there that don’t really want to hear about them. But to me this is good news: it means that we can optimize the use of vaccines to not only be strong protective effects against vaccine disease, but we can also optimize their use in terms of overall health. – PROFESSOR CHRISTINE STABELL-BENN, UNHERD

The reaction 

For a study with such a consequential conclusion, review from independent experts is crucial. In the past, such peer-review took place in anonymity, behind the closed doors of a scientific journal, with a single editor or associate editor serving as an umpire. Because of the small number of people involved in the review, the peer-review process is subject to well-known biases and long delays (months or longer). Worse, the public never had access to these deliberations and was asked to take it as an article of faith that a published peer-reviewed paper presented accurate conclusions.

A better process for the scientific review of some important papers has emerged during the pandemic – open peer review whereby the public can see the conversation among scientific experts. Though the Danish team released their paper in early April, it was an online review by vaccine safety expert and world-renowned epidemiologist Martin Kulldorff that catalyzed a discussion by scientists about it.

In his review, Kulldorff pointed to the clear implication of the results of the Danish paper. When both mRNA and adenovector vaccines are available, it’s better to take the vaccine with good randomized evidence of reductions in all-cause mortality rather than taking a vaccine where we cannot tell from the best evidence whether it reduces mortality. Kulldorff called for a new randomized controlled trial of the mRNA vaccine to find out if they can compete with the adenovirus-vector vaccines – as should occur in medicine whenever an effective intervention exists and another intervention seeks to show that it is as good or better. He also suggested that it is inappropriate to mandate vaccines for which the randomized clinical trials show a null result for mortality. 

Kulldorff’s open peer-review stoked some discussion among scientists about the feasibility of running a randomized trial comparing the vaccines. Mortality rates from covid infection – due partly to high levels of population immunity from covid recovery – are low, so a large sample size would be necessary to detect a difference. Whether such a study is even feasible is an open question, as is the importance of such a study. This kind of constructive discussion happens all the time in science.

However, some scientists – including zero-covid advocate Deepti Guradsani – reacted to Kulldorff’s article with public smears, false accusations of spreading vaccine misinformation, and the usual claims about right-wing connections. Even Jeremy Farrar, the head of the Wellcome Trust and a prominent architect of the pandemic policy in the UK, joined the fray by promoting such smears on his Twitter feed. 

Kulldorff is a prominent vaccine scientist who has presented his honest views on the covid vaccines, even when they go against the established narrative. In March 2021, he lost his position as an advisor to the US CDC for recommending against pausing the Johnson & Johnson vaccine for older Americans – an action that effectively killed the demand for the adenovirus vector vaccines in the US. He is the only person I know who the CDC has fired for being too pro-vaccine.  

When scientists slander prominent vaccine scientists, that damages vaccine confidence. Scientists should be encouraged to evaluate, compare and discuss the strengths and weaknesses of different vaccines, and to be free to advocate for one vaccine over another. Farrar’s promotion of the lies is particularly insidious because it sends a signal to scientists who might be interested in funding from the Wellcome Trust to shy away from voicing their honest thoughts about the Danish study or vaccines in general.

The stakes in the discussion about this paper are tremendously high. Of course, for the public at large, what covid vaccine is best for them is literally a life-and-death question. For scientists, at stake is the ability to participate honestly in open scientific reviews of hot button topics without having to face smears and reputational damage based on lies by other prominent scientists. If scientists lose their ability to reason publicly about studies like the ground-breaking Danish study, physicians will have no solid basis for their advice to patients on this topic or much else, and the public will have no reason to trust physicians and scientists.

COVID-19 Vaccination Considerations for Obstetric–Gynecologic Care

Last updated April 28, 2022

ACOG

This Practice Advisory was developed by the American College of Obstetricians and Gynecologists’ Immunization, Infectious Disease, and Public Health Preparedness Expert Work Group in collaboration with Laura E. Riley, MD; Richard Beigi, MD; Denise J. Jamieson, MD, MPH; Brenna L. Hughes, MD, MSc; Geeta Swamy, MD; Linda O’Neal Eckert, MD; Mark Turrentine, MD; and Sarah Carroll, MPH.

Summary of Updates

This Practice Advisory provides an overview of the currently available COVID-19 vaccines and guidance for their use in pregnant, recently pregnant, lactating, and nonpregnant individuals aged 12 years and older. For guidance and recommendations for the use of these vaccines in individuals aged 11 years or younger, please visit the website of the American Academy of Pediatrics. For additional information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and treatment, see ACOG’s Frequently Asked Questions.

This Practice Advisory has been updated to include the following:

  • Information regarding additional boosters for some individuals

Key Recommendations

  • The American College of Obstetricians and Gynecologists (ACOG) recommends that all eligible persons aged 12 years and older, including pregnant and lactating individuals, receive a COVID-19 vaccine or vaccine series.
  • The mRNA COVID-19 vaccines are preferred over the J&J/Janssen COVID-19 vaccine for all vaccine-eligible individuals, including pregnant and lactating individuals, for primary series, primary additional doses (for immunocompromised persons), and booster vaccination.
  • For patients who do not receive any COVID-19 vaccine, the discussion should be documented in the patient’s medical record. During subsequent office visits, obstetrician–gynecologists should address ongoing questions and concerns and offer vaccination again.
  • Obstetrician–gynecologists and other women’s health care practitioners should lead by example by being vaccinated and encouraging eligible patients to be vaccinated as well.
  • COVID-19 vaccines may be administered simultaneously with other vaccines. This includes vaccines routinely administered during pregnancy, such as influenza and Tdap.
  • Moderately to severely immunocompromised individuals (i.e., people who have undergone solid organ transplantation or have been diagnosed with conditions that are considered to have an equivalent level of immunocompromise) should receive an additional dose (i.e., an additional primary dose) of COVID-19 vaccine after their initial vaccine or vaccine series. The additional dose should be administered four weeks after the completion of the initial COVID-19 vaccine or vaccine series. For mRNA vaccines, this means immunocompromised individuals need a 3-dose primary series. For J&J/Janssen vaccine, immunocompromised individuals need a 2-dose primary series with the second dose being an mRNA vaccine.
  • All individuals aged 12 years and older who received an initial COVID-19 vaccine or vaccine series should receive a single booster dose of COVID-19 vaccine.
    • Individuals who received J&J/Janssen vaccine should receive a COVID-19 booster at least 2 months following their initial vaccine.
    • Individuals who received an mRNA vaccine should receive a booster at least 5 months following their initial vaccine series.
  • ACOG recommends that pregnant and recently pregnant people up to 6 weeks postpartum receive a booster dose of COVID-19 vaccine following the completion of their initial COVID-19 vaccine or vaccine series.
  • Individuals may receive any vaccine product available to them for their booster dose; they do not have to receive the same product as their initial vaccine or vaccine series; however:
    • The mRNA vaccines are preferred over the J&J/Janssen COVID-19 vaccine.
    • Adolescents aged 12–17 years are eligible for only the Pfizer-BioNTech COVID-19 vaccine.
  • Some individuals may choose to receive a second booster at least 4 months after their first booster depending on age, vaccine product received for their initial series and booster, or if they are immunocompromised. See Table 3 and CDC for details.
  • Pregnancy alone is not an indication for a second booster. However, pregnant patients who meet other criteria (age, vaccine product received for primary series and booster, and immune status) may choose to receive a second booster.

COVID-19 Vaccine Information

At the time of this publication, three COVID-19 vaccines are currently approved under a BLA or authorized under an EUA by FDA:

  • Pfizer-BioNTech COVID-19 Vaccine/COMIRNATY
  • Moderna COVID-19 Vaccine/SPIKEVAX
  • Janssen (Johnson & Johnson) COVID-19 Vaccine

For primary and booster vaccination for all populations, an mRNA COVID-19 vaccine series is preferred over the Janssen COVID-19 Vaccine.

COVID-19 vaccines are rapidly emerging and additional EUAs and BLA’s are likely to materialize. ACOG will strive to update this guidance as quickly as possible while maintaining accurate, evidence-based information.

mRNA COVID-19 Vaccines (Pfizer-BioNtech and Moderna)

The development and use of mRNA vaccines is relatively new. These vaccines consist of messenger RNA (mRNA) encapsulated by a lipid nanoparticle (LNP) for delivery into the host cells. These vaccines utilize the body’s own cells to generate the coronavirus spike protein (the relevant antigens), which, similar to all other vaccines, stimulates immune cells to create antibodies against COVID-19. The mRNA vaccines are not live virus vaccines, nor do they use an adjuvant to enhance vaccine efficacy. These vaccines do not enter the nucleus and do not alter human DNA in vaccine recipients. As a result, mRNA vaccines cannot cause any genetic changes (CDCZhang 2019Schlake 2012). Based on the mechanism of action of these vaccines and the demonstrated safety and efficacy in Phase II and Phase III clinical trials, it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals. Further, a growing body of observational data so far have not identified any safety concerns for COVID-19 vaccination during pregnancy.

Adenovirus-Vector Vaccines (J&J/Janssen Biotech Inc.)

The Janssen (J&J/Janssen) COVID-19 vaccine (Ad26.COV2.S) is based on the AdVac® technology platform and is a monovalent vaccine composed of a recombinant, replication-incompetent human adenovirus type 26 (Ad26) vector, constructed to encode a stabilized form of the SARS-CoV-2 Spike (S) protein. The Ad26 vector cannot replicate following administration to humans, and available data demonstrate that it is cleared from tissues following injection (FDA 2021).

Ad26.COV2.S is not a live virus vaccine, it does not contain preservatives, and it does not replicate in the cells. Based on data from ongoing and completed clinical trials of Ad26-vectored vaccines including COVID-19, HIV, and Ebola administered to pregnant individuals, overall, the Ad26-based vaccines have an acceptable safety and reactogenicity profile. In addition, the review of the available pregnancy data is not suggestive of a pregnancy-related safety concern (FDA 2021).

Efficacy of Available COVID-19 Vaccines

All currently available COVID-19 vaccines have demonstrated high efficacy among their respective clinical trial endpoints. Additionally, a growing body of evidence suggests that fully vaccinated people are less likely to have asymptomatic infection or transmit SARS-CoV-2 to others. Finally, emerging data indicate that while individuals may still become infected with COVID-19, those who are up to date on their COVID-19 vaccines, including boosters, are less likely to experience severe illness and serious adverse outcomes as a result of SARS-CoV-2 infection (Barda 2021).

mRNA vaccines

Based on results from clinical trials, the Pfizer-BioNTech COVID-19 vaccine was 95% effective at preventing laboratory-confirmed COVID-19 illness in people who received two doses who had no evidence of previous infection (CDC).

Based on results from clinical trials, the Moderna vaccine was 94.1% effective at preventing laboratory-confirmed COVID-19 illness in people who received two doses who had no evidence of being previously infected (CDC).

A prospective cohort study from two academic centers found that vaccinated pregnant and lactating women produced comparable immune responses to nonpregnant controls, and generated higher antibody titers than those observed following SARS-CoV-2 infection in pregnancy. Further, vaccine-generated antibodies were present in umbilical cord blood and breast milk after maternal vaccination (Gray 2021Prabhu 2021Juncker 2021).

Each of these vaccines appeared to have high efficacy in clinical trials among people of diverse age, sex, race, and ethnicity categories and among persons with underlying medical conditions. Further, during the rollout of COVID-19 vaccines, data continue to demonstrate high vaccine efficacy in preventing hospitalization and death (ACIP Slides).

Adenovirus-Vector vaccines

Based on the results from clinical trials in the U.S., the J&J/Janssen COVID-19 vaccine has been shown to be 66.9% effective at preventing moderate/severe COVID-19 illness and 76.7% effective at preventing severe/critical COVID-19 illness after a single dose. This vaccine also demonstrated 93.1% effectiveness at preventing hospitalizations 14 days following vaccination (Janssen 2021).

Safety of Available COVID-19 Vaccines

Side Effects

Expected side effects should be explained during counseling, including that they are a normal part of the body’s reaction to the vaccine and developing antibodies to protect against COVID-19 illness.

Most study participants for both the Pfizer-BioNTech and Moderna vaccines experienced mild side effects similar to influenza-like illness symptoms following vaccination (see Table 1 below). In the Pfizer-BioNTech study subgroup of persons aged 18–55 years, fever greater than 38 °C occurred in 3.7% after the first dose and 15.8% after the second dose (FDA 2020). In the Moderna vaccine trials, fever greater than 38°C was reported in 0.8% of vaccine recipients after the first dose, and 15.6% of vaccine recipients after the second dose (FDA 2020). Most of these symptoms resolved by day 3 after vaccination for both vaccines.

As is typical with adenovirus vaccines, side effects for the J&J/Janssen COVID-19 vaccine were generally mild and transient, resolving in 1–2 days following vaccination among safety study participants. In the J&J/Janssen safety study group, 9.0% of individuals receiving a COVID-19 vaccine experienced fever greater than 38°C following vaccination. Fever had a median duration of 1 day (FDA 2021).

Patients should be counseled about more severe side effects and when to seek medical care. For more information and details on side effects, see Local Reactions, Systemic Reactions, Adverse Events, and Serious Adverse Events: Pfizer-BioNTech COVID-19 Vaccine from the CDC.

Table 1. Mild Side Effects Among All Study Participants*

Injection Site ReactionsFatigueChillsMuscle PainJoint Pain Headaches
Moderna91.6%68.5%43.4% 59.6% 44.8% 63%
Pfizer-BioNTech84.10%62.90%31.90%38.30%23.60% 55.10%
J&J/Janssen48.6% 38.2% N/A 33.2% N/A 38.9%

*Fever was the least common side effect reported; see text above for data on frequency of fever

Allergic Reactions Including Anaphylaxis

Allergic reactions including anaphylaxis have been reported to be rare following COVID-19 vaccination in nonpregnant individuals. Anaphylaxis has been observed in 5 cases per million doses administered for the Pfizer-BioNTech vaccine, 4.9 cases per million doses administered of the Moderna vaccine, and 7.6 cases per million doses administered for the J&J/Janssen vaccine (ACIP August 2021).

If anaphylaxis is suspected in a pregnant individual after receiving a COVID-19 vaccination, anaphylaxis should be managed the same as in nonpregnant individuals (e.g., rapidly assess airway, breathing, circulation, and mental activity; call for emergency medical services; place the patient in a supine position, and administration of epinephrine) (CDC). Similar to nonpregnant individuals, anaphylaxis may recur after the individual begins to recover, and monitoring in a medical facility for at least several hours is advised, even after complete resolution of symptoms and signs.

For more information on the management of anaphylaxis after COVID-19 vaccination, see CDC’s website.

Thrombosis with Thrombocytopenia Syndrome

Background

FDA has added a warning about the possibility of thrombosis with thrombocytopenia syndrome (TTS) to the J&J/Janssen COVID-19 vaccine EUA and fact sheets regarding this syndrome. The EUA fact sheet should be provided to all vaccine recipients and their caregivers before vaccination with any authorized COVID-19 vaccine.

Considerations for Women of Reproductive Age and Pregnant Individuals

Most cases of TTS reported to the Vaccine Adverse Event Reporting System (VAERS) following receipt of the J&J/Janssen COVID-19 vaccine to date have occurred in women of reproductive age. None of these individuals were pregnant. While TTS is a clinically serious condition, it is critical to emphasize the rarity of this syndrome, which has occurred in approximately 10.6 out of every million doses of J&J/Janssen COVID-19 vaccine administered to females aged 30–39 years and 9.02 per million doses of J&J/Janssen COVID-19 vaccine administered to females aged 40–49 years (See 2021).

Currently available data suggest a causal relationship between J&J/Janssen COVID-19 vaccine with TTS. Although the condition is rare, based on an updated risk/benefit analysis, use of mRNA vaccines is preferred for all vaccine-eligible persons, including pregnant and lactating people. The J&J/Janssen vaccine remains an option for vaccination when there is a contraindication to mRNA COVID-19 vaccines, when a person would otherwise remain unvaccinated due to limited access to mRNA vaccines, or when a person expresses an informed preference for the J&J/Janssen COVID-19 vaccine. Any person who receives a J&J/Janssen COVID-19 vaccine should be aware of the rare risk of TTS after receipt of this vaccine and that mRNA COVID-19 vaccines are preferred.  Of note, a history of TTS following receipt of the J&J/Janssen COVID-19 vaccine or any other adenovirus vector–based COVID-19 vaccines (e.g. such as AstraZeneca’s COVID-19 vaccine, which is not authorized or approved for use in the United States) is considered a contraindication to administration of additional doses of the J&J/Janssen COVID-19 vaccine.

Although the overall general risk of thrombosis is increased during pregnancy and the postpartum period, and with certain hormonal contraceptives, experts believe that these factors do not make people more susceptible to TTS after receipt of the J&J/Janssen COVID-19 vaccine. Given these differing mechanisms, there is no recommendation to discontinue or change hormonal contraceptive methods in women who have received or plan to receive the J&J/Janssen COVID-19 vaccine. Additionally, people who take aspirin or anticoagulants as part of their routine medications, including during pregnancy, do not need to stop or alter the dose of these medications prior to receipt of the J&J/Janssen COVID-19 vaccine (CDC Clinical Considerations).

Diagnosis and Treatment

Patients receiving the J&J/Janssen COVID-19 vaccine should be informed of symptoms of TTS, including severe headache, visual changes, abdominal pain, nausea and vomiting, back pain, shortness of breath, leg pain or swelling, petechiae, easy bruising, or bleeding. Patients who experience these symptoms should be counseled to seek immediate medical evaluation. Symptoms most commonly appear 6–14 days following vaccination (ASH).

The American Society for Hematology (ASH) has issued guidance related to diagnosing and managing TTS. Of critical importance, TTS should not be treated with the same drugs used to treat other blood clots. Specifically, heparin should not be used to treat TTS. See the ASH guidance for more details on diagnosis and treatment protocols for TTS.

Myocarditis and Pericarditis

Since April 2021, cases of myocarditis (ranging from 1 per 100,000 to 2.13 per 100,000) and pericarditis (1.8 per 100,000) have been reported in the United States after mRNA COVID-19 vaccination (Pfizer-BioNTech and Moderna), particularly in adolescents and young adults (Diaz 2021Witberg 2021). There has not been a similar reporting pattern observed after receipt of the J&J/Janssen COVID-19 vaccine. Reported cases have occurred predominantly in male adolescents and young adults aged 16 years and older. Onset was typically within several days after mRNA COVID-19 vaccination, and cases have occurred more often after the second dose than the first dose. Surveillance of these cases following mRNA COVID-19 vaccination are ongoing.

Clinicians should consider the diagnoses of myocarditis and pericarditis in adolescents or young adults with acute chest pain, shortness of breath, or palpitations. In this population, coronary events are less likely to be a source of these symptoms. In most cases, patients who presented for medical care have responded well to medications and rest and had prompt improvement of symptoms. Clinicians should report all cases of myocarditis and pericarditis post COVID-19 vaccination to VAERS.

For more information, see CDC and the American Heart Association.

Guillain-Barré Syndrome

Multiple safety systems have reported a higher-than expected number of cases of Guillain-Barré syndrome following the use of the J&J/Janssen COVID-19 vaccine. However, investigations into this complex diagnosis are ongoing and additional information is needed to fully understand the potential relationship between Guillain-Barré syndrome and the J&J/Janssen COVID-19 vaccine. It appears the absolute risk of Guillain-Barré syndrome following vaccination remains very low (estimated crude reporting rate of 1 per 100,000 doses); therefore, the benefits of prevention of severe COVID-19 illness through vaccination outweigh this very rare risk (Woo 2021).

Available Safety Information Related to the Use of COVID-19 Vaccines in Pregnancy

Despite ACOG’s persistent advocacy for the inclusion of pregnant individuals in COVID-19 vaccine trials, none of the COVID-19 vaccines approved under EUA have been tested in pregnant individuals. However, studies in pregnant women have begun and post-market surveillance is underway.

Developmental and Reproductive Toxicity Data

Data from Developmental and Reproductive Toxicity (DART) studies for the Pfizer-BioNTech COVID-19 vaccine have been reported in Europe. According to the report presented to the European Medicines Agency, animal studies using the Pfizer/BioNTech COVID-19 vaccine do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/fetal development, parturition, or postnatal development (EMA).

A combined developmental and perinatal/postnatal reproductive toxicity (DART) study of Moderna’s mRNA-1273 in rats was submitted to FDA on December 4, 2020. FDA review of this study concluded that mRNA1273 given prior to mating and during gestation periods at dose of 100 µg did not have any adverse effects on female reproduction, fetal/embryonal development, or postnatal developmental except for skeletal variations, which are common and typically resolve postnatally without intervention (FDA).

In a reproductive developmental toxicity study, female rabbits were administered 1 mL of the J&J/Janssen COVID-19 vaccine (a single human dose is 0.5 mL) by intramuscular injection 7 days prior to mating and on gestation days 6 and 20 (i.e., one vaccination during early and late gestation, respectively). No vaccine-related adverse effects on female fertility, embryo-fetal or postnatal development up to postnatal day 28 were observed (FDA 2021). Further, based on data from ongoing and completed clinical trials of Ad26-vectored vaccines including COVID-19, HIV, and Ebola administered to pregnant individuals, overall, the Ad26-based vaccines have an acceptable safety and reactogenicity profile, without significant safety issues identified to date. In addition, the review of the available pregnancy data is not suggestive of a pregnancy-related safety concern (FDA 2021).

These DART studies provided the first safety data to help inform the use of the vaccine in pregnancy.

Among participants of Phase II/III COVID-19 vaccine clinical studies in nonpregnant adults, a few inadvertent pregnancies that have occurred are being followed to collect safety outcomes.

Post-Administration Pregnancy Surveillance Data

As of February 14, 2022, there have been over 201,000 pregnancies reported in CDC’s v-safe post-vaccination health checker (CDC 2021). Based on limited self-reported information, no specific safety signals have been observed in pregnant people enrolled in v-safe; however longitudinal follow-up is needed.

CDC is currently enrolling pregnant individuals in a v-safe pregnancy registry, and as of April 25, 2022, 23,711 pregnant individuals were enrolled. Data collected through February 28 from the v-safe pregnancy registry did not indicate any safety concerns based on the reactogenicity profile and adverse events observed among pregnant individuals. Additionally, side effects were similar in pregnant and nonpregnant populations. Specific neonatal outcomes data published in The New England Journal of Medicine, along with pregnancy complication data from 275 completed pregnancies presented at the March 1, 2021 ACIP meeting are included in Table 2.

No differences have been seen when comparing pregnant individuals participating in the v-safe pregnancy registry with the background rates of adverse pregnancy outcomes. It appears that the spontaneous abortion rate following COVID-19 vaccination during pregnancy is consistent with the background rate; however the ideal denominator has not appeared in published literature (Shimabukuro 2021). Data reported by CDC indicate that the proportion of spontaneous abortions reported after COVID-19 vaccination is consistent with the known background rate of this outcome. However, a risk estimate has not yet been established (Shimabukuro 2021Zauche 2021).

In addition to data reported from the v-safe pregnancy registry, multiple reports from the Vaccine Safety Datalink (VSD) continue to reinforce the safety of COVID-19 vaccination during pregnancy. A case-control study using data from the VSD found that among women with spontaneous abortions, the odds of COVID-19 vaccine exposure were not increased in the prior 28 days compared with women with ongoing pregnancies (Kharbanda 2021). In a subsequent retrospective cohort of >40,000 pregnant women in the VSD, COVID-19 vaccination during pregnancy was not associated with preterm birth or small-for-gestational age at birth overall, stratified by trimester of vaccination, or number of vaccine doses received during pregnancy, compared with unvaccinated pregnant women (Lipkind 2022).

In a research letter published in April 2022, investigators evaluated the association between COVID-19 vaccination during early pregnancy and risk of major fetal structural anomalies identified on ultrasonography. Of 2622 patients who received at least 1 dose of COVID-19 vaccine, 1149 (43.8%) were vaccinated within the teratogenic window. Results of this analysis found that vaccination within the teratogenic window was not associated with presence of a congenital anomaly identified on ultrasonography (Ruderman 2022).

Table 2. V-safe Pregnancy Registry Outcomes of Interest in COVID-19-Vaccinated Pregnant Individuals

Pregnancy ComplicationsBackground RateV-safe Pregnancy Registry Overall
Neonatal Outcomes*Background RateV-safe Pregnancy Registry Overall
Gestational diabetes7-14%10%
Preeclampsia or gestational hypertension10-15%15%
Eclampsia0.27%0%
Intrauterine growth restriction3-7%1%
Preterm birth8-15%9.4%
Congenital anomalies3%2.2%
Small for gestational age3.5%3.2%
Neonatal death0.38%0%

*Shimabukuro TT, Kim SY, Myers TR, Moro PL, Oduyebo T, Panagiotakopoulos L, et al. Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons. CDC v-safe COVID-19 Pregnancy Registry Team [published online April 21, 2021]. N Engl J Med. DOI: 10.1056/NEJMoa2104983. Available at: https://www.nejm.org/doi/10.1056/NEJMoa2104983.

Shimabukuro T. COVID-19 vaccine safety update. Advisory Committee on Immunization Practices (ACIP). Atlanta, GA: Centers for Disease Control and Prevention; 2021. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/28-03-01/05-covid-Shimabukuro.pdf. Retrieved March 1, 2021.

Evidence will continue to be gathered through these systems and will provide clinicians with critically needed data to inform future recommendations related to COVID-19 vaccination during pregnancy (ACIP slides).

General Recommendations and Considerations

ACOG strongly recommends that all eligible persons aged 12 years and older, including pregnant and lactating individuals, receive a COVID-19 vaccine or vaccine series. Obstetrician–gynecologists and other women’s health care practitioners should lead by example by being vaccinated and encouraging eligible patients to be vaccinated as well. See Table 3 for COVID-19 vaccine recommendations by product.

  • mRNA COVID-19 vaccines are preferred over J&J/Janssen COVID-19 vaccine for most individuals, including pregnant and lactating individuals, for primary series, primary additional doses (for immunocompromised persons), and booster vaccination.
    • The J&J/Janssen COVID-19 vaccine remains an option for vaccination when there is a contraindication to mRNA COVID-19 vaccines, when a person would otherwise remain unvaccinated due to limited access to mRNA vaccines, or when a person expresses an informed preference for the J&J/Janssen COVID-19 vaccine.
    • Individuals age 12 to 17 years are only eligible to receive the Pfizer-BioNTech vaccine at this time.
  • Individuals who receive either the Pfizer-BioNTech or Moderna COVID-19 vaccine should complete their primary two-dose series with the same vaccine product
  • COVID-19 vaccines may be administered simultaneously with other vaccines, including within 14 days of receipt of another vaccine. This includes vaccines routinely administered during pregnancy, such as influenza and Tdap.
  • Precautions should be discussed with any individual who reports a history of any immediate allergic reaction to any other vaccine or injectable therapy (i.e., intramuscular, intravenous, or subcutaneous vaccines or therapies not related to a component of COVID-19 vaccines or polysorbate) (CDC). Locations administering COVID-19 vaccines should adhere to CDC guidance for use of COVID-19 vaccines, including screening recipients for contraindications and precautions, having the necessary supplies available to manage anaphylaxis, implementing the recommended postvaccination observation periods, and immediately treating suspected cases of anaphylaxis with intramuscular injection of epinephrine (CDC).
  • Individuals, including those who are pregnant and/or lactating, with a history of SARS-CoV-2 infection should receive a COVID-19 vaccine. 
  • Individuals who receive a COVID-19 vaccine should be educated about and encouraged to participate in CDC’s v-safe program (see below for more information on CDC’s v-safe program).
  • Obstetrician–gynecologists are encouraged to assess and document patients’ COVID-19 vaccination status in the medical record.
  • Moderately to severely immunocompromised individuals (i.e., people who have undergone solid organ transplantation or have been diagnosed with conditions that are considered to have an equivalent level of immunocompromise) should receive an additional dose (i.e., an additional primary dose) of an mRNA COVID-19 vaccine after an initial two-dose primary mRNA COVID-19 vaccine series. The additional dose should be administered at least 28 days after the completion of the initial mRNA COVID-19 vaccine series.
  • All individuals aged 12 years and older who received an initial COVID-19 vaccine or vaccine series should receive a single booster dose of COVID-19 vaccine.
    • Individuals who received J&J/Janssen vaccine should receive a COVID-19 booster at least 2 months following their initial vaccine.
    • Individuals who received an mRNA vaccine should receive a booster 5 months following their initial vaccine series.
  • Individuals may receive any vaccine product available to them for their booster dose; they do not have to receive the same product as their initial vaccine or vaccine series; however:
    • The mRNA vaccines are preferred over the J&J/Janssen COVID-19 vaccine.
    • Adolescents aged 12–17 years are eligible for only the Pfizer-BioNTech COVID-19 vaccine.

Immunocompromised Individuals

Moderately to severely immunocompromised individuals (i.e., people who have undergone solid organ transplantation or have been diagnosed with conditions that are considered to have an equivalent level of immunocompromise) should receive an additional dose (i.e., an additional primary dose) of COVID-19 vaccine after their initial vaccine or vaccine series. The additional dose should be administered four weeks after the completion of the initial COVID-19 vaccine or vaccine series. For mRNA vaccines, this means immunocompromised individuals need a 3-dose primary series. For J&J/Janssen vaccine, immunocompromised individuals need a 2-dose primary series with the second dose being an mRNA vaccine.

Booster Doses

All individuals aged 12 years and older who received an initial COVID-19 vaccine or vaccine series should receive a single booster dose of COVID-19 vaccine.

  • Individuals who received J&J/Janssen vaccine should receive a COVID-19 booster at least 2 months following their initial vaccine
  • Individuals who received an mRNA vaccine should receive a booster at least 5 months following their initial vaccine series

Individuals may receive any vaccine product available to them for their booster dose; they do not have to receive the same product as their initial vaccine or vaccine series; however:

  • The mRNA vaccines are preferred over the J&J/Janssen COVID-19 vaccine
  • Adolescents aged 12–17 years are eligible for only the Pfizer-BioNTech COVID-19 vaccine

Moderately to severely immunocompromised individuals should receive a booster dose following their primary 2- or 3-dose series:

mRNA COVID-19 Vaccines

Moderately to severely immunocompromised individuals should receive a booster dose at least 3 months following their third primary series (additional) dose, preferably with an mRNA vaccine. If Moderna vaccine is used for the booster dose, a 50 mcg (0.25 mL) dose should be used.

J&J/Janssen COVID-19 Vaccine

A single booster dose is recommended at least 2 months after the 2nd (additional) dose, for a total of 3 doses (1 Janssen vaccine dose followed by 1 additional mRNA vaccine dose, then 1 booster dose). mRNA vaccines are preferred for the booster dose. If the Moderna vaccine is used for the booster dose, a 50 mcg (0.25 ml) dose should be used.

Some individuals may choose to receive a second booster at least 4 months after their first booster depending on age, vaccine product received for their initial series and booster, or if they are immunocompromised. See Table 3 and CDC for details.

Table 3. COVID-19 Vaccine Recommendations by Product

Vaccine ProductAge IndicationNumber of Doses in Primary SeriesAdditional Dose for Moderately-Severely Immunocompromised individualsBooster DoseSecond Booster Dose
Pfizer-BioNTech5+ years2 dosesAdministered 3–8 weeks* apart1 additional dose for individuals 5+ yearsAdministered 28 days after the 2nd dose (3 dose primary series)Single booster dose at least 5 months after the last primary series dose for individuals 12+Individuals age 12 and older can only get Pfizer-BioNTechA second booster dose at least 4 months after the first booster may be given to moderately or severely immunocompromised individuals and individuals age 50 years and older
Moderna18+ years2 dosesAdministered 4–8 weeks* apart1 additional dose for individuals 18+ yearsAdministered 28 days after the 2nd dose (3 dose primary series)Single booster dose at least 5 months after the last primary series dose for individuals 18+Moderna or Pfizer-BioNTech preferredA second booster dose at least 4 months after the first booster may be given to moderately or severely immunocompromised individuals, individuals age 50 years and older
J&J/Janssen18+ years1 dose1 additional dose of a mRNA COVID vaccine for individuals 18+ yearsAdministered 28 days after the 1st dose (2 dose primary series)The second dose should be a mRNA COVID-19 vaccineSingle booster dose at least 2 months after the first J&J/Janssen dose for individuals 18+Individuals age 18 and older should get either a Pfizer-BioNTech or Moderna boosterA second booster dose at least 4 months after the first booster may be given to moderately or severely immunocompromised individuals, individuals age 50 years and older, and people aged 18–49 years who are not moderately or severely immunocompromised and who received Janssen COVID-19 Vaccine as both their primary series dose and booster dose (must be an mRNA vaccine)

*An 8-week interval may be optimal for some people ages 12 years and older, especially for males ages 12 to 39 years. A shorter interval (3 weeks for Pfizer-BioNTech; 4 weeks for Moderna) between the first and second doses remains the recommended interval for: people who are moderately or severely immunocompromised; adults ages 65 years and older; and others who need rapid protection due to increased concern about community transmission or risk of severe disease.

The J&J/Janssen vaccine remains an option for vaccination when there is a contraindication to mRNA COVID-19 vaccines, when a person would otherwise remain unvaccinated due to limited access to mRNA vaccines, or when a person expresses an informed preference for the J&J/Janssen COVID-19 vaccine.

Obstetric Care Recommendations and Considerations

Pregnant Individuals

COVID-19 Infection Risk in Pregnancy

Pregnant and recently pregnant patients with COVID-19 are at increased risk of more severe illness compared with nonpregnant peers (Ellington MMWR 2020Collin 2020Delahoy MMWR 2020Khan 2021). Available data indicate an increased risk of ICU admission, need for mechanical ventilation and ventilatory support (ECMO), and death reported in pregnant women with symptomatic COVID-19 infection, when compared with symptomatic nonpregnant women (Zambrano MMWR 2020Khan 2021). Pregnant and recently pregnant patients with comorbidities such as obesity and diabetes may be at an even higher risk of severe illness consistent with the general population with similar comorbidities (Ellington MMWR 2020Panagiotakopoulos MMWR 2020Knight 2020Zambrano MMWR 2020Allotey 2020Metz 2021Galang 2021).

COVID-19 Vaccination

ACOG strongly recommends that pregnant individuals be vaccinated against COVID-19. The mRNA COVID-19 vaccines are preferred over the J&J/Janssen COVID-19 vaccine for pregnant individuals, similar to nonpregnant individuals. As of April 16, 2022, about 69% of pregnant individuals have been fully vaccinated against COVID-19 (CDC COVID Data Tracker). Given the potential for severe illness and death during pregnancy, the importance of completion of the initial COVID-19 vaccination series should be emphasized for this population. A recent study in Scotland found that most cases of SARS-CoV-2 infection during pregnancy were among unvaccinated individuals (Stock 2022). Further, data from the U.S. have indicated that among pregnant people with COVID-19, those who were vaccinated experienced less severe illness (Morgan 2022). Obstetrician–gynecologists and other obstetric care providers should routinely assess their pregnant patients’ vaccination status. On the basis of this assessment, they should recommend needed vaccines to their pregnant patients.

There is no evidence of adverse maternal or fetal effects from vaccinating pregnant individuals with COVID-19 vaccine, and a growing body of data demonstrate the safety of such use (Ciapponi 2021Wainstock 2021Kachikis 2021Magnus 2021Fu 2021Ruderman 2022). Therefore, individuals who are or will be pregnant should receive the COVID-19 vaccine. Emerging data indicate that vaccine-induced antibodies cross the placenta, but the degree of protection these antibodies provide to the neonate is unknown (Yang 2022). In a recent case-control study from 20 pediatric hospitals, CDC found that COVID-19 vaccination during pregnancy reduced the risk of infant hospitalization with COVID-19 by 61%, suggesting that COVID-19 vaccination during pregnancy might also help protect babies. These findings emphasize the importance of COVID-19 vaccination during pregnancy to protect pregnant people and their babies from COVID-19 (Halasa 2022). Vaccination may occur in any trimester and emphasis should be on vaccine receipt as soon as possible to maximize maternal and fetal health.

COVID-19 Booster During Pregnancy

Due to the potential for severe illness and death from SARS-CoV-2 infection during pregnancy, in addition to waning immunity (ACIP slides), ACOG recommends that pregnant and recently pregnant people up to 6 weeks postpartum receive a booster dose of COVID-19 vaccine following the completion of their initial COVID-19 vaccine or vaccine series. Specifically:

INITIAL BOOSTER
  • Pregnant and recently pregnant people who received J&J/Janssen vaccine should receive a COVID-19 booster at least 2 months following their initial vaccine.
  • Pregnant and recently pregnant people who received an mRNA vaccine should receive a booster at least 5 months following their initial vaccine series.
  • Pregnant and recently pregnant people can receive any COVID-19 vaccine available to them for their booster dose; it does not have to be the same product as their initial vaccine or vaccine series; however:
    • The mRNA vaccines are preferred over the J&J/Janssen COVID-19 vaccine.
    • Adolescents aged 12–17 years are eligible for only the Pfizer-BioNTech COVID-19 vaccine.

These recommendations also apply to pregnant and recently pregnant (e.g., up to 6 weeks postpartum) individuals who completed their initial COVID-19 vaccine or vaccine series prior to pregnancy.

SECOND BOOSTER

Pregnancy alone is not an indication for a second booster. However, pregnant patients who meet other criteria (age, vaccine product received for primary series and booster, and immune status) may choose to receive a second booster.

As stated above, efforts should be focused on increasing the initial series of COVID-19 vaccination among pregnant people.

COVID-19 Vaccine Counseling

Individuals should have access to available information about the safety and efficacy of the vaccine. A conversation between the patient and their clinical team may assist with decisions regarding COVID-19 vaccination during pregnancy. Important considerations include the potential efficacy of the vaccine, the potential risk and severity of maternal disease, including the effects of disease on the fetus and newborn, and the safety of the vaccine for the pregnant patient and the fetus. While pregnant individuals are encouraged to discuss vaccination considerations with their clinical care team when feasible, written permission or documentation of such a discussion should not be required prior to receiving a COVID-19 vaccine.

When recommending the COVID-19 vaccine, clinicians should review the available data on risks and benefits of vaccination with pregnant patients, including the risks of not getting vaccinated in the context of the individual patient’s current health status and risk of exposure, including the possibility for exposure at work or home and the possibility for exposing high-risk household members. Conversations about risk should take into account the individual patient’s values and perceived risk of various outcomes and should respect and support autonomous decision-making (ACOG 2013).

Any of the currently authorized COVID-19 vaccines can be administered to pregnant, recently pregnant, or lactating people; however, the mRNA COVID-19 vaccines are preferred over the J&J/Janssen COVID-19 vaccine for all persons, including pregnant, recently pregnant, and lactating people.

Additional Vaccination Considerations for Pregnant Individuals

  • Similar to their nonpregnant peers, vaccination of pregnant individuals with a COVID-19 vaccine may occur in any setting authorized to administer these vaccines. This includes any clinical setting and nonclinical community-based vaccination sites such as schools, community centers, and other mass vaccination locations.
  • Pregnant individuals who experience fever following vaccination should be counseled to take acetaminophen. Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.
  • Anti-D immunoglobulin (i.e. Rhogam) should not be withheld from an individual who is planning or has recently received a COVID-19 vaccine as it will not interfere with the immune response to the vaccine.
  • For patients who do not receive any COVID-19 vaccine, the discussion should be documented in the patient’s medical record. During subsequent office visits, obstetrician–gynecologists should address ongoing questions and concerns and offer vaccination again. Clinicians should reinforce the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.

Lactating Individuals

ACOG strongly recommends that lactating individuals be vaccinated against COVID-19. While lactating individuals were not included in most clinical trials, COVID-19 vaccines should not be withheld from lactating individuals who otherwise meet criteria for vaccination. Theoretical concerns regarding the safety of vaccinating lactating individuals do not outweigh the potential benefits of receiving the vaccine, and a growing body of evidence demonstrates that COVID-19 vaccination is safe during lactation (Bertrand 2021Kachikis 2021). Further, current data demonstrate that lactating people who have received mRNA COVID-19 vaccines have antibodies in their breast milk, suggesting a potential protective effect against infection in the infant, although the degree of clinical benefit is not yet known (Perl 2021Young 2021). There is no need to avoid initiation or discontinue breastfeeding in patients who receive a COVID-19 vaccine (ABM 2020).

Information for pregnant and lactating patients can be found on ACOG’s patient website: Coronavirus (COVID-19), Pregnancy, and Breastfeeding: A Message for Patients.

Gynecologic Care Recommendations and Considerations

Individuals Contemplating Pregnancy

Vaccination is strongly recommended for nonpregnant individuals aged 12 years and older. Further, ACOG recommends vaccination for individuals who are actively trying to become pregnant or are contemplating pregnancy. Additionally, it is not necessary to delay pregnancy after completing both doses of the COVID-19 vaccine.

Claims linking COVID-19 vaccines to infertility are unfounded and have no scientific evidence supporting them. Given the mechanism of action and the safety profile of the mRNA vaccines in nonpregnant individuals, COVID-19 mRNA vaccines are not a cause of infertility. Adenovirus vector vaccines such as the J&J/Janssen COVID-19 vaccine cannot replicate following administration, and available data demonstrate that it is cleared from tissues following injection. Because it does not replicate in the cells, the vaccine cannot cause infection or alter the DNA of a vaccine recipient and is also not a cause of infertility (Evans, 2021Morris 2021). Additionally, a growing body of data demonstrate that COVID-19 vaccines do not negatively impact fertility. In a prospective cohort study of couples trying to conceive, no meaningful association between COVID-19 vaccination in either partner with fecundability was found (Wesselink 2022). Further, a study from the Icahn School of Medicine at Mount Sinai investigated fertility outcomes after COVID-19 vaccination, including egg quality, embryo quality and development, pregnancy rates, and early miscarriage. The study showed no differences in rates of adverse outcomes in vaccinated compared to unvaccinated patients (Aharon 2022). Therefore, ACOG recommends vaccination for all eligible people who may consider future pregnancy.

If an individual becomes pregnant after the first dose of a COVID-19 vaccine requiring two doses (Pfizer-BioNTech or Moderna), the second dose and booster dose should be administered as indicated.

Finally, routine pregnancy testing is not recommended and should not be required prior to receiving any EUA-approved COVID-19 vaccine.

Routine Mammography

Reports of some patients developing temporary contralateral or ipsilateral lymphadenopathy after a COVID-19 vaccination have raised concerns about the possible effect on interpretation of mammogram screening results. A Radiology Expert Scientific Panel has issued a recommendation that mammograms should be conducted prior to COVID-19 vaccination or postponed, if possible, for 4–6 weeks following the second vaccine dose to avoid uncertainty in interpretation of mammogram results.

Screening mammograms are an essential part of preventive care, so postponing screening should only be considered when it does not unduly delay care. If a mammogram is performed fewer than 4–6 weeks after COVID-19 vaccination, patients should inform the mammogram technologist or radiologist when the vaccine was administered, which vaccine was received, and in which arm to aid in interpretation of screening results.

Reports of Post-Vaccination Menstrual Changes

There have been anecdotal reports of temporary changes in menstruation patterns (e.g., heavier menses, early or late onset, and dysmenorrhea) in individuals who have recently been vaccinated for COVID-19. While environmental stresses can temporarily impact menses, vaccines have not been previously associated with menstrual changes. A prospective study of nearly 4,000 women found a temporary non-clinically significant change in cycle length of less than 1 day, and no change in the length of menstrual bleeding. These temporary small variations in cycle length attenuated quickly within two postvaccine cycles (Edelman 2022). The data support that any effect of the COVID-19 vaccines on menstruation is minimal and temporary and should not be a reason for individuals to avoid vaccination. ACOG will continue to monitor and evaluate available evidence on this issue.

Additionally, there is no reason for individuals to schedule their vaccinations based on their menstrual cycles; vaccines can be given to those currently menstruating.

Information for patients can be found on ACOG’s patient website: Coronavirus (COVID-19) and Women’s Health Care: A Message for Patients.

Health Equity Considerations and Communities of Color

Communities of color have been disproportionately affected by the COVID-19 pandemic. Individuals in communities of color are more likely to have severe illness and even die from COVID-19, likely due to a range of social and structural factors including disparities in socioeconomic status, access to care, rates of chronic conditions, occupational exposures, systemic racism, and historic and continued inequities in the health care system. Access to and confidence in COVID-19 vaccines is of critical importance for all communities, but willingness to consider vaccination varies by patient context, in part due to historic and continued injustices and systemic racism that has eroded trust in some communities of color. With time, greater proportions of Black Americans have expressed desire for vaccination such that the majority surveyed affirm their intent for vaccination (Pew Research Center, 2021). Despite intent to obtain vaccination, inequities in vaccine distribution persist. Recent data suggest that, while disparities in access have narrowed over recent months, Black and Latinx populations generally remain vaccinated at lower rates than others, in part related to differential access (Kaiser Family Foundation 2021). With the spread of the more transmissible variants, which most profoundly affect unvaccinated people, equitable vaccine access remains essential.

When discussing COVID-19 vaccines with an individual who expresses concerns, it is critical to:

  • Be aware of historical and current injustices perpetuated on communities of color.
  • Actively listen to and validate expressed fears and concerns while also addressing misinformation about the vaccine.
  • Be knowledgeable of the existing avenues for vaccine access in traditionally underserved communities.
  • For patients who do not receive the vaccine, the discussion should be documented in the patient’s medical record. During subsequent office visits, obstetrician–gynecologists should address ongoing questions and concerns and offer vaccination again.

If the patient is amenable to further discussion:

  • Inform about the testing process, existing safety data, and continued monitoring of safety and efficacy data on COVID-19 vaccines; there have not been shortcuts with the testing of this vaccine.
  • Discuss the increased incidence of infection and severe illness from COVID-19 in communities of color.
  • Connect patients to trust-building resources developed by people who may have shared experiences and identities (see below for resource examples).
  • Note that individuals from communities of color were included in clinical trials (9.8% of Pfizer-BioNTech overall Phase II/III participants were Black and 26.2% were Hispanic/Latinx; 9.7% of Moderna overall Phase II/III participants were Black and 20% were Hispanic/Latinx; 13% of J&J/Janssen overall Phase II/III participants were Black and 14.7% were Hispanic/Latinx), and the vaccine was equally effective among different demographics, including race and ethnicity.

Health Equity Considerations: J&J/Janssen COVID-19 Vaccine

As discussed earlier in the document, the safety of the J&J/Janssen COVID-19 vaccine has been closely investigated. While mRNA COVID-19 vaccines are preferred, the J&J/Janssen COVID-19 vaccine remains a safe and effective preventative measure against COVID-19 that offers flexibility in distribution and implementation that could improve vaccine uptake in specific circumstances. For example, the required refrigerator temperature storage is widely available allowing for vaccine availability in areas and distribution sites that would otherwise be unable to meet the storage requirements of other vaccine options. In addition, the one-dose vaccine may be preferred by some individuals who may face barriers to obtaining a second dose.

Balancing the official preference for mRNA vaccines over the J&J/Janssen COVID-19 Vaccine (based on risk of TTS in those who receive the J&J/Janssen COVID-19 vaccine and decreased efficacy when compared to mRNA vaccines) with the need for equitable distribution of all effective COVID-19 vaccines requires nuanced evaluations of individual risk profiles and social impacts to vaccine access and uptake. Risk–benefit conversations should include consideration of an individual’s likelihood of developing severe disease from COVID-19, barriers they may face to completing a one- or two-dose vaccine series, availability of different vaccine options, as well as an individual’s risk tolerance and vaccine acceptance. These discussions are critical to individualized care and ensuring that generalized recommendations do not negatively impact overall vaccine distribution inequities.

All eligible individuals should be counseled that the mRNA COVID-19 vaccines are preferred over J&J/Janssen COVID-19 vaccine. However, any vaccine is preferable to no vaccine, and individuals who express an informed preference for the J&J/Janssen COVID-19 vaccine should have the option of receiving one if available. If any individual makes an informed choice for one type of COVID-19 vaccine over another for any reason, this decision should be supported as vaccination with any product continues to be safer than remaining unvaccinated.

Additional Health Equity Resources

Vaccine Confidence

Vaccine hesitancy, particularly around COVID-19 vaccines, exists among all populations. When communicating with patients, it is extremely important to underscore the general safety of vaccines and emphasize the fact that no steps were skipped in the development and evaluation of COVID-19 vaccines. This can be done by briefly highlighting the safety requirements of vaccines, and ongoing safety monitoring even after vaccines are made available.

The following are some messages to consider using when discussing COVID-19 vaccines with patients:

  • Vaccines are one of the greatest public health achievements of the 20th century. Before the widespread use of vaccines, people routinely died from infectious diseases, several of which have since been eradicated thanks to robust immunization programs.
  • All available COVID-19 vaccines are highly effective. Individuals can be confident in the ability of each of the vaccines to provide a high level of protection from COVID-19 illness.
  • Community members may interpret the recent preference for mRNA vaccines over the J&J/Janssen COVID-19 vaccine to mean that the J&J/Janssen vaccine is not safe. However, as described above, these complications are rare events. While mRNA vaccines are preferred, J&J/Janssen COVID-19 vaccines are still available for individuals with a contraindication to mRNA COVID-19 vaccines, for persons who would otherwise remain unvaccinated due to limited access to mRNA vaccines, or when a person expresses an informed preference for the J&J/Janssen vaccine. Individuals should be aware of the rare risk of TTS after receipt of the J&J/Janssen COVID-19 vaccine and that other FDA-authorized COVID-19 vaccines (i.e., mRNA vaccines) are available and preferred.
  • Several vaccines have safely been given to pregnant and lactating individuals for decades.
  • To date, safety data on COVID-19 vaccines administered during pregnancy do not reveal any safety concerns.
  • The rigor of COVID-19 vaccine clinical trials with regards to monitoring safety and efficacy meet the same high standards and requirements as with a typical vaccine approval process.
  • While there has been a worldwide attempt to develop COVID-19 vaccines rapidly, this does not mean that any safety standards have been relaxed. In fact, there are additional safety monitoring systems to track and monitor these vaccines, including real-time assessment.
  • Side effects such as influenza-like illness can be expected with these vaccines; however, this is a normal reaction as the body develops antibodies to protect itself against COVID-19. COVID-19 vaccines cannot cause COVID-19 infection. It is important not to be dissuaded by these side effects, because in order to get the maximum protection against COVID-19, patients need two doses of the vaccine.
  • Safety monitoring continues well beyond the EUA administration.
    • COVID-19 Vaccine Monitoring Systems for Pregnant People
    • CDC V-Safe COVID-19 Vaccine Pregnancy Registry: A registry to collect additional health information from v-safe participants who report being pregnant at the time of vaccination or a positive pregnancy test after vaccination. This information helps CDC monitor the safety of COVID-19 vaccines in people who are pregnant. V-safe is a new smartphone-based, after-vaccination health checker for people who receive COVID-19 vaccines. V-safe uses text messaging and web surveys from CDC to check in with vaccine recipients following COVID-19 vaccination. V-safe also provides second vaccine dose reminders if needed, and telephone follow-up for anyone who reports a symptom or health condition for which they seek medical attention.
    • CDC’s V-Safe: A new active surveillance smartphone-based after-vaccination health checker for people who receive COVID-19 vaccines. V-safe will use text messaging and web surveys from CDC to check in with vaccine recipients for health problems following COVID-19 vaccination. Information on pregnancy status at the time of vaccination and at subsequent follow-up time points will also be collected. The system will provide telephone follow-up to anyone who reports medically significant (important) adverse events or exposure to COVID-19 vaccines during pregnancy or periconception period. As of February 14, 2022, there have been over 201,000 pregnancies reported in CDC’s v-safe after-vaccination health checker.
    • Vaccine Adverse Event Reporting System (VAERS): A national early warning system to detect possible safety problems in U.S.-licensed vaccines. VAERS is co-managed by the CDC and the FDA. Healthcare professionals are encouraged to report any clinically significant adverse events following vaccination to VAERS, even if they are not sure if vaccination caused the event. In addition, we are anticipating that the following adverse events will be required to be reported to VAERS for COVID-19 vaccines administered under an EUA:
      • Vaccine administration errors (whether associated with an adverse event or not)
      • Serious adverse events (irrespective of attribution to vaccination) (such as death, life-threatening adverse event, inpatient hospitalization)
      • Multisystem inflammatory syndrome (MIS) in children (if vaccine is authorized in children) or adults
      • Cases of COVID-19 that result in hospitalization or death
    • CDC’s National Healthcare Safety Network (NHSN): An acute-care and long-term care facility monitoring system with reporting to VAERS
    • Vaccines and Medications in Pregnancy Surveillance System (VAMPSS): A national surveillance system designed to monitor the use and safety of vaccines and asthma medications during pregnancy
    • FDA is working with large insurer/payer databases on a system of administrative and claims-based data for surveillance and research
    • Additional safety monitoring information can be found at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety.html.

Additional Resources


References

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A Practice Advisory is a brief, focused statement issued to communicate a change in ACOG guidance or information on an emergent clinical issue (e.g., clinical study, scientific report, draft regulation). A Practice Advisory constitutes ACOG clinical guidance and is issued only on-line for Fellows but may also be used by patients and the media. Practice Advisories are reviewed periodically for reaffirmation, revision, withdrawal or incorporation into other ACOG guidelines.

This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use of this information is voluntary. This information should not be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. It is not intended to substitute for the independent professional judgment of the treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its publications may not reflect the most recent evidence. Any updates to this document can be found on www.acog.org or by calling the ACOG Resource Center.

While ACOG makes every effort to present accurate and reliable information, this publication is provided “as is” without any warranty of accuracy, reliability, or otherwise, either express or implied. ACOG does not guarantee, warrant, or endorse the products or services of any firm, organization, or person. Neither ACOG nor its officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with this publication or reliance on the information presented.