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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Vaccinated Up to 15X MORE LIKELY Than Unvaxxed to Develop Heart Inflammation Requiring Hospitalization: Peer Reviewed Study

Authors:  Julian Conradson Published April 25, 2022 at 4:14pm

A new study out of Europe has revealed that cases of heart inflammation that required hospitalization were much more common among vaccinated individuals compared to the unvaccinated.

A team of researchers from health agencies in Finland, Denmark, Sweden, and Norway found that rates of myocarditis and pericarditis, two forms of potentially life-threatening heart inflammation, were higher in those who had received one or two doses of either mRNA-based vaccine – Pfizer’s or Moderna’s.

In all, researchers studied a total of 23.1 million records on individuals aged 12 or older between December 2020 and October 2021. In addition to the increased rate overall, the massive study confirmed the chances of developing the heart condition increased with a second dose, which mirrors other data that has been uncovered in recent months.

From the *peer-reviewed study, which was published by the Journal of the American Medical Association (JAMA):

“Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273.

The risks of myocarditis and pericarditis were highest within the first 7 days of being vaccinated, were increased for all combinations of mRNA vaccines, and were more pronounced after the second dose.”

Also mirroring other data, the study confirmed that young people, especially young males, are the ones who are suffering the worst effects of the experimental jab. Young men, aged 16-24 were an astounding 5-15X more likely to be hospitalized with heart inflammation than their unvaccinated peers.

But it isn’t just young men, all age groups across both sexes – except for men over 40 and girls aged 12-15 – experienced a higher rate of heart inflammation post-vaccination when compared to the unvaxxed.

From The Epoch Times, who spoke with one of the study’s main researchers, Dr. Rickard Ljung:

“‘These extra cases among men aged 16–24 correspond to a 5 times increased risk after Comirnaty and 15 times increased risk after Spikevax compared to unvaccinated,’ Dr. Rickard Ljung, a professor and physician at the Swedish Medical Products Agency and one of the principal investigators of the study, told The Epoch Times in an email.

Comirnaty is the brand name for Pfizer’s vaccine while Spikevax is the brand name for Moderna’s jab.

Rates were also higher among the age group for those who received any dose of the Pfizer or Moderna vaccines, both of which utilize mRNA technology. And rates were elevated among vaccinated males of all ages after the first or second dose, except for the first dose of Moderna’s shot for those 40 or older, and females 12- to 15-years-old.”

Although the peer-reviewed study found a direct link between mRNA based vaccines and increased incident rate of heart inflammation, the researchers claimed that the “benefits” of the experimental vaccines still “outweigh the risks of side effects,” because cases of heart inflammation are “very rare,” in a press conference about their findings earlier this month.

However, while overall case numbers may be low in comparison to the raw numbers and thus technically “very rare,” the rate at which individuals are developing this serious condition has increased by a whopping amount. When considering the fact that 5-15X more, otherwise healthy, young men will come down with the condition – especially since the chances of Covid-19 killing them at that age are effectively zero (99.995% recovery rate) – it’s downright criminal for governments across the world to continue pushing mass vaccinations for everyone.

Dr. Peter McCullough, a world-renowned Cardiologist who has been warning about the long-term horror show that is vaccine-induced myocarditis in young people, certainly thinks so. In his expert opinion, the study does anything but give confidence that the benefits of the vaccine outweigh the risks. In “no way” is that the case, he says. Actually, it’s quite the opposite.

From McCullough, via The Epoch Times:

“In cardiology we spend our entire career trying to save every bit of heart muscle. We put in stents, we do heart catheterization, we do stress tests, we do CT angiograms. The whole game of cardiology is to preserve heart muscle. Under no circumstances would we accept a vaccine that causes even one person to stay sustain heart damage. Not one. And this idea that ‘oh, we’re going to ask a large number of people to sustain heart damage for some other theoretical benefit for a viral infection,’ which for most is less than a common cold, is untenable. The benefits of the vaccines in no way outweigh the risks.”

It’s also worth pointing out that the new study’s findings could be an indicator as to what is driving the massive spike in the excess death rates in the United States and across the world. Correlating exactly with the rollout of the experimental mRNA Covid-19 vaccines, people have been dying at record-breaking rates, especially millennials, who experienced a jaw-dropping 84% increase in excess deaths (compared to pre-pandemic) in the final four months of 2021.

With all the data that has been made available up to this point, there is no denying that the vaccine is at least partially to blame for the spike in severe illness and death, if not entirely. Nevertheless, the CDC, Fauci, Biden, and the rest of the corrupt establishment continue to push mass vaccines, just approved another booster jab (with plans for another already in the works), and are licking their chops to unleash another round of Covid hysteria and crippling restrictions come this fall.

Spike protein in mRNA COVID vaccines: One of the most bioactive substances known to mankind

Source: https://www.planet-today.com/2022/03/spike-protein-in-mrna-covid-vaccines.html

The spike protein present in Wuhan coronavirus (COVID-19) vaccines is one of the most bioactive and potentially damaging substances known to mankind. It penetrates the blood-brain barrier, cell nucleus and even affects DNA replication. The spike protein appears to reprogram the immune system in a strange way. The BNT162b2 mRNA vaccine against the COVID-19 virus has been shown to reprogram both adaptive and innate immune responses. When it penetrates the cell nuclei, the free-floating spike protein inhibits DNA repair. There had been immune system problems in the vaccinated, and it is becoming apparent that they do not actually develop broad natural immunity. Instead, they produce more S antibodies against the spike protein that they were originally vaccinated with. A recent surveillance report from the U.K. Health Security Agency showed that N antibody levels appear to be lower in individuals who acquire infection following two doses of the vaccine. This means that the vaccines interfere with the immune system’s ability to produce antibodies against the virus following infection. In the case of the N antibody, this is shown to be against the nucleocapsid protein, which serves as the shell of the virus and is an important part of the immune system response of the unvaccinated population. (Related: After you are vaccine damaged, if you complain about symptoms you will be REQUIRED to take psychiatric medications until your “disorder” is cured.) If any mutations to the spike protein of the COVID virus occur in the future, the vaccinated will be more vulnerable and may possibly be unprotected due to their inability to produce the N antibody. Meanwhile, the unvaccinated would have much better immunity to any mutations due to their ability to produce both S and N antibodies after infection. America’s Front Line Doctors also warned that vaccines are turning people’s bodies into walking spike protein factories, which causes the body to create antibodies to them. “First, these vaccines ‘mis-train’ the immune system to recognize only a small part of the virus [the spike protein]. Variants that differ, even slightly, in this protein are able to escape the narrow spectrum of antibodies created by the vaccines,” AFLDS explained. “Second, the vaccines create ‘vaccine addicts,’ meaning persons become dependent upon regular booster shots because they have been ‘vaccinated’ only against a tiny portion of a mutating virus.” The group also cited Australian Health Minister Dr. Kerry Chant, who said that COVID will become endemic and people will have to get used to taking endless vaccines. Finally, there is the simple fact that the vaccines do not, in any way, prevent infection in the nose and upper airways, which is where fully vaccinated people tend to show the highest viral loads. Immune problems and other vaccine infections Vaccinated individuals have also encountered immune problems and reinfections. These conditions, dubbed VAIDS (or Vaccine Acquired Immune Deficiency Syndrome), have been very concerning as they could be damaging to individuals. While not an official scientific term, it is important to bring attention to VAIDS, especially for those who are concerned about the immune health of their vaccinated loved ones. In late January, an anti-mandate rally in Italy reiterated the claim that COVID-19 vaccines were toxic and that they could cause a variety of medical catastrophes down the line. Professor Luc Montagnier, a Nobel Prize winner for medicine for his discovery of the human immunodeficiency virus (HIV) said himself that those who received the third dose of COVID vaccines should go to the laboratory and take AIDS tests, then sue their governments. If Montagnier and other dissident experts are correct about “the great die-off,” then around one to two billion deaths are to be expected in the near future. If the estimation seems alarming, then people should be more aware of the rising number of adverse effects, including cancers and cardiac problems, that developed worldwide. Even Pfizer itself has a long list of possible adverse events from its vaccines, with nine pages of illnesses barely scratching the surface.

SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis

Authors: RALPH TURCHIANO    • 

Abstract

Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic. Design, Setting and Participants: Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words myocarditis, pericarditis, and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic. Main outcome measures: 1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk. Results: A total of 257 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 94.0 (ages 16-17); among females, rates were 13.0 and 13.4 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 3.7-6.1 times higher than their 120-day COVID-19 hospitalization risk as of August 21, 2021 (7-day hospitalizations 1.5/100k population) and 2.6-4.3-fold higher at times of high weekly hospitalization risk (2.1/100k), such as during January 2021. For boys 16-17 without medical comorbidities, the rate of CAE is currently 2.1-3.5 times higher than their 120-day COVID-19 hospitalization risk, and 1.5-2.5 times higher at times of high weekly COVID-19 hospitalization. Conclusions: Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.

Millennials Experienced the “Worst-Ever Excess Mortality in History” – An 84% Increase In Deaths After Vaccine Mandates

The most recent data from the CDC shows that U.S. millennials, aged 25-44, experienced a record-setting 84% increase in excess mortality during the final four months of 2021, according to the analysis of financial expert and Blackrock whistleblower, Edward Dowd,

Dowd, with the assistance of an insurance industry expert, compiled data from the CDC showing that, in just the second half of 2021, the total number of excess deaths for millennials was higher than the number of Americans who died in the entirety of the Vietnam War. Between August and December, there were over 61,000 deaths in this age group, compared to 58,000 over the course of 10 years in Vietnam.

In all, excess death among those who are traditionally the healthiest Americans is up by 84%.

Intracellular Reverse Transcription of Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2 In Vitro in Human Liver Cell Line

Authors:  Markus Aldén 1,Francisko Olofsson Falla 1,Daowei Yang 1,Mohammad Barghouth 1,Cheng Luan 1,Magnus Rasmussen 2 andYang De Marinis 1,*1Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden2Infection Medicine, Department of Clinical Sciences, Lund University, 22362 Lund, Sweden

Abstract

Preclinical studies of COVID-19 mRNA vaccine BNT162b2, developed by Pfizer and BioNTech, showed reversible hepatic effects in animals that received the BNT162b2 injection. Furthermore, a recent study showed that SARS-CoV-2 RNA can be reverse-transcribed and integrated into the genome of human cells. In this study, we investigated the effect of BNT162b2 on the human liver cell line Huh7 in vitro. Huh7 cells were exposed to BNT162b2, and quantitative PCR was performed on RNA extracted from the cells. We detected high levels of BNT162b2 in Huh7 cells and changes in gene expression of long interspersed nuclear element-1 (LINE-1), which is an endogenous reverse transcriptase. Immunohistochemistry using antibody binding to LINE-1 open reading frame-1 RNA-binding protein (ORFp1) on Huh7 cells treated with BNT162b2 indicated increased nucleus distribution of LINE-1. PCR on genomic DNA of Huh7 cells exposed to BNT162b2 amplified the DNA sequence unique to BNT162b2. Our results indicate a fast up-take of BNT162b2 into human liver cell line Huh7, leading to changes in LINE-1 expression and distribution. We also show that BNT162b2 mRNA is reverse transcribed intracellularly into DNA in as fast as 6 h upon BNT162b2 exposure.

1. Introduction

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was announced by the World Health Organization (WHO) as a global pandemic on 11 March 2020, and it emerged as a devasting health crisis. As of February 2022, COVID-19 has led to over 430 million reported infection cases and 5.9 million deaths worldwide [1]. Effective and safe vaccines are urgently needed to reduce the morbidity and mortality rates associated with COVID-19.Several vaccines for COVID-19 have been developed, with particular focus on mRNA vaccines (by Pfizer-BioNTech and Moderna), replication-defective recombinant adenoviral vector vaccines (by Janssen-Johnson and Johnson, Astra-Zeneca, Sputnik-V, and CanSino), and inactivated vaccines (by Sinopharm, Bharat Biotech and Sinovac). The mRNA vaccine has the advantages of being flexible and efficient in immunogen design and manufacturing, and currently, numerous vaccine candidates are in various stages of development and application. Specifically, COVID-19 mRNA vaccine BNT162b2 developed by Pfizer and BioNTech has been evaluated in successful clinical trials [2,3,4] and administered in national COVID-19 vaccination campaigns in different regions around the world [5,6,7,8].BNT162b2 is a lipid nanoparticle (LNP)–encapsulated, nucleoside-modified RNA vaccine (modRNA) and encodes the full-length of SARS-CoV-2 spike (S) protein, modified by two proline mutations to ensure antigenically optimal pre-fusion conformation, which mimics the intact virus to elicit virus-neutralizing antibodies [3]. Consistent with randomized clinical trials, BNT162b2 showed high efficiency in a wide range of COVID-19-related outcomes in a real-world setting [5]. Nevertheless, many challenges remain, including monitoring for long-term safety and efficacy of the vaccine. This warrants further evaluation and investigations. The safety profile of BNT162b2 is currently only available from short-term clinical studies. Less common adverse effects of BNT162b2 have been reported, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia [4,9,10,11,12,13,14,15,16,17,18,19,20]. There are also studies that report adverse effects observed in other types of vaccines [21,22,23,24]. To better understand mechanisms underlying vaccine-related adverse effects, clinical investigations as well as cellular and molecular analyses are needed.A recent study showed that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the genome of human cells [25]. This gives rise to the question of if this may also occur with BNT162b2, which encodes partial SARS-CoV-2 RNA. In pharmacokinetics data provided by Pfizer to European Medicines Agency (EMA), BNT162b2 biodistribution was studied in mice and rats by intra-muscular injection with radiolabeled LNP and luciferase modRNA. Radioactivity was detected in most tissues from the first time point (0.25 h), and results showed that the injection site and the liver were the major sites of distribution, with maximum concentrations observed at 8–48 h post-dose [26]. Furthermore, in animals that received the BNT162b2 injection, reversible hepatic effects were observed, including enlarged liver, vacuolation, increased gamma glutamyl transferase (γGT) levels, and increased levels of aspartate transaminase (AST) and alkaline phosphatase (ALP) [26]. Transient hepatic effects induced by LNP delivery systems have been reported previously [27,28,29,30], nevertheless, it has also been shown that the empty LNP without modRNA alone does not introduce any significant liver injury [27]. Therefore, in this study, we aim to examine the effect of BNT162b2 on a human liver cell line in vitro and investigate if BNT162b2 can be reverse transcribed into DNA through endogenous mechanisms.

2. Materials and Methods

2.1. Cell Culture

Huh7 cells (JCRB Cell Bank, Osaka, Japan) were cultured in 37 °C at 5% CO2 with DMEM medium (HyClone, HYCLSH30243.01) supplemented with 10% (v/v) fetal bovine serum (Sigma-Aldrich, F7524-500ML, Burlington, MA, USA) and 1% (v/v) Penicillin-Streptomycin (HyClone, SV30010, Logan, UT, USA). For BNT162b2 treatment, Huh7 cells were seeded with a density of 200,000 cells/well in 24-well plates. BNT162b2 mRNA vaccine (Pfizer BioNTech, New York, NY, USA) was diluted with sterile 0.9% sodium chloride injection, USP into a final concentration of 100 μg/mL as described in the manufacturer’s guideline [31]. BNT162b2 suspension was then added in cell culture media to reach final concentrations of 0.5, 1.0, or 2.0 μg/mL. Huh7 cells were incubated with or without BNT162b2 for 6, 24, and 48 h. Cells were washed thoroughly with PBS and harvested by trypsinization and stored in −80 °C until further use.

2.2. REAL-TIME RT-QPCR

RNA from the cells was extracted with RNeasy Plus Mini Kit (Qiagen, 74134, Hilden, Germany) following the manufacturer’s protocol. RT-PCR was performed using RevertAid First Strand cDNA Synthesis kit (Thermo Fisher Scientific, K1622, Waltham, MA, USA) following the manufacturers protocol. Real-time qPCR was performed using Maxima SYBR Green/ROX qPCR Master Mix (Thermo Fisher Scientific, K0222, Waltham, MA, USA) with primers for BNT162b2, LINE-1 and housekeeping genes ACTB and GAPDH (Table 1).Table 1. Primer sequences of RT-qPCR and PCR.

Table

2.3. Immunofluorescence Staining and Confocal Imaging

Huh7 cells were cultured in eight-chamber slides (LAB-TEK, 154534, Santa Cruz, CA, USA) with a density of 40,000 cells/well, with or without BNT162b2 (0.5, 1 or 2 µg/mL) for 6 h. Immunohistochemistry was performed using primary antibody anti-LINE-1 ORF1p mouse monoclonal antibody (Merck, 3574308, Kenilworth, NJ, USA), secondary antibody Cy3 Donkey anti-mouse (Jackson ImmunoResearch, West Grove, PA, USA), and Hoechst (Life technologies, 34850, Carlsbad, CA, USA), following the protocol from Thermo Fisher (Waltham, MA, USA). Two images per condition were taken using a Zeiss LSM 800 and a 63X oil immersion objective, and the staining intensity was quantified on the individual whole cell area and the nucleus area on 15 cells per image by ImageJ 1.53c. LINE-1 staining intensity for the cytosol was calculated by subtracting the intensity of the nucleus from that of the whole cell. All images of the cells were assigned a random number to prevent bias. To mark the nuclei (determined by the Hoechst staining) and the whole cells (determined by the borders of the LINE-1 fluorescence), the Freehand selection tool was used. These areas were then measured, and the mean intensity was used to compare the groups.

2.4. Genomic DNA Purification, PCR Amplification, Agarose Gel Purification, and Sanger Sequencing

Genomic DNA was extracted from cell pellets with PBND buffer (10 mM Tris-HCl pH 8.3, 50 mM KCl, 2.5 mM MgCl2, 0.45% NP-40, 0.45% Tween-20) according to protocol described previously [32]. To remove residual RNA from the DNA preparation, RNase (100 µg/mL, Qiagen, Hilden, Germany) was added to the DNA preparation and incubated at 37 °C for 3 h, followed by 5 min at 95 °C. PCR was then performed using primers targeting BNT162b2 (sequences are shown in Table 1), with the following program: 5 min at 95 °C, 35 cycles of 95 °C for 30 s, 58 °C for 30 s, and 72 °C for 1 min; finally, 72 °C for 5 min and 12 °C for 5 min. PCR products were run on 1.4% (w/v) agarose gel. Bands corresponding to the amplicons of the expected size (444 bps) were cut out and DNA was extracted using QIAquick PCR Purification Kit (Qiagen, 28104, Hilden, Germany), following the manufacturer’s instructions. The sequence of the DNA amplicon was verified by Sanger sequencing (Eurofins Genomics, Ebersberg, Germany).

Statistics

Statistical comparisons were performed using two-tailed Student’s t-test and ANOVA. Data are expressed as the mean ± SEM or ± SD. Differences with p < 0.05 are considered significant.

2.5. Ethical Statements

The Huh7 cell line was obtained from Japanese Collection of Research Bioresources (JCRB) Cell Bank.

3. Results

3.1. BNT162b2 Enters Human Liver Cell Line Huh7 Cells at High Efficiency

To determine if BNT162b2 enters human liver cells, we exposed human liver cell line Huh7 to BNT162b2. In a previous study on the uptake kinetics of LNP delivery in Huh7 cells, the maximum biological efficacy of LNP was observed between 4–7 h [33]. Therefore, in our study, Huh7 cells were cultured with or without increasing concentrations of BNT162b2 (0.5, 1.0 and 2.0 µg/mL) for 6, 24, and 48 h. RNA was extracted from cells and a real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed using primers targeting the BNT162b2 sequence, as illustrated in Figure 1. The full sequence of BNT162b2 is publicly available [34] and contains a two-nucleotides cap; 5′- untranslated region (UTR) that incorporates the 5′ -UTR of a human α-globin gene; the full-length of SARS-CoV-2 S protein with two proline mutations; 3′-UTR that incorporates the human mitochondrial 12S rRNA (mtRNR1) segment and human AES/TLE5 gene segment with two C→U mutations; poly(A) tail. Detailed analysis of the S protein sequence in BNT162b2 revealed 124 sequences that are 100% identical to human genomic sequences and three sequences with only one nucleotide (nt) mismatch in 19–26 nts (Table S1, see Supplementary Materials). To detect BNT162b2 RNA level, we designed primers with forward primer located in SARS-CoV-2 S protein regions and reverse primer in 3′-UTR, which allows detection of PCR amplicon unique to BNT162b2 without unspecific binding of the primers to human genomic regions.

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Figure 1. PCR primer set used to detect mRNA level and reverse-transcription of BNT162b2. Illustration of BNT162b2 was adapted from previously described literature [34].RT-qPCR results showed that Huh7 cells treated with BNT162b2 had high levels of BNT162b2 mRNA relative to housekeeping genes at 6, 24, and 48 h (Figure 2, presented in logged 2−ΔΔCT due to exceptionally high levels). The three BNT162b2 concentrations led to similar intracellular BNT162b2 mRNA levels at the different time points, except that the significant difference between 1.0 and 2.0 µg/mL was observed at 48 h. BNT162b2 mRNA levels were significantly decreased at 24 h compared to 6 h, but increased again at 48 h.

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Figure 2. BNT162b2 mRNA levels in Huh7 cells treated with BNT162b2. Huh7 cells were treated without (Ctrl) or with 0.5 (V1), 1 (V2), and 2 µg/mL (V3) of BNT162b2 for 6 (green dots), 24 (orange dots), and 48 h (blue dots). RNA was purified and qPCR was performed using primers targeting BNT162b2. RNA levels of BNT162b2 are presented as logged 2−ΔΔCT values relative to house-keeping genes GAPDH and ACTB. Results are from five independent experiments (n = 5). Differences between respective groups were analyzed using two-tailed Student’s t-test. Data are expressed as the mean ± SEM. (* p < 0.05; ** p < 0.01; *** p < 0.001 vs. respective control at each time point, or as indicated).

3.2. Effect of BNT162b2 on Human Endogenous Reverse Transcriptase Long Interspersed Nuclear Element-1 (LINE-1)

Here we examined the effect of BNT162b2 on LINE-1 gene expression. RT-qPCR was performed on RNA purified from Huh7 cells treated with BNT162b2 (0, 0.5, 1.0, and 2.0 µg/mL) for 6, 24, and 48 h, using primers targeting LINE-1. Significantly increased LINE-1 expression compared to control was observed at 6 h by 2.0 µg/mL BNT162b2, while lower BNT162b2 concentrations decreased LINE-1 expression at all time points (Figure 3).

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Figure 3.LINE-1 mRNA levels in Huh7 cells treated with BNT162b2. Huh7 cells were treated without (Ctrl) or with 0.5 (V1), 1 (V2), and 2 µg/mL (V3) of BNT162b2 for 6 (green dots), 24 (red dots), and 48 h (blue dots). RNA was purified and qPCR was performed using primers targeting LINE-1. RNA levels of LINE-1 are presented as 2−ΔΔCT values relative to house-keeping genes GAPDH and ACTB. Results are from five independent experiments (n = 5). Differences between respective groups were analyzed using two-tailed Student’s t-test. Data are expressed as the mean ± SEM. (* p < 0.05; ** p < 0.01; *** p < 0.001 vs. respective control at each time point, or as indicated; † p < 0.05 vs. 6 h-Ctrl).Next, we studied the effect of BNT162b2 on LINE-1 protein level. The full-length LINE-1 consists of a 5′ untranslated region (UTR), two open reading frames (ORFs), ORF1 and ORF2, and a 3′UTR, of which ORF1 is an RNA binding protein with chaperone activity. The retrotransposition activity of LINE-1 has been demonstrated to involve ORF1 translocation to the nucleus [35]. Huh7 cells treated with or without BNT162b2 (0.5, 1.0 and 2.0 µg/mL) for 6 h were fixed and stained with antibodies binding to LINE-1 ORF1p, and DNA-specific probe Hoechst for visualization of cell nucleus (Figure 4a). Quantification of immunofluorescence staining intensity showed that BNT162b2 increased LINE-1 ORF1p protein levels in both the whole cell area and nucleus at all concentrations tested (Figure 4b–d).

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Figure 4. Immunohistochemistry of Huh7 cells treated with BNT162b2 on LINE-1 protein distribution. Huh7 cells were treated without (Ctrl) or with 0.5, 1, and 2 µg/mL of BNT162b2 for 6 h. Cells were fixed and stained with antibodies binding to LINE-1 ORF1p (red) and DNA-specific probe Hoechst for visualization of cell nucleus (blue). (a) Representative images of LINE-1 expression in Huh7 cells treated with or without BNT162b2. (bd) Quantification of LINE-1 protein in whole cell area (b), cytosol (c), and nucleus (d). All data were analyzed using One-Way ANOVA, and graphs were created using GraphPad Prism V 9.2. All data is presented as mean ± SD (** p < 0.01; *** p < 0.001; **** p < 0.0001 as indicated).

3.3. Detection of Reverse Transcribed BNT162b2 DNA in Huh7 Cells

A previous study has shown that entry of LINE-1 protein into the nucleus is associated with retrotransposition [35]. In the immunofluorescence staining experiment described above, increased levels of LINE-1 in the nucleus were observed already at the lowest concentration of BNT162b2 (0.5 µg/mL). To examine if BNT162b2 is reversely transcribed into DNA when LINE-1 is elevated, we purified genomic DNA from Huh7 cells treated with 0.5 µg/mL of BNT162b2 for 6, 24, and 48 h. Purified DNA was treated with RNase to remove RNA and subjected to PCR using primers targeting BNT162b2, as illustrated in Figure 1. Amplified DNA fragments were then visualized by electrophoresis and gel-purified (Figure 5). BNT162b2 DNA amplicons were detected in all three time points (6, 24, and 48 h). Sanger sequencing confirmed that the DNA amplicons were identical to the BNT162b2 sequence flanked by the primers (Table 2). To ensure that the DNA amplicons were derived from DNA but not BNT162b2 RNA, we also performed PCR on RNA purified from Huh7 cells treated with 0.5 µg/mL BNT162b2 for 6 h, with or without RNase treatment (Ctrl 5 and 6 in Figure 5), and no amplicon was detected in the RNA samples subjected to PCR.

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Figure 5. Detection of DNA amplicons of BNT162b2 in Huh7 cells treated with BNT162b2. Huh7 cells were treated without (Ctrl) or with 0.5 µg/mL of BNT162b2 for 6, 24, and 48 h. Genomic DNA was purified and digested with 100 µg/mL RNase. PCR was run on all samples with primers targeting BNT162b2, as shown in Figure 1 and Table 1. DNA amplicons (444 bps) were visualized on agarose gel. BNT: BNT162b2; L: DNA ladder; Ctrl1: cultured Huh7 cells; Ctrl2: Huh7 cells without BNT162b2 treatment collected at 6 h; Ctrl3: Huh7 cells without BNT162b2 treatment collected at 24 h; Ctrl4: Huh7 cells without BNT162b2 treatment collected at 48 h; Ctrl5: RNA from Huh7 cells treated with 0.5 µg/mL of BNT162b2 for 6 h; Ctrl6: RNA from Huh7 cells treated with 0.5 µg/mL of BNT162b2 for 6 h, digested with RNase.Table 2. Sanger sequencing result of the BNT162b2 amplicon.

Table

4. Discussion

In this study we present evidence that COVID-19 mRNA vaccine BNT162b2 is able to enter the human liver cell line Huh7 in vitro. BNT162b2 mRNA is reverse transcribed intracellularly into DNA as fast as 6 h after BNT162b2 exposure. A possible mechanism for reverse transcription is through endogenous reverse transcriptase LINE-1, and the nucleus protein distribution of LINE-1 is elevated by BNT162b2.Intracellular accumulation of LNP in hepatocytes has been demonstrated in vivo [36]. A preclinical study on BNT162b2 showed that BNT162b2 enters the human cell line HEK293T cells and leads to robust expression of BNT162b2 antigen [37]. Therefore, in this study, we first investigated the entry of BNT162b2 in the human liver cell line Huh7 cells. The choice of BNT162b2 concentrations used in this study warrants explanation. BNT162b2 is administered as a series of two doses three weeks apart, and each dose contains 30 µg of BNT162b2 in a volume of 0.3 mL, which makes the local concentration at the injection site at the highest 100 µg/mL [31]. A previous study on mRNA vaccines against H10N8 and H7N9 influenza viruses using a similar LNP delivery system showed that the mRNA vaccine can distribute rather nonspecifically to several organs such as liver, spleen, heart, kidney, lung, and brain, and the concentration in the liver is roughly 100 times lower than that of the intra-muscular injection site [38]. In the assessment report on BNT162b2 provided to EMA by Pfizer, the pharmacokinetic distribution studies in rats demonstrated that a relatively large proportion (up to 18%) of the total dose distributes to the liver [26]. We therefore chose to use 0.5, 1, and 2 μg/mL of vaccine in our experiments on the liver cells. However, the effect of a broader range of lower and higher concentrations of BNT162b2 should also be verified in future studies.In the current study, we employed a human liver cell line for in vitro investigation. It is worth investigating if the liver cells also present the vaccine-derived SARS-CoV-2 spike protein, which could potentially make the liver cells targets for previously primed spike protein reactive cytotoxic T cells. There has been case reports on individuals who developed autoimmune hepatitis [39] after BNT162b2 vaccination. To obtain better understanding of the potential effects of BNT162b2 on liver function, in vivo models are desired for future studies.In the BNT162b2 toxicity report, no genotoxicity nor carcinogenicity studies have been provided [26]. Our study shows that BNT162b2 can be reverse transcribed to DNA in liver cell line Huh7, and this may give rise to the concern if BNT162b2-derived DNA may be integrated into the host genome and affect the integrity of genomic DNA, which may potentially mediate genotoxic side effects. At this stage, we do not know if DNA reverse transcribed from BNT162b2 is integrated into the cell genome. Further studies are needed to demonstrate the effect of BNT162b2 on genomic integrity, including whole genome sequencing of cells exposed to BNT162b2, as well as tissues from human subjects who received BNT162b2 vaccination.Human autonomous retrotransposon LINE-1 is a cellular endogenous reverse transcriptase and the only remaining active transposon in humans, able to retrotranspose itself and other nonautonomous elements [40,41], and ~17% of the human genome are comprised of LINE-1 sequences [42]. The nonautonomous Alu elements, short, interspersed nucleotide elements (SINEs), variable-number-of-tandem-repeats (VNTR), as well as cellular mRNA-processed pseudogenes, are retrotransposed by the LINE-1 retrotransposition proteins working in trans [43,44]. A recent study showed that endogenous LINE-1 mediates reverse transcription and integration of SARS-CoV-2 sequences in the genomes of infected human cells [25]. Furthermore, expression of endogenous LINE-1 is often increased upon viral infection, including SARS-CoV-2 infection [45,46,47]. Previous studies showed that LINE-1 retrotransposition activity is regulated by RNA metabolism [48,49], DNA damage response [50], and autophagy [51]. Efficient retrotransposition of LINE-1 is often associated with cell cycle and nuclear envelope breakdown during mitosis [52,53], as well as exogenous retroviruses [54,55], which promotes entrance of LINE-1 into the nucleus. In our study, we observed increased LINE-1 ORF1p distribution as determined by immunohistochemistry in the nucleus by BNT162b2 at all concentrations tested (0.5, 1, and 2 μg/mL), while elevated LINE-1 gene expression was detected at the highest BNT162b2 concentration (2 μg/mL). It is worth noting that gene transcription is regulated by chromatin modifications, transcription factor regulation, and the rate of RNA degradation, while translational regulation of protein involves ribosome recruitment on the initiation codon, modulation of peptide elongation, termination of protein synthesis, or ribosome biogenesis. These two processes are controlled by different mechanisms, and therefore they may not always show the same change patterns in response to external challenges. The exact regulation of LINE-1 activity in response to BNT162b2 merits further study.The cell model that we used in this study is a carcinoma cell line, with active DNA replication which differs from non-dividing somatic cells. It has also been shown that Huh7 cells display significant different gene and protein expression including upregulated proteins involved in RNA metabolism [56]. However, cell proliferation is also active in several human tissues such as the bone marrow or basal layers of epithelia as well as during embryogenesis, and it is therefore necessary to examine the effect of BNT162b2 on genomic integrity under such conditions. Furthermore, effective retrotransposition of LINE-1 has also been reported in non-dividing and terminally differentiated cells, such as human neurons [57,58].The Pfizer EMA assessment report also showed that BNT162b2 distributes in the spleen (<1.1%), adrenal glands (<0.1%), as well as low and measurable radioactivity in the ovaries and testes (<0.1%) [26]. Furthermore, no data on placental transfer of BNT162b2 is available from Pfizer EMA assessment report. Our results showed that BNT162b2 mRNA readily enters Huh7 cells at a concentration (0.5 µg/mL) corresponding to 0.5% of the local injection site concentration, induce changes in LINE-1 gene and protein expression, and within 6 h, reverse transcription of BNT162b2 can be detected. It is therefore important to investigate further the effect of BNT162b2 on other cell types and tissues both in vitro and in vivo.

5. Conclusions

Our study is the first in vitro study on the effect of COVID-19 mRNA vaccine BNT162b2 on human liver cell line. We present evidence on fast entry of BNT162b2 into the cells and subsequent intracellular reverse transcription of BNT162b2 mRNA into DNA.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cimb44030073/s1.

Author Contributions

M.A., F.O.F., D.Y., M.B. and C.L. performed in vitro experiments. M.A. and F.O.F. performed data analysis. M.R. and Y.D.M. contributed to the implementation of the research, designed, and supervised the study. Y.D.M. wrote the paper with input from all authors. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009-1039, the Swedish Government Fund for Clinical Research (ALF) and the foundation of Skåne University Hospital.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data supporting the findings of this study are available within the article and supporting information.

Acknowledgments

The authors thank Sven Haidl, Maria Josephson, Enming Zhang, Jia-Yi Li, Caroline Haikal, and Pradeep Bompada for their support to this study.

Conflicts of Interest

The authors declare no conflict of interest.

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COVID-19 vaccination followed by activation of glomerular diseases: does association equal causation?

Authors: Nicholas L. Li,1P. Toby Coates,2 and Brad H. Rovin1,∗

Kidney Int. 2021 Nov; 100(5): 959–965.Published online 2021 Sep 14. doi: 10.1016/j.kint.2021.09.002 PMCID: PMC8437826PMID: 34534551

To date, >4 billion doses of the various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been administered worldwide in response to the coronavirus disease 2019 (COVID-19) pandemic. Even as widespread vaccination campaigns have contributed to declining case rates, adverse events are appearing beyond those originally reported in the clinical trials of vaccine efficacy and safety. Of particular relevance to the kidney is the increasing number of reports of de novo or reactivation of glomerular diseases (Table 1 12345678910111213141516171819202122232425). The occurrence of glomerular disease after immunization against influenza, pneumococcus, and hepatitis B has been reported in the past.262728 The reported patients developed acute onset nephrotic syndrome following vaccination, and kidney biopsies were consistent with a minimal change disease (MCD) pattern of injury. Although temporal association (median onset of 12 days) with vaccination and disease onset suggested a vaccine-related induction of immune injury, the pathophysiological mechanisms responsible have not been determined.

Table 1

Summary of reported cases of glomerular disease activation with COVID-19 vaccination

DiseaseAge, yr, median (range)% Female (n)Vaccine typeNo. of casesDe novo or flareaMaintenance immune therapyTemporal association to vaccination, dTreatmentOutcomeCOVID-IgG responseReferences
IgAN38 (13–52)58 (7 of 12)Pfizer–BioNTech, Moderna12De novo, 7 flareNo, or steroids, mycophenolic acid, calcineurin inhibitor in transplant patient1–2RASi, steroids, cyclophosphamideSpontaneous resolution, renal response to immunotherapyPositive1234567
MCD61 (22–”early 80s”)36 (4 of 11)Pfizer–BioNTech, Moderna, Astra Zeneca11De novo, 4 flareNo, or steroids, calcineurin inhibitor, rituximab1–13 (median, 7)Steroids, calcineurin inhibitorRenal response to immunotherapy in most casesPositive891011121314151617
MN68 (66–70)50 (1 of 2)Pfizer–BioNTech, Sinovac2De novo (anti-THSD7A+), 1 flare (anti-PLA2R+)No7–14RASiNRPositive18,19
AAN78 (52–81)33 (1 of 3)Moderna, Pfizer–BioNTech3De novoNo14Steroids, cyclophosphamide, plasma exchangeRenal responsePositive3,20,21
Anti-GBM60 (60–”older female”)100 (2 of 2)Moderna2De novoNo1–14Steroids, cyclophosphamide, plasma exchangeNo recoveryNR6,22
IgG4-RD660 (0 of 1)Pfizer–BioNTech1FlareRituximab14Steroids, rituximabRenal responsePositive23
LN42100 (1 of 1)Pfizer–BioNTech1FlareHydroxychloroquine7Steroids, mycophenolate mofetilPartial responsePositive24
Scleroderma renal crisis34100 (1 of 1)Pfizer–BioNTech1De novoNo1RASiResponsePositive25

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AAN, anti–neutrophil cytoplasmic antibody–associated nephritis; anti-GBM, anti–glomerular basement membrane antibody disease; COVID, coronavirus; COVID-19, coronavirus disease 2019; IgAN, IgA nephropathy; IgG4-RD, IgG4-related disease; LN, lupus nephritis; MCD, minimal change disease; MN, membranous nephropathy; NR, not reported; PLA2R, phospholipase A2 receptor; RASi, renin-angiotensin system inhibitor; THSD7a, thrombospondin type-1 domain-containing 7A.aDe novo indicates disease development in a patient not known to have a prior glomerular disease; flare indicates activation of a known, but controlled, glomerular disease.

After vaccination against COVID-19, reports of exacerbation, and in some cases, new onset of glomerular diseases began arriving at Kidney International and other nephrology journals. Although the development of de novo glomerular disease is intriguing, increased patient awareness of symptoms after vaccination may have prompted medical attention, revealing a previously undiagnosed kidney disease as opposed to a de novo disease. Indeed, chronicity on the kidney biopsy may suggest the glomerular disease preceded COVID-19 vaccination. Although nearly all approved vaccine platforms have been implicated, cases have been far more common after the mRNA-based vaccines, Pfizer–BioNTech BNT162b2 and Moderna mRNA1273 (Table 1). Of course, this may simply reflect more widespread use of these mRNA vaccines. Another interesting feature of COVID-19 vaccine-associated glomerular disease (CVAGD) is that most cases appear to be either IgA nephropathy (IgAN) or MCD (Table 1). The timing of IgAN activation is generally within a day or two after receiving the second dose of BNT162b2 or mRNA1273, whereas MCD appears to occur at a median of 7 days after the first dose (Table 1). Although these associations do not prove causation, we suggest that the volume of cases of MCD and IgAN and the consistent time course of events indicate a direct role of the mRNA vaccines in these 2 glomerular diseases. Several other glomerular diseases have occurred in smaller numbers following vaccination, sometimes quickly (scleroderma renal crisis), but more often after about 2 weeks (e.g., membranous nephropathy, anti–neutrophil cytoplasmic antibody–associated vasculitis, anti–glomerular basement membrane disease, and IgG4 renal disease). Given the small number of cases of these immune-mediated glomerular diseases, and the longer time to their appearance, it is difficult to be certain that they were activated by the vaccines. Nonetheless, considering these cases in aggregate, it appears that the COVID-19 vaccines can (re)activate autoantibody-mediated kidney disease.

It is not clear how COVID-19 vaccines, and in particular the mRNA vaccines, induce MCD, IgAN, and other autoimmune kidney diseases. mRNA-based vaccine technology has been available for some time, although the SARS-CoV-2 vaccines were the first to be investigated in large-scale phase 3 randomized trials. It has been previously demonstrated that this vaccine technology promotes more potent immune responses than inactivated viral vaccines and even natural infection. A comparison of the immune responses to the COVID-19 vaccine platforms is given in Table 2 29303132333435. This ability of the mRNA vaccines to enhance virus-specific responses over and above more traditional vaccines has likely contributed to the high efficacy in preventing disease from SARS-CoV-2, as well as the viral variants that have evolved during this pandemic. BNT162b2 or mRNA1273 deliver lipid nanoparticle encapsulated mRNA encoding the full-length SARS-CoV-2 spike protein. These vaccines were found to be safe and efficacious in preventing severe COVID-19 in both clinical trial and real-world conditions, although patients with known autoimmune diseases were not included in the initial trials.36 These lipid nanoparticle–mRNA vaccines stimulate robust antigen-specific T-cell responses, including T follicular helper (Tfh) cells, and potent germinal center B-cell responses, leading to durable neutralizing antibody production.37

Table 2

Immune responses to SARS-CoV-2 vaccine platforms

VaccineExample manufacturerT-cell responsesB-cell responsesCytokine responsesReferences
LNP-mRNAPfizer–BioNTech, ModernaAntigen-specific Th1-biased CD4+ response, CD8+ IFNɣ, IL-2Prolonged S-specific germinal center B-cell responsesIFNɣ, IL-2, type I interferon via toll-like receptor-7293031
Adenovirus-DNAAstraZeneca, Janssen/Johnson & JohnsonAntigen-specific Th1-biased CD4+ response, monofunctional and cytotoxic CD8+ responseIgG1/IgG3 predominant, low IgG2/IgG4IFNɣ, TNFα, IL-2, type 1 interferon via toll-like receptor-931,32
Inactivated whole virusSinovac BiotechTh1-biased response with minimal Th2RBD-specific binding antibody and neutralizing antibody productionIFNɣ, TNFα, IL-233,34
Recombinant protein subunitNovavaxTh1-biased response with minimal Th2S-binding antibody and neutralizing antibody productionIFNɣ, TNFα, IL-235

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IFNγ, interferon gamma; IL-2, interleukin 2; LNP, lipid nanoparticle; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Th1, T-helper cell 1; Th2, T-helper cell 2; TNFα, tumor necrosis factor alpha.

In the cases of IgAN, disease symptoms occurred right after vaccination, suggesting a rapid immune mechanism, such as a memory recall response or mobilization of cells positioned to secrete galactose-deficient IgA1 antibodies. Although purely speculative, we wonder if the COVID-19 vaccines can robustly stimulate the gut-associated lymphoid tissue (Peyer patches) responsible for IgA1 production, as they do in other lymphoid tissues. IgA1 hyperresponsiveness has been observed in patients with IgAN following influenza vaccination.38 In the case of COVID-19 vaccination, circulating IgA responses following administration have been observed to be similar in kinetics to IgG responses, with levels reaching a plateau 18 to 21 days after first mRNA dose, and further increases after a second dose peaking at 7 days after dose.39 The temporal associations with hematuria onset following vaccination on the order of days argues against the contribution of spike protein-specific IgA molecules from participating in disease. However, it is known that patients with IgAN have increased circulating galactose-deficient IgA1, and perhaps bystander activation of the immune system with mRNA COVID-19 vaccination may act as a trigger for the formation of immune complexes and subsequent glomerular injury.

In contrast, the development of MCD following vaccination takes some time, suggesting a role for cellular immunity. Central to the pathogenesis of MCD is the development of podocyte injury due to dysregulated T-cell activation.29 The COVID-19 mRNA vaccines trigger enhanced Tfh responses that peak 7 days after immunization. A potential contribution to the pathogenesis of MCD by Tfh cells has been suggested by observations that circulating subsets of Tfh cells are increased in patients with MCD, and the frequency of these populations is reduced in patients who are successfully treated with steroids.40 Given these findings, and the reported onset of disease at a time point that correlates with Tfh response, perhaps mRNA vaccine-induced alterations in the Tfh population and/or their associated cytokine profile in a susceptible individual could promote podocyte injury and the development of nephrotic syndrome and MCD.

The later appearing cases of autoantibody-mediated glomerular disease may be due to the induction of vaccine-associated autoimmunity. Vaccine-associated autoimmunity has been postulated to occur by antigen-specific and nonspecific mechanisms. Antigen-specific triggers for vaccine-mediated autoimmunity are thought to be secondary to molecular mimicry. That is, exposure to a non–self-antigen, such as SARS-CoV-2 spike protein, could elicit responses directed against host tissues if there was sufficient sequence homology to allow for cross-recognition. The SARS-CoV-2 spike protein shares homology with several human proteins, which may then be subject to off-target immune attack after vaccination.41 Consistent with the mimicry hypothesis, it has been suggested that homologous sequences between human alveolar surfactant-related proteins and SARS-CoV-2 spike glycoproteins contribute to host immune attack and the subsequent pulmonary pathology seen with COVID-19 infection.42 Similarly, mimicry of viral antigens with host proteins has been proposed to contribute to immune attack in the central nervous system, exacerbating neurologic complications in COVID-19.43

Antigen nonspecific mechanisms of autoimmunity with vaccination are thought to occur through bystander activation. In this model, the vaccine-stimulated immune response may trigger cellular damage and exposure of normally hidden self-antigens, which are then recognized by host immunity. Alternatively, by this model, innate immune responses may upregulate cytokine signaling and self-antigen presentation by antigen-presenting cells to potentially autoreactive T cells. Either of these mechanisms could conceivably contribute to the development of glomerular disease in response to vaccination, with perhaps different disease phenotypes resulting from each.

Interestingly, to date, there has been only one report of an exacerbation of lupus nephritis (LN) after COVID-19 vaccination, and this was with the BNT162b2 vaccine. This paucity of cases is somewhat unexpected. Tfh cells, robustly activated by mRNA-based COVID-19 vaccines, are important for autoantibody development in lupus.44 Germinal center and peripheral leukocyte cytokine profiles after vaccination are reminiscent of cytokine profiles from lupus patients, with especially high levels of interferon-α, interleukin-6, and tumor necrosis factor-α.45 In the reported case, a patient with known class V LN in remission developed nephrotic syndrome following the first vaccine injection, and kidney biopsy revealed International Society of Nephrology/Renal Pathology Society class II and V LN with an activity index of 0. Given the robust immune activation achieved with the mRNA vaccines, it is surprising that in this case immune complex deposits were limited to the subepithelial compartment and there was no development of proliferative LN. The absence of proliferative LN cases may arguably be because many patients who have lupus nephritis are maintained on long-term immunosuppression. Most patients who developed CVAGD were not on immunosuppression (Table 1). Perhaps a baseline level of immunosuppression is sufficient to blunt the immune response to mRNA vaccination and prevent autoimmune reactions. This is supported by the observation that solid organ transplant patients on various forms of immune suppression, including those typically used in lupus nephritis, such as glucocorticoids and mycophenolate mofetil, demonstrate a weaker response to 2 doses of BNT162b2 vaccination.46 However, considering the few reports of patients on immunosuppression who still developed glomerular injury after vaccination, including one kidney transplant patient, being on immunosuppression is clearly not the only factor determining who will develop kidney disease with these vaccines. Ultimately, there are likely individual patient-specific factors involved that determine whether vaccination results in immune protection or autoimmune injury.

In the published cases of CVAGD, glomerulonephritis was often managed with the usual therapeutic options for these diseases, frequently leading to a clinical response (Table 1). Although evidence is limited, we support a management strategy of CVAGD that is consistent with the conventional therapy of glomerular diseases not associated with vaccination, including the use of immunosuppression if typical indications develop. It is not unreasonable to extrapolate from the management of glomerulonephritis in general, given the presumption in CVAGD that the same disease mechanisms and pathways of vaccine-independent glomerular disease are activated by COVID-19 vaccination. However, management decisions should be tailored to individual cases given the rarity of these events.

As the worldwide COVID-19 vaccination campaign continues to accelerate, it is probable that we will continue to see CVAGD. Not all cases have been, or will be, reported, there is likely reporting bias, and the number of patients with known glomerular disease who have been vaccinated is not known, so the true incidence of CVAGD will be difficult to determine. As multiple doses of vaccines are now being offered, close observation to watch for an increase in CVAGD will be needed. However, in the context of the billions of doses of COVID-19 vaccine that have been administered, the relatively small number of cases thus far suggests a low incidence. Care providers should consider the possibility of glomerulonephritis in patients who develop gross hematuria or edema after vaccination to aid in the prompt diagnosis and management of these diseases. The possibility of CVAGD should not, however, prompt vaccine hesitancy. Most reported cases were easily managed and resolved on their own or responded to typical therapy. Also, COVID-19 infection itself has been linked to the development of immune-mediated kidney diseases.47 The benefits of COVID-19 vaccination appear to greatly outweigh the risks of glomerular disease occurrence or recurrence, and vaccination remains the best method of preventing the morbidity and mortality associated with SARS-CoV-2 infection. Therefore, we are offering vaccination to all of our patients with glomerular diseases, with the following considerations.

Patients in remission and off all immunosuppression should be followed up closely after vaccination and be told to report hematuria or swelling immediately for early intervention. For patients undergoing active immunosuppressive treatment with anti-metabolites (e.g., mycophenolate mofetil or azathioprine), cytotoxic drugs (e.g., cyclophosphamide), anti–B-cell therapies (e.g., rituximab), and costimulation blockers (e.g., abatacept), antibody response to COVID-19 vaccines is likely to be poor.48 , 49 It is probably reasonable to postpone vaccination until these intensive therapies have been tapered or completed. Timing is also important for anti-CD20 B-cell therapies as these have prolonged effects after dosing. For such patients, it is important to continue all preventative measures in place before vaccines were available, and all individuals within the patient’s “bubble” should be vaccinated to provide an additional layer of protection. Finally, it is difficult to speculate on the management of patients who develop CVAGD after the first injection of an mRNA-based vaccine. Checking SARS-CoV-2 antibody response after the first dose may provide some confidence that the patient developed an immune response and may not need the second dose, but of course this does not equate with protection against COVID-19. A change in vaccine platform could also be considered for a second dose. Alternatively, if the CVAGD was mild and readily resolved, administration of the follow-up dose could be considered.

The Immunonephrology Working Group of the European Renal Association–European Dialysis and Transplant Association recently published recommendations on the use of COVID-19 vaccines in patients with autoimmune kidney diseases and supports the vaccination of all individuals without known contraindications.50 However, these recommendations did not advise on whether vaccination with one vaccine platform was preferable to another. Despite the higher number of reports of glomerular disease activation or reactivation with mRNA COVID-19 vaccines compared with the traditional vaccines, it remains difficult to make a recommendation against the mRNA platform. As CVAGD has been seen with non-mRNA vaccines, avoiding Pfizer–BioNTech or Moderna vaccines does not completely eliminate autoimmune risk. Furthermore, the differences in efficacy between the various vaccines cannot be overlooked. Ultimately, as with all decisions in medicine, theoretical risks must be balanced against known benefits of interventions, and discussions between care providers and patients in this regard are important.Go to:

Disclosure

All the authors declared no competing interests.

See the article “A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccination” in Kidney Int, volume 100 on page 238.See the article “Minimal change disease and acute kidney injury following the Pfizer-BioNTech COVID-19 vaccine” in Kidney Int, volume 100 on page 461.See the article “Relapse of primary membranous nephropathy after inactivated SARS-CoV-2 virus vaccination” in Kidney Int, volume 100 on page 464.See the article “Post-vaccinal minimal change disease” in Kidney Int, volume 100 on page 459.See the article “Minimal change disease following the Moderna mRNA-1273 SARS-CoV-2 vaccine” in Kidney Int, volume 100 on page 463.See the article “Histologic correlates of gross hematuria following Moderna COVID-19 vaccine in patients with IgA nephropathy” in Kidney Int, volume 100 on page 468.See the article “Anti-GBM nephritis with mesangial IgA deposits after SARS-CoV-2 mRNA vaccination” in Kidney Int, volume 100 on page 471.See the article “Relapse of minimal change disease following the AstraZeneca COVID-19 vaccine” in Kidney Int, volume 100 on page 459.See the article “Relapse of class V lupus nephritis after vaccination with COVID-19 mRNA vaccine” in Kidney Int, volume 100 on page 941.See the article “Letter regarding “Minimal change disease relapse following SARS-CoV-2 mRNA vaccine”” in Kidney Int, volume 100 on page 458.See the article “A case of membranous nephropathy following Pfizer–BioNTech mRNA vaccination against COVID-19” in Kidney Int, volume 100 on page 938.See the article “Minimal change disease relapse following SARS-CoV-2 mRNA vaccine” in Kidney Int, volume 100 on page 457.See the article “Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy” in Kidney Int, volume 99 on page 1487.See the article “ANCA glomerulonephritis after the Moderna COVID-19 vaccination” in Kidney Int, volume 100 on page 473.See the article “Relapse of IgG4-related nephritis following mRNA COVID-19 vaccine” in Kidney Int, volume 100 on page 465.See the article “IgA nephropathy presenting as macroscopic hematuria in 2 pediatric patients after receiving the Pfizer COVID-19 vaccine” in Kidney Int, volume 100 on page 705.See the article “Gross hematuria following SARS-CoV-2 vaccination in patients with IgA nephropathy” in Kidney Int, volume 100 on page 466.See the article “Is COVID-19 vaccination unmasking glomerulonephritis?” in Kidney Int, volume 100 on page 469.See the article “De novo vasculitis after mRNA-1273 (Moderna) vaccination” in Kidney Int, volume 100 on page 474.See the article “Scleroderma renal crisis following mRNA vaccination against SARS-CoV-2” in Kidney Int, volume 100 on page 940.This article has been cited by other articles in PMC.

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