Drug-Induced Liver Injury After COVID-19 Vaccine

Authors: Monitoring Editor: Alexander Muacevic and John R AdlerRupinder Mann,1Sommer Sekhon,2 and Sandeep Sekhon3 Cureus. Published onlined doi: 10.7759/cureus.16491 PMCID: PMC8372667PMID: 34430106

Abstract

The first case of coronavirus disease 2019 (COVID-19) was reported in December 2019 in China. World Health Organization declared it a pandemic on March 11, 2020. It has caused significant morbidity and mortality worldwide. Persistent symptoms and serious complications are being reported in patients who survived COVID-19 infection, but long-term sequelae are still unknown. Several vaccines against COVID-19 have been approved for emergency use around the globe. These vaccines have excellent safety profiles with few reported side effects. Drug-induced hepatotoxicity is mainly seen with different drugs or chemicals. There are only a few reported cases of hepatotoxicity with vaccines. We present a case of liver injury after administration of the vaccine against the COVID-19 infection.

Introduction

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) causing coronavirus disease 2019 (COVID-19) emerged in December 2019 in Wuhan, China, resulting in an ongoing pandemic [1]. To date, it has caused more than 173 million cases and over 3.7 million death worldwide as per World Health Organization [2]. Although the respiratory system is the most common system affected by this disease, it affects multiple organ manifestations [3]. Despite international efforts to develop treatments for this disease, there are still limited therapeutic options available with remdesivir as the only Food and Drug Administration-approved drug [4]. Given the rapid spread, high morbidity, and mortality worldwide, a coordinated effort led to developing the vaccine in a year of first diagnosed case. Multiple COVID vaccines have been developed at an unprecedented rate. These vaccines have excelled safety and efficacy profiles [57]. The most common adverse effects reported with these vaccines included mild effects like pain at the vaccine site, fever, fatigue, headache, arthralgia, myalgia, lymphadenopathy, and severe effects like anaphylactic reaction [8]. Drug-induced hepatotoxicity is a common adverse event seen with prescription and nonprescription drugs [9]. There are few reported hepatotoxicity cases due to vaccines, namely anti-rabies vaccination-induced hepatotoxicity and autoimmune hepatitis due to influenza virus and hepatitis A and B vaccines [1017]. We report a case of liver injury after receiving the COVID vaccine.Go to:

Case presentation

A 61-year-old female with a known history of irritable bowel disease and cholecystectomy presented to the emergency department with generalized weakness, body aches, dry heaving, and a low-grade temperature of 99.9 Fahrenheit. The patient received a second dose of the Pfizer COVID-19 vaccine nine days before the start of symptoms. She was noted to have conjunctival icterus, mild generalized abdominal tenderness without guarding, or rigidity on physical examination. On admission, the patient’s vitals were stable except for tachycardia with a heart rate between 90 and 110 beats/min.

Laboratory analysis was remarkable for elevated alkaline phosphatase (ALP) of 207 U/L, total bilirubin of 6.2 mg/dL, direct bilirubin of 3.9 mg/dL, white blood cell (WBC) count of 17.2 x 109/L, and mildly elevated aspartate transaminase of 37 U/L (Table ​(Table11 and Figure 1). Abdominal ultrasound showed increased echogenicity within the liver compatible with fatty infiltrates, and common duct diameter was measured to be 6 mm. At the same time, CT of the abdomen with contrast showed no acute abnormalities. The patient was admitted to the hospital and started on empiric antibiotics for presumed cholangitis. Gastroenterology consultation was obtained. Magnetic resonance cholangiopancreatography without contrast showed no filling defect within the biliary duct, status post cholecystectomy, bile duct diameter within a normal range, and unremarkable liver. The patient remained afebrile, WBC trended down, and abdominal pain improved over the course of the hospital stay. Given these findings, infectious disease specialist recommended discontinuing antibiotics. Antibodies to liver/kidney microsomal type 1, smooth muscle, anti-mitochondrial, alpha-1 antitrypsin came back negative, and, additionally, ceruloplasmin, antinuclear antibody, alpha-fetoprotein, and viral serologies for hepatitis A, B, and C came back negative (Table ​(Table2).2). Liver biopsy showed minimal pallor suggesting slight edema along with scattered inflammatory cells consisting of small lymphocytes, scattered polymorphonuclear leukocytes, and few eosinophils, no evidence of florid duct lesion on interface hepatitis, and no evidence of fibrosis on trichrome and reticulin stain. 

Table 1

Liver function tests trend

DateAspartate transaminase (U/L)Alanine transaminase (U/L)Total bilirubin (mg/dL)Alkaline phosphate (U/L)Albumin (g/dL)
4/6/201816201913.7
1/29/202137376.22073
1/30/202128306.51813
1/31/202120225.72084.4
2/1/202120223.62543.1
2/2/202129203.62932.8
2/3/202136223.33673.1
2/4/202134202.53483
2/5/2021291923292.8
2/6/202130201.73662.9
2/19/202135251.22313.9
3/9/202124160.91624.1
4/8/2021151111304.1
6/2/202114111.3964.1

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Table 2

Immunologic and infectious work-up for liver disease

TestResults
Gamma-glutamyl transpeptidase103 U/L (1-24 U/L reference range)
Hepatitis A IgM antibodyNegative
Hepatitis B surface antigenNegative
Hepatitis B core IgM antibodyNegative
Hepatitis C antibodyNegative
Anti-liver/kidney microsomal antibodyNegative (≤20 = negative, reference range)
Ferritin975.2 ng/mL (10.0-291.0 reference range)
Antinuclear antibody reflexNegative
Smooth muscle antibodyNegative
Anti-mitochondrial antibodyNegative (≤20 = negative, reference range)
Ceruloplasmin38 mg/dl (18-53 mg/dL reference range)

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Figure 1

An external file that holds a picture, illustration, etc.
Object name is cureus-0013-00000016491-i01.jpg

Graphs showing liver function test trends

Given that all work-up for infection, autoimmune diseases, and any obstruction came back negative, the patient’s clinical picture and laboratory findings were attributed as a liver injury due to the COVID-19 vaccine. Her liver function levels continued to trend down, and she was discharged from the hospital after a week of hospitalization. On the patient’s follow-up with a gastroenterologist, abdominal pain was resolved, and her liver function test values normalized (Table ​(Table11 and Figure ​Figure11).Go to:

Discussion

Drug-induced hepatotoxicity leads to nearly 10% of all cases of acute hepatitis and more than 50% cases of liver failure [18]. It is one of the common reasons for the withdrawal of medications from the market and modification of use [19]. It can be either type A (predictable), dose-related and short latent period in days, or type B (idiosyncratic), dose-independent, unpredictable, and variable latency [20,21]. Based on population-based studies, drug-induced liver injury incidence varies between 13.9 and 19.1 cases per 100,000 people per year [22,23]. Patients have either hepatocellular injury (three times upper limit of transaminase in comparison to ALP), cholestatic injury (three times increase in ALP comparison to transaminase), or mixed pattern (where both ALP and aminotransferase are three times upper limit) [2426]. Most patients improve spontaneously after the removal of the offending drug. If acute liver failure (ALF) is suspected, early liver transplant referral is important due to high ALF mortality [25,27]. From the spontaneous reports from patients who received Pfizer/BioNTech BNT162b2 mRNA in the UK between 9/12/20 and 26/05/2021, there are reports of 45 patients having abnormal liver function analysis and three patients having drug-induced liver injury [28].

In this case, the review of medications and history did not reveal any other reason for hepatotoxicity. She also denied the use of any over-the-counter medications or supplements. Although it is rare with vaccination, the COVID-19 vaccine is likely the cause of hepatotoxicity in our patient based on a diagnosis of exclusion. In this case, the patient had a cholestatic pattern with elevated ALP and bilirubin with mild elevation in the transaminases.

Pfizer/BioNTech BNT162b2 mRNA trial included only 0.6% (217/37,706) patients with liver disease. Among patients with liver disease, 214 were with mild liver disease and only three with moderate to severe liver disease. This patient has underlying fatty liver disease. It is unclear if that was a likely risk factor for hepatotoxicity in this case [5].  Although only a small number were included in trials for Pfizer/BioNTech BNT162b2 mRNA, Moderna mRNA-1273, and the AstraZeneca/University of Oxford ChAdOx1-nCoV-19 chimpanzee adenovirus vector vaccine, both the American Association for Study of Liver Diseases and European Association for the Study of Liver recommend vaccination against SARS-COV-2 with these highly effective and safe vaccines, given a greater risk of health consequences from SARS-COV-2 infection in these patients [29,30].

Hepatotoxicity can occur with vaccines, even though it is more common with prescription and nonprescription drugs. So, the clinician should be watchful in patients showing clinical signs and symptoms after a vaccine.Go to:

Conclusions

In summary, we presented a case of liver injury after the COVID-19 vaccine. We attributed the cause of liver injury to the COVID-19 vaccine, given no other cause in our patient after extensive work-up. There are reports of drug-induced liver injury and abnormal liver function analysis from the spontaneous reports from patients who received Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine in the UK. The purpose of this manuscript is to raise awareness of potential side effects; it should not alter the recommendation of healthcare providers regarding vaccinations.Go to:

Notes

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

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Liver injury after mRNA-based SARS-CoV-2 vaccination in a liver transplant recipient

Authors: Jérôme Dumortiera,b,⁎ Clin Res Hepatol Gastroenterol. 2022 Jan; 46(1):101743.16.  doi: 10.1016/j.clinre.2021.101743 PMCID: PMC8214934PMID: 34146727

Coronavirus disease-2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an ongoing global pandemic of major concern, started at the end of 2019. Patients with comorbidities are at high risk of developing severe disease and this includes solid organ transplant recipients [1]. Therefore, Covid-19 vaccine is highly recommended in this population. Neverthless, immunocompromised patients, including solid organ transplant recipients, were not included in the Covid-19 vaccine large trials, especially of Pfizer/BioNTech and Moderna mRNA vaccines, and therefore, safety and efficacy data are lacking in this population. Recently, a significantly reduced immunogenicity of the mRNA SARS-CoV-2 vaccines has been reported [2,3]. Regarding the massive number of patients receiving this vaccination, identification of clinically relevant imputable side-effects of the vaccines is very difficult and therefore a major goal.

Herein we report the case of a 46-year-old male, who received the first injection of BNT162b2 mRNA vaccine 123 days after a liver transplantation for alcohol-associated liver disease. At the time of vaccination, the patient was on maintenance immunosuppression therapy with tacrolimus and mycophenolate mofetil, and liver function tests were within normal range. According to systematic biological follow-up, 12 days after vaccination, laboratory findings were as follows: AST 99 U/l (normal: 10–45), ALT 287 U/l (normal: 10–45), alkaline phosphatase (ALP) 270 U/l (normal: 38–120), gamma glutamyl transferase (GGT) 797 U/l (normal: 7–65), total bilirubin 9 mmol/l (normal: 0–20). The patient was totally asymptomatic. Serum HBsAg, anti-HBs, anti-HBc IgM, anti-HAV IgM, anti-HEV IgM, EBV-DNA (PCR), CMV-DNA (PCR), antinuclear antibody, anti-smooth muscle antibody, and anti-liver kidney microsomal antibody were negative. The patient did not consume alcohol on a regular or irregular basis. Other than immunosuppressive treatments included only aspirin. Abdominal Doppler ultrasound was normal. The diagnosis of liver damage related to vaccination was considered and no further investigation was performed, including no liver biopsy. Similarly, no modification of immunosuppressive regimen was done. The second vaccine injection was contra-indicated. Biological evolution was rapidly favourable. One month after initial biological liver injury, laboratory findings were as follows: AST 19 U/l (normal: 10–45), ALT 24 U/l (normal: 10–45), ALP 117 U/l (normal: 38–120), GGT 101 U/l (normal: 7–65), total bilirubin 8 mmol/l (normal: 0–20).

We report herein the case of a liver transplant recipient who presented mild liver injury probably due to the first injection of BNT162b2 mRNA vaccine. Evolution was spontaneously favourable. Perturbation of liver function tests was transitory, but detected because of regular systematic (monthly) biological follow-up, less than one year after transplantation. In this context, such diagnosis must be considered together with more usual cause of liver graft injury, such as rejection, in face of significant liver function test abnormalities. Moreover, in the absence of severe liver injury, deleterious manoeuvres (diagnostic or therapeutic) must be ovoid and close biological follow-up performed. The most intuitive expected toxicity of mRNA vaccine (but also all vaccines) is related to immune activation. Therefore, benign and common reported symptoms include soreness, fatigue, myalgia, headache, chills, fever, joint pain, nausea, muscle spasm, sweating, dizziness, flushing, feelings of relief, brain fogging, anorexia, localized swelling, decreased sleep quality, itching, tingling, diarrhoea, nasal stuffiness and palpitations [4]. The flip side of the possibly beneficial adjuvant inflammation, however, is potential toxicity of the mRNA vaccines. And remember that this type of vaccine has also been evaluated as an anti-cancer treatment. With the Covid-19 vaccines, we are using this new type of vaccine for the first time on a very large scale. From preliminary animal and human studies on previous mRNA vaccines, the clinical adverse effects have included myopathy (caused by mitochondrial toxicity), lipodystrophy, lactic acidosis, pancreatitis, liver steatosis, and nerve damage and some were severe [5]. A better understanding of the toxicity of Covid-19 vaccines, particularly mRNA vaccines, can only be based on comprehensive reporting of even apparently mild cases. These cases will be more easily identified in special populations under close clinical and biological surveillance, such as transplant patients, as reported in our patient. Perhaps these patients are also at greater risk.Go to:

Footnotes

Conflicts of interest and sources of funding: None to declare.

Author contributions: J.D. clinically managed the patient and wrote the manuscript.Go to:

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CDC: No Documents Supporting Claim Vaccines Don’t Cause Variants

Authors:  Zachary Stieber May 13, 2022 The Epoch Times

The Centers for Disease Control and Prevention (CDC) says it does not have documents backing its claim that COVID-19 vaccines do not cause variants of the virus that causes COVID-19.

The CDC’s website calls it a myth that the vaccines cause variants.

“FACT: COVID-19 vaccines do not create or cause variants of the virus that causes COVID-19. Instead, COVID-19 vaccines can help prevent new variants from emerging,” the website states.

“New variants of a virus happen because the virus that causes COVID-19 constantly changes through a natural ongoing process of mutation (change). As the virus spreads, it has more opportunities to change. High vaccination coverage in a population reduces the spread of the virus and helps prevent new variants from emerging,” it also says.

The Informed Consent Action Network (ICAN), a nonprofit, asked the CDC in Freedom of Information Act requests for documentation supporting the claim.

In one request, the group asked for “All documents sufficient to support that COVID-19 vaccines do not create or cause variants of the virus that causes COVID-19.”

Another requested “All documents sufficient to support that the immunity conferred by COVID-19 vaccines does not contribute to virus evolution and the emergence of variants.”

The CDC has now responded to both requests, saying a search “found no records responsive” to them.

The first response came in January (pdf); the second came on May 4 (pdf).

If the CDC is making declaratory statements, the agency should have documents supporting them, Aaron Siri, an attorney representing ICAN, told The Epoch Times.

The responses are “very troubling,” Siri said. “I thought the CDC was a data-driven organization, that they made their decisions based on the studies and the science and the data.”

The CDC did not respond to a request for comment.

ICAN has been one of the more prolific requesters of information from the CDC during the pandemic. Many requests have yielded information. Others have not.

In this case, the CDC should act to ensure continued public trust, Siri says.

“Remove the language or provide the evidence,” he said. “There obviously are going to be instances where recommendations from the CDC might prove helpful or useful. And I think they do a disservice to everybody by hurting their own credibility by making statements that they either don’t have support or won’t produce the support for.”

Scientists outside the CDC have also said that vaccines can help prevent new variants.

“As more people get vaccinated, we expect virus circulation to decrease, which will then lead to fewer mutations,” the World Health Organization says on its site.

But many of the claims relied on the vaccines being able to stop infection from the CCP (Chinese Communist Party) virus, which causes COVID-19. The vaccines are increasingly unable to do so, particularly against the newest dominant strain, Omicron.

Dr. Geert Vanden Bossche, a virologist, is among those who say that the vaccines themselves are behind new variants.

“All COVID-19 vaccines fail in blocking viral transmission, especially transmission of more infectious variants. This is a huge problem as viral transmission is now increasingly taking place among healthy people in general and vaccinees in particular (as their S-specific Abs do not sufficiently neutralize S variants),” Vanden Bossche says on his website. “The resulting suboptimal S-directed immune pressure serves as a breeding ground for even more infectious variants.”

Acute hepatitis with autoimmune features after COVID-19 vaccine: coincidence or vaccine-induced phenomenon?

Authors: José M Pinazo-Bandera 1Alicia Hernández-Albújar 1Ana Isabel García-Salguero 2Isabel Arranz-Salas 2Raúl J Andrade 1 3Mercedes Robles-Díaz 1 3

Gastroenterol Rep (Oxf) 2022 Apr 27;10:goac014. doi: 10.1093/gastro/goac014. eCollection 2022.

Introduction

Autoimmune diseases result from a breach of immunological self-tolerance and tissue damage by autoreactive T lymphocytes. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is characterized by an inflammatory dysregulation that has been associated with the development of autoimmune processes [1].

Molecular mimicry has been suggested as a potential mechanism for these associations as well as ‘bystander activation’ where the infection may lead to activation of antigen presenting cells that may activate autoreactive T-cells, with the production of pro-inflammatory mediators and tissue damage [1].

There is a potential antigenic cross-reactivity between SARS-CoV-2 and human tissue possibly linked to an increase in autoimmune diseases. A recent study showed that antibodies against the spike protein S1 of SARS-CoV-2 had high affinity against some human tissue proteins such as transglutaminase 2 and 3, or myelin basic protein, among others [2].

As both mRNA vaccine (Comirnaty BioNTech BNT162b2 and Spikevax ARNm-1273) and vectorial vaccine (ChAdOx1nCoV-19 Vaxzevria/Covishield) give rise to the production of protein S, the antibodies produced against this protein after vaccination may also trigger autoimmune conditions in predisposed individuals.

Thirteen case reports (including 16 patients) have recently reported an association between COVID-19 vaccines and acute hepatitis development [3–15].

Here we report two new cases of liver injury possibly related to COVID-19 vaccination.

Case 1

A 77-year-old woman developed intense malaise, vomiting and disorientation 2 days after receiving the second dose of Comirnaty vaccine and was hospitalized the following day. She did not have a history of autoimmune disorders. She denied alcohol drinking and was on long-term therapy with bromazepam, losartan, and omeprazole. Her previous liver tests back in 2020 were normal.

Physical examination was normal except for scleral icterus. Liver test showed acute hepatocellular injury: total bilirubin (TB) 3.1 mg/dL (reference, <1 mg/dL), aspartate aminotransferase (AST) 474 U/L (reference, <40 UI/L), alanine aminotransferase (ALT) 552 U/L (reference, <40 U/L), and alkaline phosphatase (ALP) 159 U/L (reference, <117 U/L). Immunoglobulin G levels were within normal ranges (reference, 800–1,600 mg/dL), while anti-nuclear antibody and anti-mitochondrial antibody M2 were detected with 1/160 and 1/40 titre, respectively. Human leukocyte antigen (HLA) testing was positive for HLA-DR4. All the other possible aetiologies were ruled out.

The patient was discharged and closely monitored. Due to increased transaminase levels, she underwent a liver biopsy (Supplementary Figure 1.1), which showed findings compatible with autoimmune hepatitis (AIH).

Prednisone 60 mg/day on tapering dose was initiated and 3 weeks later liver test had markedly improved. Azathioprine was added 2 months later, but it had to be withdrawn due to rash. Prednisone was then replaced by budesonide 9 mg/day. Five months after onset, transaminases were within the normal range; however, the subject was hospitalized with neurologic symptoms in relation to brain lesions in both hemispheres of probable infectious origin and died 1 month later.

Case 2

A 23-year-old man presented with mononucleosis syndrome-like symptoms and jaundice at the emergency room, 10 days after receiving the second dose of Spikevax vaccine. He did not suffer from previous autoimmune disorders. He denied having taken any conventional drug treatments as well as alcohol consumption.

Physical examination was unremarkable except for scleral icterus. Liver tests showed acute hepatocellular injury: TB 2.3 mg/dL, AST 702 U/L, ALT 587 U/L, and ALP 202 U/L. Immunoglobulin G levels were minimally elevated (1,647 mg/dL), while autoantibodies resulted as negative. HLA testing was positive for HLA-DR3. Serology ruled out viral causes and abdominal ultrasonography was normal. After admission to the hospital, a thoracic-abdominal scan was performed and revealed generalized lymphadenopathy.

He underwent a liver biopsy (Supplementary Figure 1.2), which showed findings compatible with AIH.

Prednisone 60 mg/day on tapering dose was initiated and 1 month later lymphadenopathies were undetectable and liver test had significantly improved. Three months after onset, transaminases were within the normal range and he is still on low-dose prednisone 10 mg/day.

Discussion

These new cases of liver injury compatible with AIH, which developed post COVID-19 vaccination, along with 13 prior published case reports (16 patients) reinforce that this association could be more than coincidental. In the previously published case reports, all the patients, except three, were females and their age ranged from 35 to 80 years [3–15]. Twelve of these patients received one of the mRNA vaccines [35–121415], while four patients received vectorial vaccines [41213]. In 6 of the 16 patients, liver biopsy revealed infiltration with eosinophils [347914] and IgG levels were increased in 12 cases [4–1215].

Fourteen reported patients were successfully treated with prednisolone whereas two died due to acute liver failure [412] (Table 1).

Table 1.

Characteristics of patients with liver injury after SARS-CoV-2 vaccine (published cases and two new cases)

AuthorVaccineDoseDays until clinical onsetGenderAgeLiver-injury patternAutoimmune disease historyAuto- antibodiesIgGBiopsySteroid responseDeath
Compatible (Yes/No)Eosinophils infiltration (Yes/No)
Bril et al. [3Comirnaty BioNTech BNT162b2 1st 13 35 Hep None ANAAnti-dsDNA Normal Yes Yes Yes No 
Rela et al. [4(2 cases) ChAdOx1nCoV-19 Covishield (both patients) NA 20 38 NAa None ANA High Yes Yes Yes No 
NA 16 65 NAa None NA NA Yes Yes No Yes 
Rocco et al. [5Comirnaty BioNTech BNT162b2 2nd 80 Hep Hashimoto disease ANA High Yes No Yes No 
Londoño et al. [6Spikevax, ARNm-1273 2nd 41 Hep None ANASMASLALC-1 High Yes No Yes No 
Tan et al. [7Spikevax, ARNm-1273 1st 35 56 Hep None ANASMA High Yes Yes Yes No 
McShane et al. [8Spikevax, ARNm-1273 1st 71 Hep None SMA High Yes No Yes No 
Ghielmet-ti et al. [9Spikevax, ARNm-1273 1st 63 Hep None ASMAANCAANA High Yes Yes Yes No 
Garrido et al. [10Spikevax, ARNm-1273 1st 14 65 Hep None ANA High Yes No Yes No 
Avci et al. [11Comirnaty BioNTech BNT162b2 NA 14 61 Mix Hashimoto disease ANASMA High Yes No Yes No 
Erard et al. [12(3 cases) Spikevax, ARNm-1273(two first patients)ChAdOx1nCoV-19 Vaxzevria(third one) 2nd 10 80 NAa None Negative High Yes No Yes No 
1st 21 73 NAa None Negative High Yes No Yes No 
1st 20 68 NAa None Negative High Yes No No Yes 
Clayton-Chubb et al. [13ChAdOx1nCoV-19 Vaxzevria 1st 26 36 Hep None ANA Normal Yes No Yes No 
Lodato et al. [14Comirnaty BioNTech BNT162b2 1st 15 43 NAa None Negative Normal Yes Yes Yes No 
Vuille-Lessard et al. [15Spikevax, ARNm-1273 1st 76 Hep Hashimoto disease ANA High Yes No Yes No 
Pinazo et al. (2 cases) Comirnaty BioNTech BNT162b2(First one)Spikevax, ARNm-1273(second one) 2nd 77 Hep None ANAAMANegative Normal Yes Yes Yes Yesb 
2nd 10 23 Hep None High Yes No Yes No 

M, male; F, female; NA, not available; Hep, hepatocellular; Mix, mixed; IgG, immunoglobulin G; ANA, anti-nuclear antikor; SMA, smooth muscle antibodies; dsDNA, double-stranded DNA antibodies; LC1, liver sitozol antibody; anti-SLA, soluble liver antigen antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; AMA, anti-mitochondrial antibodies.a

ALP (alkaline phosphatase) not available.b

The patient died due to an extrahepatic cause (brain lesions in both hemispheres of probable infectious origin).Open in new tab

In both cases of the present study, a number of laboratory (including HLA testing) and histological features supported the autoimmune nature of the liver injury. In our first case, the short period elapsed after vaccine administration, the laboratory and histopathological findings (showing moderate liver fibrosis), the positive HLA-DR4, and the response to therapy suggest unmasking of AIH by the vaccine. However, in our second case, the medical history negative for liver and autoimmune diseases, the short time interval after vaccination, the typical onset of symptoms to which was added generalized lymphadenopathy, the elevated immunoglobulin G levels, the positive HLA-DR3, histopathological findings with absence of liver fibrosis, and the response to therapy reinforce the hypothesis of SARS-CoV-2 vaccine as a trigger of an autoimmune liver injury debut. We realize that there are no pathognomonic (laboratory or histological) features of AIH, but the appropriate exclusion of viral and metabolic causes of liver injury makes the autoimmune mechanisms the more likely explanation for both cases.

Taking into account the large number of vaccinated subjects worldwide, the suspicion of vaccine-related AIH carries important clinical implications. It is unknown whether prolonged immunosuppression would be required in these cases or whether re-exposure to a new dose of COVID-19 vaccine might trigger fulminant liver injury. Nevertheless, the risk of receiving another dose must be balanced against the risk of contracting SARS-CoV-2 infection. In addition, it remains unclear whether patients who have developed liver injury after vaccination with one type of vaccine can receive other COVID-19 vaccine with a different mechanism of action.

Post COVID-19 vaccination, AIH has been rarely reported so far [3–15], which might be due to either minimal awareness of this disease or because patients without jaundice often do not seek medical attention. However, given the growing number of cases compatible with AIH reported after SARS-CoV-2 vaccination, regulators should consider the inclusion of this potential adverse event in the label of COVID-19 vaccines.

In conclusion, clinicians should be aware of the potential association between the vaccines and the onset of immune mediated disorders such as AIH. However, this rare complication should not discourage people from getting vaccinated.

References

1 Ehrenfeld M, Tincani A, Andreoli L et al.  Covid-19 and autoimmunity. Autoimmun Rev 2020;19:102597.

2 Google ScholarCrossrefPubMed2Vojdani 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 Inmunol 2020;217:108480.

3 Google ScholarCrossref3Bril F, Al Diffalha S, Dean M et al.  Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty? J. Hepatol 2021; 2021 Jul;75:222–224.

4 Google ScholarCrossrefPubMed4Rela M, Jothimani D, Vij M et al.  Auto-immune hepatitis following COVID vaccination. J Autoimmun 2021;123:102688.

5 Google ScholarCrossrefPubMed5Rocco A, Sgamato C, Compare D et al.  Autoimmune hepatitis following SARS-CoV-2 VACCINE: MAY not be a casualty. J Hepatol 2021;75:728–9.

6 Google ScholarCrossrefPubMed6Londoño MC, Gratacós-Ginès J, Sáez-Peñataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination: still casualty. J Hepatol 2021;75:1248–1249.

7 Google ScholarCrossrefPubMed7Tan CK, Wong YJ, Wang LM et al.  Autoimmune hepatitis following COVID-19 vaccination: true causality or mere association? J Hepatol 2021;S0168-8278(21)00424-4.

8 Google Scholar8McShane C, Kiat C, Rigby J et al.  The mRNA COVID-19 vaccine—a rare trigger of autoimmune hepatitis? J Hepatol 2021;S0168-8278(21)01896-1.

9 Google Scholar9Ghielmetti M, Schaufelberger HD, Mieli-Vergan G et al.  Acute autoimmune-like hepatitis with atypical anti-mitochondrial antibody after mRNA COVID-19 vaccination: a novel clinical entity? J Autoimmun 2021;123:102706.

10 Google ScholarCrossrefPubMed10Garrido I, Lopes S, Sobrinho Simões M et al.  Autoimmune hepatitis after COVID-19 vaccine—more than a coincidence. J Autoimmun 2021;125:102741.

11 Google ScholarCrossrefPubMed11Avci E, Abasiyanik F. Autoimmune hepatitis after SARS-CoV-2 vaccine: new-onset or flare-up? J Autoimmun 2021;125:102745.

12 Google ScholarCrossrefPubMed12Erard D, Villeret F, Lavrut PM et al.  Autoimmune hepatitis developing after COVID 19 vaccine: presumed guilty? Clin Res Hepatol Gastroenterol 2022;46:101841.

13 Google ScholarCrossrefPubMed13Clayton-Chubb D, Schneider D, Freeman E et al. ; Comment to the letter of Bril F. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty? J Hepatol 2021;75:1249–1250.

14 Google ScholarCrossrefPubMed14Lodato F, Larocca A, D’Errico A et al.  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;75:1254–6.

14Google ScholarCrossrefPubMed15Lessard EV, Montani M, Bosch J et al.  Autoimmune hepatitis triggered by SARS-CoV-2 vaccination. J Autoimmun 2021;123:102710.

Exclusive: Pilots Injured by COVID Vaccines Speak Out: ‘I Will Probably Never Fly Again’

Authors: MICHAEL NEVRADAKIS  MAY 8, 2022 The Epoch Times Originally Published Children’s Defense Fund

In interviews with The Defender, pilots injured by COVID-19 vaccines said despite a “culture of fear and intimidation” they are compelled to speak out against vaccine mandates that rob pilots of their careers — and in some cases their lives.

As a commercial pilot, Bob Snow had long looked forward to seeing his daughter follow in his footsteps by helping her learn to fly an airplane.

However, having received the COVID-19 vaccine “under duress,” this dream is no longer a possibility for Snow.

“I will probably never fly again,” Snow said in a video he made about his story. “I was hoping to teach my daughter to fly. She wants to be a pilot. That will probably never happen, all courtesy of the vaccine.”

Snow is one of a growing number of pilots coming forward to share stories of injuries they experienced after getting a COVID-19 vaccine.

Some of these accounts are “hair-raising and deeply disturbing,” according to Maureen Steele, a paralegal and head of media relations for the John Pierce Law Firm.

The firm represents U.S. Freedom Flyers (USFF), an organization opposing vaccine and mask mandates for pilots and airline staff, in a series of legal actions against the U.S. Federal Aviation Administration (FAA) and several airlines.

Josh Yoder, a pilot with a major commercial airline, Army combat veteran and former flight medic, is a co-founder of USFF.

In a recent interview with The Defender, Yoder said the FAA has been aware of cases of pilots suffering vaccine injuries since at least December 2021, when the California-based Advocates for Citizens’ Rights hand-delivered an open letter to the FAA, major airlines and their insurers.

Yoder said USFF “has received hundreds of phone calls from airline employees who are experiencing adverse reactions post COVID-19 vaccination,” describing the stories as “heartbreaking.”

According to Yoder, the warnings contained in the letter, including testimony by “world-renowned experts,” were “completely ignored,” adding that “we are now beginning to see the consequences.”

This is leading an increasing number of pilots to “come forward to expose the truth regarding these toxic injections,” Yoder said.

The Defender recently reported on a series of reports that have been submitted to the Vaccine Adverse Event Reporting System, or VAERS, involving pilots who sustained severe injuries and side effects following the COVID-19 vaccine.

Congressional testimony from Cody Flint, an agricultural pilot who has logged more than 10,000 flight hours, was included in this letter.

“The FAA has created a powder keg and lit the fuse,” Flint said in an interview with The Defender.

“We are now seeing pilots experiencing blood clots, myocarditis, pericarditis, dizziness and confusion at rates never seen before. Pilots are losing their careers and having to call in sick or go on medical leave from medical issues developing almost immediately after vaccination.”

Vaccine-Injured Pilots Share Stories With the Defender

Several pilots, including Bob Snow, shared their stories with The Defender in a recent series of interviews.

Snow, a captain with a major U.S. airline, told The Defender he received the Johnson & Johnson COVID-19 vaccine on Nov. 4, 2021, “as a result of an unambivalent company mandate to receive the vaccine or be terminated.”

According to Snow, he “began experiencing issues a little over two months” after receiving the vaccine. Due to a history of gastroenteritis, he underwent an endoscopy and an abdominal CT scan.

The results of the endoscopy were normal and Snow was awaiting the results of the CT scan when he suffered cardiac arrest on April 9, immediately after landing at Dallas-Forth Worth International Airport.

As Snow described it:

“I was very lucky to have collapsed when and where I did, as the aircraft was shut down at the gate post-flight and care was immediately provided.

“There was absolutely no warning preceding my collapse in the cockpit. It was literally as if someone ‘pulled the plug.’”

After receiving CPR and AED (automated external defibrillator) shocks to be revived, Snow spent almost a week in the hospital, where he was diagnosed with having sustained sudden cardiac arrest (SCA).

Medical studies indicate survival rates for out-of-hospital SCA cases are estimated at 10.8% to 11.4%.

Snow said:

“Needless to say, that’s not an encouraging number and I feel very, very lucky to have survived.

“Had this happened in a hotel, in flight, at home or almost anywhere else, I do not believe I would be here right now.”

Snow said prior to this incident, he had “no history of prior significant cardiac issues,” based on two EKGs (electrocardiograms) per year for each of the previous 10 years — none of which, according to Snow, “provided any indication of incipient issues that might lead to cardiac arrest.”

“I have no known family history to indicate a predisposition to developing significant cardiac issues at this point in my life,” Snow added.

Snow has been recuperating at home since April 15, while awaiting more tests that will provide a prognosis for his long-term survival.

However, it is likely that he will never fly again in any capacity.

Snow said, “[f]or now, it appears my flying career — indeed, likely all flying as a pilot —  has come to a rapid and unexpected conclusion as SCA is a red flag to FAA medical certification.”

This, according to Snow, has resulted “in a significant loss of income and lifestyle,” adding that he has a college student and high school student at home and a non-working spouse who relied on his livelihood.

‘Last Thing I Remember Is . . . Praying I Would Make It’

Like Snow, Cody Flint had no prior medical history to indicate he was at risk.

“I have been extremely healthy my whole life with no underlying conditions,” said Flint, adding:

“As a pilot that held a second-class medical [certification], I was required to get a yearly FAA flight physical to show I was healthy enough to safely operate an airplane.

“I have renewed my medical every year since I was 17. The last FAA medical I received was on January 19, 2021. The medical showed I was perfectly healthy just 10 days before receiving the COVID-19 vaccine.”

Flint got his first (and only) dose of the Pfizer COVID-19 vaccine on Feb. 1, 2021. He told The Defender:

“Within 30 minutes, I developed a severe burning headache at the base of my skull and blurred vision. After a few hours, the pain was constant, but didn’t seem to be getting worse. I thought the pain would go away, eventually. It did not.”

Two days later began his seasonal job as an agricultural pilot, which typically runs from February to October of each year, Flint said.

He said:

“Approximately one hour into my flight, I felt my condition starting to rapidly decline and I was developing severe tunnel vision. I pulled my airplane up to turn around to head home and immediately felt an extreme burst of pressure in my skull and ears.”

Flint initially considered landing on a nearby highway, unsure he’d make it back to the airstrip, but chose not to so as not to put the public in danger.

Instead, according to Flint:

“The last thing I remember is seeing our airstrip from a few miles out and praying I would make it.

“Later, my coworkers told me I landed and immediately stopped my plane. They described me as being unresponsive, shaking and slumped over in my seat … I do not remember landing or being pulled from the plane.”

Flint said various doctors, including his longtime hometown doctor, refused to consider that his recent COVID-19 vaccination caused his symptoms. Instead, he was prescribed Meclizine for vertigo and Xanax for panic attacks.

According to Flint, doctors told him he would be “completely better within two days.” But two days later, Flint “could barely walk without falling over.”

Seeking a second opinion, Flint visited the Ear & Balance Institute in Louisiana, where he was diagnosed with left and right perilymphatic fistulas (a lesion in the inner ear), and highly elevated intracranial pressure due to swelling in his brainstem.

As Flint described it, “[m]y intracranial pressure had risen so high that it caused both of my inner ears to ‘blow out.’” Doctors told him this is usually caused by major head trauma.

“Obviously, I did not have head trauma,” said Flint. “What I did have, though, was an unapproved and experimental ‘vaccine’ just two days prior to suffering this bodily damage.”

“My doctors [at the Ear & Balance Institute] clearly stated my health issues were a direct result of a severe adverse reaction to the Pfizer COVID-19 vaccine,” he added.

Flint says he now cannot receive renewed medical certification from the FAA due to the injuries he sustained, the physical condition he is currently in and “the fact that I will be on the FAA-unapproved medicine Diamox for the foreseeable future.”

Like Snow, Flint believes “it is … highly unlikely that I’ll ever be able to fly again,” adding, “On most days, I am too dizzy to even safely drive a vehicle.”

Greg Pierson, like Snow and Flint, shared a similar story. A commercial pilot with a major U.S. airline that is also a federal contractor, he was mandated to get vaccinated.

Pierson told The Defender:

“I felt extremely pressured to consider getting vaccinated, even though I am adamant against any mandates that violate personal freedom choices.

“I did research and consulted several medical professionals regarding the associated risks.

“I have never had a flu shot in my lifetime, so this was not something I wanted to do. I reluctantly received the first dose of the Pfizer vaccine on August 26, 2021.”

For Pierson, the onset of symptoms was almost immediate, beginning “approximately 14 hours” after receiving the vaccine, when he experienced “an extremely erratic and highly elevated heart rate.”

Pierson visited a local emergency room, where he was diagnosed with atrial fibrillation. His condition was stabilized and he was soon discharged, though he remained on medication to help his heart return to a normal rhythm.

While Pierson says he has not experienced any further episodes, he nevertheless still has not been cleared to return to the cockpit.

“I successfully passed all the required protocols to re-obtain my certification that will allow me to return to work,” he said, adding the FAA has had his records and test results since Feb. 16, but he still hasn’t received a determination.

“I have been on disability since this occurrence, and combined with the leave, the personal and financial impacts have been significant,” Pierson said.

Pierson also described a similar experience to that of Flint, regarding the attitudes of some medical professionals regarding the possibility that his condition was brought on by the COVID-19 vaccine.

“When I brought the subject up to the ER cardiologist, that it was obvious what triggered my onset, she simply stated ‘s*it happens,’” Pierson said.

Widow Describes Husband’s Last Days

Snow, Flint and Pierson are fortunate in that they have managed to survive, even if their flying careers are in jeopardy.

But other pilots have not been so lucky.

American Airlines pilot Wilburn Wolfe suffered a major seizure following his COVID-19 vaccination, which cost him his life. Fortunately, Wolfe was not on duty when his seizure hit.

Claudia Wolfe, his widow, shared her late husband’s story with The Defender.

Wolfe, a former Marine just a few years from retirement, “was definitely against getting this vaccine but was put in the position to take it or lose his job as a captain,” Claudia Wolfe said.

He received the Johnson & Johnson vaccine on Nov. 9, 2021.

Claudia Wolfe told The Defender:

“[The] first 10 days were without any event … [on] day 11, it started with a migraine-like headache which got better that afternoon after taking a couple of aspirin.

“Unfortunately, the migraine came back and he was hoping that it’s nothing else but a migraine.

“On November 22, 13 days after the COVID vaccine, he had a seizure. When paramedics arrived and my husband came out of the seizure, he was paralyzed on his right side, arm and leg, and was taken to the emergency room.”

At the emergency room, a CT scan showed he was experiencing brain bleeding, and he was admitted into intensive care. There, according to Claudia Wolfe, “he continued to have convulsions on his right hand … shortly after he was admitted, he had another seizure and doctors decided to sedate him and put him on a ventilator.”

“That was the last time I talked to my husband, before the seizure in the ICU,” Claudia Wolfe said.

Wolfe never regained consciousness and died on Nov. 26, 2021 — only 17 days after receiving the COVID-19 vaccine. Even if he had survived, he likely would not have been able to work as a pilot again.

As Claudia Wolfe explained:

“Doctors told me that he couldn’t work as a pilot anymore because he would have to be on seizure medication.

“But as the bleeding continued to spread I was told that he probably would not recognize me or his family and he probably would need a 24-hour facility to help him.

“This man was so strong and never needed a doctor, he was never sick enough to need one, and [he] just had a physical a couple months prior for his job as a pilot.”

Pilots Describe Culture of Fear and Reluctance to Come Forward

Pilots who spoke to The Defender described a culture of intimidation that has led to many of their colleagues fearing professional or personal consequences if they speak publicly about injuries following COVID-19 vaccination.

According to Yoder, “Many pilots and other airline employees capitulated to the tactics of threats, harassment and intimidation perpetrated by the very companies they serve.”

Yoder described airlines, as well as aviation industry unions, as “state actors” illegally “working in lockstep with the U.S. government” to “enforce unconstitutional mandates via a culture of fear.”

Snow told The Defender several of his colleagues shared stories of vaccine injuries with him:

“Since my SCA I have heard from several other airline personnel regarding potential vaccine injuries up to and including cardiac issues (chest pain and myocarditis).

“Many crewmembers are very reluctant to divulge potential significant health issues for fear of losing their FAA medical certification and, potentially, their careers.”

According to Snow, such fear exists “due to both concern for one’s career and also the fear of being portrayed as a vaccine skeptic.”

“There seems to be genuine reluctance on the part of corporations, businesses, government and the medical community in general to acknowledge the potential for COVID vaccine injury,” Snow said.

Claudia Wolfe also shared her experience, stating that following her husband’s death, she learned “of others that died after the COVID vaccine,” adding that “not many talk about it or believe this vaccine can harm or kill you.”

Pierson also expressed concerns, telling The Defender, “Some things I have stated publicly could have consequences in this regard.”

This culture of intimidation appears to extend beyond just accusations of being a “vaccine skeptic.”

Steele described incidents of airline employees’ non-work and online activities seemingly being monitored by their employers, who are then using this as a justification to question or harass those employees.

“I believe the airlines have people on staff that must be trolling the social media of employees and when they find a conservative, or someone they believe to be, they attack,” Steele said.

Steele said female employees appear to be particular targets of the airlines, as they “appear to be isolated and intimidated for hours on end.”

Flint connected incidents such as those described above to political interests, telling The Defender the FAA approved COVID-19 vaccines for pilots just two days after the U.S. Food and Drug Administration (FDA) issued its first Emergency Use Authorization (EUA) for such vaccines, on Dec. 10, 2020.

“I thought to myself, how could the FAA analyze the data and determine it was safe for pilots in just two days, when it took the FDA months to go over the trial data?” Flint said.

Flint said that was an especially jarring development, in light of the increased risk that pilots and cabin crew face:

“I was also extremely curious to know how the FAA is so certain that this vaccine will be safe for pilots when it’s obvious that Pfizer did not do a trial solely on pilots to find out if it would cause some of the serious health problems that immediately started to show up once the mass vaccination campaign [began].”

In the process, Flint stated, the FAA violated its own regulations.

Under the Guide for Aviation Medical Examiners: Pharmaceuticals (Therapeutic Medications) Do Not Issue – Do Not Fly, the FAA has a long-standing rule that states:

“FAA requires at least one year of post-marketing experience with a new drug before consideration for aeromedical certification purposes. This observation allows time for uncommon, but aeromedically significant, adverse reactions to manifest themselves.”

Flint said it “became painfully obvious” the FAA issued this guidance based not on science or safety, but political reasons.

“Why did the FAA abandon its own rules by encouraging pilots to take a brand-new experimental drug?” Flint asked. “This action by the FAA was totally unprecedented and extremely dangerous.”

Providing an example of such danger, Flint said, “it is now widely reported that mRNA COVID-19 vaccines can cause blood clots,” adding that several peer-reviewed studies going back more than a decade “show pilots are approximately 60% more likely to experience blood clots due to the ‘nature of the job.’”

Supporting this assertion, on May 5, the FDA announced that it would restrict who could receive doses of the Johnson & Johnson COVID-19 vaccine, due to the risk of blood clots.

Pierson also believes politics are at play in the medical community, telling The Defender even his longtime doctor told the FAA, in paperwork aimed at restoring Pierson’s suspended medical certification, that “it is impossible for the vaccine to have caused” his condition, though “he could not provide any explanation for an alternative hypothesis” — a stance Pierson characterized as “medical malpractice.”

Such politics are also found in professional organizations within the aviation industry, according to Pierson, who described his experience with one such entity:

“I approached the medical division of ALPA, the Air Line Pilots Association, to which I am a member, and presented them with data to substantiate my concerns.

“It was initially seemingly a concerned, open dialogue, which quickly was dismissed at the highest levels.”

Legal Actions to Follow Against the FAA, Federal Agencies, Airlines

The USFF, according to Yoder, is currently pursuing several legal actions related to the vaccine injuries that pilots and air staff are increasingly reporting.

He told The Defender:

“The U.S. Freedom Flyers have always taken a strong stance against the threats of government and corporate totalitarianism.

“We are filing massive, individual plaintiff lawsuits against the FAA, DOT [U.S. Department of Transportation] and commercial airlines to hold them accountable for the criminal and civil atrocities they’ve committed against our members.

“We will not rest until justice is served and constitutional American freedom is restored.”

Steele added:

“We are teeing up lawsuits for all the major airlines, with thousands of potential plaintiffs on our plaintiff lists.

“We also are going to be holding the FAA and the [U.S. Department of Transportation] accountable for their part in this atrocity.”

Steele said USFF “will be seeking retribution and restitution for these crimes against humanity,” mirroring remarks made by Pierson, who described the actions taken in the name of the pandemic as “nothing short of the highest crimes against humanity ever.”

According to Steele, unions are, in part, responsible for the injuries being sustained by pilots and other employees, as a result of their acceptance of vaccine mandates.

“Unfortunately the unions — from all industries — have let their members down,” Steele told The Defender. “They simply are rolling over and are in bed with the state and the corporations.”

Flint, in turn, assigned a significant amount of blame to the federal agencies:

“The FAA has failed at its duties in the most spectacular fashion, causing pilots to lose their lives, livelihoods and careers.

“The federal government, including the FAA, has not helped one single person injured by the COVID-19 vaccine.

“They [the federal agencies] have not publicly acknowledged there is a problem. They haven’t even so much as adjusted their ‘guidance’ to prevent this from happening in the future.”

Are Passengers at Risk From Pilot Vaccine Mandates?

When Snow suffered cardiac arrest, it occurred only a few minutes after he had landed a commercial airliner, full of passengers, at one of the most heavily trafficked airports in the U.S.

This begs the question: Are passengers — and the public at large — at risk due to potential adverse effects that may impact vaccinated pilots during flight?

According to Pierson, there is indeed a risk of a “catastrophic” incident:

“I became an outspoken critic of the vaccines after my injury, and due to becoming much more knowledgeable of all the potential health and safety risks from the vaccines.

“It became very clear to me that the implications of having an immediate, severe adverse reaction could be catastrophic if actively piloting an aircraft.”

Flint believes such a disaster may be an inevitability.

“It is only a matter of time before a pilot has a medically significant event from an adverse reaction to this [COVID-19] vaccine and crashes an airliner, killing a few hundred American citizens in the process.”

He added:

“When will the FAA finally do the right thing by trying to adhere to its own mission statement, which is ‘to provide the safest, most efficient aerospace system in the world’?

“How many more pilots have to die or be severely injured before the FAA acknowledges the horrible and dangerous problem it has created?”

In addition to the risk of a disaster involving casualties among passengers and the general public, the difficulties that pilots are experiencing as a result of vaccine-related adverse reactions are creating other disruptions for the airline industry and the flying public, such as flight cancellations and delays.

Yoder described this as a “ripple effect”:

“Vaccine mandates are having a ripple effect in the aviation industry that will continue for years to come.

“Pilot shortages were a concern pre-mandate, [and] have now been amplified due to early retirements and medical disqualification due to certain adverse vaccine reactions which prohibit pilots from maintaining medical certification.”

Pilots, Advocates Describe Importance of Speaking Out

The pilots, legal professionals and advocates who spoke to The Defender all expressed their hope that by speaking out and sharing their stories and experiences, they will make a difference.

Snow said:

“I hope to shine the spotlight on the potential for significant safety issues that exist within the airlines, commercial vehicles/transportation, and other safety-sensitive work that might be affected by [the] sudden onset of health issues that could be attributed to the COVID vaccines.

“It is in our collective best interest that real research and data analysis be undertaken to address this potentially dangerous situation.

“Why is there such a reluctance to investigate these EUA COVID vaccines which are still being aggressively marketed to, if not outright forced upon, the global public?”

Snow went on to discuss the history of unsafe drugs and therapies that had initially received FDA approval and the importance of “clinical and scientific studies to evaluate the possibility of injuries and deaths” instead of “parroting the marketing mantra ‘safe and effective.’”

Flint described the FAA’s handling of the issue as “one of the most glaring instances of incompetence and corruption I have ever witnessed,” adding that “the Pfizer COVID-19 vaccine has taken nearly everything from myself and my family … my health and my career have been taken from me.”

He added that due to his inability to fly, he is facing mounting debt and unpaid taxes, with an income “20% of what it was before vaccination.”

Steele, who also organized the People’s Convoy, expressed her view that “[t]he only way to push back on the government and corporate overstep is demanding accountability … to hold these policymakers unequivocally accountable.”

She specifically referenced the importance of pursuing legal claims, telling The Defender:

“The only way to ensure it never happens again is to hit them in the pocketbook … In doing so, the awarded damages will also assist the victims of these policies that have been so grievously harmed.”

Yoder described the resistance he has observed to such private and government mandates, saying that “Americans have rallied in defiance to the totalitarian dictators dubbed ‘government,’” adding that “American patriots will never succumb to totalitarianism.”

Steele drew upon her experience with the People’s Convoy to share her own observation of wide public opposition to such mandates, while expressing a message of hope:

“My greatest takeaway and the most refreshing finding on the Convoy was that patriotism is alive and well in our great country.

“The American people have had it with the nonsense with the overstepping, with the ‘PC police,’ the degrading of morality in our country. They are simply over it and looking for actionable items that they can do.

“They want to see accountability. They want to see our country restored … It is important for people to know they are absolutely not alone. In fact, we are the majority.”

Worse Than the Disease? Reviewing Some Possible Unintended Consequences of the mRNA Vaccines Against COVID-19

Authors: Stephanie Seneff Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge MA, 02139, USA, Greg Nigh Naturopathic Oncology, Immersion Health, Portland, OR 97214, USA International Journal of Vaccine Theory, Practice, and Research

Abstract

Operation Warp Speed brought to market in the United States two mRNA vaccines, produced by Pfizer and Moderna. Interim data suggested high efficacy for both of these vaccines, which helped legitimize Emergency Use Authorization (EUA) by the FDA. However, the exceptionally rapid movement of these vaccines through controlled trials and into mass deployment raises multiple safety concerns. In this review we first describe the technology underlying these vaccines in detail. We then review both components of and the intended biological response to these vaccines, including production of the spike protein itself, and their potential relationship to a wide range of both acute and long-term induced pathologies, such as blood disorders, neurodegenerative diseases and autoimmune diseases. Among these potential induced pathologies, we discuss the relevance of prion-protein-related amino acid sequences within the spike protein. We also present a brief review of studies supporting the potential for spike protein “shedding”, transmission of the protein from a vaccinated to an unvaccinated person, resulting in symptoms induced in the latter. We finish by addressing a common point of debate, namely, whether or not these vaccines could modify the DNA of those receiving the vaccination. While there are no studies demonstrating definitively that this is happening, we provide a plausible scenario, supported by previously established pathways for transformation and transport of genetic material, whereby injected mRNA could ultimately be incorporated into germ cell DNA for transgenerational transmission. We conclude with our recommendations regarding surveillance that will help to clarify the long-term effects of these experimental drugs and allow us to better assess the true risk/benefit ratio of these novel technologies.

How Vaccine Messaging Confused The Public

Authors: John Gibson the Brownstone Institute 

Pivotal randomized control trials (RCTs) underpinning approval of Covid-19 vaccines did not set out to, and did not, test if the vaccines prevent transmission of the SARS-CoV-2 virus. Nor did the trials test if the vaccines reduce mortality risk. A review of seven phase III trials, including those for Moderna, Pfizer/BioNTech and AstraZeneca vaccines, found the criterion the vaccines were trialled against was just reduced risk of Covid-19 symptoms

There should be no secret about these facts, as they were discussed in August 2020 in the BMJ (formerly the British Medical Journal); one of the oldest and most widely cited medical journals in the world. Moreover, this was not an isolated article, as the editor-in-chief also gave her own summary of the vaccine-testing situation, which has proved very prescient:

“…we are heading for vaccines that reduce severity of illness rather than protect against infection [and] provide only short-lived immunity, … as well as damaging public confidence and wasting global resources by distributing a poorly effective vaccine, this could change what we understand a vaccine to be. Instead of long-term, effective disease prevention it could become a suboptimal chronic treatment.”It was not just the BMJ covering these features of the RCTs. When health bureaucrats Rochelle Walensky, Henry Walke and Anthony Fauci claimed (in the Journal of the American Medical Association) that “clinical trials have shown that the vaccines authorized for use in the US are highly effective against Covid-19 infection, severe illness and death” this was felt sufficiently false that the journal published a comment simply titled “Inaccurate Statement.”

The basis of the comment was that the primary endpoint for the RCTs was symptoms of Covid-19; a less exacting standard than testing to show efficacy against infection, severe illness, and death.

Yet these aspects of the vaccine trials discussed in medical journals are largely unknown by the general public. To measure public understanding of the Covid-19 vaccine trials I added a question about the vaccine testing to an ongoing nationally representative survey of adult New Zealanders.

While not top-of-mind for most readers, New Zealand is a useful place for finding out about public understanding of the vaccine trials. Until recently, when a few doses of AstraZeneca and Novavax vaccines were allowed, it was 100% Pfizer, making it easy to word the survey question very specifically about the Pfizer vaccine trials.

Also, New Zealanders were vaccinated in a very short period, just prior to the survey. In late August 2021 New Zealand was last in the OECD in dosing rates but by December, when the survey was fielded, it had jumped into the top half of the OECD, with vaccinations rising by an average of 110 doses per 100 people in just over three months. 

This rapid rise in vaccination was partly driven by mandates, for health, education, police, and emergency workers and also by a vaccine passport system that blocked the unvaccinated from most places. The mandates were strictly applied, and even people suffering adverse reactions after their first shot, such as Bell’s Palsy and pericarditis, still had to get the second shot. The vaccine passport law had gone through Parliament just prior to the survey, so the vaccines, and what was expected of them, should have been utmost in peoples’ minds. 

The other relevant factor about New Zealand is the government-dominated media, which is either publicly funded, or is heavily subsidized by a “public interest journalism fund” and by generous government advertising of the Covid-19 vaccines. Also, supposedly independent commentators prominent in the media got their talking points about the vaccines from the government in a carefully orchestrated public relations campaign. 

Thus, it was mainly overseas journalists who expressed concern when New Zealand’s Prime Minister made the Orwellian claim that in matters of Covid-19 and vaccines: “Dismiss anything else, we will continue to be your single source of truth.”

Yet a government-controlled media and a vaccine advertising blitz yielded widespread public misunderstanding about the testing the vaccines underwent in pivotal trials. The survey asked if the Pfizer vaccine had been trialled against: (a) preventing infection and transmission of SARS-CoV-2, or (b) reducing risk of getting symptoms of Covid-19, or (c) reducing risk of getting serious sick or dying, or (d) all of the above. The correct answer is (b), the trials only set out to test if the vaccines reduced the risk of getting Covid-19 symptoms.

Only four percent of respondents got the right answer. In other words, 96 percent of adult New Zealanders thought the Covid-19 vaccines were tested against more demanding criteria than is actually the case. 

Currently, most Covid-19 cases in New Zealand are post-vaccination. And despite almost everyone being vaccinated, and most boosted, the rate of new confirmed Covid-19 cases is one of the highest in the world. As people see with their own eyes that one can still get infected they may question what they have been led to (mis)understand about the vaccines.

Elsewhere it is noted that vaccine fanaticism—especially denying natural immunity—fuels vaccine scepticism. As people see that public health authorities lied about natural immunity they will wonder if they also lied about vaccine efficacy. Likewise, as they realise they were given a misleading impression about what the vaccines were trialled against they might doubt other claims about vaccines.

In particular, by believing the vaccines were tested against more demanding criteria than was actually so, public expectations of what vaccination would achieve were likely too high. As the public witnesses a failure of mass vaccination to prevent SARS-CoV-2 infections, and a failure to reduce overall mortality, scepticism about these and other vaccines will grow.

In New Zealand this issue is exacerbated by the Prime Minister creating a false equivalence between Covid-19 vaccines and measles vaccines. Currently the paediatric vaccination rate (which includes the measles vaccine) for indigenous Maori has dropped 12 percentage points in two years and 0.3 million measles vaccines had to be discarded after expiring due to lack of demand. The advertising for Covid-19 vaccines particularly targets Maori, with claims that boosters will protect them against Omicron. The progress of infections is likely to prove this claim to be largely untrue, and so Maori are likely to be even more sceptical about future vaccination, even for vaccines that truly can be described as ‘safe and effective.’

If politicians and health bureaucrats had been honest with the public, setting out the criteria the Covid-19 vaccines were trialed against, and what could and could not be expected of the vaccines, then this widespread misunderstanding need not have occurred. Instead, their lack of honesty is likely to damage future vaccination efforts and harm public health.

Protection by a Fourth Dose of BNT162b2 against Omicron in Israel

Authors: Yinon M. Bar-On, M.Sc., Yair Goldberg, Ph.D., Micha Mandel, Ph.D., Omri Bodenheimer, M.Sc., Ofra Amir, Ph.D., Laurence Freedman, Ph.D., Sharon Alroy-Preis, M.D., Nachman Ash, M.D., Amit Huppert, Ph.D., and Ron Milo, Ph.D. April 5, 2022 DOI: 10.1056/NEJMoa2201570 NEW ENGLAND JOURNAL OF MEDICINE

Abstract

BACKGROUND

On January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine to persons 60 years of age or older. Data are needed regarding the effect of the fourth dose on rates of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and of severe coronavirus disease 2019 (Covid-19).

METHODS

Using the Israeli Ministry of Health database, we extracted data on 1,252,331 persons who were 60 years of age or older and eligible for the fourth dose during a period in which the B.1.1.529 (omicron) variant of SARS-CoV-2 was predominant (January 10 through March 2, 2022). We estimated the rate of confirmed infection and severe Covid-19 as a function of time starting at 8 days after receipt of a fourth dose (four-dose groups) as compared with that among persons who had received only three doses (three-dose group) and among persons who had received a fourth dose 3 to 7 days earlier (internal control group). For the estimation of rates, we used quasi-Poisson regression with adjustment for age, sex, demographic group, and calendar day.

RESULTS

The number of cases of severe Covid-19 per 100,000 person-days (unadjusted rate) was 1.5 in the aggregated four-dose groups, 3.9 in the three-dose group, and 4.2 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of severe Covid-19 in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 3.5 (95% confidence interval [CI], 2.7 to 4.6) and was lower than that in the internal control group by a factor of 2.3 (95% CI, 1.7 to 3.3). Protection against severe illness did not wane during the 6 weeks after receipt of the fourth dose. The number of cases of confirmed infection per 100,000 person-days (unadjusted rate) was 177 in the aggregated four-dose groups, 361 in the three-dose group, and 388 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of confirmed infection in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 2.0 (95% CI, 1.9 to 2.1) and was lower than that in the internal control group by a factor of 1.8 (95% CI, 1.7 to 1.9). However, this protection waned in later weeks.

CONCLUSIONS

Rates of confirmed SARS-CoV-2 infection and severe Covid-19 were lower after a fourth dose of BNT162b2 vaccine than after only three doses. Protection against confirmed infection appeared short-lived, whereas protection against severe illness did not wane during the study period.

During late December 2021, with the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, the prevalence of confirmed infection rose sharply in Israel. Some of the contributing factors were increased immune evasion by the variant1 and the passage of more than 4 months since most adults had received their third vaccine dose. In an effort to address the challenges presented by the omicron variant and to reduce the load on the health care system, on January 2, 2022, Israeli authorities approved the administration of a fourth dose of the BNT162b2 vaccine (Pfizer–BioNTech) to persons who were 60 years of age or older, as well as to high-risk populations and health care workers, if more than 4 months had passed since receipt of their third dose. The real-world effectiveness of the fourth dose against confirmed infection and severe illness remains unclear. In this study, we used data from the Israeli Ministry of Health national database to study the relative effectiveness of the fourth dose as compared with only three doses against confirmed infection and severe illness among older persons in the Israeli population.

Methods

STUDY POPULATION

For this analysis, we included persons who, on January 1, 2022, were 60 years of age or older and had received three doses of BNT162b2 at least 4 months before the end of the study period (March 2). We excluded the following persons from the analysis: those who had died before the beginning of the study period (January 10); those for whom no information regarding their age or sex was available; those who had had a confirmed SARS-CoV-2 infection before the beginning of the study, determined with the use of either a polymerase-chain-reaction (PCR) assay or a state-regulated rapid antigen test; those who had received a third dose before its approval for all older residents (i.e., before July 30, 2021); those who had been abroad for the entire study period (January 10 to March 2; persons were considered to be abroad 10 days before traveling until 10 days after their return to Israel); and those who had received a vaccine dose of a type other than BNT162b2.

For persons who met the inclusion criteria, we extracted information on March 4, 2022, regarding SARS-CoV-2 infection (confirmed either by state-regulated rapid antigen test or by PCR) and severe Covid-19 (defined with the use of the National Institutes of Health definition2 as a resting respiratory rate of >30 breaths per minute, an oxygen saturation of <94% while breathing ambient air, or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <300) during the 14 days after confirmation of infection. During the study period, infections were overwhelmingly dominated by the omicron variant.3 We also extracted data regarding vaccination (dates and brands of first, second, third, and fourth doses) and demographic variables such as age, sex, and demographic group (general Jewish, Arab, or ultra-Orthodox Jewish), as determined by the person’s statistical area of residence (similar to a census block4).

STUDY DESIGN

The study period started on January 10, 2022, and ended on March 2, 2022, for confirmed infection and ended on February 18, 2022, for severe illness. The starting date was set to 7 days after the start of the vaccination campaign (January 3, 2022) so that at least the first four-dose group (days 8 to 14 after vaccination) would be represented throughout the study period (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The end dates were chosen to minimize the effects of missing outcome data due to delays in reporting PCR or antigen test results and to allow time for the development of severe illness.

The design of the study was similar to that of a previous study in which we assessed the protection conferred by the third vaccine dose as compared with the second dose.5 We calculated the total number of person-days at risk and the incidence of confirmed infection and of severe Covid-19 during the study period defined for each outcome. For persons who received the fourth dose, treatment groups were defined according to the number of weeks that had passed since receiving that dose, starting from the second week (8 to 14 days after vaccination). These four-dose groups were compared with two control groups. The first control group included persons who were eligible for a fourth dose but had not yet received it (three-dose group). Because persons who received the fourth dose might have differed from those who had not according to unmeasured confounding variables, a second control group was defined as persons who had received a fourth dose 3 to 7 days earlier (internal control group). This control group included the same persons as the four-dose groups, but during a period in which the fourth dose was not expected to affect the rate of confirmed infection or severe illness. The membership in these groups was dynamic, and participants contributed risk days to different study groups on different calendar days, depending on their vaccination status.

OVERSIGHT

The study was approved by the institutional review board of the Sheba Medical Center. All the authors contributed to the conceptualization of the study, critically reviewed the results, approved the final version of the manuscript, and made the decision to submit the manuscript for publication. The authors vouch for the accuracy and completeness of the data in this report. The Israeli Ministry of Health and Pfizer have a data-sharing agreement, but only the final results of this study were shared.

STATISTICAL ANALYSIS

Using quasi-Poisson regression, we estimated the rates of confirmed infection and severe Covid-19 per 100,000 person-days for each study group (included as factors in the model), with adjustment for the following demographic variables: age group (60 to 69 years, 70 to 79 years, or ≥80 years), sex, and demographic group (general Jewish, Arab, or ultra-Orthodox Jewish). Because incidences of both confirmed infection and severe illness increased rapidly during January 2022, the risk of exposure at the beginning of the study period was lower than at the end of the study period. Moreover, the fraction of the population in each study group changed throughout the study period (Fig. S1). Therefore, we included calendar date as an additional covariate to account for changing exposure risk.6 The end of the study period for severe Covid-19 was set to 14 days before the date of data retrieval (March 4), allowing at least 14 days of follow-up time for the development of severe illness. To ensure the same follow-up time for severe Covid-19 in all persons, we considered only cases of severe illness that developed within 14 days after confirmation of infection. The date used for counting events of severe Covid-19 was defined as the date of the test confirming the infection that subsequently led to the severe illness.

Persons who received four doses were assigned to groups according to the numbers of weeks that had passed since receipt of the fourth dose; for each outcome, we estimated the incidence rate in each of these four-dose groups and in the two control groups. We calculated two rate ratios for each treatment group and each outcome: first, the ratio of the rate in the three-dose group to that in each four-dose group; and second, the ratio of the rate in the internal control group to that in each four-dose group. Note that the higher this rate ratio is, the greater the protection conferred by the fourth dose of vaccine. In addition, adjusted rate differences per 100,000 person-days during the study period were estimated with a method similar to that used in our previous analysis.7 Confidence intervals were calculated by exponentiating the 95% confidence intervals for the regression coefficients, without adjustment for multiplicity. Thus, the confidence intervals should not be used to infer differences between study groups.

To check for possible biases, we performed several sensitivity analyses. First, we estimated the rate ratios for confirmed infection using an alternative statistical method that relied on matching (similar to that used by Dagan et al.8), as described in detail in the Supplementary Appendix; this approach could not be applied to the analysis of severe Covid-19 because of the small case numbers. Second, we examined the results of using data on infections confirmed only by PCR testing and excluding data on those confirmed by state-regulated antigen testing. Third, we repeated the analyses with data from the general Jewish population only. Fourth, we analyzed the data while accounting for the exposure risk over time in each person’s area of residence. Fifth, we analyzed the data while accounting for the time of vaccination since the third dose. Further details of the sensitivity analyses are provided in the Supplementary Appendix.

Results

STUDY POPULATION

Figure 1.Study Poplation.Table 1.Demographic and Clinical Characteristics of the Persons in the Study Groups.

A total of 1,252,331 persons met the criteria for inclusion in the study (Figure 1). The total number of events and person-days at risk in each of the study groups, along with the distribution of covariates used in the analysis, are shown in Table 1, which provides statistics aggregated across weeks since receipt of the fourth dose from the second week onward. The information for each treatment group according to the week since receipt of the fourth dose is provided in Table S1. Overall, the distributions of covariates in the aggregated treatment groups are similar to those in the internal control group. As compared with the three-dose group, the aggregated four-dose groups and the internal control group included more person-days over the age of 80 years (24.9% and 25.1%, respectively, vs. 16.2%) and more person-days from the general Jewish population (94.2% and 93.7% vs. 84.4%). Those in the three-dose group had a larger number of risk days than did those in the aggregated four-dose groups (31.0 million person-days vs. 23.9 million person-days) but had more confirmed infections (111,780 vs. 42,325) and more severe cases (1210 vs. 355).

PROTECTION CONFERRED BY THE FOURTH DOSE

As shown in Table 1, the unadjusted rate of confirmed infection was 177 cases per 100,000 person-days in the aggregated four-dose groups, 361 cases per 100,000 person-days in the three-dose group, and 388 cases per 100,000 person-days in the internal control group. The unadjusted rate of severe Covid-19 was 1.5 cases per 100,000 person-days in the aggregated four-dose groups, 3.9 cases per 100,000 person-days in the three-dose group, and 4.2 cases per 100,000 person-days in the internal control group.Table 2.Results of the Quasi-Poisson Regression Analysis of Confirmed SARS-CoV-2 Infection.Table 3.esults of the Quasi-Poisson Regression Analysis of Severe Covid-19.Figure 2.Adjusted Rate Ratios for Confirmed Infection and Severe Illness.

The results of the quasi-Poisson regression analysis are summarized in Table 2 for confirmed infection and in Table 3 for severe illness. Figure 2 provides a graphical representation of the results for both confirmed infection and severe illness.

The adjusted rate of confirmed infection was lower in the four-dose groups than in the two control groups. The adjusted rate among persons in the fourth week (22 to 28 days) after receipt of the fourth dose was lower by a factor of 2.0 (95% confidence interval [CI], 1.9 to 2.1) than that in the three-dose group and was lower by a factor of 1.8 (95% CI, 1.7 to 1.9) than that in the internal control group. The adjusted rate of confirmed infection (after rounding) in the fourth week after the fourth dose was 171 cases per 100,000 person-days (95% CI, 165 to 177), as compared with 340 cases per 100,000 person-days (95% CI, 337 to 343) in the three-dose group and 308 cases per 100,000 person-days (95% CI, 299 to 317) in the internal control group (Table S2). In the analysis of adjusted rate differences, the group in the fourth week after the fourth dose had 170 fewer confirmed infections per 100,000 person-days (95% CI, 162 to 176) than the three-dose group, and 137 fewer confirmed infections per 100,000 person-days (95% CI, 125 to 148) than the internal control group. From the fifth week (29 to 35 days) onward, the rate ratio for confirmed infection started to decline. The adjusted rate of infection in the eighth week after the fourth dose was very similar to those in the control groups; the rate ratio for the three-dose group as compared with the four-dose group was 1.1 (95% CI, 1.0 to 1.2), and the rate ratio for the internal control group as compared with the four-dose group was only 1.0 (95% CI, 0.9 to 1.1).

The rate ratios comparing the control groups with the four-dose groups were larger and longer-lasting for severe Covid-19. For persons in the fourth week after receipt of the fourth dose, the adjusted rate of severe illness was lower by a factor of 3.5 (95% CI, 2.7 to 4.6) than that in the three-dose group and was lower by a factor of 2.3 (95% CI, 1.7 to 3.3) than that in the internal control group. The adjusted rate of severe Covid-19 (after rounding) in the fourth week after the fourth dose was 1.6 cases per 100,000 person-days (95% CI, 1.2 to 2.0), as compared with 5.5 cases per 100,000 person-days (95% CI, 5.2 to 5.9) in the three-dose group and 3.6 cases per 100,000 person-days (95% CI, 3.0 to 4.5) in the internal control group (Table S2). The adjusted rate differences were 3.9 fewer cases per 100,000 person-days (95% CI, 3.4 to 4.5) and 2.1 fewer cases per 100,000 person-days (95% CI, 1.4 to 3.0) than the three-dose group and the internal control group, respectively. Severe illness continued to occur at lower rates in the four-dose groups than in the control groups in later weeks after receipt of the fourth dose, and no signs of waning were evident by the sixth week after receipt of the fourth dose (Figure 2).

SENSITIVITY ANALYSES

The results of the matched analysis of confirmed infection were similar to the results obtained in the main analysis (Fig. S3). In addition, restricting the quasi-Poisson regression analysis to the general Jewish population, adding as a covariate the exposure risk over time in each individual’s area of residence, or adding as a covariate the time since administration of the third dose did not substantially change the results of the main analysis (Figs. S4 and S5).

As described in the Supplementary Appendix, the testing policy in Israel was changed in early January 2022 (before the study period) for persons younger than 60 years of age. Even though the testing policy for the study population (persons ≥60 years of age) did not change, we tested the possible effect of the type of diagnostic test used to confirm infection by repeating the analysis counting only infections confirmed by positive PCR tests. This resulted in only very minor changes to the estimated level of protection conferred by the fourth dose (Figs. S4 and S5). In addition, we compared the testing rate and test type (PCR or antigen) among persons who received the fourth dose as compared with those who received only three doses and found the differences to be of limited extent (Fig. S2).

Discussion

The omicron variant is genetically divergent from the ancestral SARS-CoV-2 strain for which the BNT162b2 vaccine was tailored. The results presented here indicate that as compared with three vaccine doses given at least 4 months earlier, a fourth dose provides added short-term protection against confirmed infections and severe illness caused by the omicron variant. The incidence rate for confirmed infection was lower by a factor of 2 and the rate of severe disease lower by a factor of 3 among persons in the fourth week after receiving the fourth dose than among eligible persons who did not receive the fourth dose.

Comparing the rate ratio over time since the fourth dose (Figure 2) suggests that the protection against confirmed infection with the omicron variant reaches a maximum in the fourth week after vaccination, after which the rate ratio decreases to approximately 1.1 by the eighth week; these findings suggest that protection against confirmed infection wanes quickly. In contrast, protection against severe illness did not appear to decrease by the sixth week after receipt of the fourth dose. More follow-up is needed in order to evaluate the protection of the fourth dose against severe illness over longer periods.

Although our analysis attempts to address biases such as confounding, some sources of bias may not have been measured or adequately controlled for — for example, behavioral differences between persons who received the fourth dose and those who did not. For severe illness, differences in the prevalence of coexisting conditions could potentially have affected the results; however, this information is not recorded in the national database, and therefore we did not adjust for such differences. Differences in coexisting conditions could also be associated with differential treatment with antiviral drugs such as ritonavir-boosted nirmatrelvir, which could have affected the results. To address some of these biases, we compared the rate of confirmed infection and severe illness within the group of people who received the fourth dose. Estimates of the rate ratio during the first days after vaccination could include the effect of transient biases (Fig. S6). These potential biases include the “healthy vaccinee” bias,9 in which people who feel ill tend not to get vaccinated in the following days, which leads to a lower number of confirmed infections and severe disease in the four-dose group during the first days after vaccination. Moreover, one would expect that detection bias due to behavioral changes, such as the tendency to perform fewer tests after vaccination, is more pronounced shortly after receipt of the dose.

Thus, we compared the rates of confirmed infections and severe illness at different weeks after the fourth dose, from the second week onward, with the rates on days 3 to 7 after its receipt, a period during which the transient biases would have diminished but before the vaccine would be expected to have affected the rate of the outcomes of interest.6 The rate ratios obtained for confirmed infections were very similar to those obtained when comparing the treatment groups with the persons who did not receive a fourth dose. For severe illness, the rate ratios relative to the internal control group were lower than the rate ratios relative to the three-dose group. Even when the internal control group was the basis for comparison, the rate ratios for severe illness were still higher than those for confirmed infection and did not show signs of waning immunity.

In addition, several sensitivity analyses were performed to assess the robustness of the results to further potential biases. First, we performed the analyses using data only from the general Jewish population, since the participants in that group are more common in the population that received the fourth dose. Second, we included in the model the risk of exposure in the person’s area of residence. The results of these analyses were similar to the results of the main analysis.

Overall, these analyses provided evidence for the effectiveness of a fourth vaccine dose against severe illness caused by the omicron variant, as compared with a third dose administered more than 4 months earlier. For confirmed infection, a fourth dose appeared to provide only short-term protection and a modest absolute benefit. Several reports have indicated that the protection against hospital admission conferred by a third dose given more than 3 months earlier is substantially lower against the omicron variant than the protection of a fresh third dose against hospital admission for illness caused by the B.1.617.2 (delta) variant.1,10,11 In our study, a fourth dose appeared to increase the protection against severe illness relative to three doses that were administered more than 4 months earlier.