Another rare virus puzzle: They got sick, got treated, got covid again

Authors: Carolyn Y. Johnson  April 27, 2022 The Washington Post

Shortly after he served on a jury in March, Gregg Crumley developed a sore throat and congestion. The retired molecular biologist took a rapid test on a Saturday and saw a dark, thick line materialize — “wildly positive” for the coronavirus.

Crumley, 71, contacted his doctor two days later. By the afternoon, friends had dropped off a course of Paxlovid, a five-day regimen of antiviral pills that aims to keep people from becoming seriously ill.

The day he took his last dose, his symptoms were abating. He tested each of the next three days: all negative.

Then, in the middle of a community Zoom meeting, he started feeling sick again. Crumley, who is vaccinated and boosted, thought it might be residual effects of his immune response to the virus. But the chills were more prolonged and unpleasant. He tested. Positive. Again.

Crumley, like other patients who have experienced relapses after taking Paxlovid, is puzzled — and concerned. On Twitter, physicians and patients alike are engaged in a real-time group brainstorm about what might be happening, with scant evidence to work with.

It is the latest twist — and newest riddle — in the pandemic, a reminder that two years in, the world is still on a learning curve with the coronavirus.

Infectious-disease experts agree that this phenomenon of the virus rebounding after some patients take the drug appears to be real but rare. Exactly how often it occurs, why it happens and what — if anything — to do about it remain matters of debate.

What’s clear is that patients should be warned it is possible so they don’t panic — and so that they know to test again if they start feeling ill. More data is needed to understand what is going on. Paxlovid, made by the drug giant Pfizer, remains a useful drug, even though it has sparked a new mystery.Biden administration boosts access to antivirals as covid cases rise

“I’m not negative on Paxlovid,” said Crumley, who lives in Philadelphia and whose last positive test was a week after his second wave of illness began. “I don’t know whether it’s just stopping [viral] replication for that five-day period of time, and it comes back.”

One of the top worries accompanying antiviral drugs is the threat of resistance, when the virus evolves to evade the treatment. A Food and Drug Administration analysis of Pfizer’s clinical trial of the drug showed the virus rebounded in several subjects about 10 to 14 days after their initial symptoms but found no reason and no evidence that their infections were resistant to the treatment.

Michael E. Charness, chief of staff at the VA Boston Healthcare System, published a detailed case study of one 71-year-old patient who had a relapse. The man, who was vaccinated and boosted, received Paxlovid and quickly felt better. When he developed cold symptoms a week after his case of covid had resolved, researchers sequenced the virus’s genetic code and found it was the same virus surging back. That ruled out a reinfection, the emergence of a variant or the virus becoming resistant.

Charness would like to see more data and other questions answered. Should antivirals be given longer, to assure the virus is cleared? Should people be treated a second time? What are the implications for people returning to their normal lives?

“If you have a resurgence of viral load, and that happens on day 10, when CDC says you’re back to work, no mask, what are you supposed to do about isolation? Is that a moment when you’re contagious again?” Charness said. “The person we studied, we advised to isolate until their viral load was gone the second time.”

Pfizer is collecting data, in clinical trials and in real-world monitoring of the drug’s use. The company’s trial data indicates there is a late uptick in viral load in “a small number” of people who take the drug, but the rates appear to be similar among study participants given a placebo, according to company spokesman Kit Longley. The people who experienced such increases also did not develop severe disease the second time around.

Those findings suggest that Paxlovid isn’t the reason people are relapsing, because that’s happening in untreated people, too.

If that turns out to be true, it raises the concern that some people — whether they have taken the drug or not — could be infectious long after they think they are in the clear, and after guidelines suggest they can stop taking precautions.

“Although it is too early to determine the cause, this suggests the observed increase in viral load is unlikely to be related to Paxlovid,” Longley wrote in an email. “We have not seen any resistance to Paxlovid, and remain very confident in its clinical effectiveness.”

The limited evidence leaves most physicians favoring the idea that Paxlovid knocks the virus down but doesn’t knock it out completely. It’s possible that by holding the virus in check, the immune response doesn’t fully ramp up, because it doesn’t see enough virus. Once the treatment ends, the virus can start multiplying again in some people.

Philip Bretsky, a primary care doctor in Santa Monica, Calif., said he has encountered two cases among patients, both of whom were vaccinated and boosted at least once.

A double-boosted 72-year-old who had chronic medical conditions that raised his risk for severe illness started to feel unwell at the end of March. He tested positive and began a course of Paxlovid. He felt better and tested negative. Then, 12 days later, he started feeling crummy again — and tested positive.

Reinfection seemed improbable, and Bretsky thought resistance was unlikely with a five-day course of treatment.

In well-vaccinated people, being reinfected so quickly would be “like getting struck by lightning or winning the lottery,” Bretsky said. “I don’t think this is reinfection. I think this is recrudescence of the original infection.”

Experts don’t know how common this phenomenon is. Many people may not test if they get sick again after their initial infection has receded, making it hard to track.

That almost happened to Holly Teliska, 42, of San Francisco. Teliska got sick shortly after returning home from a trip to New York. She has a risk factor for severe illness and got access to Paxlovid right away. When she finished her treatment course, she took a home PCR test that was negative and felt much better, though remained fatigued.

Four days later, she came down with a runny nose and cough. She assumed she had caught her daughter’s cold and powered through. Five days later, with plans to visit an immunocompromised friend, she took a test.

Teliska almost felt silly testing herself. She had been vaccinated and boosted, then infected.

“We’ve been saying I’m her safest friend now, now that I’ve had covid, so for three months, I can go spend time with her pretty safely,” Teliska said. “That really threw that narrative out the window. … This entire experience has been a real reminder there is still so much to learn.”

Paxlovid is new. It only began to be used in December, so reports people share on social media of resurgent illness may be the tip of the iceberg — or might simply reflect the eagerness to learn more about a rare, intriguing outcome.

If such cases turn out to be exceedingly rare, then these case reports may be a sporadic curiosity — something to warn patients could happen. If more common, it could lead to tweaks in treatment regimens.

The mounting anecdotes are compelling to many physicians, but it’s also possible the virus might rarely rebound. Yonatan Grad, an associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, has studied the viral loads of NBA players and staff during the course of an infection. That data, he said, shows that viral loads can bounce around.

What’s “exceptionally uncommon,” Grad said, is for the viral load to plunge for a few days to a level that suggests they are negative and then go up again.

Paul Sax, an infectious-diseases specialist at Brigham and Women’s Hospital in Boston, recently shared the story of a patient who became infected and then relapsed after taking Paxlovid. He has heard from lots of colleagues with similar stories. But the anecdotes raise more questions than they answer.

Even if the virus has not been shown to develop resistance to the treatment during a resurgence, that’s doesn’t mean it won’t happen, he points out. Does the treatment knock the virus down so successfully that people aren’t generating a robust immune response? That could have implications for understanding whether being infected acts as a potent booster.

The phenomenon is so new that many doctors aren’t aware of it. Jennifer Charness, a 31-year-old nurse who lives in Brookline, Mass., had the benefit of knowing about her father’s work at the Boston VA.

Charness started sneezing in early April and got a blaringly positive coronavirus test. She has a history of asthma and was prescribed Paxlovid. As she took the drug, she saw her positive test line grow fainter and her symptoms resolve. She swabbed to make sure she was negative before going back to work, as a precaution. Then, two days later, she felt the symptoms come back and tested positive — again.

“I’m so frustrated,” Charness said. “I don’t think I’m going to get very sick. It’s the concern of what does this mean for my viral load, and how contagious am I? And when will I not be contagious? I’m stuck back in my home again.”

Charness’s primary concern is that she doesn’t pose a risk to anyone else. She consulted a doctor via telemedicine Friday. The practice hadn’t heard of any cases like hers and decided to treat it as a reinfection and reset the isolation clock.

“I’m Day 4,” she said. “Or am I Day 13?”

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.

Spectrum of neurological complications following COVID-19 vaccination

Authors: Ravindra Kumar Garg1 and Vimal Kumar Paliwal2 Neuro 2022; 43(1): 3–40.Published online 2021 Oct 31. doi: 10.1007/s10072-021-05662-9PMCID: PMC8557950PMID: 34719776

Abstract

COVID-19 vaccines have brought us a ray of hope to effectively fight against deadly pandemic of COVID-19 and hope to save lives. Many vaccines have been granted emergency use authorizations by many countries. Post-authorization, a wide spectrum of neurological complications is continuously being reported following COVID-19 vaccination. Neurological adverse events following vaccination are generally mild and transient, like fever and chills, headache, fatigue, myalgia and arthralgia, or local injection site effects like swelling, redness, or pain. The most devastating neurological post-vaccination complication is cerebral venous sinus thrombosis. Cerebral venous sinus is frequently reported in females of childbearing age, generally following adenovector-based vaccination. Another major neurological complication of concern is Bell’s palsy that was reported dominantly following mRNA vaccine administration. Acute transverse myelitis, acute disseminated encephalomyelitis, and acute demyelinating polyneuropathy are other unexpected neurological adverse events that occur as result of phenomenon of molecular mimicry. Reactivation of herpes zoster in many persons, following administration of mRNA vaccines, has been also recorded. Considering the enormity of recent COVID-19-vaccinated population, the number of serious neurological events is miniscule. Large collaborative prospective studies are needed to prove or disprove causal association between vaccine and neurological adverse events occurring vaccination.

SARS-CoV-2 is a novel coronavirus that can rapidly affect human beings and can result in coronavirus disease (COVID-19). COVID-19 is dominantly characterized by lung damage and hypoxia. The first case of COVID-19, in Wuhan, China, was reported on December 8, 2019. Later, the World Health Organization announced COVID-19 as a worldwide health emergency, on January 30, 2020. On March 11, 2020, COVID-19 was declared a pandemic. As per the latest World Health Organization report, there were 196,553,009 confirmed cases as on August 1, 2021 along with 4,200,412 deaths [1].

Early this year, COVID-19 vaccines has brought a ray of hope to effectively fight against this deadly pandemic and save precious human lives. Currently, four major vaccine types are being used. These vaccine types include viral vector-based vaccines, COVID-19 mRNA-based vaccines, inactivated or attenuated virus vaccine, and protein-based vaccines. In viral vector-based vaccines, adenovirus is used to deliver a part of SARS-COV-2 genome to human cells. Human cells use this genetic material to produce SARS-COV-2 spike protein. Human body recognizes this protein to start a defensive response. The mRNA-based vaccines consist of SARS-COV-2 RNA. Once introduced, genetic material helps in making SARS-COV-2-specific protein. This protein is recognized by human body to start defensive immune reaction. In inactivated or attenuated vaccines, killed or attenuated SARS-COV-2 virus triggers immune response. Protein-based vaccines use the spike protein or its fragments for inciting immune response. These COVID-19 vaccines have received emergency approvals in different countries for human use [2]. As per the latest World Health Organization report, until August 1, 2021, globally, a total of 3,839,816,037 COVID-19 vaccine doses have been globally administered [1].

In fact, all kinds of vaccines are associated with the risk of several serious neurological complications, like acute disseminated encephalomyelitis, transverse myelitis, aseptic meningitis, Guillain-Barré syndrome, macrophagic myofasciitis, and myositis. Influenza vaccine has been found associated with narcolepsy in young persons. Several pathogenic mechanisms, like molecular mimicry, direct neurotoxicity, and aberrant immune reactions, have been ascribed to explain these vaccines associated with neurological complications [3]. Even COVID-19 vaccines are not free from neurological complications. In this article, we have focused on the neurological complications following COVID-19 vaccination that were reported after their emergency use authorizations.

Search strategy

We reviewed available data regarding neurological complications (post-authorization) described following the World Health Organization–approved COVID-19 vaccination. We classified COVID-19 vaccination associated with neurological complications in two broad groups: (1) common but mild and (2) rare but severe. We searched PubMed, Google, and Google Scholar databases using the keywords “COVID‐19” or “SARS‐CoV‐2” and “vaccination” or “vaccine,” to identify all published reports on neurological complications of COVID‐19 vaccines. We in this review will focus on spectrum of published neurological adverse events following COVID-19 vaccination. Last search was done on August 1, 2021.

Mild neurological events

Neurological adverse events following COVID-19 vaccination are generally mild and transient, like fever/chills, headache, fatigue, myalgia and arthralgia, or local injection site effects like swelling, redness, or pain. These mild neurological symptoms are common following administration of all kinds of COVID-19 vaccines.

Anxiety-related events, like feeling of syncope and/or dizziness, are particularly common. For example, Centers for Disease Control and Prevention, in a report published on April 30, 2021, recorded 64 anxiety-related events (syncope in 17) among 8,624 Janssen COVID-19 vaccine recipients. None of the event was labeled as serious [4].

In Mexico (data available in form of preprint) among 704 003 subjects who received first doses of the Pfizer-BioNTech mRNA COVID-19 vaccine, 6536 adverse events following immunization were recorded. Among those, 4258 (65%) had at least one neurologic manifestation, mostly (99.6%) mild and transient. These events included headache (62·2%), transient sensory symptoms (3·5%), and weakness (1%). In this study, there were only 17 serious adverse events, seizures (7), functional syndromes (4), Guillain-Barré syndrome (3), and transverse myelitis (2) [5].

In South Korea, Kim and co-workers collected data of post-vaccination adverse events following first dose of adenovirus vector vaccine ChAdOx1 nCoV-19 (1,403 subjects) and mRNA vaccine BNT162b2 (80 subjects) vaccinations. Data were collected daily for 7 days after vaccination. Authors noted that 91% of adenovirus-vectored vaccine and 53% of mRNA vaccine recipients had mild adverse reactions, like injection-site pain, myalgia, fatigue, headache, and fever [6]. A mobile-based survey among healthcare workers (265 respondents) who received both doses of the BNT162b2 mRNA vaccine was conducted. The most common adverse effects were muscle ache, fatigue, headache, chills, and fever. Adverse reactions were higher after the second dose compared with that after the first dose [7].

Headache

Headache is one of the most frequent mild neurological complaints reported by a large number of COVID-19 vaccine recipients, soon after they receive vaccine.

A review of headache characteristic noted that among 2464 participants, headache begun 14.5 ± 21.6 h after AstraZeneca adenovirus vector vaccine COVID-19 vaccination and persisted for 16.3 ± 30.4 h. Headaches, in majority, were moderate to severe in intensity and generally localized to frontal region. Common accompanying symptoms were fatigue, chills, exhaustion, and fever [8]. In a multicenter observational cohort study, Göbel et al. recorded clinical characteristic of headache occurring after the mRNA BNT162b2 mRNA COVID-19 vaccination. Generally, headache started 18.0 ± 27.0 h after vaccination and persisted for 14.2 ± 21.3 h. In majority, the headaches were bifrontal or temporal, dull aching character and were moderate to severe in intensity. The common accompanying symptoms were fatigue, exhaustion, and muscle pain [8].

Severe neurological adverse events

Serious adverse reaction following immunization is defined as a post-vaccination event that are either life-threatening, requires hospitalization, or result in severe disability. The World Health Organization listed Guillain-Barré syndrome, seizures, anaphylaxis, syncope, encephalitis, thrombocytopenia, vasculitis, and Bell’s palsy as serious neurologic adverse events. Instances of serious adverse events following COVID-19 vaccinations are continuously pouring in the current scientific literature and are source of vaccine hesitancy in many persons [9] (Fig. 1).

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Fig. 1

A flow diagram depicts the spectrum of severe neurological complications following COVID-19 vaccinations (ADEM, acute disseminated encephalomyelitis; CVST, cerebral venous sinus thrombosis; LETM, longitudinally extensive transverse myelitis; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorders; PRES, posterior reversible encephalopathy syndrome; TIA, transient ischemic attacks)

Functional neurological disorders

Functional neurological disorders are triggered by physical/emotional stress following an injury, medical illness, a surgery, or vaccination. Functional neurological disorders often remain misdiagnosed despite extensive workup.

After availability of COVID-19 vaccine, many YouTube videos depicted continuous limb and trunk movements and difficulty walking immediately after COVID-19 vaccine administration. These videos were of concern as they were the source of “vaccine hesitancy” [10]. Kim and colleagues reviewed several such social media videos demonstrating motor movements consistent with functional motor symptoms occurring after administration of COVID-19 vaccine. Motor movements were bizarre asynchronous and rapidly variable in frequency and amplitude consistent with functional neurological disorder. The Functional Neurological Disorder Society has lately clarified that movement disorder is consistent with functional in nature. The spread of these videos are important because these functional disorders created concerns for vaccine hesitancy [11].

Several other kinds of functional neurological disorders have also been reported. Butler and colleagues described two young ladies, who presented with functional motor deficits mimicking stroke. Both these patients had variability in weakness and had many non-specific symptoms. A detailed workup and neuroimaging failed to demonstrate any specific abnormality [12]. Ercoli and colleagues described a middle-aged man who, immediately after vaccine administration, reported bilateral facial paralysis along with failure to blink. These manifestations resolved quickly within 40 min. Immediately after administration of second dose of vaccine, he complained of respiratory distress and swollen tongue. Again, all these symptoms resolved quickly following treatment with corticosteroids, however, he developed new symptoms in the form of right hemiparesis. Two weeks later, he developed facial hypoesthesia. A detailed workup of the patient failed to demonstrate any abnormality. A diagnosis of functional neurological disorder was, finally, made [13].

Cerebral vascular events

As a matter of concern, increasing number of reports about adenoviral vector vaccine-induced cerebral vascular adverse events, like cerebral venous thrombosis, arterial stroke, and intracerebral hemorrhage, is getting published in leading medical journals. These reports are alarming as post-vaccination vascular events culminate either in severe disability or death. Vaccine-induced cerebral vascular adverse events are generally associated with severe immune-mediated thrombotic thrombocytopenia. Thrombocytopenia generally clinically manifests within 5 to 30 days after administration of adenovirus vector-based vaccines. In post-vaccination thrombotic thrombocytopenia, a picture similar to that of heparin-induced thrombocytopenia is encountered. When heparin binds platelet factor 4, there is generation of antibodies against platelet factor 4. Antibodies against platelet factor 4 result in platelet destruction and trigger the intravascular blood clotting [14]. The post-mortem examination, in patients with vaccine-induced thrombocytopenia, demonstrated extensive involvement of large venous vessels. Microscopic findings showed vascular thrombotic occlusions occurring in the vessels of multiple body organs along with marked inflammatory infiltration [15]. The vector-based vaccines contain genetic material of SARS-COV-2 that is capable of encoding the spike glycoprotein. Possibly, leaked genetic material binds to platelet factor 4 that subsequently activates formation of autoantibodies. These autoantibodies destroy platelets [1617].

Cerebral venous thrombosis

Cerebral venous thrombosis is the one of the most feared devastating COVID-19 vaccine-associated neurological complication. Cerebral venous thrombosis should be suspected in all vaccinated patients, who has persistent headache. Headache is generally unresponsive to the analgesics, and some patients may have focal neurological deficits. Affected patients are generally females of younger ages (Table ​(Table1)1) [1846].

Table 1

Clinical, magnetic resonance imaging findings, and outcome details of patients who developed cerebral venous sinus thrombosis after vaccination against SARS-CoV-2

ReferenceNeurological complicationsCountryAge/sexVaccine typeDuration of onset after vaccinationClinical featuresNeuroimagingTreatment given
Castelli et al. [18]Cerebral venous sinus thrombosisItaly50/MCOVID-19 vaccine AstraZeneca10 daysSevere headache, right hemiparesis, unsteady gait, and visual impairment of 4 days Patient needed ICU care and mechanical ventilationIntra-parenchymal hemorrhage CT angiography = left transverse and sigmoid venous sinuses thrombosisFibrinogen concentrate (10 g total) and platelet (4 units total) a bilateral decompressive craniectomy
D’Agostino et al. [19Cerebral venous thrombosis and disseminated intravascular coagulationItaly54/FThe AstraZeneca vaccine12 daysAltered sensorium and hemiparesis Myocardial infarctionMultiple subacute lobar hemorrhages basilar artery thrombosis associated with the superior sagittal sinus thrombosis Bilateral adrenal hemorrhageIntensive care unit
Scully et al. (report of 23 patients) [20]Thrombocytopenia (23 patients) Cerebral venous thrombosis (13 patients)London12 years (Median)ChAdOx1 nCoV-19 vaccine (AstraZeneca)6 to 24 days13 patients with cerebral venous thrombosisNot availableNot available
Franchini et al. [21]Cerebral venous thrombosisItaly50/MCOVID-19 vaccine AstraZeneca7 daysComa thrombocytopeniaIntra-parenchymal hemorrhage Angiography cerebral venous sinus thrombosisIntensive care unit
Mehta et al. [22]Cerebral venous sinus thrombosisUK32/MVaxzevria vaccine9 daysThunderclap headache Left hemiparesis, left-sided incoordination Thrombocytopenia and rapidly evolving comaSuperior sagittal sinus and cortical vein thrombosis and significant cortical edema with small areas of parenchymal and subarachnoid hemorrhageIntensive care unit
25/MVaxzevria vaccine6 daysHeadache hemiparesis, left hemisensory loss Seizures, agitation, decerebrate posturing, reduced GCS ThrombocytopeniaSuperior sagittal sinus thrombosis with extension into the cortical veins and hemorrhage in lobar and sub-arachnoid locationsIntensive care unit
Bersinger et al. [23]Cerebral venous sinus thrombosisFrance21/FChAdOx1 nCoV-19 vaccine9 daysHeadaches, seizures, hemiplegia, expressive aphasia, and no pupillary abnormalities and altered sensorium The platelet count was 61,000 per cubic millimeterCT of the head showed massive thrombosis in the deep and superficial cerebral veins, thrombosis of the left jugular vein, and left frontoparietal venous hemorrhagic infarctionA selective arterial embolization was performed immediately after decompressive craniectomy IV immunoglobulin Fondaparinux
Ramdeny et al. [24]Cerebral venous sinus thrombosisUnited Kingdom54/MCOVID-19 Vaccine AstraZeneca21 daysWorsening headache, bruising and unilateral right calf swelling Thrombocytopenia D-dimer = 60,000 ng/ml Anti-platelet factor 4Cerebral venous sinus thrombosisIntravenous immunoglobulin
Zakaria et al. [25]Cerebral venous sinus thrombosisMalaysia49/MFirst dose of mRNA SARS-CoV-2 vaccine16 daysNew onset of mild to moderate headache and giddinessCT) of the brain showed cordlike hyperattenuation within the left transverse and sigmoid sinus suggestive of cord or dense clot sign CT cerebral venography a long segment-filling defect and empty delta sign within the superior sagittal sinus extending into the torcula Herophili, left transverse sinus, and sigmoid sinus to proximal internal jugular veinSubcutaneous Clexane improved
Ryan et al. [26]Cerebral venous sinus thrombosisIreland35/FAZD1222 (COVID-19 Vaccine AstraZeneca)10 daysHeadache thrombocytopenia bruising and petechiae Antibody to platelet factor 4MR venogram showed cerebral venous sinus thrombosisApixaban
Graf et al. [27]Cerebral venous sinus thrombosisGermany29/MChAdOx1 nCov-19, AstraZeneca9 daysSevere headache and hematemesis thrombocytopeniaComplete thrombosis of the left transverse and sigmoid sinus down to the left proximal jugular vein Temporo-parietal intracranial hemorrhage CT angiography revealed extensive thrombosis of the mesenteric and portal veinHigh-dose immunoglobulins Argatroban
George et al. [28]Cerebral venous sinus thrombosisUSA40/FChAdOx1 nCov-19, AstraZeneca7 daysHeadache thrombocytopenia Antibody to platelet factor 4Venous thrombosis involving the left transverse sigmoid sinus and internal jugular veinA direct thrombin inhibitor (bivalirudin) Intravenous immune globulin (IVIG)
Jamme et al. [29]Cerebral venous sinus thrombosisFrance69/FFirst dose of Oxford–AstraZeneca vaccine11 daysHeadache associated with behavioral symptomsBilateral frontal hemorrhage cerebral venous thrombosis of the left internal jugular vein, sigmoid sinus, and superior sagittal sinusNone
Tiede et al. (report of 5 patients) [30]Cerebral venous sinus thrombosisGermany41 and 67 years All femalesChAdOx1 COVID-19 vaccine (AZD1222, Vaxzevria)5 to 11 days after first vaccinationCerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), arterial cerebral thromboembolism, and thrombotic microangiopathy thrombocytopenia Autoantibodies against platelet factor 4Brain hematomas infarcts, presence of thrombi in major vesselsIntravenous immunoglobulin or corticosteroids Argatroban
Schulz et al. (report of 45 cases) [31]Cerebral venous thrombosisGermany46.5 years (mean)/35 femalesBNT162b2, ChAdOx1, and mRNA-1273Within 30 days of vaccinationThrombocytopenia in all patientsCerebral venous thrombosisIntravenous immunoglobulins, plasmapheresis, corticosteroids, anticoagulants
Bourguignon et al. [32]A report three patients one had cerebral venous sinus thrombosisCanada69/MChAdOx1 nCov-19, AstraZeneca12 daysDiabetes mellitus, hypertension, obstructive sleep apnea, recently diagnosed prostate cancer Headache and confusion left-sided weakness Thrombocytopenia Autoantibodies against platelet factor 4Right middle cerebral-artery stroke with hemorrhagic transformation Right cerebral transverse and sigmoid sinuses, right internal jugular vein, hepatic vein, and distal lower-limb vein; pulmonary embolismIntravenous immunoglobulin Plasmapheresis
Gattringer et al. [33]Cerebral venous sinus thrombosisAustria39/FThe first vaccination with ChAdOx1 nCov-19 (AstraZeneca)8 daysHeadache since 2 days thrombocytopenia (84 × 10 [8]/L)Left sigmoid/transverse sinus thrombosis without brain parenchymal involvementIntravenous immunoglobulin
Ikenberg et al. [34]Cerebral venous sinus thrombosisGermanyearly 30 s/FThe first dose of ChAdOx1 nCov-19 (AstraZeneca)Headache Gait ataxia, and amnestic difficulties as well as aphasia Thrombocytopenia of 37 000/µLCVST of the left transverse and sigmoidal sinus with a left-temporal and left-cerebellar intracerebral hemorrhageIntravenous immunoglobulin argatroban
Clark et al. [35]Cerebral venous sinus thrombosisUSA40/FThe Ad26.COV2.S (Johnson & Johnson/ Jansen) vaccine5 daysWorsening headaches thrombocytopeniaCerebral venous sinus thrombosis involving the left transverse and sigmoid sinuses, extending into the left internal jugular veinBivalirudin infusion Intravenous immunoglobulin
Bonato et al. [36]Cerebral venous sinus thrombosisItaly26/FChAdOx1 nCoV-19 vaccine14 daysheadache non-responsive to drugs right-sided weakness and visual disturbances rapidly deteriorated with decreased consciousnessMultifocal venous thrombosis with bilateral occlusion of parietal cortical veins, straight sinus, vein of Galen, internal cerebral veins, and inferior sagittal sinus. Right parietal and left frontoparietal lobes an extensive venous infarction with hemorrhagic transformation Platelet-factor 4 (PF4)–heparin IgG antibodies – elevated thrombocytopeniaDexamethasone Intravenous immunoglobulin argatroban
Wang et al. [37]Cerebral venous sinus thrombosisTaiwan41/FFirst vaccination with ChAdOx1 nCoV-197 daysFever and headache thrombocytopenia positive anti-PF4 antibodiesMR venography revealed cerebral venous sinus thrombosisIntravenous immunoglobulin
Dutta et al. [38]Cerebral venous sinus thrombosisIndia51/MFirst-dose of COVISHIELD6 daysHeadache double vision papilledema Platelet count was normalMR venography revealed thrombosis in superior sagittal sinus and transverse sinusLow-molecular-weight heparin
Aladdin et al. [39]Cerebral venous sinus thrombosisSaudi Arabia36/FFirst dose of the ChAdOx1 nCoV-19 vaccine14 daysVomiting and severe headache left upper limb weakness thrombocytopenia Disseminated intravascular coagulationBrain computed tomography (CT) scan showed superior sagittal thrombosis with thickened cortical veins and bilateral hypodensities in the parietal lobesLow-molecular-weight heparin ICU care
Lavin et al. (a series of 4 patients) [40]Cerebral venous sinus thrombosisIreland29/F 38/M 50/F 35/FVaxzevria vaccine (ChAdOx1 nCoV-19, AstraZeneca)10 days 16 days 23 days 14 daysVisual disturbance followed by a headache, nausea, vomiting, bruising and petechiae severe thunderclap headache, nausea and vomiting headache, persistent bruising and petechiae all had thrombocytopeniaDural venous sinus thrombosis in one patient only other had abdominal abnormalitiesIntravenous immunoglobulin
Tølbøll Sørensen et al. [41]Cerebral venous sinus thrombosisUK30/FChAdOx1 nCoV-19Headache and general malaise portal vein thrombosis thrombocytopenia and consumption coagulopathy Anti-platelet antibodies were detectedNormalTinzaparin
Fan et al. [42] (a series of 3 patients)Cerebral venous sinus thrombosisSingapore54/M 62/F 60/FBNT162b2 mRNA vaccination1 day 9 days 8 daysSevere headache and vomiting and acute left hemiparesis Headache and vomiting Right ataxic hemiparesis There was no thrombocytopeniaA large right temporo-parietal lobe intraparenchymal hemorrhage Acute right cerebral bleed involving occipital and temporal lobes associated with subarachnoid hemorrhage Venous infarct in bilateral perirolandic gyri Venogram confirmed cerebral venous sinus thrombosis in all threeLow-molecular-weight heparin decompressive craniectomy
Suresh and Petchey  [43]Cerebral venous sinus thrombosisUK27/MChAdOx1 nCOV-19 vaccine2 daysWorsening headache and new homonymous hemianopia Thrombocytopenia Anti-platelet antibodies were detectedAcute parenchymal bleed with subdural extension CT venogram confirmed significant cerebral venous sinus thrombosisDabigatran and intravenous immunoglobulins
Dias et al. (a series of 2 patients) [44]Cerebral venous sinus thrombosisPortugal47/F 67/FBNT162b2 mRNA SARS-CoV-2 vaccine6 days 3 daysHeadache, nausea and photophobia a sudden left motor deficit Sudden right lower limb clonic movements, followed by motor deficit, loss of consciousness and headache There was no thrombocytopenia Anti-platelet antibodies were not detectedMRI with venography revealed thrombosis of superior sagittal, right lateral, transverse, sigmoid sinuses, and jugular vein and left sigmoid sinus, together with right frontal subarachnoid hemorrhage and a cortical venous infarct Brain MRI showed thrombosis of high convexity cortical veins, superior sagittal, right transverse, and sigmoid sinus and jugular veinAcetazolamide and enoxaparin Levetiracetam 500 mg bid and enoxaparin
Guan et al. [45]Cerebral venous sinus thrombosisTaiwan52/MThe first dose of ChAdOx1 nCov-19 (AstraZeneca)10 daysNausea and thunderclap headache thrombocytopenia Platelet factor 4 antibodies detectedHyperdensity of the sinus, including cord sign and dense vein sign at the left transverse and sigmoid sinuses CT venogram revealed CVST at the left transverse sinus and sigmoid sinuses and thrombosis of the left internal jugular veinApixaban Outcome not provided
Varona et al. [46]Cerebral venous sinus thrombosis and primary adrenal insufficiencySpain47/MAdenoviral (ChAdOx1) vector-based COVID-19 vaccine10 daysHeadache, somnolence, and mild confusion Blateral segmentary pulmonary embolism Thrombocytopenia Anti-platelet antibodies were detectedConsistent with cerebral venous thrombosisIntravenous immunoglobulins and subcutaneous fondaparinux hydrocortisone Patient improved

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In Europe, since March 2021, cases of cerebral venous thrombosis started pouring in following COVID-19 vaccination, particularly after administration of viral vector based (AstraZeneca ChAdOx1 nCoV-19 and the Johnson and Johnson Ad26. COV2.S) vaccines [22]. Scully and colleagues recently reported findings of 23 patients, who presented with thrombosis and thrombocytopenia (platelet counts below 10 × 109/L). These patients developed thrombosis and thrombocytopenia 6 to 24 days after they received the first dose of the viral vector-based vaccines. In a significant observation, authors, in majority of patients, demonstrated the presence of autoantibodies against platelet factor 4. Additionally, D-dimer levels were found elevated [20]. Tiede and co-workers reported five German cases of prothrombotic immune thrombocytopenia after vaccination with viral vector-based vaccine (Vaxzevria). In these patients, acute vascular events clinically manifested as cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and/or thrombotic microangiopathy within 2 weeks post vaccination. All five patients had low platelet counts and markedly raised D-dimer. In all, autoantibodies against platelet factor 4 were also demonstrated [30].

Pottegård et al. in Denmark and Norway evaluated incidence of arterial events, venous thromboembolism, thrombocytopenia, and bleeding among vaccinated population. The vaccinated cohorts comprised of 148,792 Danish people and 132,472 persons from Norway. All has received their first dose of viral vector-based vaccine (ChAdOx1-S). An excess rate of venous thromboembolism (like cerebral venous thrombosis) was observed among vaccine recipients, within 28 days of vaccine administration. Authors estimated an increased rate for venous thromboembolism corresponding to 11 excess events per 100,000 vaccinations with 2.5 excess cerebral venous thrombosis events per 100,000 vaccinations [47].

Krzywicka et al., from the Netherlands, collected data of 213 cases with post-vaccination (187 after adenoviral vector vaccines and 26 after a mRNA vaccine) cerebral venous sinus thrombosis; they noted thrombocytopenia in 107/187 (57%) post-vaccination cerebral venous sinus thrombosis cases. Thrombocytopenia was not recorded in any of patients, who received an mRNA-based vaccine. Cerebral venous sinus thrombosis after adenoviral vector vaccines carried poorer prognosis. Approximately, 38% (44/117) patients in adenoviral vector vaccine group died, while in mRNA vaccine group, 20% (2/10) had died [48].

Recently published National Institute for Health and Care Excellence (NICE) guidelines recommend that the patients with clinical diagnosis of vaccine-induced immune thrombocytopenia and thrombosis should be treated with intravenous administration of human immunoglobulin, at a dose of 1 g/kg. If there is no response or there is further deterioration, second dose of human immunoglobulin should be given. In patients with insufficient response, methylprednisolone 1 g intravenously for 3 days or dexamethasone 20 to 40 mg for 4 days can be used [49].

Heparin needs to be avoided, instead alternative anticoagulants like argatroban, bivalirudin, fondaparinux, rivaroxaban, or apixaban should be used for anticoagulation [4951]. NICE guidelines further recommend that patients with very low platelet count should be treated either alone with a argatroban or a combination of argatroban and platelet transfusion [49].

Arterial events

Several acute arterial events, like arterial thrombosis, intracerebral hemorrhage, transient global amnesia, and spinal artery ischemia, have also been reported following vaccination [31].

Simpson and colleagues, in Scotland, estimated the incidence of vaccine-associated thrombocytopenia and vascular events following administration of first dose of viral vector-based vaccine (ChAdOx1) or mRNA (BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna) vaccination. First dose of viral vector-based vaccine was associated with small enhanced risk of idiopathic thrombocytopenic purpura; in addition, up to 27 days after vaccination, there was possibility of an increased risk for thromboembolic and hemorrhagic events. No such adverse associations were noted with mRNA vaccines [52]. The reports of COVID-19 vaccine-related intracerebral hemorrhage and ischemic stroke are summarized in Table ​Table22 [5361].

Table 2

Clinical, neuroimaging and outcome details of patients who suffered strokes (other than cerebral venous thrombosis) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Athyros and Doumas [53]Intracerebral hemorrhageGreece71/FModerna anti-COVID-19 vaccine3 daysRight hemiplegia, aphasia, agnosia Acute hypertensive crisisLeft basal ganglia hemorrhageClonidine, furosemideDied
Bjørnstad-Tuveng [54]Intracerebral hemorrhageNorwayThirties/FAstraZeneca’s vaccine ChAdOx1 nCoV-199 daysSlurred speech, left hemiparesis, and reduced consciousnessRight intracerebral hemorrhage on CT, thrombosis in transverse sinus and pulmonary artery on postmortemICU managementDied
de Mélo Silva et al. [55]Intracerebral hemorrhage with intraventricular extensionBrazil57/FChAdOx1 nCoV-19 vaccine5 daysLeft hemiparesis, vomiting, and somnolenceA large right deep frontal lobe parenchymal hematomaICU management Decompressive craniectomySurvived with disabilities
Bayas et al. [56]Bilateral superior ophthalmic vein thrombosis, ischemic stroke, and immune thrombocytopeniaGermany55/FSARS-CoV-2— ChAdOx1 nCoV-1910 daysFlu-like illness, diplopia, vision loss, a transient, mild, right-sided hemiparesis, and aphasia, focal seizuresMRI showed superior ophthalmic vein thrombosis An MRI showed an ischemic stroke in the left parietal lobe, middle cerebral artery territory, with restricted diffusionIntravenous dexamethasone AnticoagulantsImproved
Al-Mayhani et al. [57Ischemic stroke with thrombocytopeniaLondon35/F 37/F 43/FChAdOx1 nCoV-19 vaccine ChAdOx1 nCoV-19 vaccine ChAdOx1 nCoV-19 vaccine11 days 12 days 21 daysLeft face, arm, leg weakness and drowsiness Headache, left visual field loss, confusion, left arm weakness DysphasiaRight middle-cerebral artery infarct Bilateral acute border zone infarcts Left middle-cerebral artery infarctDecompressive hemicraniectomy Intravenous immunoglobulin Intravenous immunoglobulinDied Improved Stable
Blauenfeldt et al. [58]Ischemic strokeDenmark60/MmRNA-based vaccine BNT162b2 (Pfizer/BIOTECH)7 daysBilateral adrenal hemorrhages A massive right sided ischemic stroke Thrombocytopenia Platelet factor 4 (PF‐4) reactive antibodiesAngiography showed occlusion of the right internal. Carotid arteryIntensive care unitPalliative care
Malik et al. [59]transient ischemic attackUSA43/FJohnson and Johnson COVID-19 Ad26.COV2.S vaccination10 daysHeadache, fever, body aches, chills, mild dyspnea and light-headedness thrombocytopenia numbness and tingling of her face and right armRight internal carotid artery (ICA) thrombusFondaparinuxImproved
Finsterer and Korn [60]AphasiaAustria52/MThe second dose of an mRNA-based SARS-CoV-2 vaccine7 daysSudden-onset reading difficulty and aphasia motor aphasia with paraphasiaA lobar bleeding in the left temporal lobeSupportiveImproved
Walter et al. [61]Ischemic stroke Main stem occlusion of middle cerebral arteryGermanyFirst dose ChAdOx1 nCov-19 vaccineacute headache, aphasia, and hemiparesis Platelet count and fibrinogen level were normalMain stem occlusion of middle cerebral artery A wall-adherent, non-occluding thrombus in the ipsilateral carotid bulb was notedWithin 1 h after start of IV thrombolysisThrombus dissolved and patient improved

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Intracerebral hemorrhage

Athyros and Doumas reported a 71-year-old female. who developed intracerebral hemorrhage after she received the first dose of the Moderna mRNA vaccine.

On the third post-vaccination day, the patient developed right hemiplegia, aphasia, and agnosia along with accelerated hypertension. Computed tomography revealed a hematoma in the left basal ganglia. On the 9th day, she died [53].

In another report, Bjørnstad-Tuveng et al. described a young woman, who had a fatal cerebral event following vaccination with AstraZeneca’s ChAdOx1 nCoV-19 vaccine. She was found to have severe thrombocytopenia. The patient died the next day of the event. Post-mortem examination revealed antibodies against platelet factor 4 and the presence of small thrombi in the transverse sinus, frontal lobe, and pulmonary artery [54].

Acute ischemic stroke

Bayas and co-workers described a case that presented with superior ophthalmic vein thrombosis, ischemic stroke, and immune thrombocytopenia, after administration of viral vector-based vaccine. Intravenous dexamethasone resulted in marked improvement in platelet count [56]. Al-Mayhani et al. described three cases of vaccine-induced thrombotic thrombocytopenia, all presented with arterial strokes. Authors opined that young patients with arterial stroke after receiving the COVID-19 vaccine should always be evaluated for vaccine-induced thrombotic thrombocytopenia. Other laboratory tests, like platelet count, D-dimers, fibrinogen level, and testing for platelet factor 4 antibodies, should also be performed [57].

Blauenfeldt et al. described a 60-year-old woman, who presented with intractable abdominal pain, 7 days after receiving the adenoviral (ChAdOx1) vector-based COVID-19 vaccine. Abdominal computed tomography revealed bilateral adrenal necrosis. Later, a massive right cerebral infarction, secondary to occlusion of the right internal carotid artery, occurred that led to death of the patient. Blood tests showed thrombocytopenia, elevated in D-dimer and platelet factor 4 antibodies [58].

Many reports of acute brain disorders like encephalopathy, seizures, acute disseminated encephalopathy, neuroleptic malignant syndrome, and post-vaccine encephalitis were described secondary to COVID-19 vaccine. These are summarized in Table ​Table33 [6275].

Table 3

Clinical, neuroimaging and outcome details of patients who presented with an acute brain disorder (other than cerebral venous thrombosis and arterial stroke) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Baldelli et al. [62]Reversible encephalopathyItaly77/MThe first dose of ChAdOx1 nCoV-19 vaccine (AstraZeneca)1 dayDelirium A significant increase of interleukin (IL)-6 in both CSF and serumNormalCorticosteroids
Aladdin and Shirah [63]New-onset refractory status epilepticusSaudi Arabia42/FChAdOx1 nCoV-19 vaccine10 daysHeadache and fever first-ever generalized tonic–clonic seizure lorazepam, levetiracetam, and phenytoin failed to controlIncrease in the signal on FLAIR images at bilateral hippocampi and insulaMidazolam and propofol Plasma exchangeImproved
Ghosh et al. [64]SeizuresIndia68/MCovishield vaccine4 daysFocal onset non-motor seizurePeriventricular leukoaraiosis and cortical atrophybrivaracetamImproved
Liu et al. [65] (two cases)Associated with non-convulsive status epilepticusUSA86/F 73/MModerna COVID-19 vaccine7 days 21 daysDiastolic dysfunction, chronic kidney disease and diabetes mellitus with acute encephalopathy Acute confusion with visual hallucinations EEG demonstrated non-convulsive focal status epilepticus Acute encephalopathy with non-convulsive status epilepticusNormalAntiepileptic therapy and ICU careBoth improved
Naharci and Tasc [66]DeliriumTurkey88/Ffirst dose of CoronaVac–-an inactivated COVID-19 vaccineAcute confusion, hallucinations, agitation, and sleep disturbanceNoneHaloperidol and trazodoneImproved
Salinas et al. [67]Transient akathisiaUSA36/FPfizer-BioNTech vaccineWithin 24 h of second doseRestless body syndrome had fever after 5 h of motor restlessness resolved after 24 hNoneNoneImproved
Zavala-Jonguitud et al. [68]DeliriumMexico89/MThe first dose of BNT162b2 RNA vaccine24 hAcute confusion, fluctuating attention, anxiety and inversion of the sleep–wake cycle History of type 2 diabetes mellitus, hypertension, stage III‐b chronic kidney disease, prostatic hyperplasiaNot doneQuetiapineImproved
Alfishawy et al. [69]Neuroleptic malignant syndromeKuwait74/FBNT162b2 mRNA COVID-19 vaccine16 daysOld case of dementia and bipolar disorder and was receiving memantine, donepezil, and quetiapine presented with fever, delirium, rigidity, and elevated CPKNormalSymptomaticImproved
Ozen Kengngil et al. [70]Acute disseminated encephalomyelitis like MRI lesionsTurkey46/FInactivated SARS-CoV-2 vaccine of Sinovac1 MonthSeizures, normal examinationT2, FLAIR hyperintensity in thalamus, and corona radiataMethyl prednisoloneNo recurrence of seizures
Cao and Ren [71]Acute disseminated encephalomyelitisChina24/FSARS-CoV-2 Vaccine (Vero Cell), Inactivated2 weeksSomnolence and memory decline, MMSE-11 inflammatory changes in CSFT2/FLAIR white matter hyperintensity in both temporal lobesIV immunoglobulinImproved
Raknuzzaman et al. [72]Acute disseminated encephalomyelitisBangladesh55/MBNT162b2 mRNA COVID-19 vaccine3 weeksDelirium followed by loss of consciousnessT2/FLAIR white matter hyperintensities in periventricular regionMethyl prednisoloneImproved
Torrealba-Acosta et al. [73]Acute encephalitis, myoclonus and Sweet syndromeUSA77/MmRNA-1273 vaccine1 dayConfusion, fever and generalized rash; later headache, dizziness and double vision leading to severe encephalopathy Intermittent orofacial movements and upper extremity myoclonus CSF showed increased cells and protein. Skin biopsy showed vasculitis changesNormalMethylprednisoloneImproved
Vogrig et al. [74]Acute disseminated encephalomyelitisItaly56/FPfizer-BioMTech COVID-19 vaccine (Comirnaty)2 weeksHorizontal gaze-evoked nystagmus, Mild weakness on left upper limb, left hemi-ataxic gaitT2/FLAIR white matter hyperintensity in left cerebellar peduncle prednisone improved FLAIR sequences were observed, the largest in the left centrum semiovalePrednisoneImproved
Zuhorn et al. [75]Postvaccinal encephalitis Similar to autoimmune encephalitisGermany21/FChAdOx1 nCov-19 vaccine the first dose5 daysHeadache and progressive neurological symptoms including attention and concentration difficulties and a seizure CSF lymphocytic pleocytosis EEG slow delta rhythmNormalPrednisoneImproved
63/FChAdOx1 nCov-19 vaccine6 daysGait disorder, a vigilance disorder and a twitching all over her body Opsoclonus-myoclonus syndrome CSF lymphocytic pleocytosis EEG slow delta rhythmNormalMethylprednisoloneImproved
63/MChAdOx1 nCov-19 vaccine8 daysIsolated aphasia and fever CSF lymphocytic pleocytosis EEG normalNormalNoneMild improvement despite no treatment

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Encephalopathy

Some patients developed encephalopathy following administration of COVID-19 vaccines. Acute encephalopathy is defined as rapidly evolving disorder of the brain. Acute encephalopathy clinically manifests either with delirium, decreased consciousness, or coma.

Delirium

Delirium is characterized with fluctuating disturbance in attention and awareness. Zavala-Jonguitud and Pérez-García described an 89-year-old man, who developed delirium after mRNA vaccination. Within 24 h, patient developed confusion, fluctuating attention, anxiety, and inversion of the sleep–wake cycle. Patient had many comorbidities (diabetes mellitus, hypertension, and chronic kidney disease). Patient improved after he was treated with quetiapine [68].

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a life-threatening complication of many antipsychotic drugs characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. In an isolated report, neuroleptic malignant syndrome, in a 74-year-old female with dementia and bipolar disorder 16 days after COVID-19 vaccination, has been described [69].

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demyelinating disorder of the central nervous system. In the majority, ADEM is a post-infectious entity; in many cases, it even develops after vaccination [76]. In two cases, acute disseminated encephalomyelitis following COVID-19 vaccination has been reported. In first such case a 46-year-old woman received Sinovac inactivated SARS-CoV-2 vaccine before onset of clinical manifestations. Patient was presented with seizures, and magnetic resonance imaging revealed multiple, discrete T2/FLAIR periventricular. hyperintense lesions. Patient improved following methylprednisolone treatment [70] Another patient was a 24-year-old female who presented with encephalopathy along with limb weakness of 1-day duration. Two weeks prior, patient was vaccinated with inactivated SARS-CoV-2 vaccine. Magnetic resonance imaging revealed multiple, discrete T2/FLAIR hyperintense lesions in the brain. Patient improved following treatment with antiepileptics and intravenous immunoglobulins [71].

Post-vaccinal encephalitis

Zuhorn et al. reported a case series 3 patients, who presented with post-vaccinal encephalitis, akin to autoimmune encephalitis, 7 to 11 days after administration of adenovirus-based ChAdOx1 nCov-19 vaccine. All patients fulfilled the diagnostic criteria for possible autoimmune encephalitis. One interesting case had presented with opsoclonus-myoclonus syndrome. Two patients presented with cognitive decline, seizures, and gait disorder. Neuroimaging did not reveal any abnormality. CSF pleocytosis was noted in all three patients. All patients responded well to corticosteroids [75].

Transverse myelitis

Acute transverse myelitis is an inflammatory spinal cord disorder that clinically manifests with the paraparesis/quadriparesis, transverse sensory level, and bowel or bladder dysfunction. Acute transverse myelitis usually is a postinfectious disorder. Magnetic resonance imaging demonstrates T2/FLAIR hyperintensity extending several spinal cord segments. Autoimmunity via mechanism of molecular mimicry is usually responsible for spinal cord dysfunction. Adenoviral vector-based COVID-19 vaccines are more frequently associated with causation of transverse myelitis. In isolated cases, even inactivated virus vaccine and mRNA-based vaccines had precipitated acute demyelination spinal cord syndromes, like multiple sclerosis and neuromyelitis optica. Reports of myelitis associated with vaccination for SARS-CoV-2 are summarized in Table ​Table44 [7783].

Table 4

Clinical, neuroimaging, and outcome details of patients who presented with spinal cord involvement after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Malhotra et al. [77]Transverse myelitisIndia36/MViral-vectored, recombinant ChAdOX1 nCoV-19 Covishield vaccine (AstraZeneca vaccine by Serum Institute of India)On the 8th post-vaccination dayAbnormal sensations in lower limbs with truncal levelT2-hyperintense lesion in the dorsal aspect of spinal cord at C6 and C7 vertebral levelsMethylprednisoloneImproved
Fitzsimmons and Nance [78]Transverse myelitisUSA63/MSecond dose of the Moderna vaccineWithin 1 dayLower back pain, paresthesia in both feet, and pain in lower extremities difficulty in walking and urinary retentionIncreased T2 cord signal seen in the distal spinal cord and conusIntravenous immunoglobulin and methylprednisoloneImproved
Tahir et al. [79]Transverse myelitisUSA44/FAd26.COV2.S (Johnson & Johnson) vaccine10 daysCervical cord transverse myelopathy CSF increased cellsIncreased T2 cord signal seen in the spinal cord extending from the C2-3 segment into the upper thoracic regionPlasma exchange and methylprednisoloneImproved
Pagenkopf and Südmeyer [80]Longitudinally extensive transverse myelitisGermany45/MFirst dose COVID-19-vaccine (AZD1222, AstraZeneca)11 daysThoracic back pain and urinary retentionT2 hyperintense signal of the spinal cord with wide axial and longitudinal extent reaching from C3 to Th2PrednisoloneImproved
Helmchen et al. [81]Optic neuritis with longitudinal extensive transverse myelitis in stable multiple sclerosisGermany40/FAstra Zeneca, COVID19 Vaccine®; Vaxzevria2 weeksBlindness paraplegia, with absent tendon reflexes in the legs, incontinence, and a sensory deficit for all qualities below Th5. CSF showed severe pleocytosis and elevated proteinIncreased longitudinal centrally located signal intensities throughout the thoracic spinal cordCorticosteroids and plasmapheresisImproved
Havla et al. [82]First manifestation of multiple sclerosisGermany28/FPfizer-BioNTech COVID-19 vaccine6 days first doseMyelitis oligoclonal bandsMRI revealed multiple (> 20), partially confluent lesions with spatial dissemination but no gadolinium enhancement. Contrast-enhancing lesion at the T6 level, suggestive of myelitisMethylprednisolone and plasma exchangeImproved
Chen et al. [83]Neuromyelitis optica spectrum disorderChinaMiddle-aged femaleThe first dose of inactivated virus vaccine3 daysDizziness and unsteady walking AQP4-positiveMRI scanning of the brain revealed area postrema and bilateral hypothalamus lesionsMethylprednisoloneImproved

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Malhotra and colleagues reported a 36-year-old patient, who had short-segment myelitis 21 days after first dose of adenoviral vector-based (Oxford/AstraZeneca, COVISHIELD™) vaccine. Patient recovered completely after treatment with methylprednisolone [77]. Fitzsimmons and Nance reported another patient of acute transverse myelitis following Moderna vaccine (an mRNA vaccine). The 63-year-old patient developed symptoms of acute myelopathy within 24 h of vaccination. MRI revealed increased T2 cord signal seen in the distal spinal cord and conus. Patient improved considerably following treatment with methylprednisolone and intravenous immunoglobulin [78].

Earlier, in phase III trial of Oxford/AstraZeneca vaccine, 2 patients had developed transverse myelitis. One of the case of transverse myelitis was reported 14 days after booster vaccination. The expert committee considered that this case was the most likely an idiopathic, short segment transverse myelitis. The second case was reported 68 days post-vaccination. Experts believed that in this case, transverse myelitis was not likely to be associated with vaccination. This patient was earlier diagnosed as a case of multiple sclerosis [8485].

The pathogenesis of acute transverse myelitis following COVID-19 vaccination remains unknown. Possibly, SARS-CoV-2 antigens present in the COVID-19 vaccine or its adenovirus adjuvant induce immunological reaction in the spinal cord. The occurrence of 3 reported acute transverse myelitis adverse effects among 11,636 participants in the vaccine trials was considered high and a cause of concern [86].

Bell’s palsy

Several cases of Bell’s palsy have occurred following COVID-19 vaccination. (Table ​(Table5)5) [8795]. The instances of Bell’s palsy are most often associated with mRNA vaccines [96]. Vaccine-associated Bell’s palsy generally responds very well to the oral corticosteroids. The exact pathogenesis remains speculative.

Table 5

Summary of reported patients, who suffered from Bell’s palsy after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Shemer et al. (a report of 9 cases) [87]Bell’s palsyIsrael35–86 (M = 5 and F = 4)BNT162b2 SARS-CoV-2 vaccine4–30 days after first dose 3 received 2nd doseAcute facial weakness One had herpes zoster ophthalmicus and herpes zoster oticusNoneCorticosteroidsNot given
Repajic et al. [88]Bell’s palsyUSA57/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine36 h after second dose3 previous episodes of Bell’s palsy ageusia Facial weaknessNonePrednisoneImproved
Colella et al. [89]Bell’s palsyItaly37/MmRNA vaccine BNT162b25 days after first doseAcute facial weaknessNot doneCorticosteroidsImproved
Martin-Villares et al. [90]Bell’s palsySpain34/FModerna COVID-19 vaccine2 daysGrade III facial palsy She developed a right Bell’s palsy in 2012 during pregnancy (5th month)NoneCorticosteroidsImproved
Nishizawa et al. [91]Bell’s palsyJapan62/FAd26.COV2.S vaccination20 daysHouse-Brackmann score 4 Bell’s PalsyNormalNoneNone
Gómez de Terreros et al. [92]Bell’s palsySpain50/MPfizer-BNT162b2 mRNA vaccine9 daysMuscle weakness on the left side of his faceNormalCorticosteroidsImproved
Burrows et al. [93]Sequential contralateral facial nerve palsiesUKFirst and second doses of the Pfizer-BioNTech COVID-19 vaccineRight palsy, 5 h Left palsy after 2 daysTwo discrete contralateral episodes of Bell’s palsyNormalPrednisoloneImproved both the time
Obermann et al. [94]Bell’s palsyGermany21/FFirst dose of SARS-CoV-2 mRNA vaccine Comirnaty (BNT162b2, BioNTech/Pfizer)2 dayFacial muscle paralysis SARS-CoV-2 antibodies were present in blood and CSFNormalPrednisoloneImproved
Iftikhar et al. [95]Bell’s palsyQatar36/MSecond dose of the mRNA-1273 vaccine1 dayFacial palsyNormalPrednisoloneImproved

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In a case–control study, Shemer et al. compared clinical parameters of patients with Bell’s palsy following mRNA vaccination with that of patients with Bell’s palsy without vaccination. Out of 37 patients, 21 had received vaccination. Bell’s palsy developed within 2 weeks following first dose of COVID-19 vaccination. There was no difference in any of the clinical parameter between vaccinated or unvaccinated groups [97].

Earlier, in the Pfizer-BioNTech clinical trial, which included 44,000 participants, 4 people had Bell’s palsy. No case of Bell’s palsy was reported in the placebo arm. In the Moderna trial, which included 30,400 participants, 3 vaccine recipients reported Bell’s palsy. One person was in the placebo arm [98]. An article, published in the Lancet, analyzed the combined phase 3 data of Pfizer and Moderna trials and noted that the rate of Bell’s palsy was higher than expected [98].

Other cranial nerve involvement

In isolated instances, mRNA vaccines were found associated with olfactory dysfunction and sixth cranial nerve palsy (Table ​(Table6)6) [99104].

Table 6

Summary of reported patients, who suffered from cranial nerve involvement (other than Bell’s palsy) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Konstantinidis et al. [99] Report of 2 patientsOlfactory dysfunctionGreeceBoth femalePfizer-BioNTech BNT162b23 and 5 days after second doseHyposmia after their second doseNoneOlfactory trainingImproved
Keir et al. [100]PhantosmiaUSA57/FPfizer-BioNTech COVID-19 vaccination Second doseNoneFeeling weak, fatigued, with random episodes of ‘‘smelling smoke’’ associated with hyposmiaPostcontrast CT demonstrates faint enhancement left olfactory tract MRI enhancement of the left greater than right olfactory bulb and bilateral olfactory tractsNoneNone
Reyes-Capo et al. [101]Acute abducens nerve palsyUSA59/FPfizer-BioNTech COVID-19 vaccine2 daysFever for 1 day followed by diplopiaNormal MRI of brain and orbitsNot availableSensory-motor examination remained unchanged in recent follow-up
Parrino et al. [102]TinnitusItaly37/F 63/ 30/MBNT162b2 mRNA-vaccine7-h first dose 20 h 7 daysSudden unilateral tinnitusNormal MRICorticosteroids, in twoImproved all
Tseng et al. [103 ] PMID: 34,297,133Reversible tinnitus and cochleopathyTaiwan32/MFirst dosage of the AstraZeneca COVID-19 vaccine5 hHigh-pitch tinnitus and disturbed the normal hearing high fever with chills and myalgiaNot doneCorticosteroidsImproved
Narasimhalu et al. [104]Trigeminal and cervical radiculitisSingapore52/FPfizer-BioNTech vaccination (tozinameran)3 h first doseNumbness, swelling and pain over the left face and neckMRI of trigeminal nerve revealed thickening and perineural sheath enhancement of the V3 segment of the left trigeminal nerve The MRI of the cervical spine revealed spondylotic changesPregabalinImproved

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Olfactory dysfunction

Olfactory dysfunction is the most frequent neurological complication of COVID-19. Konstantinidis and colleagues reported two cases of smell impairment after second dose of the BioNTechBNT162b2 vaccine (Pfizer) administration [51].

Keir and colleagues reported phantosmia following administration of Pfizer COVID-19 vaccine. Patient complained of constantly “smelling smoke” and headaches. MRI of brain of the patient showed enhancement of the olfactory bulbs and bilateral olfactory tracts [100].

Abducens nerve palsy

Reyes-Capo et al. reported a 59-year-old lady, who presented with an abducen nerve palsy 2 days post-vaccination (Pfizer-BioNTech mRNA vaccine). Neuroimaging in this patient was normal..

Otologic manifestations

A variety of otologic manifestations has been noted following COVID-19 vaccination. Parrino and colleagues described three patients with sudden unilateral tinnitus following BNT162b2 mRNA vaccine administration. Tinnitus rapidly resolved in 2 cases. Wichova and colleagues in a retrospective review recorded 30 patients, who either had significantly exacerbated otologic symptoms or had a new symptom after getting mRNA vaccine. Post-vaccination otologic manifestations included hearing loss with tinnitus, dizziness, or with vertigo. In some patients, with Menière’s disease or autoimmune inner ear disease, vaccine led to exacerbation of the pre-existing otologic symptoms [102,105].

Acute vision loss

Santovito and Pinna reported an unusual patient, who developed acute visual impairment following the 2nd dose of the Pfizer-BioNTech COVID-19 vaccine. Prior to visual symptoms, patient experienced unilateral headache. He also reported mild confusion, asthenia, and profound nausea. His symptoms got relieved after taking analgesics. Possibly, patient had an acute attack of migraine with aura that got precipitated by the vaccine [106].

Guillain-Barré syndrome

Guillain-Barré syndrome is a post-infectious disorder of peripheral nerve manifesting with lower motor neuron type of sensory-motor quadriparesis. Acute motor weakness is frequently preceded by an antecedent microbial infection. There are numerous reports indicating that COVID-19 infection can trigger Guillain-Barré syndrome. The US Food and Drug Administration has recently expressed its concern regarding a possible association between the Johnson and Johnson COVID-19 vaccine with Guillain-Barré syndrome [107].

After emergency use approvals, all kinds of COVID-19 vaccines were found associated with Guillain-Barré syndrome. Adenovector-based vaccines were more frequently associated with Guillain-Barré syndrome. Earlier, in phase 3 trial of Johnson and Johnson adenovirus vector-based COVID-19 vaccine, 2 patients developed Guillain-Barré syndrome. One patient belonged to vaccine group and other to placebo group. Both patients had Guillain-Barré syndrome within 2 weeks of receiving injections. The Guillain-Barré syndrome in the vaccine arm was preceded by chills, nausea, diarrhea, and myalgia [108109].

Post-vaccination Guillain-Barré syndrome generally affects older adults within 2 weeks of vaccine administration. Clinical presentation is similar to acute demyelinating neuropathy; nerve conduction studies show demyelinating pattern, and CSF examination shows cyto-albuminic dissociation. Many patients present only with facial diplegia. Response to immunotherapy is generally good. (Table ​(Table7)7) [110126].

Table 7

Summary of reported patients, who developed an acute peripheral nerve disorder after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Waheed et al. [110]Guillain-Barré syndromeUSA82/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine2 weeksAreflexic paraparesis with distal sensory loss CSF showed albuminocytologic dissociationenhancement of cauda equina nerve rootsIV immunoglobulinImproved
Márquez Loza et al. [111]Guillain-Barré syndromeUSA60/FJohnson & Johnson, d26.COV2.S, a recombinant adenovirus serotype 26 (Ad26) vector vaccine2 weeksOphthalmoplegia, facial diplegia and Areflexic quadriparesis CSF showed albuminocytologic dissociationEnhancement of cauda equina nerve rootsIV immunoglobulinImproved
Patel et al. [112]Guillain-Barré syndromeUK37/MCOVID-19 ChAdOx1 vaccine adenovirus-vectored vaccine Oxford AstraZeneca2 weeksSymmetrical, progressive ascending muscle weakness areflexic bilaterally in the lower limbsCauda equina nerve root enhancementIntravenous immunoglobulinImproved
Razok et al. [113]Guillain-Barré syndromeQatar73/MPfizer-BioNTech COVID-19 vaccine20 days Second doseAcute bilateral lower limb weaknessNoneIVIGImproved
Ogbebor et al. [114]Guillain-Barré syndromeUS86/3FPfizer-BioNTech COVID-19 vaccine1 dayWeakness in her bilateral lower extremities and by day 6, she could no longer walk CSF = a protein 162 mg/dL and glucose (49 mg/dL)NoneIntravenous immunoglobulinImproved
Finsterer  [115]Exacerbating Guillain-Barré syndromeAustria32/MA vector-based COVID-19 vaccine8 daysParesthesia and dysphagia bilateral frontal and nuchal headacheNoneIntravenous immunoglobulinImproved
Marammatom et al. [116] Report of 7 casesGuillain-Barré syndromeIndiaChAdOx1-S/nCoV-19 adenovector-based vaccineWithin 2 weeks of the first doseAll patients progressed to areflexic quadriplegia 2 cases required mechanical ventilation All 7 cases had bilateral facial paresis Four patients (57%) also developed other cranial neuropathies (4th and 5th)In two patients, MRI brain and spine were normalIntravenous immunoglobulinOne recovered Rest six still bed bound
Allen et al. [117] Report of 4 casesGuillain-Barré syndrome variantUK20–57 all malesOxford-AstraZeneca SARS-CoV2 vaccineWithin 3 weeksFacial weakness in 1 facial diplegia in 3 areflexic quadriparesis in 1 Cyto-albuminic dissociation in allMRI of the brain and whole spine with contrast showed enhancement of the facial nerve within the right internal auditory canalIntravenous immunoglobulin, oral steroids, or no treatmentAll improved
Kohli et al. [118]Guillain-Barré syndromeIndia71/MCovishield, AstraZeneca, University of Oxford6 daysAreflexic quadriparesis with bulbar palsy NCV- demyelinating patternNoneIntravenous immunoglobulin and mechanical ventilationImproved
Azam et al. [119]Guillain-Barré syndromeUK67/MThe first dose of the AstraZeneca COVID-1915 daysAreflexic quadriparesis with facial diplegiaNCV- demyelinating patternNormalIntravenous immunoglobulinImproved
Hasan et al. [120]Guillain-Barré syndromeUK62/FFirst dose of the Oxford/AstraZeneca COVID-19 vaccineWeakness of bilateral lower limbs preceded by paresthesia and numbness a flaccid-type paraplegia NCV- demyelinating pattern CSF-albumin-cytological dissociationNormalIntravenous immunoglobulinThe patient remains in the ICU
Theuriet et al. [121]Guillain-Barré syndromeFrance72/MFirst dose of ChAdOx1 nCoV-19 vaccine (VaxZevria/Oxford-AstraZeneca)3 weeksAreflexic quadriparesis with facial diplegia NCV- demyelinating patternNoneIntravenous immunoglobulinThe patient remains in the ICU
Bonifacio et al. [122] (A series of 5 cases)Guillain-Barré syndromeUK43/M 51 M 53/M 66/m 71/fVaxzevria AstraZeneca, University of Oxford COVID-19 vaccine11 days 7 days 7 days 8 days 12 daysBilateral facial weakness with paresthesia variant of Guillain-Barré syndrome NCV- demyelinating pattern in 4 patientsBilateral contrast enhancement along whole facial nerve in 3 patientsIntravenous immunoglobulin Was given in 2 patientsAll improved
Nasuelli et al. [123]Guillain-Barré syndromeItaly59/MChAdOx1 nCoV-19 vaccine10 daysAreflexic quadriparesis with facial diplegia NCV- demyelinating pattern in 4 patients CSF-albumin-cytological dissociationNormalIntravenous immunoglobulinImproved
Jain et al. [124]Guillain-Barré syndromeUSA65/FAd26.COV2.S (Johnson & Johnson) vaccine19 daysFacial diplegiaNormalIntravenous immunoglobulin And plasmapheresisImproved
McKean and Chircop [125]Guillain-Barré syndromeMalta48/MVaxzevria AstraZeneca, University of Oxford COVID-19 vaccine First dose10 daysFacial diplegia and severe back pain ascending paresthesia and bilateral progressive areflexic lower limb weakness. CSF-albumin-cytological dissociation NCV multifocal sensorimotor demyelinating polyneuropathyNormalIntravenous immunoglobulin and oral prednisoloneImproved
Bonifacio et al. [126] (a report of 5 cases)Guillain-Barré syndromeUK
Waheed et al. [127]Small fiber neuropathyUSA57/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine (Second dose)Subacute onsetIntense burning dysesthesias in the feet gradually spreading to the calves and minimally into the hands (Nerve biopsy proved small fiber neuropathy)NoneGabapentinSymptomatic improvement

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Proposed pathogenesis of Guillain-Barré syndrome is an autoantibody-mediated immunological damage of peripheral nerves via mechanism of molecular mimicry between structural components of peripheral nerves and the microorganism. Lately, several cases of Guillain-Barré syndrome following COVID-19 vaccination have also been reported.

Small fiber neuropathy

Waheed et al. described a 57-year-old female, who presented with painful neuropathy following administration of the mRNA COVID-19 vaccine. Patient subacutely presented with intense peripheral burning sensations. Electrodiagnostic studies were normal. Skin biopsy proved small fiber neuropathy. Patient responded to gabapentin.(Table ​gabapentin.(Table7)7) [127].

Parsonage-Turner syndrome

Parsonage-Turner syndrome or neuralgic amyotrophy is clinically manifested with acute unilateral shoulder pain followed by brachial plexopathy. Parsonage-Turner syndrome is usually triggered by any infection, surgery, or rarely vaccination. In many reports, Parsonage-Turner syndrome has been described following COVID-19 vaccination.(Table ​vaccination.(Table8)8) [128130].

Table 8

Summary of reported patients, who developed neuralgic amyotrophy after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Mahajan et al. [128]Parsonage-Turner syndromeUSA50/MCOVID-19 BNT162b2 vaccination7 daysSudden onset of severe left periscapular pain after first dose One week after the second dose, the patient developed left hand grip and left wrist extension weakness. Electromyography showed decreased motor unit recruitmentNormalCorticosteroidsImproved
Diaz-Segarra et al. [129]Painless idiopathic neuralgic amyotrophyUSA35/FPfizer-BioNTech COVID-19 vaccine9 daysNew-onset painless left arm weakness, numbness, and paresthesiasCervical spine computed tomography showed mild degenerative changes without foraminal narrowingHigh-dose prednisoneImproved
Antonio Crespo Burillo et al. [130]Parsonage-Turner syndromeSpain38/MVaxzevria (AstraZeneca)4 daysShoulder and arm pain Electrophysiology suggested brachial plexopathyMRI of the shoulder revealed a mild left subacromial tendinopathyMethylprednisoloneImproved

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Herpes zoster

Herpes zoster occurs following reactivation of varicella zoster virus. Patients with herpes zoster present with the classic maculopapular rash, which is unilateral, confined to a single dermatome. The rash disappears in 7 to 10 days. Postherpetic neuralgia is the frequent complication of herpes zoster, which is noted in 1 in 5 patients. McMahon and co-workers recorded 414 cutaneous reactions to mRNA COVID-19 vaccines, and 5 (1.9%) were diagnosed with herpes zoster [131]. Other types of COVID-19 vaccines are infrequently associated with post-vaccination reactivation of herpes zoster. It has been suggested that vaccine-induced immunomodulation, resulting in dysregulation of T cell function, is responsible for reactivation of herpes zoster virus [132133]. Reports of herpes zoster reactivation after vaccine against SARS-CoV-2 are summarized in Table ​Table99 [134142].

Table 9

Summary of reported patients, who developed Herpes zoster after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Tessas and Kluger [134]Herpes zosterFinland44/MBNT162b2 mRNA COVID-19 vaccine7 daysHerpetiform vesicular and erythematous rash on the left upper backNoneOral valacyclovirImproved
Rodríguez-Jiménez et al. [135] A report of 5 casesHerpes zosterSpain39–58 F = 3BNT162b2 mRNA COVID-19vaccine (Pfizer)1–16 (4 less than 7 days)Painful herpetiform dermatomal rashNoneNoneNone
Eid et al. [136]Herpes zosterLebanon79/MmRNA COVID vaccine6 daysPainful herpetiform dermatomal rashNoneAntiviral treatmentImproved
Bostan and Yalici-Armagan [137]Herpes zosterTurkey78/MInactivated COVID-19 vaccineErythematous, painful, and pruritic lesions on chest
Furer et al. [138] (a report of 6 cases)Herpes zosterIsrael36–61 All femalesBNT162b2 mRNA vaccination3 -14 daysAll had autoimmune inflammatory rheumatic diseases Herpes zoster ophthalmicus in one Truncal herpes zoster in othersNot doneNANA
Aksu and Öztürk et al. [139]Herpes zosterTurkey68/MThe inactivated COVID-19 vaccine5 daysmultiple pinheaded vesicular lesions upon an erythematous base occupying an area on his right mammary region and back corresponding to T3–T5 dermatomesNot doneValacyclovir paracetamolImproved
Chiu et al. [140] (a report of 3 cases)Herpes zosterTaiwan71/M 46/M 42/MPfizer-BNT162b2 mRNA and Moderna mRNA-12732 days 7 days 2 daysErythematous papules and vesicle in dermatomal patternNot doneOral acyclovirAll improved
Alpalhão and Filipe et al. [141] (a report of 4 cases)Herpes zosterPortugalNAPfizer’s Comirnaty™ vaccine AstraZeneca Vaxzevria™ vaccine3–6 daysErythematous papules and vesicle in dermatomal patternNot doneValacyclovirAll improved
Channa et al. [142]Herpes zosterUSA81/MmRNA-1273 (Moderna) Covid-19 vaccine3 daysA dermatomal rashNot doneNot availableNot available

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Myositis and rhabdomyolysis

There are reports, which have indicated that COVID-19 vaccines have potential to damage the skeletal muscles as well (Table ​(Table10)10) [143147]. Tan and colleagues described a patient with a known carnitine palmitoyltransferase-II deficiency disorder, who developed fever, vomiting, shortness of breath, frank haematuria, myalgia and muscle weakness within four hours of receiving AstraZeneca COVID-19 vaccine [143]. Theodorou and colleagues described a 56-year-old woman who, 8 days after a second dose of vaccine administration, developed severe left upper arm pain along restricted shoulder movements. Her serum creatine kinase was elevated suggesting skeletal muscle damage. MRI revealed severely edematous deltoid muscles. Contrast-enhanced imaging demonstrated enhancement of deltoid muscles suggestive of myositis [146].

Table 10

Summary of reported patients, who developed an acute muscular disorder following vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Tan et al. [143]Rhabdomyolysis in a patient with Carnitine palmitoyltransferase II deficiencyUK27/MCOVID-19 vaccine AstraZeneca5 hFever, vomiting, shortness of breath, frank hematuria, and myalgia CK concentration of 105,000 U/L and deranged liver function tests (ALT 300 U/L and AST 1496 U/L)NoneContinuous intravenous dextrose 10% and a high carbohydrate dietImproved
Mack et al. [144]RhabdomyolysisUSA80/MSecond dose of Moderna COVID-19 vaccine2 daysGeneralized body aches, nausea, and vomiting elevated CKNoneIV fluidsImproved
Nassar et al. [145]RhabdomyolysisUSA21/MFirst Pfizer/BioNTech COVID-19 vaccine1 daySevere back pain with radiation to his left lateral thigh Creatinine phosphokinase (CPK) level more than 22,000 U/LNormalIV fluidsImproved
Theodorou et al. [146]MyositisGreece56/FModified mRNA COVID-19 vaccine8 days after second doseThere was tenderness over the deltoid muscle, guarding, and decreased abduction of the shoulder and arm along with elevated CPKOn MRI, the deltoid muscle was edematous. On contrast enhancement, muscle exhibited enhancement indicating inflammationSymptomaticImproved
Godoy et al. [147]Myositis ossificansBrazil51/M3 monthsRight upper arm pain, soreness and palpable massIntramuscular nodule n the proximal fibers of the brachii muscle with perilesional muscle edema One week later, CT showed a hypoattenuating intramuscular nodule with internal calcificationsNSAIDsImproved

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Conclusion

Post-authorization, a wide spectrum of serious neurological complications has been reported following COVID-19 vaccination. The most devastating neurological complication is cerebral venous sinus thrombosis that has been reported in females of childbearing age following adenovector-based vaccines. Another major neurological complication of concern is Bell’s palsy that was reported dominantly following mRNA vaccine administration. Transverse myelitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome are other severe unexpected post-vaccination complications that can occur as result of molecular mimicry and subsequent neuronal damage. Most of other serious neurological complications are reported in either in form of isolated case reports or small cases series. A causal association of these adverse events is controversial; large collaborative prospective studies are needed to prove causality.

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Pfizer Hired 600 Employees Due To ‘Large Increase In Adverse Event

Authors: Zachary Stieb The Epoch Times  March 9, 2022

Pfizer hired 600 employees in the months after its COVID-19 vaccine was authorized in the United States due to the “large increase” of reports of side effects linked to the vaccine, according to a document prepared by the company.

Pfizer has “taken multiple actions to help alleviate the large increase in adverse event reports,” according to the document. “This includes significant technology enhancements, and process and workflow solutions, as well as increasing the number of data entry and case processing colleagues.”

At the time when the document—from the first quarter of 2021—was sent to the U.S. Food and Drug Administration (FDA), Pfizer had onboarded about 600 extra full-time workers to deal with the jump.

“More are joining each month with an expected total of more than 1,800 additional resources by the end of June 2021,” Pfizer said.

The document was titled a “cumulative analysis of post-authorization adverse event reports” of Pfizer’s vaccine received through Feb. 28, 2021. It was approved by the FDA on April 30, 2021.

The document was not made public until the Public Health and Medical Professionals for Transparency sued the FDA after the agency claimed it needed decades to produce all the documents relating to the emergency use authorization granted to the company for the vaccine.

Under an agreement reached in February, the FDA must produce a certain number of pages each month.

The analysis of adverse event reports was previously disclosed to the health transparency group, but certain portions were redacted (pdf), including the number of workers Pfizer onboarded to deal with the jump in adverse event reports.

“We asked that the redactions on page 6 of this report be lifted and the FDA agreed without providing an explanation,” Aaron Siri, a lawyer representing the plaintiffs, told The Epoch Times in an email.

After the document was produced, the FDA determined that the three redactions on that page “could be lifted,” an FDA spokesperson told The Epoch Times via email.

The redactions had been made under (b) (4) of the Freedom of Information Act, which lets agencies “withhold trade secrets and commercial or financial information obtained from a person which is privileged or confidential.”

The unredacted version of the document also now shows that approximately 126 million doses of Pfizer were shipped around the world since the company received the first clearance, from U.S. regulators, on Dec. 1, 2020. The shipments took place through Feb. 28, 2021.

It was unclear how many of those doses had been administered as of that date.

Pfizer did not respond to emailed questions, including how many workers it has onboarded to deal with adverse events.

The companies that manufacture the other two COVID-19 vaccines that U.S. regulators have cleared, Moderna and Johnson & Johnson, did not respond when asked if they have seen an increase in adverse events and if they have hired more employees to deal with reports.

The number of post-vaccination adverse event reports to the Vaccine Adverse Event Reporting System, jointly run by the FDA and the Centers for Disease Control and Prevention, has spiked since the vaccines were first cleared.

Problems linked to the vaccines include heart inflammation, blood clotting, and severe allergic shock.

Federal officials say the vaccines’ benefits outweigh the risks, but some experts are increasingly questioning that assertion, particularly for certain populations.

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.

Second COVID booster shot extends protection for just a few weeks, study shows

Authors: Joseph Wilkinson, New York Daily NewsWed, April 6, 2022, 9:23 PM·2 min read

A fourth shot of the Pfizer COVID-19 vaccine increased protection against viral infection for only four to seven weeks, according to a massive study published Tuesday.

The study included 1.25 million people age 60 and over in Israel who received their fourth dose between January and March. Israel uses only the Pfizer vaccine.

People who got the fourth dose were half as likely to test positive for COVID-19 four weeks later when compared to people who only had three doses, according to the study.

But by the eighth week, the groups were almost equally likely to catch COVID-19, researchers found.

The fourth shot was the subject of much debate before U.S. regulators approved it last week for people age 50 and older. The second booster had already been approved for immunocompromised people. President Joe Biden, 79, got his on March 30.

While increased protection against infection was short-lived, the fourth booster continued to protect against severe illness for at least six weeks, the study found. The research period actually ended before the protection did, leading researchers to suggest future studies.

The study compared only people with the fourth dose to people with a third dose. Previous research had suggested that the third dose provided a significant bump in infection protection over zero, one or two doses.

Only about 30% of the U.S. population, 98 million people, has received a third dose, according to Centers for Disease Control data.

“For confirmed infection, a fourth dose appeared to provide only short-term protection and a modest absolute benefit,” the study’s authors wrote.

“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.”

Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities

The I-TECH Randomized Clinical Trial February 18, 2022

Authors:

Steven Chee Loon Lim, MRCP1Chee Peng Hor, MSc2,3Kim Heng Tay, MRCP4et alAnilawati Mat Jelani, MMed5Wen Hao Tan, MMed6Hong Bee Ker, MRCP1Ting Soo Chow, MRCP7Masliza Zaid, MMed8Wee Kooi Cheah, MRCP6Han Hua Lim, MRCP9Khairil Erwan Khalid, MRCP10Joo Thye Cheng, MRCP2Hazfadzila Mohd Unit, MRCP11Noralfazita  An, MMed12Azraai Bahari Nasruddin, MRCP13Lee Lee Low, MRCP14Song Weng Ryan Khoo, MRCP15Jia Hui Loh, MRCP16Nor Zaila Zaidan, MMed17Suhaila Ab Wahab, MMed18Li Herng Song, MD19Hui Moon Koh, MClinPharm20Teck Long King, BPharm21Nai Ming Lai, MRCPCH22Suresh Kumar Chidambaram, MRCP4Kalaiarasu M. Peariasamy, MSc23

for the I-TECH Study Group Article Information

Abstract

Importance  Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed.

Objective  To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19.

Design, Setting, and Participants  The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients’ symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease.

Interventions  Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.

Main Outcomes and Measures  The primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events.

Results  Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group).

Conclusions and Relevance  In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.

Trial Registration  ClinicalTrials.gov Identifier: NCT04920942Introduction

Despite the success of COVID-19 vaccines and the implementation of nonpharmaceutical public health measures, there is an enormous global need for effective therapeutics for SARS-CoV-2 infection. At present, repurposed anti-inflammatory drugs (dexamethasone, tocilizumab, and sarilumab),13 monoclonal antibodies,46 and antivirals (remdesivir, molnupiravir, and nirmatrelvir/ritonavir)79 have demonstrated treatment benefits at different stages of COVID-19.10

In Malaysia, about 95% of patients with COVID-19 present early with mild disease, and less than 5% progress to a hypoxic state requiring oxygen supplementation. Notably, patients 50 years and older with comorbidities are at high risk for severe disease.11 Potentially, an antiviral therapy administered during the early viral replication phase could avert the deterioration. Although molnupiravir and nirmatrelvir/ritonavir have shown efficacy in the early treatment of COVID-19,8,9 they can be too expensive for widespread use in resource-limited settings.

Ivermectin, an inexpensive, easy-to-administer, and widely available antiparasitic drug, has been used as an oral therapy for COVID-19. An in vitro study demonstrated inhibitory effects of ivermectin against SARS-CoV-2.12 Although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19,13,14 these studies had methodologic weaknesses.15

In 2021, 2 randomized clinical trials from Colombia16 and Argentina17 found no significant effect of ivermectin on symptom resolution and hospitalization rates for patients with COVID-19. A Cochrane meta-analysis18 also found insufficient evidence to support the use of ivermectin for the treatment or prevention of COVID-19.

These findings notwithstanding, ivermectin is widely prescribed for COVID-19, contrary to the World Health Organization (WHO) recommendation to restrict use of the drug to clinical trials.19 In the present randomized clinical trial, we studied the efficacy of ivermectin for preventing progression to severe disease among high-risk patients with COVID-19 in Malaysia.MethodsTrial Design and Patients

The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was a multicenter, open-label, randomized clinical trial conducted at 20 government hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. The study was approved by the local Medical Research and Ethics Committee (NMRR-21-155-58433) and registered in ClinicalTrials.gov (NCT04920942). This trial was conducted in accordance with the Declaration of Helsinki and the Malaysian Good Clinical Practice Guideline. All participants provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

In Malaysia, mandatory notification to public health authorities applies to all COVID-19 cases. Patients with mild to moderate disease at risk of disease progression are referred for hospitalization or admitted to a COVID-19 quarantine center to allow close monitoring for 10 or more days from symptom onset and timely intervention in the event of deterioration.

The study enrolled patients with reverse transcriptase–polymerase chain reaction (RT-PCR) test–confirmed or antigen test–confirmed COVID-19 who were 50 years or older with at least 1 comorbidity and presented with mild to moderate illness (Malaysian COVID-19 clinical severity stage 2 or 3; WHO clinical progression scale 2-4)20,21 within 7 days from symptom onset. Patients were excluded if they were asymptomatic, required supplemental oxygen, or had pulse oximetry oxygen saturation (Spo2) level less than 95% at rest. Other exclusion criteria were severe hepatic impairment (alanine transaminase level >10 times of upper normal limit), acute medical or surgical emergency, concomitant viral infection, pregnancy or breastfeeding, warfarin therapy, and history of taking ivermectin or any antiviral drugs with reported activity against COVID-19 (favipiravir, hydroxychloroquine, lopinavir, and remdesivir) within 7 days before enrollment. Eligibility criteria are detailed in the study protocol (Supplement 1). Study investigators collected information on ethnicity based on the patient’s Malaysian identification card or passport (for non-Malaysian citizens).

All patients with COVID-19 were managed in accordance with the national COVID-19 Management Guidelines,20 developed by a local expert panel based on consensus, WHO recommendations, and the US National Institutes of Health guidelines. High-risk patients were defined as those aged 50 years or older with comorbidity. Patients were staged according to clinical severity at presentation and disease progression: stage 1, asymptomatic; stage 2, symptomatic without evidence of pneumonia; stage 3, evidence of pneumonia without hypoxia; stage 4, pneumonia with hypoxia requiring oxygen supplementation; and stage 5, critically ill with multiorgan involvement. Stages 2 and 3 were classified as mild and moderate diseases (WHO scale 2-4), while stages 4 and 5 were referred to as severe diseases (WHO scale 5-9). The standard of care for patients with mild to moderate disease consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.Randomization and Data Collection

All study data were recorded in case report form and transcribed into the REDCap (Research Electronic Data Capture) platform.22,23 Patients were randomized in a 1:1 ratio to either the intervention group receiving oral ivermectin (0.4 mg/kg body weight daily for 5 days) plus standard of care or the control group receiving the standard of care alone (Figure). The randomization was based on an investigator-blinded randomization list uploaded to REDCap, which allocated the patients via a central, computer-generated randomization scheme across all study sites during enrollment. The randomization list was generated independently using random permuted block sizes 2 to 6. The randomization was not stratified by site.Intervention

The ivermectin dosage for each patient in the intervention arm was calculated to the nearest 6-mg or 12-mg whole tablets (dosing table in the study protocol, Supplement 1). The first dose of ivermectin was administered after randomization on day 1 of enrollment, followed by 4 doses on days 2 through 5. Patients were encouraged to take ivermectin with food or after meals to improve drug absorption. Storage, dispensary, and administration of ivermectin were handled by trained study investigators, pharmacists, and nurses.Outcome Measures

The primary outcome was the proportion of patients who progressed to severe COVID-19, defined as the hypoxic stage requiring supplemental oxygen to maintain Spo2 95% or greater (Malaysian COVID-19 clinical severity stages 4 or 5; WHO clinical progression scale 5-9). The Spo2 was measured using a calibrated pulse oximeter per the clinical monitoring protocol.

Secondary outcomes were time of progression to severe disease, 28-day in-hospital all-cause mortality, mechanical ventilation rate, intensive care unit admission, and length of hospital stay after enrollment. Patients were also assessed on day 5 of enrollment for symptom resolution, changes in laboratory test results, and chest radiography findings. Adverse events (AEs) and serious AEs (SAEs) were evaluated and graded according to Common Terminology Criteria for Adverse Events, version 5.0.24 All outcomes were captured from randomization until discharge from study sites or day 28 of enrollment, whichever was earlier.Subgroup Analyses

Subgroup analyses were predetermined according to COVID-19 vaccination status, age, clinical staging, duration of illness at enrollment, and common comorbidities.Procedures

Patients’ clinical history, anthropometric measurements, blood samples for complete blood cell count, kidney and liver profiles, C-reactive protein levels, and chest radiography were obtained at baseline. Blood sampling and chest radiography were repeated on day 5 of enrollment. Study investigators followed up patients for all outcome assessments and AEs. All study-related AEs were reviewed by an independent Data and Safety Monitoring Board.Sample Size Calculation

The sample size was calculated based on a superiority trial design and primary outcome measure. The expected rate of primary outcome was 17.5% in the control group, according to previous local data of high-risk patients who presented with mild to moderate disease.11 A 50% reduction of primary outcome, or a 9% rate difference between intervention and control groups, was considered clinically important. This trial required 462 patients to be adequately powered. This sample size provided a level of significance at 5% with 80% power for 2-sided tests. Considering potential dropouts, a total of 500 patients (250 patients for each group) were recruited.Statistical Analyses

Primary analyses were performed based on the modified intention-to-treat principle, whereby randomized patients in the intervention group who received at least 1 ivermectin dose and all patients in the control group would be followed and evaluated for efficacy and safety. In addition, sensitivity analyses were performed on all eligible randomized patients, including those in the intervention group who did not receive ivermectin (intention-to-treat population).

Descriptive data were expressed as means and SDs unless otherwise stated. Categorical data were analyzed using the Fisher exact test. Continuous variables were tested using the t-test or Mann-Whitney U test. The primary and categorical secondary outcome measures were estimated using relative risk (RR). The absolute difference of means of time of progression to severe disease and lengths of hospitalization between the study groups were determined with a 95% CI. Mixed analysis of variance was used to determine whether the changes of laboratory investigations were the result of interactions between the study groups (between-patients factor) and times (within-patient factor), and P < .05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp).

Interim analyses were conducted on the first 150 and 300 patients, with outcome data retrieved on July 13 and August 30, 2021, respectively. The overall level of significance was maintained at P < .05, calculated according to the O’Brien-Fleming stopping boundaries. Early stopping would be considered if P < .003 for efficacy data. The results were presented to the Data and Safety Monitoring Board, which recommended continuing the study given no signal for early termination.Results

Between May 31 and October 9, 2021, 500 patients were enrolled and randomized. The last patient completed follow-up on October 25, 2021. Four patients were excluded after randomization. One patient in the control arm was diagnosed with dengue coinfection; in the intervention arm, 2 failed to meet inclusion criteria owing to symptom duration greater than 7 days and negative COVID-19 RT-PCR test result, while 1 had acute coronary syndrome before ivermectin initiation. In addition, 6 patients in the intervention arm withdrew consent before taking a dose of ivermectin. The modified intention-to-treat population for the primary analysis included 490 patients (98% of those enrolled), with 241 in the intervention group and 249 in the control group (Figure). Drug compliance analysis showed that 232 patients (96.3%) in the intervention group completed 5 doses of ivermectin.

Baseline demographics and characteristics of patients were well balanced between groups (Table 1). The mean (SD) age was 62.5 (8.7) years, with 267 women (54.5%); 254 patients (51.8%) were fully vaccinated with 2 doses of COVID-19 vaccines. All major ethnic groups in Malaysia were well represented in the study population. The majority had hypertension (369 [75.3%]), followed by diabetes mellitus (262 [53.5%]), dyslipidemia (184 [37.6%]), and obesity (117 [23.9%]).

The mean (SD) duration of symptoms at enrollment was 5.1 (1.3) days. The most common symptoms were cough (378 [77.1%]), fever (237 [48.4%]), and runny nose (149 [30.4%]). Approximately two-thirds of patients had moderate disease. The average baseline neutrophil-lymphocyte ratio and serum C-reactive protein level were similar between groups. There were no significant differences in the concomitant medications prescribed for both groups. In sensitivity analyses, baseline characteristics were similar in the intention-to-treat population (eTable 1 in Supplement 2).Primary Outcome

Among the 490 patients, 95 (19.4%) progressed to severe disease during the study period; 52 of 241 (21.6%) received ivermectin plus standard of care, and 43 of 249 (17.3%) received standard of care alone (RR, 1.25; 95% CI, 0.87-1.80; P = .25) (Table 2). Similar results were observed in the intention-to-treat population in the sensitivity analyses (eTable 2 in Supplement 2).Secondary Outcomes

There were no significant differences between ivermectin and control groups for all the prespecified secondary outcomes (Table 2). Among patients who progressed to severe disease, the time from study enrollment to the onset of deterioration was similar across ivermectin and control groups (mean [SD], 3.2 [2.4] days vs 2.9 [1.8] days; mean difference, 0.3; 95% CI, −0.6 to 1.2; P = .51). Mechanical ventilation occurred in 4 patients (1.7%) in the ivermectin group vs 10 (4.0%) in the control group (RR, 0.41; 95% CI, 0.13 to 1.30; P = .17) and intensive care unit admission in 6 (2.5%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27 to 2.20; P = .79). The 28-day in-hospital mortality rate was similar for the ivermectin and control groups (3 [1.2%] vs 10 [4.0%]; RR, 0.31; 95% CI, 0.09 to 1.11; P = .09), as was the length of hospital stay after enrollment (mean [SD], 7.7 [4.4] days vs 7.3 [4.3] days; mean difference, 0.4; 95% CI, −0.4 to 1.3; P = .38).

By day 5 of enrollment, the proportion of patients who achieved complete symptom resolution was comparable between both groups (RR, 0.97; 95% CI, 0.82-1.15; P = .72). Findings of chest radiography without pneumonic changes or with resolution by day 5 were also similar (RR, 1.03; 95% CI, 0.76-1.40; P = .92). No marked variation was noted in blood parameters (eTable 3 in Supplement 2). There was no significant difference in the incidence of disease complications and highest oxygen requirement (eTables 4 and 5 in Supplement 2).Subgroup Analyses

Subgroup analyses for patients with severe disease were unremarkable (Table 3). Among fully vaccinated patients, 22 (17.7%) in the ivermectin group and 12 (9.2%) in the control group developed severe disease (RR, 1.92; 95% CI, 0.99-3.71; P = .06). Post hoc analyses on clinical outcomes by vaccination status showed that fully vaccinated patients in the control group had a significantly lower rate of severe disease (P = .002; supporting data in eTable 6 in Supplement 2).Adverse Events

A total of 55 AEs occurred in 44 patients (9.0%) (Table 4). Among them, 33 were from the ivermectin group, with diarrhea being the most common AE (14 [5.8%]). Five events were classified as SAEs, with 4 in the ivermectin group (2 patients had myocardial infarction, 1 had severe anemia, and 1 developed hypovolemic shock secondary to severe diarrhea), and 1 in the control group had inferior epigastric arterial bleeding. Six patients discontinued ivermectin, and 3 withdrew from the study owing to AEs. The majority of AEs were grade 1 and resolved within the study period.

Among the 13 deaths, severe COVID-19 pneumonia was the principal direct cause (9 deaths [69.2%]). Four patients in the control group died from nosocomial sepsis. None of the deaths were attributed to ivermectin treatment.Discussion

In this randomized clinical trial of early ivermectin treatment for adults with mild to moderate COVID-19 and comorbidities, we found no evidence that ivermectin was efficacious in reducing the risk of severe disease. Our findings are consistent with the results of the IVERCOR-COVID19 trial,17 which found that ivermectin was ineffective in reducing the risk of hospitalization.

Prior randomized clinical trials of ivermectin treatment for patients with COVID-19 and with 400 or more patients enrolled focused on outpatients.16,17 In contrast, the patients in our trial were hospitalized, which permitted the observed administration of ivermectin with a high adherence rate. Furthermore, we used clearly defined criteria for ascertaining progression to severe disease.

Before the trial started, the case fatality rate in Malaysia from COVID-19 was about 1%,25 a rate too low for mortality to be the primary end point in our study. Even in a high-risk cohort, there were 13 deaths (2.7%). A recent meta-analysis of 8 randomized clinical trials of ivermectin to treat SARS-CoV-2 infection, involving 1848 patients with 71 deaths (3.8%), showed that treatment with the drug had no significant effect on survival.26

The pharmacokinetics of ivermectin for treating COVID-19 has been a contentious issue. The plasma inhibitory concentrations of ivermectin for SARS-CoV-2 are high; thus, establishing an effective ivermectin dose regimen without causing toxic effects in patients is difficult.27,28 The dose regimens that produced favorable results against COVID-19 ranged from a 0.2-mg/kg single dose to 0.6 mg/kg/d for 5 days2932; a concentration-dependent antiviral effect was demonstrated by Krolewiecki et al.29 Pharmacokinetic studies have suggested that a single dose of up to 120 mg of ivermectin can be safe and well tolerated.33 Considering the peak of SARS-CoV-2 viral load during the first week of illness and its prolongation in severe disease,34 our trial used an ivermectin dose of 0.4 mg/kg of body weight daily for 5 days. The notably higher incidence of AEs in the ivermectin group raises concerns about the use of this drug outside of trial settings and without medical supervision.Limitations

Our study has limitations. First, the open-label trial design might contribute to the underreporting of adverse events in the control group while overestimating the drug effects of ivermectin. Second, our study was not designed to assess the effects of ivermectin on mortality from COVID-19. Finally, the generalizability of our findings may be limited by the older study population, although younger and healthier individuals with low risk of severe disease are less likely to benefit from specific COVID-19 treatments.Conclusions

In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.

Accepted for Publication: January 22, 2022.

Published Online: February 18, 2022. doi:10.1001/jamainternmed.2022.0189

Corresponding Author: Steven Chee Loon Lim, MRCP, Department of Medicine, Raja Permaisuri Bainun Hospital, Jalan Raja Ashman Shah, 30450 Ipoh, Perak, Malaysia (stevenlimcl@gmail.com).

Author Contributions: Dr S. Lim and Mr King had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: S. Lim, Tan, Chow, Cheah, Cheng, An, Low, Song, Chidambaram, Peariasamy.

Acquisition, analysis, or interpretation of data: S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Zaid, Cheah, H. Lim, Khalid, Mohd Unit, An, Nasruddin, Khoo, Loh, Zaidan, Ab Wahab, Koh, King, Lai.

Drafting of the manuscript: S. Lim, Hor, Tay, Mat Jelani, Tan, Zaid, H. Lim, An, Low, Ab Wahab, King, Peariasamy.

Critical revision of the manuscript for important intellectual content: S. Lim, Hor, Tan, Ker, Chow, Cheah, Khalid, Cheng, Mohd Unit, An, Nasruddin, Khoo, Loh, Zaidan, Song, Koh, King, Lai, Chidambaram.

Statistical analysis: S. Lim, Hor, Tan, King, Lai.

Administrative, technical, or material support: S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Chow, Zaid, Cheah, H. Lim, Khalid, Low, Khoo, Loh, Zaidan, Ab Wahab, Song, Koh, Chidambaram.

Supervision: S. Lim, Tan, Ker, Chow, Zaid, Cheng, Khoo, Loh, Song, Peariasamy.

Conflict of Interest Disclosures: None reported.

The I-TECH Study Group: Members of the I-TECH Study Group are listed in Supplement 3.

Data Sharing Statement: See Supplement 4.

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14.Kory  P, Meduri  GU, Varon  J, Iglesias  J, Marik  PE.  Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19.   Am J Ther. 2021;28(3):e299-e318. doi:10.1097/MJT.0000000000001377PubMedGoogle ScholarCrossref

15.Garegnani  LI, Madrid  E, Meza  N.  Misleading clinical evidence and systematic reviews on ivermectin for COVID-19.   BMJ Evid Based Med. Published online April 22, 2021. doi:10.1136/bmjebm-2021-111678PubMedGoogle Scholar

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17.Vallejos  J, Zoni  R, Bangher  M,  et al.  Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19): a randomized, double-blind, placebo-controlled trial.   BMC Infect Dis. 2021;21(1):635. doi:10.1186/s12879-021-06348-5PubMedGoogle ScholarCrossref

18.Popp  M, Stegemann  M, Metzendorf  MI,  et al.  Ivermectin for preventing and treating COVID-19.   Cochrane Database Syst Rev. 2021;7(7):CD015017.PubMedGoogle Scholar

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20.COVID-19 management guidelines in Malaysia. Ministry of Health, Malaysia. Accessed February 2, 2022. https://covid-19.moh.gov.my/garis-panduan/garis-panduan-kkm

21.Marshall  JC, Murthy  S, Diaz  J,  et al; WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection.  A minimal common outcome measure set for COVID-19 clinical research.   Lancet Infect Dis. 2020;20(8):e192-e197. doi:10.1016/S1473-3099(20)30483-7PubMedGoogle ScholarCrossref

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24.National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. US Department of Health and Human Services; 2017.

25.COVIDNOW in Malaysia. Ministry of Health, Malaysia. Accessed February 2, 2022. https://covidnow.moh.gov.my/deaths

26.Hill  A, Garratt  A, Levi  J,  et al.  Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection.   Open Forum Infect Dis. 2021;8(11):ofab358. doi:10.1093/ofid/ofab358PubMedGoogle Scholar

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28.Momekov  G, Momekova  D.  Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens.   Biotechnology & Biotechnological Equipment. 2020;34(1):469-474. doi:10.1080/13102818.2020.1775118Google Scholar

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Covid infections in Britain are rising again, and 90 percent of the dead are vaccinated. Have mRNA jabs ruined our chance at herd immunity?

Authors: Alex Berenson

New figures from Britain raise bright red flags about the direction of Covid in wealthy countries that used mRNA and DNA shots to attempt to defeat the coronavirus last year.

Hospitalizations and deaths remain stubbornly high and overwhelmingly occur in vaccinated people. In February, 90 percent of the 1,000 Britons who died each week of Covid were vaccinated.

New infections are not only far higher than they were before the Omicron variant emerged, they are rising again after a brief fall in February. And even boosters appear to offer no protection against hospitalizations in younger people.

British data are crucial both because Britain vaccinated and boosted early and because its datasets are far more complete and less politicized than those in the United States.

Day by day, week by week, the figures are becoming more worrisome. They hint that mRNA and DNA shots may have slowed if not completely halted the natural progression to herd immunity that occurred in earlier respiratory virus epidemics.

In fact, Britain now reports 99 percent of adults have antibodies to Covid, mostly as the result of vaccination. That level is far higher than epidemiologists believed would be necessary to support herd immunity. Yet Covid infections, hospitalizations, and deaths continue unabated. Almost 12,000 Britons are now hospitalized with Covid, more than at this time last year.

The most stunning chart is this one. Each week the British government releases a “surveillance report” which includes Covid deaths by vaccine status.

SOURCE

In the four weeks ending February 27, 397 unvaccinated Britons died of Covid, compared to 3,512 who were vaccinated. Using a broader definition, which may include more incidental deaths unrelated to Covid infections, the numbers are even worse, with 5,871 vaccinated people dying compared to 570 unvaccinated. (The United States does not publicly provide this data; it is not even clear American public health authorities collect it comprehensively.)

The report also shows for the first time that adults under 50 are now just as likely to be hospitalized for Covid whether they are boosted or unvaccinated. The report does not provide a similar hospitalization estimate for people who were vaccinated but unboosted, but based on the raw numbers it does provide, those rates are the highest of all.

Meanwhile, new Covid infections have nearly doubled in Britain in the last two weeks, and now top 60,000 a day. British media outlets have connected the rise to Britain’s “freedom day” on Feb. 24, which marked the legal end of Covid restrictions.

But Britain had already been moving toward normality throughout February, and cases were falling sharply. It is not clear that the legal end to restrictions made much difference behaviorally.

Britain is not alone.

Though elite media outlets have sharply deemphasized reporting on Covid, the epidemic continues unabated in advanced countries. In Europe and the United States, overall death and hospitalization rates remain high as the epidemic enters its third spring. Meanwhile, in South Korea and Japan, which largely avoided serious problems before mRNA vaccinations and the Omicron variant, infections are soaring and deaths following.

In contrast, many poorer countries that used older “inactivated virus” vaccines, or have low overall vaccination rates, have seen their coronavirus epidemics progress in a more traditional pattern.

Infections have risen and then fallen rapidly in distinct seasonal waves. Omicron has not caused off-the-charts spikes in new infections – probably because previous immunity from natural infection is far broader and more valuable against Omicron than vaccine-generated protection.

Here’s India, for example:

India no doubt undertests for Covid cases compared to Western countries, but the pattern is clear. Meanwhile, with a population one-twentieth as large, Britain now has more reported Covid deaths, more than 10 times as many infections, and shows no signs of emerging from its epidemic.

Britain:

When the mRNA jabs began to become available in December 2020, vaccine advocates predicted that poor countries that lacked access to them would face the misery of unceasing Covid epidemics, while wealthy nations would emerge quickly.

Pfizer’s COVID-19 Vaccine Goes Into Liver Cells And Is Converted To DNA: Study

Authors Meiling Lee THURSDAY, MAR 03, 2022 – 07:40 PM

The messenger RNA (mRNA) from Pfizer’s COVID-19 vaccine is able to enter human liver cells and is converted into DNA, according to Swedish researchers at Lund University.

A nurse prepares the Pfizer COVID-19 vaccine in Southfield, Mich., on Nov. 5, 2021. (Jeff Kowalsky/AFP via Getty Images)

The researchers found that when the mRNA vaccine enters the human liver cells, it triggers the cell’s DNA, which is inside the nucleus, to increase the production of the LINE-1 gene expression to make mRNA.

The mRNA then leaves the nucleus and enters the cell’s cytoplasm, where it translates into LINE-1 protein. A segment of the protein called the open reading frame-1, or ORF-1, then goes back into the nucleus, where it attaches to the vaccine’s mRNA and reverse transcribes into spike DNA.

Reverse transcription is when DNA is made from RNA, whereas the normal transcription process involves a portion of the DNA serving as a template to make an mRNA molecule inside the nucleus.

In this study we present evidence that COVID-19 mRNA vaccine BNT162b2 is able to enter the human liver cell line Huh7 in vitro,” the researchers wrote in the study, published in Current Issues of Molecular Biology. “BNT162b2 mRNA is reverse transcribed intracellularly into DNA as fast as 6 [hours] after BNT162b2 exposure.”

BNT162b2 is another name for the Pfizer-BioNTech COVID-19 vaccine that is marketed under the brand name Comirnaty.

The whole process occurred rapidly within six hours. The vaccine’s mRNA converting into DNA and being found inside the cell’s nucleus is something that the Centers for Disease Control and Prevention (CDC) said would not happen.

The genetic material delivered by mRNA vaccines never enters the nucleus of your cells,” the CDC said on its web page titled “Myths and Facts about COVID-19 Vaccines.”

This is the first time that researchers have shown in vitro or inside a petri dish how an mRNA vaccine is converted into DNA on a human liver cell line, and is what health experts and fact-checkers said for over a year couldn’t occur.

The CDC says that the “COVID-19 vaccines do not change or interact with your DNA in any way,” claiming that all of the ingredients in both mRNA and viral vector COVID-19 vaccines (administered in the United States) are discarded from the body once antibodies are produced. These vaccines deliver genetic material that instructs cells to begin making spike proteins found on the surface of SARS-CoV-2 that causes COVID-19 to produce an immune response.

Pfizer didn’t comment on the findings of the Swedish study and said only that its mRNA vaccine does not alter the human genome.

Our COVID-19 vaccine does not alter the DNA sequence of a human cell,” a Pfizer spokesperson told The Epoch Times in an email. “It only presents the body with the instructions to build immunity.

More than 215 million or 64.9 percent of Americans are fully vaccinated as of Feb. 28, with 94 million having received a booster dose.

Autoimmune Disorders

The Swedish study also found spike proteins expressed on the surface of the liver cells that researchers say may be targeted by the immune system and possibly cause autoimmune hepatitis, as “there [have] been case reports on individuals who developed autoimmune hepatitis after BNT162b2 vaccination.”

The authors of the first reported case of a healthy 35-year-old female who developed autoimmune hepatitis a week after her first dose of the Pfizer COVID-19 vaccine said that there is a possibility that “spike-directed antibodies induced by vaccination may also trigger autoimmune conditions in predisposed individuals” as it has been shown that “severe cases of SARS-CoV-2 infection are characterized by an autoinflammatory dysregulation that contributes to tissue damage,” which the virus’s spike protein appears to be responsible for.

Spike proteins may circulate in the body after an infection or injection with a COVID-19 vaccine. It was assumed that the vaccine’s spike protein would remain mostly at the injection site and last up to several weeks like other proteins produced in the body. But studies are showing that is not the case.

The Japanese regulatory agency’s biodistribution study (pdf) of the Pfizer vaccine showed that some of the mRNAs moved from the injection site and through the bloodstream, and were found in various organs such as the liver, spleen, adrenal glands, and ovaries of rats 48 hours following injection.

In a different study, the spike proteins made in the body after receiving a Pfizer COVID-19 shot have been found on tiny membrane vesicles called exosomes—that mediate cell-to-cell communication by transferring genetic materials to other cells—for at least four months after the second vaccine dose.

The persistence of the spike protein in the body “raises the prospect of sustained inflammation within and damage to organs which express the spike protein,” according to experts at Doctors for COVID Ethics, an organization consisting of physicians and scientists “seeking to uphold medical ethics, patient safety, and human rights in response to COVID-19.”

“As long as the spike protein can be detected on cell-derived membrane vesicles, the immune system will be attacking the cells that release these vesicles,” they said.

Dr. Peter McCullough, an internist, cardiologist, and epidemiologist, wrote on Twitter that the Swedish study’s findings have “enormous implications of permanent chromosomal change and long-term constitutive spike synthesis driving the pathogenesis of a whole new genre of chronic disease.”

Whether the findings of the study will occur in living organisms or if the DNA converted from the vaccine’s mRNA will integrate with the cell’s genome is unknown. The authors said more investigations are needed, including in whole living organisms such as animals, to better understand the potential effects of the mRNA vaccine.

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,” the authors said.

Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies

Nature Microbiology volume 5, pages1185–1191 (2020)

Abstract

Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.

Main

The emergence and rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in substantial global morbidity and mortality along with widespread social and economic disruption. SARS-CoV-2 is a betacoronavirus closely related to SARS-CoV (with ~80% sequence identity), which caused the SARS outbreak in 2002. Its next closest human coronavirus relative is Middle East respiratory syndrome-related coronavirus (MERS-CoV; ~54% sequence identity), which caused Middle East respiratory syndrome in 2012 (refs. 1,2). SARS-CoV-2 is also genetically related to other endemic human coronaviruses that cause milder infections: HCoV-HKU1 (~52% sequence identity), HCoV-OC43 (~51%), HCoV-NL63 (~49%) and HCoV-229E (~48%)1. SARS-CoV-2 is even more closely related to coronaviruses identified in horseshoe bats, suggesting that horseshoe bats are the primary animal reservoir with a possible intermediate transmission event in pangolins3.

Cellular entry of SARS-CoV-2 is mediated by the binding of the viral spike (S) protein to its cellular receptor, angiotensin-converting enzyme 2 (ACE2)4,5. Other host entry factors have been identified, including neuropilin-1 (refs. 6,7) and TMPRSS2, a transmembrane serine protease involved in S protein maturation4. The SARS-CoV-2 S protein consists of the S1 subunit, which contains the receptor binding domain (RBD), and the S2 subunit, which mediates membrane fusion for viral entry8. A major goal of vaccine and therapeutic development is to generate antibodies that prevent the entry of SARS-CoV-2 into cells by blocking either ACE2–RBD binding interactions or S-mediated membrane fusion.

One potential hurdle for antibody-based vaccines and therapeutics is the risk of exacerbating COVID-19 severity via antibody-dependent enhancement (ADE). ADE can increase the severity of multiple viral infections, including other respiratory viruses such as respiratory syncytial virus (RSV)9,10 and measles11,12. ADE in respiratory infections is included in a broader category named enhanced respiratory disease (ERD), which also includes non-antibody-based mechanisms such as cytokine cascades and cell-mediated immunopathology (Box 1). ADE caused by enhanced viral replication has been observed for other viruses that infect macrophages, including dengue virus13,14 and feline infectious peritonitis virus (FIPV)15. Furthermore, ADE and ERD has been reported for SARS-CoV and MERS-CoV both in vitro and in vivo. The extent to which ADE contributes to COVID-19 immunopathology is being actively investigated.

In this Perspective, we discuss the possible mechanisms of ADE in SARS-CoV-2 and outline several risk mitigation principles for vaccines and therapeutics. We also highlight which types of studies are likely to reveal the relevance of ADE in COVID-19 disease pathology and examine how the emerging data might influence clinical interventions.

Box 1 ADE and ERD

ERD

ERD describes severe clinical presentations of respiratory viral infections associated with medical interventions (especially vaccines). Similar clinical presentations can occur as a result of natural infections, and so ERD is detected during preclinical and clinical trials by comparing the distribution of disease severities between the intervention and placebo study arms. ERD can be associated with a broad range of molecular mechanisms, including FcR-dependent antibody activity and complement activation (that is, ADE), but also to other antibody-independent mechanisms such as tissue cell death, cytokine release and/or local immune cell activation.

ADE

ADE can be broadly categorized into two different types based on the molecular mechanisms involved:

ADE via enhanced infection. Higher infection rates of target cells occur in an antibody-dependent manner mediated by Fc–FcR interactions. ADE via enhanced infection is commonly measured using in vitro assays detecting the antibody-dependent infection of cells expressing FcγRIIa, such as monocytes and macrophages. The link between in vitro ADE assay results and clinical relevance is often implied, rather than directly observed. Dengue virus represents the best documented example of clinical ADE via enhanced infection.

ADE via enhanced immune activation. Enhanced disease and immunopathology are caused by excessive Fc-mediated effector functions and immune complex formation in an antibody-dependent manner. The antibodies associated with enhanced disease are often non-neutralizing. ADE of this type is usually examined in vivo by detecting exacerbated disease symptoms, including immunopathology and inflammatory markers, and is most clearly associated with respiratory viral infections. RSV and measles are well-documented examples of ADE caused by enhanced immune activation.

ERD and ADE (of the second type described above) are often identified by clinical data, including symptom prevalence and disease severity, rather than by the specific molecular mechanisms that drive severe disease. The presence of complex feedback loops between different arms of the immune system makes it very difficult (although not impossible) to conclusively determine molecular mechanisms of ADE and ERD in human and animal studies, even if the clinical data supporting ADE and ERD are quite clear. Many different measurements and assays are used to track ADE and ERD, which can vary based on the specific virus, preclinical and/or clinical protocols, biological samples collected and in vitro techniques used.

Respiratory ADE is a specific subset of ERD.Show more

Mechanisms of ADE

ADE has been documented to occur through two distinct mechanisms in viral infections: by enhanced antibody-mediated virus uptake into Fc gamma receptor IIa (FcγRIIa)-expressing phagocytic cells leading to increased viral infection and replication, or by excessive antibody Fc-mediated effector functions or immune complex formation causing enhanced inflammation and immunopathology (Fig. 1, Box 1). Both ADE pathways can occur when non-neutralizing antibodies or antibodies at sub-neutralizing levels bind to viral antigens without blocking or clearing infection. ADE can be measured in several ways, including in vitro assays (which are most common for the first mechanism involving FcγRIIa-mediated enhancement of infection in phagocytes), immunopathology or lung pathology. ADE via FcγRIIa-mediated endocytosis into phagocytic cells can be observed in vitro and has been extensively studied for macrophage-tropic viruses, including dengue virus in humans16 and FIPV in cats15. In this mechanism, non-neutralizing antibodies bind to the viral surface and traffic virions directly to macrophages, which then internalize the virions and become productively infected. Since many antibodies against different dengue serotypes are cross-reactive but non-neutralizing, secondary infections with heterologous strains can result in increased viral replication and more severe disease, leading to major safety risks as reported in a recent dengue vaccine trial13,14. In other vaccine studies, cats immunized against the FIPV S protein or passively infused with anti-FIPV antibodies had lower survival rates when challenged with FIPV compared to control groups17. Non-neutralizing antibodies, or antibodies at sub-neutralizing levels, enhanced entry into alveolar and peritoneal macrophages18, which were thought to disseminate infection and worsen disease outcome19.

figure 1
Fig. 1: Two main ADE mechanisms in viral disease.

In the second described ADE mechanism that is best exemplified by respiratory pathogens, Fc-mediated antibody effector functions can enhance respiratory disease by initiating a powerful immune cascade that results in observable lung pathology20,21. Fc-mediated activation of local and circulating innate immune cells such as monocytes, macrophages, neutrophils, dendritic cells and natural killer cells can lead to dysregulated immune activation despite their potential effectiveness at clearing virus-infected cells and debris. For non-macrophage tropic respiratory viruses such as RSV and measles, non-neutralizing antibodies have been shown to induce ADE and ERD by forming immune complexes that deposit into airway tissues and activate cytokine and complement pathways, resulting in inflammation, airway obstruction and, in severe cases, leading to acute respiratory distress syndrome10,11,22,23. These prior observations of ADE with RSV and measles have many similarities to known COVID-19 clinical presentations. For example, over-activation of the complement cascade has been shown to contribute to inflammatory lung injury in COVID-19 and SARS24,25. Two recent studies found that S- and RBD-specific immunoglobulin G (IgG) antibodies in patients with COVID-19 have lower levels of fucosylation within their Fc domains26,27—a phenotype linked to higher affinity for FcγRIIIa, an activating Fc receptor (FcR) that mediates antibody-dependent cellular cytotoxicity. While this higher affinity can be beneficial in some cases via more vigorous FcγRIIIa-mediated effector functions28,29, non-neutralizing IgG antibodies against dengue virus that were afucosylated were associated with more severe disease outcomes30. Larsen et al. further show that S-specific IgG in patients with both COVID-19 and acute respiratory distress syndrome had lower levels of fucosylation compared to patients who had asymptomatic or mild infections26. Whether the lower levels of fucosylation of SARS-CoV-2-specific antibodies directly contributed to COVID-19 immunopathology remains to be determined.

Importantly, SARS-CoV-2 has not been shown to productively infect macrophages31,32. Thus, available data suggest that the most probable ADE mechanism relevant to COVID-19 pathology is the formation of antibody–antigen immune complexes that leads to excessive activation of the immune cascade in lung tissue (Fig. 1).

Evidence of ADE in coronavirus infections in vitro

While ADE has been well documented in vitro for a number of viruses, including human immunodeficiency virus (HIV)33,34, Ebola35,36, influenza37 and flaviviruses38, the relevance of in vitro ADE for human coronaviruses remains less clear. Several studies have shown increased uptake of SARS-CoV and MERS-CoV virions into FcR-expressing monocytes or macrophages in vitro32,39,40,41,42. Yip et al. found enhanced uptake of SARS-CoV and S-expressing pseudoviruses into monocyte-derived macrophages mediated by FcγRIIa and anti-S serum antibodies32. Similarly, Wan et al. showed that a neutralizing monoclonal antibody (mAb) against the RBD of MERS-CoV increased the uptake of virions into macrophages and various cell lines transfected with FcγRIIa39. However, the fact that antigen-specific antibodies drive phagocytic uptake is unsurprising, as monocytes and macrophages can mediate antibody-dependent phagocytosis via FcγRIIa for viral clearance, including for influenza43. Importantly, macrophages in infected mice contributed to antibody-mediated clearance of SARS-CoV44. While MERS-CoV has been found to productively infect macrophages45, SARS-CoV infection of macrophages is abortive and does not alter the pro-inflammatory cytokine gene expression profile after antibody-dependent uptake41,42. Findings to date argue against macrophages as productive hosts of SARS-CoV-2 infection31,32.

ADE in human coronavirus infections

No definitive role for ADE in human coronavirus diseases has been established. Concerns were first raised for ADE in patients with SARS when seroconversion and neutralizing antibody responses were found to correlate with clinical severity and mortality46. A similar finding in patients with COVID-19 was reported, with higher antibody titres against SARS-CoV-2 being associated with more severe disease47. One simple hypothesis is that greater antibody titres in severe COVID-19 cases result from higher and more prolonged antigen exposure due to higher viral loads48,49. However, a recent study showed that viral shedding in the upper respiratory tract was indistinguishable between patients with asymptomatic and symptomatic COVID-19 (ref. 50). Symptomatic patients showed higher anti-SARS-CoV-2 antibody titres and cleared the virus from the upper respiratory tract more quickly, contradicting a simpler hypothesis that antibody titres are simply caused by higher viral loads. Other studies showed that anti-SARS-CoV-2 T-cell responses could be found at high levels in mild and asymptomatic infections51,52. Taken together, the data suggest that strong T-cell responses can be found in patients with a broad range of clinical presentations, whereas strong antibody titres are more closely linked to severe COVID-19. One important caveat is that viral shedding was measured in the upper respiratory tract rather than in the lower respiratory tract50. The lower respiratory tract is likely more important for severe COVID-19 lung pathology, and it is unclear how closely SARS-CoV-2 viral shedding in the upper and lower respiratory tracts correlate throughout the disease course.

Beyond the host response to new SARS-CoV-2 infections, the potential of pre-existing antibodies against other human coronavirus strains to mediate ADE in patients with COVID-19 is another possible concern53. Antibodies elicited by coronavirus strains endemic in human populations (such as HKU1, OC43, NL63 and 229E) could theoretically mediate ADE by facilitating cross-reactive recognition of SARS-CoV-2 in the absence of viral neutralization. Preliminary data show that antibodies from SARS-CoV-2-naïve donors who had high reactivity to seasonal human coronavirus strains were found to have low levels of cross-reactivity against the nucleocapsid and S2 subunit of SARS-CoV-2 (ref. 54). Whether such cross-reactive antibodies can contribute to clinical ADE of SARS-COV-2 remains to be addressed.

Risk of ERD for SARS-CoV-2 vaccines

Safety concerns for SARS-CoV-2 vaccines were initially fuelled by mouse studies that showed enhanced immunopathology, or ERD, in animals vaccinated with SARS-CoV following viral challenge55,56,57,58. The observed immunopathology was associated with Th2-cell-biased responses55 and was largely against the nucleocapsid protein56,58. Importantly, immunopathology was not observed in challenged mice following the passive transfer of nucleocapsid-specific immune serum56, confirming that the enhanced disease could not be replicated using the serum volumes transferred. Similar studies using inactivated whole-virus or viral-vector-based vaccines for SARS-CoV or MERS-CoV resulted in immunopathology following viral challenge59,60,61, which were linked to Th2-cytokine-biased responses55 and/or excessive lung eosinophilic infiltration57. Rational adjuvant selection ensures that Th1-cell-biased responses can markedly reduce these vaccine-associated ERD risks. Candidate SARS-CoV vaccines formulated with either alum, CpG or Advax (a delta inulin-based adjuvant) found that while the Th2-biased responses associated with alum drove lung eosinophilic immunopathology in mice, protection without immunopathology and a more balanced Th1/Th2 response were induced by Advax62. Hashem et al. showed that mice vaccinated with an adenovirus 5 viral vector expressing MERS-CoV S1 exhibited pulmonary pathology following viral challenge, despite conferring protection. Importantly, the inclusion of CD40L as a molecular adjuvant boosted Th1 responses and prevented the vaccine-related immunopathology63.

Should it occur, ERD caused by human vaccines will first be observed in larger phase II and/or phase III efficacy trials that have sufficient infection events for statistical comparisons between the immunized and placebo control study arms. Safety profiles of COVID-19 vaccines should be closely monitored in real time during human efficacy trials, especially for vaccine modalities that may have a higher theoretical potential to cause immunopathology (such as inactivated whole-virus formulations or viral vectors)64,65.

Risk of ADE for SARS-CoV-2 vaccines

Evidence for vaccine-induced ADE in animal models of SARS-CoV is conflicting, and raises potential safety concerns. Liu et al. found that while macaques immunized with a modified vaccinia Ankara viral vector expressing the SARS-CoV S protein had reduced viral replication after challenge, anti-S IgG also enhanced pulmonary infiltration of inflammatory macrophages and resulted in more severe lung injury compared to unvaccinated animals66. They further showed that the presence of anti-S IgG prior to viral clearance skewed the wound-healing response of macrophages into a pro-inflammatory response. In another study, Wang et al. immunized macaques with four B-cell peptide epitopes of the SARS-CoV S protein and demonstrated that while three peptides elicited antibodies that protected macaques from viral challenge, one of the peptide vaccines induced antibodies that enhanced infection in vitro and resulted in more severe lung pathology in vivo67.

In contrast, to determine whether low titres of neutralizing antibodies could enhance infection in vivo, Luo et al. challenged rhesus macaques with SARS-CoV nine weeks post-immunization with an inactivated vaccine, when neutralizing antibody titres had waned below protective levels68. While most immunized macaques became infected following viral challenge, they had lower viral titres compared to placebo controls and did not show higher levels of lung pathology. Similarly, Qin et al. showed that an inactivated SARS-CoV vaccine protected cynomolgus macaques from viral challenge and did not result in enhanced lung immunopathology, even in macaques with low neutralizing antibody titres69. A study in hamsters demonstrated that despite enhanced in vitro viral entry into B cells via FcγRII, animals vaccinated with the recombinant SARS-CoV S protein were protected and did not show enhanced lung pathology following viral challenge70.

SARS-CoV immunization studies in animal models have thus produced results that vary greatly in terms of protective efficacy, immunopathology and potential ADE, depending on the vaccine strategy employed. Despite this, vaccines that elicit neutralizing antibodies against the S protein reliably protect animals from SARS-CoV challenge without evidence of enhancement of infection or disease71,72,73. These data suggest that human immunization strategies for SARS-CoV-2 that elicit high neutralizing antibody titres have a high chance of success with minimal risk of ADE. For example, subunit vaccines that can elicit S-specific neutralizing antibodies should present lower ADE risks (especially against S stabilized in the prefusion conformation, to reduce the presentation of non-neutralizing epitopes8). These modern immunogen design approaches should reduce potential immunopathology associated with non-neutralizing antibodies.

Vaccines with a high theoretical risk of inducing pathologic ADE or ERD include inactivated viral vaccines, which may contain non-neutralizing antigen targets and/or the S protein in non-neutralizing conformations, providing a multitude of non-protective targets for antibodies that could drive additional inflammation via the well-described mechanisms observed for other respiratory pathogens. However, it is encouraging that a recent assessment of an inactivated SARS-CoV-2 vaccine elicited strong neutralizing antibodies in mice, rats and rhesus macaques, and provided dose-dependent protection without evidence of enhanced pathology in rhesus macaques74. Going forward, increased vaccine studies in the Syrian hamster model may provide critical preclinical data, as the Syrian hamster appears to replicate human COVID-19 immunopathology more closely than rhesus macaque models75.

ADE and recombinant antibody interventions

The discovery of mAbs against the SARS-CoV-2 S protein is progressing rapidly. Recent advances in B-cell screening and antibody discovery have enabled the rapid isolation of potent SARS-CoV-2 neutralizing antibodies from convalescent human donors76,77 and immunized animal models78, and through re-engineering previously identified SARS-CoV antibodies79. Many more potently neutralizing antibodies will be identified in the coming weeks and months, and several human clinical trials are ongoing in July 2020. Human trials will comprise both prophylactic and therapeutic uses, both for single mAbs and cocktails. Some human clinical trials are also incorporating FcR knockout mutations to further reduce ADE risks80. Preclinical data suggest a low risk of ADE for potently neutralizing mAbs at doses substantially above the threshold for neutralization, which protected mice and Syrian hamsters against SARS-CoV-2 challenge without enhancement of infection or disease81,82. ADE risks could increase in the time period where mAb concentrations have waned below a threshold for protection (which is analogous to the historical mother–infant data that provided important clinical evidence for ADE in dengue83). The sub-protective concentration range will likely occur several weeks or months following mAb administration, when much of the initial drug dose has cleared the body. Notably, Syrian hamsters given low doses of an RBD-specific neutralizing mAb prior to challenge with SARS-CoV-2 showed a trend for greater weight loss than control animals82, though differences were not statistically significant and the low-dose animals had lower viral loads in the lung compared to control animals. Non-neutralizing mAbs against SARS-CoV-2 could also be administered before or after infection in a hamster model to determine whether non-neutralizing antibodies enhance disease. Passive transfer of mAbs at various time points after infection (for example, in the presence of high viral loads during peak infection) could also address the question of whether immune complex formation and deposition results in the enhancement of disease and lung immunopathology. If ADE of neutralizing or non-neutralizing mAbs is a concern, the Fc portion of these antibodies could be engineered with mutations that abrogate FcR binding80. Animal studies can help to inform whether Fc-mediated effector functions are crucial in preventing, treating or worsening SARS-CoV-2 infection, in a similar way to previous studies of influenza A and B infection in mice84,85 and simian-HIV infection in macaques86,87. An important caveat for testing human mAbs in animal models is that human antibody Fc regions may not interact with animal FcRs in the same way as human FcRs88. Whenever possible, antibodies used for preclinical ADE studies will require species-matched Fc regions to appropriately model Fc effector function.

ADE and convalescent plasma interventions

Convalescent plasma (CP) therapy has been used to treat patients with severe disease during many viral outbreaks in the absence of effective antiviral therapeutics. It can offer a rapid solution for therapies until molecularly defined drug products can be discovered, evaluated and produced at scale. While there is a theoretical risk that CP antibodies could enhance disease via ADE, case reports in SARS-CoV and MERS-CoV outbreaks showed that CP therapy was safe and was associated with improved clinical outcomes89,90. One of the largest studies during the SARS outbreak reported the treatment of 80 patients with SARS in Hong Kong91. While there was no placebo control group, no CP-associated adverse effects were detected and there was a higher discharge rate among patients treated earlier in infection. Several small studies of individuals with severe COVID-19 disease and a study of 5,000 patients with COVID-19 have shown that CP therapy appears safe and may improve disease outcomes92,93,94,95,96, although the benefits appear to be mild97. However, it is difficult to determine whether CP therapy contributed to recovery as most studies to date were uncontrolled and many patients were also treated with other drugs, including antivirals and corticosteroids. The potential benefits of CP therapy in patients with severe COVID-19 is also unclear, as patients with severe disease may have already developed high antibody titres against SARS-CoV-2 (refs. 47,98). CP has been suggested for prophylactic use in high-risk populations, including people with underlying risk factors, frontline healthcare workers and people with exposure to confirmed COVID-19 cases99. CP for prophylactic use may pose an even lower ADE risk compared to its therapeutic use, as there is a lower antigenic load associated with early viral transmission compared to established respiratory infection. As we highlighted above with recombinant mAbs, and as shown in historical dengue virus mother–infant data, the theoretical risk of ADE in CP prophylaxis is highest in the weeks following transfusion, when antibody serum neutralization titres fall to sub-protective levels. ADE risks in CP studies will be more difficult to quantify than in recombinant mAb studies because the precise CP composition varies widely across treated patients and treatment protocols, especially in CP studies that are performed as one-to-one patient–recipient protocols without plasma pooling.

To mitigate potential ADE risks in CP therapy and prophylaxis, plasma donors could be pre-screened for high neutralization titres. Anti-S or anti-RBD antibodies could also be purified from donated CP to enrich for neutralizing antibodies and to avoid the risks of ADE caused by non-neutralizing antibodies against other SARS-CoV-2 antigens. Passive infusion studies in animal models are helping to clarify CP risks in a well-controlled environment, both for prophylactic and therapeutic use. Key animal studies (especially in Syrian hamsters, and ideally with hamster-derived CP for matched antibody Fc regions) and human clinical safety and efficacy results for CP are now emerging contemporaneously. These preclinical and clinical data will be helpful to deconvolute the risk profiles for ADE versus other known severe adverse events that can occur with human CP, including transfusion-related acute lung injury96,100.

Conclusion

ADE has been observed in SARS, MERS and other human respiratory virus infections including RSV and measles, which suggests a real risk of ADE for SARS-CoV-2 vaccines and antibody-based interventions. However, clinical data has not yet fully established a role for ADE in human COVID-19 pathology. Steps to reduce the risks of ADE from immunotherapies include the induction or delivery of high doses of potent neutralizing antibodies, rather than lower concentrations of non-neutralizing antibodies that would be more likely to cause ADE.

Going forwards, it will be crucial to evaluate animal and clinical datasets for signs of ADE, and to balance ADE-related safety risks against intervention efficacy if clinical ADE is observed. Ongoing animal and human clinical studies will provide important insights into the mechanisms of ADE in COVID-19. Such evidence is sorely needed to ensure product safety in the large-scale medical interventions that are likely required to reduce the global burden of COVID-19.

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