On Saturday, CDC Director Rochelle Walensky announced a new recommendation to vaccinate all 20 million children 6 months to 5 years of age. Here are some things left out of the announcement that parents should know.
1. The research was inconclusive
The studies were too small to achieve statistical significance when evaluating efficacy against mild or severe COVID-19 infection. As a result, the FDA allowed both companies to extrapolate effectiveness by measuring antibody levels, pointing to data from older children and adults.
There were no cases of severe COVID illness in either the vaccine or placebo group. The Moderna vaccine had 4,774 children and the Pfizer vaccine had 4,526 (including those who received the placebo).
Pfizer concluded that their vaccine was 80% effective in preventing symptomatic COVID-19, but based it on 3 cases in the vaccine group and 7 cases in the placebo group in a subset of children who received a third dose.
Even this was not statistically significant. In fact, it had a confidence statistic so wide, you could drive an aircraft carrier through it. (They reported the largest confidence interval I have ever seen in my 20-year research career). At one end of the range of possibilities indicated by the confidence interval, the vaccine could be associated with a 370% increased risk of getting COVID-19. The Moderna trial reported a short-term efficacy of 38% in preventing symptomatic illness–an effect well-known to be transient.
Ironically, there were more overall hospitalizations (unspecified) in the vaccine group. Out of a total of 7 children requiring hospitalization, 6 were in the vaccine group and 1 was in the placebo group, which was half as large.
The CDC even said in its own slides at their deliberation meeting that data assessing efficacy were poor, characterizing them as “very low certainty” and noting that there are “very serious concerns for imprecision due to study size”. They also noted the very short follow-up time of 1.3 months.
2. The FDA lowered their standards for acceptable vaccine efficacy needed to approve
In 2020, the FDA and public health officials said they would authorize a COVID vaccine that showed at least a 50% efficacy. But weeks before the vaccines were authorized for babies and toddlers, the FDA’s Dr. Peter Marks lowered the pre-set bar, saying on May 6, “If these vaccines seem to be mirroring efficacy in adults and just seem to be less effective against Omicron like they are for adults, we will probably still authorize.”
There is absolutely zero clinical evidence to support vaccinating healthy children who already had COVID. Natural immunity, inexplicably ignored by public health officials, confers strong protection against severe disease.
3. Most children have natural immunity
The CDC reported reported that, as of February 2022, 75% of children 0-17 years-old already had COVID-19. Given how rampant the Omicron strain has circulated since then, upwards of 80-90% of children have likely had COVID-19. There is absolutely zero clinical evidence to support vaccinating healthy children who already had COVID. Natural immunity, inexplicably ignored by public health officials, confers strong protection against severe disease.
4. Safety was based on a small sample
The small size of the studies in children under 5 makes it nearly impossible to observe rates of rare complications such as myocarditis, which occurs in 1 in 2,650 12-17 year-old boys after the 2nd dose. This complication has been associated with EKG changes in children and even concerning MRI findings months after recovering from myocarditis.
The New England Journal of Medicine reported one case of vaccine-associated myocarditis death in a 22-year-old in an Israeli population study. Keep in mind that babies can’t tell you when they have myocarditis.
Each of the Moderna and Pfizer COVID studies in children under 5 reported one serious adverse event after receiving the vaccine. Less serious adverse events (pain, swelling, local reactions) were similar across the vaccine and placebo groups (7.7% vs 4.1% for Moderna; 1% vs 1.5% for Pfizer). These data do suggest a good safety profile, likely due to the low dose given. However, time will tell.
As Dr. Eric Rubin, the editor-in-chief of the New England Journal of Medicine, said in October 2021, “But we’re never going to learn about how safe this vaccine is unless we start giving it. That’s just the way it goes.”
Establishing safety takes time. The infant rotavirus vaccine, Rotashield, was first thought to be safe. In the original trial, the adverse event (an intestinal malfunction requiring surgery) had been noted in 5 of 10,054 vaccine recipients, but the side effect was not deemed statistically significant. Ultimately, that vaccine was pulled from the market after many more complications were observed. Similarly, J&J’s vaccine was bannered to be safe until the FDA said otherwise.
5. Healthy children have a very low risk of a serious consequence from COVID-19
Healthy children have a radically different risk profile and a different need for vaccination compared to children with comorbid conditions. A German population study found that all deaths in children 5-17 were in children with a comorbidity. That is, no healthy child 5-17 died in that country unvaccinated.
Alasdair Munro analyzed UK data and determined that 75% of deaths of children from COVID in the UK occurred in the 8% of children who have other serious health issues. That’s why the risk-benefit ratio is radically different for a child with comorbidity than a healthy child.
The CDC’s risk analysis lumps all children together. It also makes the mistake of counting hospitalizations and death where COVID was an incidental finding. An NHS report found that up to 68% of COVID hospitalization are not “for” COVID.
For children with a medical condition such as diabetes or immune suppression, I would recommend COVID vaccination with two doses 8 to 12 weeks apart, if the child does not already have natural immunity. The case to vaccinate healthy children is not compelling.
6. CDC’s announcement lacked humility
On Saturday, a beaming Dr. Walensky said “We now know based on rigorous scientific review that the vaccines….can be used safely and effectively in children under 5.” The review might have been rigorous, but the underlying data was not.
A more appropriate announcement would have been “We approved the COVID vaccine for babies and toddlers based on very little data. While we believe it is safe in this age group, the study size was too low to make a definitive conclusion about safety. Moreover, the studies were conducted in children who did not have COVID previously.”
Less absolutism and more humility by public health officials would go a long way in rebuilding public trust. Not surprisingly, only 18% of parents said they were planning give the COVID vaccine to their child under five anytime soon.
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.
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.
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 .
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 . 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 .
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 . 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.
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 .
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) .
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 . 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 .
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 . 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 .
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  (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” . 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 .
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 . 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 .
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 . 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 . 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 [16, 17].
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) [18–46].
Clinical, magnetic resonance imaging findings, and outcome details of patients who developed cerebral venous sinus thrombosis after vaccination against SARS-CoV-2
New onset of mild to moderate headache and giddiness
CT) 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 vein
Complete 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 vein
A report three patients one had cerebral venous sinus thrombosis
ChAdOx1 nCov-19, AstraZeneca
Diabetes mellitus, hypertension, obstructive sleep apnea, recently diagnosed prostate cancer Headache and confusion left-sided weakness Thrombocytopenia Autoantibodies against platelet factor 4
Right 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 embolism
headache non-responsive to drugs right-sided weakness and visual disturbances rapidly deteriorated with decreased consciousness
Multifocal 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 thrombocytopenia
Visual disturbance followed by a headache, nausea, vomiting, bruising and petechiae severe thunderclap headache, nausea and vomiting headache, persistent bruising and petechiae all had thrombocytopenia
Dural venous sinus thrombosis in one patient only other had abdominal abnormalities
Severe headache and vomiting and acute left hemiparesis Headache and vomiting Right ataxic hemiparesis There was no thrombocytopenia
A 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 three
Headache, 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 detected
MRI 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 vein
Acetazolamide and enoxaparin Levetiracetam 500 mg bid and enoxaparin
Nausea and thunderclap headache thrombocytopenia Platelet factor 4 antibodies detected
Hyperdensity 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 vein
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 . 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 . 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 .
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 .
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 .
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 .
Heparin needs to be avoided, instead alternative anticoagulants like argatroban, bivalirudin, fondaparinux, rivaroxaban, or apixaban should be used for anticoagulation [49–51]. 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 .
Several acute arterial events, like arterial thrombosis, intracerebral hemorrhage, transient global amnesia, and spinal artery ischemia, have also been reported following vaccination .
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 . The reports of COVID-19 vaccine-related intracerebral hemorrhage and ischemic stroke are summarized in Table Table22 [53–61].
Clinical, neuroimaging and outcome details of patients who suffered strokes (other than cerebral venous thrombosis) after vaccination against SARS-CoV-2
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 .
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 .
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 . 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 .
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 .
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 [62–75].
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
Diastolic 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 epilepticus
Confusion, 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 changes
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 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 .
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 .
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 . 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  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 .
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 .
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 [77–83].
Clinical, neuroimaging, and outcome details of patients who presented with spinal cord involvement after vaccination against SARS-CoV-2
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 . 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 .
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 [84, 85].
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 .
Several cases of Bell’s palsy have occurred following COVID-19 vaccination. (Table (Table5)5) [87–95]. The instances of Bell’s palsy are most often associated with mRNA vaccines . Vaccine-associated Bell’s palsy generally responds very well to the oral corticosteroids. The exact pathogenesis remains speculative.
Summary of reported patients, who suffered from Bell’s palsy after vaccination against SARS-CoV-2
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 .
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 . 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 .
Other cranial nerve involvement
In isolated instances, mRNA vaccines were found associated with olfactory dysfunction and sixth cranial nerve palsy (Table (Table6)6) [99–104].
Summary of reported patients, who suffered from cranial nerve involvement (other than Bell’s palsy) after vaccination against SARS-CoV-2
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 .
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 .
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..
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 .
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 .
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 [108, 109].
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) [110–126].
Summary of reported patients, who developed an acute peripheral nerve disorder after vaccination against SARS-CoV-2
All 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)
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) .
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) [128–130].
Summary of reported patients, who developed neuralgic amyotrophy after vaccination against SARS-CoV-2
Sudden 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 recruitment
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 . 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 [132, 133]. Reports of herpes zoster reactivation after vaccine against SARS-CoV-2 are summarized in Table Table99 [134–142].
Summary of reported patients, who developed Herpes zoster after vaccination against SARS-CoV-2
There are reports, which have indicated that COVID-19 vaccines have potential to damage the skeletal muscles as well (Table (Table10)10) [143–147]. 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 . 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 .
Summary of reported patients, who developed an acute muscular disorder following vaccination against SARS-CoV-2
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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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.
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
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).
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.
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.
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.
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).
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.
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.
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.
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).
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).
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.
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.”
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.
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),1–3 monoclonal antibodies,4–6 and antivirals (remdesivir, molnupiravir, and nirmatrelvir/ritonavir)7–9 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 days29–32; 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.
Corresponding Author: Steven Chee Loon Lim, MRCP, Department of Medicine, Raja Permaisuri Bainun Hospital, Jalan Raja Ashman Shah, 30450 Ipoh, Perak, Malaysia (firstname.lastname@example.org).
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.
11.Sim BLH, Chidambaram SK, Wong XC, et al. Clinical characteristics and risk factors for severe COVID-19 infections in Malaysia: A nationwide observational study. Lancet Reg Health West Pac. 2020;4:100055. doi:10.1016/j.lanwpc.2020.100055PubMedGoogle Scholar
13.Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Ther. 2021;28(4):e434-e460. doi:10.1097/MJT.0000000000001402PubMedGoogle ScholarCrossref
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
23.Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-381. doi:10.1016/j.jbi.2008.08.010PubMedGoogle ScholarCrossref
24.National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. US Department of Health and Human Services; 2017.
27.Schmith VD, Zhou JJ, Lohmer LRL. The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther. 2020;108(4):762-765. doi:10.1002/cpt.1889PubMedGoogle Scholar
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
31.Abu Taiub Mohammed Mohiuddin C, Mohammad S, Md Rezaul K, Johirul I, Dan G, Shuixiang H. A comparative study on ivermectin doxycycline and hydroxychloroquine azithromycin therapy on COVID-19 patients. Research Square. 2021.Google Scholar
32.Hashim HA, Maulood MF, Rasheed AM, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv. 2020. doi:10.1101/2020.10.26.20219345Google Scholar
34.Magleby R, Westblade LF, Trzebucki A, et al. Impact of Severe Acute Respiratory Syndrome Coronavirus 2 viral load on risk of intubation and mortality among hospitalized patients with coronavirus disease 2019. Clin Infect Dis. 2021;73(11):e4197-e4205. doi:10.1093/cid/ciaa851PubMedGoogle Scholar
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.
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.
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.
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.
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.
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.
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.