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Long Read: The Future of Covid-19 Vaccines? Why Nasal Sprays, Not Needles, Could be Better in the Long Run

Half a Greek alphabet and two years into the pandemic, the world is coming to terms with the notion that Covid-19 is here to stay. As new variants emerge, millions are still falling ill, increasing the risk of even harder-hitting strains. While coronavirus vaccines are among the greatest medical achievements of all time, reaching the market in less than a year and saving millions of lives, anyone who has received three doses and still got infected will understand that the virus is a resilient opponent.

Marty Moore says he can beat it.

“Covid isn’t just a sprint, it’s a marathon,” says Moore, the relentlessly upbeat founder of Meissa Vaccines. Today’s vaccines have largely won the sprint of preventing serious disease, “and thank goodness for that”, he says. “But now we need something else to gain control of the virus.”

Moore is among a growing cohort of virologists proposing we spray vaccines up people’s noses rather than inject them into arms. The advantage of that approach, they argue, is it can trigger the body to develop infection-blocking defences in the sinuses and throat and allow it to start fighting illness much faster than an injected vaccine can.

There are only two ways to stop the spread of the disease, according to Christian Drosten, Germany’s most prominent virologist. One would be for enough people to build up protection via repeated illness that increases immunity at the front end of the respiratory tract.

“The alternative would be to have a live vaccine that gets sprayed in the nose or throat,” he said on a podcast in March. Or, as Moore says, to build protection where the battle begins, like putting guards in front of a building rather than inside it.

In early 2020, Moore’s company was just beginning its first human test of a vaccine against respiratory syncytial virus, or RSV, which kills tens of thousands of children a year worldwide. Moore immediately saw the potential to retool his product to bring the coronavirus to heel and set to work adapting it.

For the past year, Meissa has been conducting human trials of a candidate formula, and Moore expects to have results by the autumn. That means it could start going into noses within a year if regulators fast track it as they did the first round of Covid-19 vaccines – a big “if” given pandemic fatigue and the growing sense of resignation about the disease.

Yet with the progress he has made so far, Moore says he is more convinced than ever that nasal sprays can do the job. “People didn’t realise how long we were going to be fighting Covid,” he says. “It’s sinking in that there’s this new normal, and you are forced to accept it. But we don’t accept it.”

For any nasal spray Covid-19 vaccine to make a difference, it will first have to overcome towering structural challenges, ranging from the scientific to the economic to the logistical.

While the Pfizer-BioNTech and Moderna shots offer robust protection against hospitalisation and death, their effectiveness against infection – running the marathon, in Moore’s analogy – fades as time passes and new variants emerge. Future vaccines should offer improvement when it comes to tolerability, length of protection, or ability to actually block infections, he says.

And that, he insists, is where nasal sprays can help – though they are tough to pull off.

It is relatively easy to stick a needle in an arm and get a precise dose of medication. With a squirt up the nose, it is difficult to get the right amount, every time, past the body’s thicket of natural defences: nostril hairs, sneezing and the dense layer of mucus that lines the respiratory tract.

Those challenges help explain why, of the 153 Covid-19 vaccines undergoing clinical trials, only six are nasal sprays. Among the contenders, a team at the University of Hong Kong is using an influenza virus filled with genetic instructions for making a piece of the coronavirus spike, which the body learns to attack.

India’s Bharat Biotech International, which makes a widely used Covid-19 shot, employs a chimpanzee adenovirus to deliver the genetic information payload. And there is a joint effort from New York-based Codagenix and the Serum Institute of India that uses a weakened version of the coronavirus strain first seen in China.

Meissa’s candidate, too, uses a weakened virus to do the dirty work, making it a so-called live-attenuated vaccine. The advantage of this is that viruses are particularly deft at penetrating the body’s defences to infect cells. But to employ them as a medicine, they first must be attenuated, or weakened, to make sure they are safe. That is no simple process.

If they are too weak, they won’t trigger an adequate immune response. But the weakened virus, once inside the body, must also never mutate to the point that it might make a person sick.

Because of this, the pharmaceutical industry in recent decades has focused on alternatives such as introducing only a piece of a virus, even if these approaches aren’t always as powerful.

Live-attenuated vaccines are “an art that’s hard to master”, says Paul Offit, director of the Vaccine Education Centre at the Children’s Hospital of Philadelphia. “You have to prove it’s attenuated enough that it does not cause disease, but not so attenuated that it does not induce a vigorous immune response.”

Even if you clear those hurdles, nasal spray vaccines can still be a tough sell.

Consider FluMist, the influenza fighter that’s the only one ever to make it to market. Since its debut in 2003, it has failed to live up to predictions that it would dominate the field. It is an attenuated form of the flu virus, designed to replicate only in the cooler environment of the nose, not the lungs or other, warmer parts of the body.

Yet regulators, fearing the safety mechanism might fail in the elderly, are reluctant to recommend it to anyone older than 50, the biggest chunk of the flu-vaccine market.

And it has traditionally been tough for start-ups to break into a business long dominated by the likes of Pfizer, Merck, Sanofi and GlaxoSmithKline.

To start selling a product, companies must clear an exceptionally high bar in terms of safety and show clear superiority over existing options. The pandemic blew open that dynamic, catapulting technologies such as messenger RNA to centre stage.

That enabled the meteoric rise of Moderna and BioNTech, which co-developed its product with Pfizer. And it has brought in multitudes of investors, allowing smaller players to compete in a market that brokerage Jefferies predicts will reach US$50 billion by 2025.

Moore says he can win a piece of that business, even though his company remains tiny compared with many other newcomers.

To appreciate the promise of nasal sprays, it helps to understand what happens when the coronavirus infects you.
First, messenger cells capture bits of the virus from your airways, sense something is wrong and make an hours-long journey to the nearest lymph node to warn of the intruder.

If you’ve had your Covid-19 shots, there are B cells and T cells on hand, ready to fight back. These weapons multiply and begin a slow voyage through the body in search of the virus. This works well in preventing severe infection, but it all takes a couple of days to play out while the virus is replicating fast, so people often infect others before they know they are sick.

A nasal spray might more accurately mimic the natural protection a person gains from a recent infection. That is because once the immune system encounters the virus (in this instance, from the nasal vaccine), it stations Covid-ready B and T cells in the nose and throat.

What’s more, it fosters the development of antibodies called IgA, which take up residence in the mucus lining and can stop the virus from ever reaching the cells lining your airways. You can’t get that from a shot, only from a vaccine that enters the body as a virus would.

And the added protections give the immune system an advantage of as much as a day and a half in fighting Covid-19, says Frances Lund, director of the Immunology Institute at the University of Alabama at Birmingham in the US.
“You get a jump-start on clearing it out,” she says. “Your viral load is going to be lower, which means fewer clinical symptoms for you and less virus that you can spew out to everybody else.”

Nasal delivery works best with live-attenuated vaccines, Moore says, because they are so effective at getting to the most important cells. And Meissa employs a new way of attenuating a virus that can uncouple it from the safety-VS-efficacy see-saw.

The approach is inspired by its work with RSV, which has been weakened not by making it harder for the virus to replicate – the traditional method – but by genetically removing its ability to hide from the immune system.
In theory, you could get dosed with a large amount of this mutant version of RSV, generating a massive immune response while posing little to no threat of making you sick. “If you block the blocker, then you unleash the immunogenic potential of that virus,” Moore says.

In lab studies, Meissa’s vaccine has offered signi­ficant protection against the alpha and beta variants, and tests for delta and omicron are in the works.

To make its Covid-19 vaccine, Meissa stuck the coronavirus spike protein onto the RSV shell. In tests on monkeys, the company found its product induced antibodies both in the mucus and in the blood, protecting the animals from the virus.

Meissa is about halfway through an early-stage clinical trial in 130 people, for which it has reported positive preliminary data showing no serious safety problems. Meanwhile, a single dose stimulated about the same level of IgA antibodies as what is seen in people recently infected with Covid-19.

The company expects to produce full results from the human trial this year. It has already added participants to test it as a booster and plans to soon begin studying it in children.

Ultimately, the product could be particularly well suited to youngsters, Moore says, as they tend to be afraid of needles and they play a big role in spreading most respiratory diseases.

In lab studies, Meissa’s vaccine has offered signi­ficant protection against the Alpha and Beta variants, and tests for Delta and Omicron are in the works. Moore says the vaccine’s potential ability to protect against a range of strains may be a result of its physics.

Whereas many vaccines – including mRNA – offer a rigid version of the coronavirus spike to the immune system, the live-attenuated approach sends the spike right into the wilderness of the body.

During its journey it gets bent this way and that, just like a virus does as it seeks to latch on to cells. This exposes the immune system to a fuller picture of the spike in action, giving it “better coverage to mismatched strains”, Moore says.

Moore has been fixated on respiratory viruses since his days as a graduate student at the University of Georgia. But in the early 2000s, as he was presenting his doctoral research into a type of adenovirus that infects mice, a distinguished professor stood up and said, “Nice work, Marty. Next time pick an important virus,” Moore recalls.
Taking the feedback to heart, he holed up in a library and built a spreadsheet to identify viruses that affect humans but get scant attention. His analysis revealed two candidates.

The first was a coronavirus that had just emerged in China, causing severe acute respiratory syndrome, or Sars. That disease would vanish within months. The second was RSV.

Long a thorny challenge in virology, RSV infects almost everyone by their second birthday, then repeatedly throughout life. It typically inflicts just a common cold, but it can be dangerous for young children, with their smaller airways.

During postdoctoral research at Vanderbilt University, Moore devised a way to reliably produce RSV of a specific genetic design, giving him a platform for dissecting the virus, which he further developed after landing a faculty position at Emory University, in Atlanta.

Scientists had been stuck when it came to producing vaccines against RSV. In the 1960s, when they tried giving infants an inactivated form of the virus, the approach backfired, killing two trial participants.

And they had abandoned efforts to create a live-attenuated vaccine for it, because every time they weakened the virus enough to make it safe to administer to kids, it no longer elicited a sufficiently strong immune response.

Moore conceived of a new approach. The reason RSV can repeatedly infect us has nothing to do with quick mutations, which are a key factor for influenza and, to a lesser extent, the current coronavirus. Instead, its proteins block the immune system’s ability to see that it’s there.

What would happen, he wondered, if you were to remove the proteins that let RSV sneak in undetected? Theoretically, you could spray that genetically engineered RSV into the nose, where it might replicate like normal – leading the immune system to unleash a barrage of B and T cells to kill it. Those weapons would then remain in the nose and throat, offering protection for months and perhaps as long as a year or two.

It would be a new way to deliver a live-attenuated vaccine for various respiratory diseases.

When Moore presented this idea at a conference in Portugal in 2013, a major pharmaceutical company offered to license the technology, but he wanted to develop it himself.

In 2014, he started Meissa Vaccines, naming it after the star in the Orion constellation that forms the mythical hunter’s head. In 2017, Meissa landed a spot at JLabs, an incubator space in San Francisco backed by Johnson & Johnson, allowing Moore to apply for federal business grants.

He and co-founder Roderick Tang, a scientist who had worked at the company behind FluMist, quit their jobs to focus full time on Meissa. Moore moved his family to California and devoted himself to raising funds, while Tang spent his days in the lab seeking to prove that Meissa’s genetically modified version of RSV could make for a safe and powerful vaccine.

In 2019, the company got US$30 million from a venture capital firm and filed paperwork with US regulators to start clinical trials.

After a hiring spree that made things crowded in the tiny space at JLabs, Moore mapped out a plan to move into a bigger office near Stanford. As 2020 began, Meissa was on the cusp of spraying the first dose of its RSV vaccine into a human, a culmination of his life’s work.

On a Saturday in mid-January, Moore rose at 4am in his San Carlos, California, home. Under the yellow street light streaming into the room, he filled a mug of coffee and settled in behind a wooden desk that had once belonged to his father. Scientists had just posted the genome sequence of a novel pathogen wreaking havoc in Wuhan, and Moore downloaded the code.

Feeding it into his laptop, he arranged four rows of genetic sequences on his screen, stacked on top of one another like sheet music. Each corresponded to the spike protein of a coronavirus, and Moore was shocked when his eyes scanned a portion of the spike’s genetic make-up that suggested the virus could quickly latch on to human cells.
“You look at that sequence and think, ‘A lot of things can happen, and most of them are bad’, ” he says.

As he pondered developing a vaccine against the new virus, Moore feared he might jeopardise everything he had been chasing for two decades with RSV. Yet the stakes were obvious and overwhelming.

The coronavirus, he suspected, would be with us for years, and few scientists would attempt to stop it with a nasal spray. So he grabbed a pen and pad and sketched out how he might insert the coronavirus spike into Meissa’s RSV platform.

As patients around the world flooded hospitals, Moore settled on various virus constructs that might work as a vaccine. The crucial step was attaching most of the coronavirus’ spike to the root of RSV’s surface protein. Absent this connection, the RSV platform would expel the spike, rendering the candidate useless. The Meissa team translated those models into a genetic sequence and ordered small vials of a solution containing that DNA from a supplier.
With the Bay Area in lockdown, Moore phoned Mariana Tioni, a newly hired virologist, to ask if she’d be willing to come into JLabs. She said yes, and soon she, Tang and Moore were spending their days clad in N95 masks, booties, smocks and hair covers. Returning home at night, they’d change clothes in the garage and sleep isolated from their families.

When the DNA samples arrived, the trio injected them one by one into cells, using the process Moore had developed at Vanderbilt. The goal is for the cell to start pumping out copies of the genetically engineered virus, a process that can take days.

The team inserted a fluorescent protein marker that glows red if the virus is spreading. Meissa’s first few attempts showed no glow, fuelling fears the idea wasn’t going to work. Then, a couple of days after injecting a candidate known as MV-014-210, Moore peered into a microscope, focused the lens, and saw a sea of red. “We were jumping up and down,” he recalls.

For the next month, the team harvested the mutant virus while planning the animal experiments required to convince regulators that the vaccine was safe and promising enough to justify testing on humans.

By that point, Pfizer and Moderna had started human trials for their mRNA candidates, and governments began directing all their resources towards the leaders. In November 2020, when the companies presented data showing their vaccines were more than 90 per cent effective, many people proclaimed the pandemic’s end was near.

Moore was pleased that his rivals had developed their vaccines so quickly, and he looked forward to getting shots himself. But he disagreed with the notion that the pandemic was almost over. He has been proven right: even as deaths have fallen by half globally in the past year, daily infections have roughly doubled – a testament to both the strengths and limitations of Covid-19 shots.

The bar for new candidates, though, has become higher because they must unseat established products.
There is reason to believe nasal sprays might, at minimum, serve as effective boosters for those who have been vaccinated or have been infected with Covid-19.

Lymph nodes in these people will already have coronavirus-ready B and T cells, so only a small amount of a vaccine would need to penetrate the nose’s defences – at which point the immune system, recognising a familiar foe, would spring into action.

Moore acknowledges there is a long road ahead to prove his Covid-19 candidate is safe, effective and superior in at least some respects to the shots. If trial results are strong, the next step would be broader tests, which can cost hundreds of millions of dollars – many multiples of the capital Moore currently has.

“They need a lot more money to do this right,” says Sam Fazeli, an analyst at Bloomberg Intelligence.

Meissa has relocated to a bigger facility, allowing Moore to increase his staff to about 25 people. They have expanded the study of their RSV candidate into infants and are doing early work on fighting two other respiratory viruses.

Even if Meissa’s spray arrives too late to have a big impact on Covid-19, the company aims to be prepared to quickly make a vaccine in response to the next pandemic. And for now, Moore remains convinced there’s ample reason to build immunity against Covid-19 in the nose and throat.

“You’re going to need this, you’re going to want this, because it’s the endgame,” Moore says. Sure, boosters of the current vaccines can reduce infections, but only temporarily, like tapping snooze on an alarm clock.

“Then it just repeats,” he says. “If you want to stop hitting the snooze button, we need to actually block transmission.”

Source : SCMP

COVID-19 Vaccination — Becoming Part of the New Normal

Peter Marks, Janet Woodcock, and Robert Califf wrote . . . . . . . . .

As the US emerges from the recent Omicron surge of the COVID-19 pandemic following close to a million deaths in the country attributable to COVID-19, many people are hoping that the worst is over. Widespread vaccine- and infection-induced immunity, combined with the availability of effective therapeutics, could blunt the effects of future outbreaks. Nonetheless, it is time to accept that the presence of SARS-CoV-2, the virus that causes COVID-19, is the new normal. It will likely circulate globally for the foreseeable future, taking its place alongside other common respiratory viruses such as influenza. And it likely will require similar annual consideration for vaccine composition updates in consultation with the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC). A recent meeting of the VRBPAC on April 6, 2022, resulted in a lively discussion and agreement on many considerations for planning for upcoming approaches to COVID-19 vaccine strain composition decision-making, development, and recommendations.

COVID-19 vaccines, developed and deployed in record time based on foundational scientific and clinical research conducted over the preceding decade, have conservatively saved tens of thousands of lives in the US and many more across the globe. Although data show that third doses of the mRNA COVID-19 vaccines provide more durable protection against the severe outcomes of hospitalization and death, only 45% of the US population has received a third vaccine dose, including only about 68% of those older than 65 years—the individuals at greatest risk of adverse outcomes from COVID-19. Because fourth doses of the mRNA COVID-19 vaccines were only recently authorized for those older than 50 years, it is too early to assess their effects on protection against serious outcomes of COVID-19 in the US. However, robust observational data from Israel with a large sample size showed additional protection against hospitalization and death in that population.

During this coming fall-to-winter period, 3 factors may come together to place the country’s population at risk of COVID-19, particularly those who are unvaccinated or who are not up-to-date with vaccination. These factors include (1) waning immunity from prior vaccine or prior infection, (2) further evolution of SARS-CoV-2, and (3) seasonality of respiratory virus infection, waves of which are generally more severe in the fall to winter months when individuals move their activities indoors.

By summer, decisions will need to be made for the 2022-2023 season about who should be eligible for vaccination with additional boosters and regarding vaccine composition. Administering additional COVID-19 vaccine doses to appropriate individuals this fall around the time of the usual influenza vaccine campaign has the potential to protect susceptible individuals against hospitalization and death, and therefore will be a topic for FDA consideration.

Those at greatest risk who might benefit most from vaccination include immunocompromised individuals and people older than 50 years, given the prevalence of comorbidities that increase the risk of severe disease and death in this latter group. Additional groups that might benefit include those who are unvaccinated (including children) or not up-to-date with vaccination (eg, those who have received only 1 dose of a COVID-19 vaccine or have not received a booster dose). The benefit of giving additional COVID-19 booster vaccines to otherwise healthy individuals 18 to 50 years of age who have already received primary vaccination and a first booster dose is not likely to have as marked an effect on hospitalization or death as in the other populations at higher risk (noted above). However, booster vaccinations could be associated with a reduction in health care utilization (eg, emergency department or urgent care center visits).

Around the same time that a decision is made regarding who should be eligible for vaccination, a decision will also need to be made on the COVID-19 vaccine composition. To provide maximal benefit across the entire age spectrum, careful consideration will need to be given to the choice of the SARS-CoV-2 variant(s) to cover in the COVID-19 vaccines for the fall and winter of the 2022-2023 season. This is because the variant(s) covered by the vaccine may have an important influence on both the extent and duration of protection against a future SARS-CoV-2 variant(s) that may circulate. Better alignment between the variant(s) covered by the vaccine and circulating variant(s) of SARS-CoV-2 might be expected to prevent a broader spectrum of disease, potentially for a longer time. In the event of a major fall or winter wave, a vaccine with optimal variant coverage might facilitate significant reductions in lost productivity and health care utilization from both acute and chronic complications of COVID-19, including postacute COVID-19 syndrome. Of note, in the past, such an overall public health benefit in an otherwise healthy younger population has been considered during the annual influenza vaccine campaign.

In terms of practical considerations, at the recent meeting of the VRBPAC, there was relatively uniform agreement that a single vaccine composition used by all manufacturers was desirable and that data would be needed to inform and drive the selection of a monovalent, bivalent, or multivalent COVID-19 vaccine.8 There was also general agreement that, should a new vaccine composition be recommended based on the totality of the available clinical and epidemiologic evidence, optimally it could be used for both primary vaccination as well as booster administration.

The timeframe to determine the composition of the COVID-19 vaccine for the 2022-2023 season, to use alongside the seasonal influenza vaccine for administration in the Northern Hemisphere beginning in about October, is compressed because of the time required for manufacturing the necessary doses. A decision on composition will need to be made in the US by June 2022. Because of this timing, the FDA, in consultation with the VRBPAC, will need to arrive at a recommendation for the future composition of the US COVID-19 vaccines for 2022-2023 based on the available evidence and predictive modeling, with the understanding that there will be some inherent residual uncertainty about the further evolution of SARS-CoV-2. To date, the original, or prototype, vaccine composition deployed has been reasonably good at protecting against severe outcomes from COVID-19. However, a greater depth and duration of protection might be achieved with a vaccine covering currently circulating variants.

As plans are being developed for the coming fall and winter, it is critical that patients and caregivers understand the profound benefit of a booster dose of the mRNA vaccines or a second vaccine dose of any kind after the Janssen/Johnson & Johnson vaccine and that this understanding leads to action now in the face of a current uptick in infection rates. Clinicians should not be susceptible to inertia and should continue to recommend that patients get their COVID-19 vaccination status up to date, meaning primary vaccination and relevant booster(s). There is no evidence that getting vaccinated now will have adverse effects or toxicity that would preempt the administration of an additional vaccine dose in the fall months if there is evidence of waning of immunity, a new variant, or an adverse seasonal pattern.

Vaccines, as public health interventions, have been responsible over the past century for reducing an unimaginable amount of morbidity and for saving millions of lives. The eradication of smallpox and near elimination of several other infectious diseases are an unambiguous triumph of modern medicine. During the 2022-2023 COVID-19 vaccine planning and selection process, it is important to recognize that the fall season will present a major opportunity to improve COVID-19 vaccination coverage with the goal of minimizing future societal disruption and saving lives. With the plan for implementation of this year’s vaccine selection process, society is moving toward a new normal that may well include annual COVID-19 vaccination alongside seasonal influenza vaccination.

Source : JAMA Network

Innate Immune Suppression by SARS-CoV-2 mRNA Vaccinations: The Role of G-quadruplexes, Exosomes, and MicroRNAs

Stephanie Seneff, Greg Nigh, Anthony M.Kyriakopoulos and Peter A.McCullough wrote . . . . . . . . .


The mRNA SARS-CoV-2 vaccines were brought to market in response to the public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious disease has no precedent.

The many alterations in the vaccine mRNA hide the mRNA from cellular defenses and promote a longer biological half-life and high production of spike protein. However, the immune response to the vaccine is very different from that to a SARS-CoV-2 infection.

In this paper, we present evidence that vaccination induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health. Immune cells that have taken up the vaccine nanoparticles release into circulation large numbers of exosomes containing spike protein along with critical microRNAs that induce a signaling response in recipient cells at distant sites. We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances potentially have a causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell’s palsy, liver disease, impaired adaptive immunity, impaired DNA damage response and tumorigenesis.

We show evidence from the VAERS database supporting our hypothesis. We believe a comprehensive risk/benefit assessment of the mRNA vaccines questions them as positive contributors to public health.

Read the full paper at ScienceDirect . . . . .

43,898 Dead 4,190,493 Injured Following COVID-19 Vaccines in European Database of Adverse Reactions

Brian Shilhavy wrote . . . . . . . . .

The European (EEA and non-EEA countries) database of suspected drug reaction reports is EudraVigilance, verified by the European Medicines Agency (EMA), and they are now reporting 43,898 fatalities, and 4,190,493 injuries following injections of five experimental COVID-19 shots:


From the total of injuries recorded, almost half of them (1,914,927 ) are serious injuries.

“Seriousness provides information on the suspected undesirable effect; it can be classified as ‘serious’ if it corresponds to a medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation, results in another medically important condition, or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect.”

A Health Impact News subscriber in Europe ran the reports for each of the four COVID-19 shots we are including here. It is a lot of work to tabulate each reaction with injuries and fatalities, since there is no place on the EudraVigilance system we have found that tabulates all the results.

Since we have started publishing this, others from Europe have also calculated the numbers and confirmed the totals.

Here is the summary data through April 23, 2022.

Source: Health Impact News

Have People Been Given the Wrong Vaccine?

Martin Kulldorff wrote . . . . . . . . .

Randomized controlled trials show all-cause mortality reduction from the Covid adenovirus-vector vaccines (RR=0.37, 95%CI: 0.19-0.70) but not from the mRNA vaccines (RR=1.03, 95%CI 0.63-1.71).

That is the verdict from a new Danish study by Dr. Christine Benn and colleagues. Have people been given vaccines that don’t work (Pfizer/Moderna) instead of vaccines that do work (AstraZeneca/Johnson & Johnson)? Let’s put this study into context and then delve into the numbers.

In medicine, the gold standard for evidence is randomized controlled trials (RCT), as they avoid study bias for or against the vaccine. Moreover, the key outcome is death. Do these vaccines save lives? Hence, the Danish study answers the right question with the right data.

It is the first study to do so.

When the Pfizer and Moderna mRNA vaccines were approved by the US Food and Drug Administration (FDA), that decision was based on RCTs. The RCTs submitted to the FDA showed that the vaccines reduce symptomatic Covid infections. By recruiting mostly younger and middle-aged adults, who are unlikely to die from Covid no matter what, the studies were not designed to determine whether the vaccines also reduce mortality.

That was assumed as a corollary, although it may or may not be true. Neither were the RCTs designed to determine whether the vaccines reduce transmission, but that is a different story for another time.

The vaccines were developed for Covid, but to properly evaluate a vaccine, we must look at non-Covid deaths as well. Are there unintended adverse reactions leading to death? We do not want a vaccine that saves the lives of some people but kills an equal number of other people. There may also be unintended benefits, such as incidental protection against other infections. For a fair comparison, that should also be part of the equation.

While each individual RCT was unable to determine whether the Covid vaccine reduced mortality, the RCTs recorded all deaths, and to increase sample size, the Danish study pooled multiple RCTs. There are two different types of Covid vaccines, adenovirus-vector vaccines (AstraZeneca, Johnson & Johnson, Sputnik) and mRNA vaccines (Pfizer and Moderna), and they did one pooled analysis for each type. Here are the results:

There is clear evidence that the adenovirus-vector vaccines reduced mortality. For every 100 deaths in the unvaccinated, there are only 37 deaths among the vaccinated, with a 95% confidence interval of 19 to 70 deaths. This result comes from five different RCTs for three different vaccines, but it is primarily driven by the AstraZeneca and Johnson & Johnson vaccines.

For the mRNA vaccines, on the other hand, there was no evidence of a mortality reduction. For every 100 deaths among the unvaccinated, there are 103 deaths among the vaccinated, with a 95% confidence interval of 63 to 171 deaths. That is, the mRNA vaccines may reduce mortality a little bit, or they may increase it; we do not know. The Pfizer and Moderna vaccines contributed equally to this result, so there is no evidence that one is better or worse than the other.

While all-cause mortality is what matters for public health, there is scientific interest in knowing how the different vaccines affect different types of mortality. The Danish scientists contacted RCT investigators to get information on whether each death was due to Covid, cardiovascular disease, accidents, or other causes.

For the mRNA vaccines, there was a reduction in Covid deaths but an increase in cardiovascular deaths, but neither was statistically significant. So, either result could be due to random chance. Alternatively, the vaccines may reduce the risk for Covid deaths while increasing the risk for cardiovascular deaths. We do not know, and Pfizer and Moderna did not design the RCTs to let us know.

For the adenovirus-vector vaccines, there were statistically significant decreases in both Covid and cardiovascular deaths, unlikely to be due to chance. There was a slight decrease in other deaths, which may be due to chance.

The strength of the Danish study is that it is based on randomized controlled trials. The primary weakness is that the follow-up time is short. This is because the manufacturers ended the clinical trials prematurely, after the vaccines received emergency use authorization.

Another weakness is that the data does not allow us to determine how these results may differ by age. While anyone can get infected, there is more than a thousand-fold difference in the risk of dying from Covid between the old and the young.

Are the vaccines primarily reducing deaths in older people? That is a reasonable guess. What about younger people? We don’t know. This is not the fault of the Danish investigators. They have done a brilliant job extracting as much information as possible from the industry-sponsored RCTs.

Some may criticize the Danish study for not yet being peer-reviewed, but it has been. It was peer-reviewed by me and several colleagues, and all of us have decades of experience with these types of studies. That it has not yet been peer-reviewed by anonymous journal reviewers is inconsequential.

The mRNA vaccines were approved based on a reduction in symptomatic infections instead of mortality. That Pfizer and Moderna did not design their RCTs to determine whether the vaccines reduced mortality is inexcusable, as they could easily have done so.

That the FDA still approved them for emergency use is understandable. Many older Americans were dying from Covid, and they had to base the decision on whatever information was available at the time.

Now we know more. If Pfizer and Moderna want to continue to sell these vaccines, we should demand that they conduct a proper randomized clinical trial that proves that the vaccines reduce mortality.

Equally important, the government, corporations and universities should stop mandating vaccines when randomized controlled trials show a null result for mortality.

Source : Brownstone Institute

Increases in COVID-19 Are Unrelated to Levels of Vaccination Across 68 Countries and 2947 Counties in the United States

S. V. Subramanian and Akhil Kumar wrote . . . . . . . . .

Vaccines currently are the primary mitigation strategy to combat COVID-19 around the world. For instance, the narrative related to the ongoing surge of new cases in the United States (US) is argued to be driven by areas with low vaccination rates. A similar narrative also has been observed in countries, such as Germany and the United Kingdom. At the same time, Israel that was hailed for its swift and high rates of vaccination has also seen a substantial resurgence in COVID-19 cases. We investigate the relationship between the percentage of population fully vaccinated and new COVID-19 cases across 68 countries and across 2947 counties in the US.

We used COVID-19 data provided by the Our World in Data for cross-country analysis, available as of September 3, 2021. We included 68 countries that met the following criteria: had second dose vaccine data available; had COVID-19 case data available; had population data available; and the last update of data was within 3 days prior to or on September 3, 2021. For the 7 days preceding September 3, 2021 we computed the COVID-19 cases per 1 million people for each country as well as the percentage of population that is fully vaccinated.

For the county-level analysis in the US, we utilized the White House COVID-19 Team data, available as of September 2, 2021. We excluded counties that did not report fully vaccinated population percentage data yielding 2947 counties for the analysis. We computed the number and percentages of counties that experienced an increase in COVID-19 cases by levels of the percentage of people fully vaccinated in each county. The percentage increase in COVID-19 cases was calculated based on the difference in cases from the last 7 days and the 7 days preceding them. For example, Los Angeles county in California had 18,171 cases in the last 7 days (August 26 to September 1) and 31,616 cases in the previous 7 days (August 19–25), so this county did not experience an increase of cases in our dataset. We provide a dashboard of the metrics used in this analysis that is updated automatically as new data is made available by the White House COVID-19 Team (https://tiny.cc/USDashboard).

At the country-level, there appears to be no discernable relationship between percentage of population fully vaccinated and new COVID-19 cases in the last 7 days. In fact, the trend line suggests a marginally positive association such that countries with higher percentage of population fully vaccinated have higher COVID-19 cases per 1 million people. Notably, Israel with over 60% of their population fully vaccinated had the highest COVID-19 cases per 1 million people in the last 7 days. The lack of a meaningful association between percentage population fully vaccinated and new COVID-19 cases is further exemplified, for instance, by comparison of Iceland and Portugal. Both countries have over 75% of their population fully vaccinated and have more COVID-19 cases per 1 million people than countries such as Vietnam and South Africa that have around 10% of their population fully vaccinated.

Across the US counties too, the median new COVID-19 cases per 100,000 people in the last 7 days is largely similar across the categories of percent population fully vaccinated. Notably there is also substantial county variation in new COVID-19 cases within categories of percentage population fully vaccinated. There also appears to be no significant signaling of COVID-19 cases decreasing with higher percentages of population fully vaccinated.

Percentage of counties that experienced an increase of cases between two consecutive 7-day time periods by percentage of population fully vaccinated across 2947 counties as of September 2, 2021

Of the top 5 counties that have the highest percentage of population fully vaccinated (99.9–84.3%), the US Centers for Disease Control and Prevention (CDC) identifies 4 of them as “High” Transmission counties. Chattahoochee (Georgia), McKinley (New Mexico), and Arecibo (Puerto Rico) counties have above 90% of their population fully vaccinated with all three being classified as “High” transmission. Conversely, of the 57 counties that have been classified as “low” transmission counties by the CDC, 26.3% (15) have percentage of population fully vaccinated below 20%.

Since full immunity from the vaccine is believed to take about 2 weeks after the second dose, we conducted sensitivity analyses by using a 1-month lag on the percentage population fully vaccinated for countries and US counties. The above findings of no discernable association between COVID-19 cases and levels of fully vaccinated was also observed when we considered a 1-month lag on the levels of fully vaccinated.

We should note that the COVID-19 case data is of confirmed cases, which is a function of both supply (e.g., variation in testing capacities or reporting practices) and demand-side (e.g., variation in people’s decision on when to get tested) factors.

The sole reliance on vaccination as a primary strategy to mitigate COVID-19 and its adverse consequences needs to be re-examined, especially considering the Delta (B.1.617.2) variant and the likelihood of future variants. Other pharmacological and non-pharmacological interventions may need to be put in place alongside increasing vaccination rates. Such course correction, especially with regards to the policy narrative, becomes paramount with emerging scientific evidence on real world effectiveness of the vaccines.

For instance, in a report released from the Ministry of Health in Israel, the effectiveness of 2 doses of the BNT162b2 (Pfizer-BioNTech) vaccine against preventing COVID-19 infection was reported to be 39%, substantially lower than the trial efficacy of 96%. It is also emerging that immunity derived from the Pfizer-BioNTech vaccine may not be as strong as immunity acquired through recovery from the COVID-19 virus. A substantial decline in immunity from mRNA vaccines 6-months post immunization has also been reported. Even though vaccinations offers protection to individuals against severe hospitalization and death, the CDC reported an increase from 0.01 to 9% and 0 to 15.1% (between January to May 2021) in the rates of hospitalizations and deaths, respectively, amongst the fully vaccinated.

In summary, even as efforts should be made to encourage populations to get vaccinated it should be done so with humility and respect. Stigmatizing populations can do more harm than good. Importantly, other non-pharmacological prevention efforts (e.g., the importance of basic public health hygiene with regards to maintaining safe distance or handwashing, promoting better frequent and cheaper forms of testing) needs to be renewed in order to strike the balance of learning to live with COVID-19 in the same manner we continue to live a 100 years later with various seasonal alterations of the 1918 Influenza virus.

Source : National Library of Medicine

Study: mRNA Vaccines Alter Human Liver DNA In Vitro

Pfizer’s BioNTech vaccine causes intracellular reverse transcription of BNT162b2 mRNA into human DNA in vitro, renewing concerns that vaccines may introduce spike protein into the nuclei of cells.

The findings emerged Friday in a peer-reviewed article entitled “Intracellular Reverse Transcription of Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2 In Vitro in Human Liver Cell Line” in the Current Issues in Molecular Biology Journal, an imprint of MDPI, the largest open-access publisher in the world and the fifth-largest publisher overall in terms of journal paper output.

Researchers Warn: Pfizer Vaccine May Affect Integrity of Genomic DNA

“Our study shows that BNT162b2 can be reverse transcribed to DNA in liver cell line Huh7, and this may give rise to the concern if BNT162b2-derived DNA may be integrated into the host genome and affect the integrity of genomic DNA, which may potentially mediate genotoxic side effects,” the authors warn.

The study, authored by a team of Swedish researchers at Lund University, concluded that Pfizer’s COVID-19 mRNA vaccine entered the human liver cell line Huh7 in vitro and BNT162b2 mRNA was subsequently transcribed intracellularly into DNA within six hours of exposure.

An “Immortal” Human Cell Line

The Huh7 cell line is a permanent line of liver cells derived from male hepatoma tissue that was surgically removed from a 57-year-old Japanese man in 1982. For the next 40 years, Huh7 and its derivatives were used in thousands of laboratories across the planet as a convenient experimental substitute for primary hepatocytes.

Hepatocytes, the major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes also activate innate immunity against invading microorganisms by secreting innate immunity proteins.

In Vitro Vs. In Vivo Caveats

Researchers who conduct in vitro studies commonly remind that results that emerge from laboratories and test tubes often differ from results which are derived in living, fully intact organisms. And the Huh7, itself, has limitations that could introduce errors or anomalies into laboratory results.

Still, the study conducted by researchers at one of Europe’s oldest and most prestigious research institutions raises serious questions about Pfizer’s mRNA vaccines’ impact on human DNA, which have yet to be subjected to the typical years-long (or decades-long) battery of long-term safety monitoring protocols.

Changes in Gene Expression of LINE-1

The study authors exposed Huh7 cells to Pfizer’s BNT162b2 mRNA and then performed a quantitative polymerase chain reaction on RNA extracted from the cells. The research team discovered high levels of BNT162b2 in Huh7 cells and changes in gene expression of long interspersed nuclear element-1, or LINE-1, which is an endogenous reverse transcriptase.

BNT162b2 mRNA Reverse Transcribed Into DNA Within Six Hours Of Exposure

The authors conclude that BNT162b2 transfects into human liver cell line huh7 in vitro, altering LINE-1 expression and distribution. The authors also find that “BNT162b2 mRNA is reverse transcribed intracellularly into DNA in as fast as six hours upon BNT162b2 exposure.”

BNT162b2 is a lipid nanoparticle (LNP)–encapsulated, nucleoside-modified RNA vaccine (modRNA) which resembles gene therapy platforms. Pfizer’s mRNA vaccine encodes the full-length of SARS-CoV-2 spike protein. That spike protein is modified by two proline mutations to ensure antigenically optimal pre-fusion conformation, mimicking the intact virus to elicit virus-neutralizing antibodies.

A recent study showed that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the genome of human cells, which the authors said led them to investigate whether spike transfected by mRNA vaccines might have comparable effects.

CDC Says mRNA Vaccines Does Not Enter Nuclei or Interact With DNA

mRNA vaccines were not designed to invade human cells’ nuclei. In fact, the United States Centers for Disease Control claimed in December that “COVID-19 vaccines do not change or interact with your DNA in any way.”

“The genetic material delivered by mRNA vaccines never enters the nucleus of your cells, which is where your DNA is kept,” the government agency website said. “Viral vector COVID-19 vaccines deliver genetic material to the cell nucleus to allow our cells to build protection against COVID-19. However, the vector virus does not have the machinery needed to integrate its genetic material into our DNA, so it cannot alter our DNA.”

The Nucleus is the “Brain” of Human Cells, Site of DNA Replication

Some biologists refer to the nucleus, metaphorically, as the “brain” of the cell. The nucleus is the most prominent of cells’ organelles and contain genetic information in the form of deoxyribonucleic acid (DNA) and is the site of DNA replication. The nucleus is also the site for the synthesis of ribonucleic acid (RNA) which is the template for synthesis of other cell proteins and for protein factories of the cell called ribosomes.

Transfection of spike protein into the nucleus opens the possibility of DNA modification, the authors wrote.

mRNA Vaccines Effect on “Genomic Integrity” Should Be Studied

“At this stage, we do not know if DNA reverse transcribed from BNT162b2 is integrated into the cell genome,” the authors wrote. “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.”

Source: Trial Site News

Read the full article at MDPI . . . . .

Read also at Life Site

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New Zealand High Court Determined a Government-ordered Vaccination Mandate for Police and NZDF Is Unlawful

Ethan Griffiths and Caitlan Johnston wrote . . . . . . . . .

A High Court challenge questioning the legality of Covid-19 vaccination mandates for Police and Defence Force employees has been upheld, with the court determining that the government mandate is an unjustified incursion on the Bill of Rights.

In a decision released today, Justice Francis Cooke determined that ordering frontline police officers and Defence staff to be vaccinated or face losing their job was not a “reasonably justified” breach of the Bill of Rights.

The lawyer for the police and Defence staff at the centre of the claim is now calling for the suspended workers to return to their jobs immediately, saying many have given decades of service to their community and are still committed to their jobs.

The challenge, put forward by a group of Defence force and police employees, questioned the legality of making an order under the Covid-19 Public Health Response Act to require vaccination for frontline employees.

The challenge was supported by a group of 37 employees affected by the mandate, who submitted written affidavits to the court.

Minister of Workplace Relations and Safety Michael Wood, Deputy Police Commissioner Tania Kura and NZDF Chief People Officer Brigadier Matthew Weston filed affidavits defending the mandate.

As it stands, 164 of the overall police workforce of nearly 15,700 were affected by the mandate after choosing not to be vaccinated. For NZDF, the mandate affected 115 of its 15,500 staff.

The group relied on two aspects of the Bill of Rights – the right to decline a medical procedure and the right to religious freedom.

On the religious freedom argument, a number of those who made submissions referred to their fundamental objection to taking the Pfizer vaccine, given that it was tested on the cells that were derived from a human foetus.

Justice Cooke agreed with the claim, saying that “an obligation to receive the vaccine which a person objects to because it has been tested on cells derived from a human foetus, potentially an aborted foetus, does involve a limitation on the manifestation of a religious belief.”

Source : NZ Herald

Chart: 122 Countries on Track to Miss COVID-19 Vaccine Goal

Source : Statista

Is the Next Great COVID Vaccine an Inhaled One?

Dennis Thompson wrote . . . . . . . . .

“The jab” might soon be replaced with something like “the huff” as slang for a COVID-19 vaccine dose.

Some experts believe that an inhaled vaccine could be a checkmate move in the world’s ongoing chess match against COVID-19.

They argue that inhaled vaccines could not only deliver more effective protection, but could do it at a lower dosage and thus make vaccines available for more people around the globe.

“Targeting vaccines to specific anatomic areas of the body where immunity is most important, could provide more durable and extensive protection than injectable vaccines when it comes to respiratory viruses,” said Dr. Amesh Adalja, a senior scholar with the Johns Hopkins Center for Health Security, in Baltimore.

A newly developed inhaled COVID-19 vaccine just emerged out of Canada, where researchers at McMaster University completed a lab study showing that their new vaccine was safe in mice and produced a robust immune response.

The investigators have now moved their new vaccine to a phase 1 clinical trial, to see if it will boost immunity in healthy adults who’ve already had two shots of a COVID mRNA vaccine.

The Canadian researchers deliver their vaccine through a nebulizer, a device that turns liquid into an aerosol that’s inhaled through the mouth and deep into the lungs.

“We know that when we stimulate immunity in the lung, the qualities of that immunity are intrinsically different than the types of responses that we stimulate when we inject someone with a vaccine the typical way, in their muscle,” said study co-lead author Matthew Miller. He is an associate professor at McMaster University’s Michael G. DeGroote Institute for Infectious Disease Research, in Ontario.

Inhaled vaccine more potent

Shots delivered in the arm have proven effective, but they produce an immune response that has to circulate throughout the body before antibodies wind up in the nose and the lungs — the place where you’d want the most powerful protection against a respiratory virus like COVID-19, Miller said.

The response prompted by an inhaled vaccine “is much more potent because it recruits cells that essentially live in the lung waiting for exposure to pathogen, in this case to SARS-CoV-2. Those cells are not present when we give vaccines intramuscularly,” Miller said.

Inhaled vaccines also have a better chance to promote immunity in the deepest parts of the lungs, where COVID-19 can wreak the most damage, Miller added.

There’s another benefit to that effectiveness, besides personal protection — you don’t have to use as much vaccine to get the same response.

“By focusing that immune response in the lungs, we can use a lot less vaccine and it still goes a lot further,” Miller said. “During this pandemic, we’ve experienced global shortages in the availability of vaccines. Having this dose-sparing effect means we could produce a hundred times more vaccine, or vaccinate a hundred times more people in the same amount of time with the same amount of material.”

Inhaled vaccines also would be “greatly advantageous” in promoting COVID-19 vaccination around the world, Adalja said, “as they free vaccines from needles and syringes, which can be difficult to obtain in certain resource-poor settings, as well as opening up vaccination to needle-phobic individuals.”

A vaccine for the needle-phobic should not be overlooked, said Dr. Corey Casper, CEO of the Infectious Disease Research Institute in Seattle.

“In surveys, about 20% of individuals who are not vaccinated say they would take one if it were not delivered with a shot. That’s not a small fraction, and we need to focus on that,” Casper said.

Miller and his colleagues aren’t the only ones investigating the benefits of an inhaled vaccine.

The Indian firm Bharat Biotech has developed a COVID-19 vaccine that would be sprayed into the nose. The company received approval in January to begin phase 3 clinical trials in humans.

Respiratory viruses best match for nasal, lung delivery of vaccines

And a group of Yale University researchers recently issued a study of lab mice showing that a COVID-19 nasal spray vaccine could boost immune memory cells and antibodies in the nose and throat. The study appeared on bioRxiv, a pre-print site for cutting-edge science that has not yet been peer-reviewed.

“Improving upon current vaccine platforms to provide mucosal immunity is important to curb this current pandemic, and certainly will be important to combat the next,” the Yale team wrote.

But the McMaster researchers think their vaccine has another added benefit: it promotes an antibody response against three different parts of the COVID coronavirus, making it more likely that immunity would be longer lasting than current vaccines that only target the virus’ spike protein.

“While targeting the spike protein made a lot of sense for first-generation vaccines, that approach was going to be inherently limited because this was a virus that was going to continue to evolve. The spike protein was going to mutate and inevitably those vaccines were going to need to be updated,” Miller said.

The Canadian vaccine targets the spike protein, which is the part of the virus that helps it infect cells. However, it also produces an immune response against parts of the virus that protect its genetics and help it replicate — targets that are hidden inside the virus until after it infects a cell, and therefore less likely to mutate away from a vaccine, Miller said.

Miller said his team is working to get their inhaled vaccine approved under an accelerated timeline, possibly within two years.

“I do think inhaled vaccines will be that next major innovation in vaccine design, and hold the promise of really improving the protectiveness of vaccines for respiratory pathogens, including things like influenza for which our current seasonal vaccines are far short of optimal in terms of the average vaccine effectiveness we see on a yearly basis,” Miller said.

The McMaster vaccine research was published online in the journal Cell.

Other research teams don’t plan to stop with COVID.

Casper said inhaled vaccines make a lot of sense for other respiratory infections, including influenza, RSV and tuberculosis.

“The number one infectious disease killer around the world is still tuberculosis — not incredibly common in the United States, but more people are dying of tuberculosis than any other infectious disease on the planet,” Casper said. “There’s really good evidence to suggest that inhaled vaccines, whether it be in the lung or in the nose, would be highly effective against tuberculosis.”

Source: HealthDay