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A Declaration of Independence from Covid Fear

Out of Great Barrington, Massachusetts came a declaration of independence, of sorts—independence from the ruling epidemiological consensus on the current pandemic. Originally signed by three prominent epidemiologists at Harvard, Stanford, and Oxford, the Great Barrington Declaration addresses the current pandemic from a heterodox perspective. It advocates for something called “Focused Protection” in lieu of our current collection of wildly different Covid policies across the US and around the world. While many details aren’t included, the authors vaguely define focused protection as shifting “the central aim” of Covid prevention policies to the protection of those most at risk. For those less at risk, the authors believe that “herd immunity” should be the goal, in conjunction with a vaccine once one is available. Otherwise, the less vulnerable should be allowed to go on living their lives. The authors present this in contrast to the “unfocused” approach that seems prevalent in most of the world.

The declaration cites as its raison d’etre the significant health trade-offs that have come with the current public health strategies. In particular, it notes that stricter limits on human activity to prevent the transmission of the virus have led to “lower childhood vaccination rates, worsening cardiovascular disease outcomes, fewer cancer screenings and deteriorating mental health—leading to greater excess mortality in years to come, with the working class and younger members of society carrying the heaviest burden. Keeping students out of school is a grave injustice.”

To say this document has set off a controversy would be an understatement. The Trump administration has embraced it. The New York Times quoted an expert who described the declaration’s “herd immunity” approach as “nonsense.” Tyler Cowen has significant doubts about the approach. The Los Angeles Times editorial board calls the declaration a “deception”.

I for one am not a disease expert, although I have opinions about the problems with a “one size fits all” approach to Covid. And while I have mixed feelings about the content of the Great Barrington Declaration, I appreciate how this project has generated a discussion about our current explicit policy goals in the fight against Covid.

Balancing Risks

Back in March, before the world got weird, the argument for lockdowns and restrictions was simple and powerful. In the wake of the Italian healthcare system’s catastrophic failure to handle its first major Covid outbreak, public health officials and political leaders across the globe almost unanimously decided to pursue a lockdown for what they claimed would be a few weeks in order to “flatten the curve” and avoid overwhelming hospital systems. Trust me on this, you didn’t dream it.

Now more than eight months into those “few weeks,” the Great Barrington Declaration is forcing us in the developed West to answer a question that we have needed to discuss honestly and publicly for a while: what’s the goal now? What are we trying to accomplish with the myriad of frequently changing collections of Covid policies that are still in place in some locales and may be reimposed on others?

We don’t hear about curve bending, let alone flattening anymore. Instead, we hear about “public safety,” “protecting Grandma and Grandpa,” mask wearing, and social distancing. There have been recent threats of more “targeted” lockdowns because of increasing cases. None of these are goals—they are practices without a clear end in sight. No one in the White House, Congress, state legislatures, or governors’ mansions is articulating a clear goal or timeline. What’s more, the trade-offs associated with this messy collection of policies have been significant and deadly.

Public health experts talk about “excess deaths,” which are essentially additional deaths in a place over a time period above what you would have predicted under normal conditions. Since the beginning of the year, the US has experienced about 300,000 excess deaths, which is a lot. The number directly attributable to Covid is “only” about 200,000. So Covid has killed 200,000, but another 100,000 Americans have died while these policies have been in place. Health officials widely point to higher rates of serious health problems that aren’t being treated because of fear associated with Covid. For example, the heart attack death rate has doubled since the pandemic began. Many of those other excess deaths might be attributable to our Covid policies, not the virus. That’s a failure on both counts. We haven’t prevented 200,000 deaths from Covid, and our lockdowns and draconian approaches lasting for months have at the very least contributed to another 100,000. Individuals who cannot afford to do so are forgoing basic health services. Heart attacks, strokes, and many other significant health problems are occurring and not being treated because of fears related to the pandemic. And perhaps most dangerously, these extra deaths not directly attributable to Covid are occurring among younger Americans between 30 and 60 who are not at high risk of dying from the virus, but are foregoing treatment because of misplaced fear.

Waiting in isolation for months without a clear set of goals decreases cohesion and trust among the governed. At the regime level, this opens up the possibility for a growing chasm between the governed and governors.

This is to say nothing of the suffering the virus and the containment policies have caused in the developing world where millions of people live from day to day. They aren’t rich enough to stay at home, watch Netflix, and chill. There are no virtual classes in poor public schools in Latin America, Africa, and Asia. We in the US are rich enough to temporarily get away with this odd, bifurcated world where many of the wealthy work from home and their children receive private tutoring online, while other “essential” workers continue to work in their jobs and accept more risks.

Constructing public policy takes not only expertise, but a proper balance between risk and reward. Aaron Wildavsky’s work on this topic points out two reasons why public officials, in conjunction with citizens, must accept tradeoffs in the creation of safety policy. As Wildavsky argues, and the discussion of excess deaths clearly illustrates, seeking safety will inevitably increase danger in other areas. For instance, Wildavsky discusses attempts by the city of Los Angeles to promote the demolition of many older buildings throughout its metropolitan area because they were deemed unsafe in the event of an earthquake. City officials were trying to be proactive against possible deaths from older buildings collapsing. But as he notes, displacing 17,000 residents from those buildings and disrupting the commercial activity in many of them had consequences for health and safety. The same is true when new drugs are placed on the market. Many citizens benefit from the drugs, but a few can have severe side-effects.

Conversely, Wildavsky argues, somewhat paradoxically, that accepting risks can promote safety. Take any standard table or floor lamp. At the time that electric lamps were invented, people were somewhat concerned about running electric current right to their fingertips, but compared to burning gas and candles, it turned out to be much safer. The tradeoff was worth it and only through risk-taking experimentation did we discover that it was safe.

The problem with our current regulatory environment, as Wildavsky sees it, is twofold: resilience is not valued, and regulators and policymakers seek what he calls “perfect safety.” Our policymakers today are rejecting resiliency, making us poorer, less socially stable, less well-educated, and more divided. The second problem is that our health experts also seek some sort of ideal or perfect safety when it comes to Covid mitigation. When policymakers compete in a race to the bottom for draconian measures that fight Covid outbreaks only with brute force, they are lauded as being proactive without careful consideration of the harm these policies inflict.

A Healthy Society

More fundamentally, what have all of these Covid mitigation policies done for human flourishing? If we could reach the perfectly safe Covid life, would it be worth it? Aristotle reminds us of the problems that arise when individuals do not live socially. As he notes in the Politics, our natural state is in a social order like the city, the center of the ancient Greek world. He famously noted that the man not suited to social life in the city was either “a beast or a god.” But what often gets left out is the next sentence, where he writes, “There is then in all persons a natural impetus to associate with each other in this manner, and he who first founded civil society was the cause of the greatest good.” Our end goal should be the promotion of human flourishing, which requires the maintenance of civil society—the social world where we practice politics, associate freely, and achieve justice through the rules that evolve from our regular interactions. This process is halted in the Covid world.

But it’s not merely our rules and sense of justice that come from social life. Our friendships, described by Aristotle in book 8 of the Nicomachean Ethics, are profoundly important not only because of the good they do for us and our friends, but also because friendship is a substitute for state-enforced justice. When friendship is rich and deep in a political system, leaders do not need to resort to coercion and force. By instilling fear among all of us, politicians are fracturing friendship and subjecting us to lives that are not natural. We can easily see the roots of our recent civil unrest, rioting, and lawlessness during this pandemic in the isolation and breakdown of social and economic life.

None of these forced and consciously chosen disruptions were done in bad faith. However, isolation and separation from our friends, loved ones, and social life is not natural and not without cost. It can fracture our social fabric irreparably. Waiting for months without a clear set of goals decreases cohesion and trust among the governed. At the regime level, this opens up the possibility for a growing chasm between the governed and governors. Such a situation invites potential abuses of power.

The Great Barrington Declaration may not have all the answers, but considering how poorly we have done so far it may be a step in the right direction. This virus has perplexed and surprised us all, even the experts. This declaration is forcing us to start a much-needed conversation about what we are doing, what our goals are, and what’s necessary for us to reach them. Such a conversation is necessary because we still live in a representative, liberal, relatively open society. It’s time we returned to discussion as a pathway to policy: It’s time policymakers listened to alternative viewpoints and discussed them. It’s time leaders trust citizens again, lest the reciprocal trust of the citizenry in its leaders be inexorably ruptured. It’s also time that we acknowledge that a year lost in isolation may not be worth the risk to many millions of people throughout the world.

It’s not unreasonable to decide that relatively “normal” life is worth the tradeoff. It is unreasonable to not even allow discussion of the choice.

Reader Discussion

Law & Liberty welcomes civil and lively discussion of its articles. Abusive comments will not be tolerated. We reserve the right to delete comments - or ban users - without notification or explanation.

on November 13, 2020 at 08:19:45 am

This is a quite thoughtful piece by Lynch. As an economist, I sum it up this way - policy makers have focused exclusively on (alleged) benefits of draconian lockdowns, universal masking, and the like, and entirely ignored costs of these policies. Hence “two weeks” of “curve flattening” becomes months of disruption of normal life with no end in sight. After all, if one refuses to consider any cost to a policy, then even the tiniest alleged benefit justifies continuing the policy. Lunch does a fine job of dissecting this.

The one point on which I strongly disagree with Lynch is his assertion “None of these forced and consciously chosen disruptions were done in bad faith.” I have no idea how he concludes that, apparently he assumes policy makers are universally motivated by good faith then, and that political opportunism plays no role. That’s impossible for me to believe. For example, the World Economic Forum has explicitly used draconian lockdowns as a vehicle for implementing their “Great Reset,” a proposed global restructuring of economic, political, and social systems and a top-down implementation of a new social contract. In the United States, Democrat policy makers have clearly used disruptions from lockdowns to try to defeat the incumbent President. Here in a Michigan, our Governor has attempted to use Covid—19 to justify indefinite rule by executive order without consultation with the legislature.

If we persist in ignoring such things as ulterior motives, opportunism, bad faith, and “never letting a crisis go to waste,” we’ll fail to notice that for some people the costs *are* benefits, and that for them it is quite reasonable “to not even allow discussion of the choice.”

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Charles N. Steele
on November 13, 2020 at 09:24:42 am

Thoughtful overview of a well-covered topic.

Yet, as Charles Steele argues, it is untenable to conclude that none of this over-regulation was done in bad faith. Indeed, after June, 2020, given the clear conflict between the mounting political opportunities which lockdowns presented and the compelling scientific evidence against lockdowns, it can be argued that the lockdowns were done cynically and in complete bad faith.

The essayist's assertion of good faith lockdowns is not only facially-naive, it is strongly contradicted by mountains of contemporary political and scientific evidence. And it flies in the face of what we know human nature to have always been, fallen and corrupted, especially man in the polis under the thumb of government. A wise American preacher and theologian, Reinhold Niebuhr, once said that original sin is the most empirically-verifiable Biblical proposition. As for government, Lord Acton's "Power tends to corrupt, and absolute power corrupts absolutely." is such commonplace wisdom, such empirically-verifiable insight that it has become a cliche.

The empirical evidence is simply overwhelming that the Democrats deployed their China Plague lockdowns as political weapons, that they imposed mob and crowd controls selectively for political reasons and that the Democrats artfully demagogued epidemic fears for political advantage, particularly to sway the 2020 election against Trump, to support their crony capitalists like Amazon, and to punish their political enemies, like small business owners and churchgoers. That BLM was allowed to run wild, loot and burn in Blue Cities, while a Trump Rally was banned in Democrat Minnesota and that Democrat-supporter Amazon had its greatest sales in 2020 while tens of thousands of mostly Republican small businesses went bust were neither coincidences nor the unintended bad consequence of regulatory decisions made in good faith.

Last night Justice Alito touched on this reality in his key-note address to the Federalist Society, when he pointed out the hypocrisy of Nevada authorities (Democrat) allowing large crowds in gambling casinos (the state's largest employer and political donor) while restricting worship services to 50 people, and, worse, for the Supreme Court recently to have turned a blind eye to such horrendous denial of religious liberty.

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paladin
on November 16, 2020 at 13:53:42 pm

I am reminded of this:

https://lawliberty.org/how-many-hospital-beds-are-enough/

Paladin, keep The Faith!

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N.D.
on November 16, 2020 at 13:56:12 pm

And this: https://lawliberty.org/time-to-disobey-religious-liberty/

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N.D.
on November 13, 2020 at 13:19:12 pm

I am seventy years old. And I believe that my children fear for me more than my wife and I fear for ourselves. She and I have both lost all of our parents. We know that is a difficult experience, and yet a necessary and natural one, and at the end there is relief and opportunity.
But we live in a litigious society. When things go badly, it is someone's fault. And so the message is that everyone must 'avoid risks' lest their risky behavior endanger not only themselves but their precious elders. Lynch cites the example of the electric table lamp as a case where a new technology, whatever its new risks, actually does a great deal to mitigate older and worse risks. And it's a useful example -- we are certainly coming at this from the wrong direction. But is in large part because, without Faith in something greater than ourselves, and Belief only in the power of Technology, Fear is powerful.
And I agree with Steele and Paladin: there is some intentional use of that fear at work.

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cmcc_aus
on November 13, 2020 at 14:43:03 pm

Some hypotheses:

1. The biology of SARS-CoV-2 is much more complex and robust than anyone understands, and the persistent notion that "policy" can keep it from running its natural course is fallacious. Nature not only gets a vote it gets a veto.

2. We do not understand herd immunity nearly as well as we think we do. The intrinsic immune system may contribute much more than our simplistic models allow.

3. "Covid fear" as used in the title of the above essay is largely the result of an incompetent, unethical, biased and bumbling media.

4. COVID exposes the inherent weaknesses of "experts," models, and fiat science. The reason that we cannot model COVID with any useful degree of accuracy is that we lack a useful degree of understanding.

5. The lost opportunity to understand the behavior of viral pathogens, their interaction with mammalian biology, and the the prospects for future pandemics is unconscionable. The acquiescence of the "scientists," bureaucrats, media lackeys and politicians in prioritizing political considerations and cynical opportunism over public welfare and scientific integrity is a failure that will not be treated favorably in history.

6. The intrusions on personal liberty, social institutions, and civic life are not worth the benefits; benefits which now appear to be increasingly imaginary and the result of an unfortunate mixture of arrogance, stupidity, and pettiness. In particular, many governors have demonstrated that they cannot and should not be trusted with open-ended emergency powers.

7. London handled the Great Plague better than our mediocre elites handled COVID.

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z9z99
on November 13, 2020 at 18:55:28 pm

Agreed with all commenters and the essayist EXCEPT the unfounded assertion that covid equivalent of viral penology (cuz that is what it amounts to) was not done in bad faith.
BULLSHIT! It may not have been initiated in bad faith; however, the opportunities for either personal or political / cultural gain, of forced lockdowns, restricted liberty and impositions upon people of faith, and the inconsistent applications of social distances requirements for political gatherings, were simply too great to ignore.

Paladin characterizes the essayists claim as "facially naive," It is certainly that BUT it is also willfully ignorant and indicative of a disposition that is unwilling or unable to confront the hard reality of the viciousness and pettiness of our elite overlords.
"Not bad faith" - witness Governor Cuomo who avers that it is a "bad thing" that the vaccine (such as it is) was created and may be distributed during Trump's tenure.
Not bad faith???????? Really, now!

No, elite actions, behaviours, attitudes and rhetoric during the ChiComm Flu regimen was simply another prop in the Resistance's plot to take down the President.
Bidens new COS, Mr Klain is famous for, among other things, his "Rules" for debates, one of which is that a debate may be won in the first 20 minutes. Note how Chris Wallace drilled Trump during that time frame in the debate he *moderated*
Note laso how there was never any favorable coverage of The Trumpster's more than adequate response to ChiComm Flu.
Note how those who castigated his travel ban on china as racist are now arguing that is what they would have done - Mr Klain included.
Note the hyperbole over Trumps claims on hydroxychloroquine (HCQ), many of which claims were substantiated by real studies and prominent scientists and agencies. Note the contradictory statements on HCQ by the media darling Fauci.
No, ChiComm Flu presented too good of an opportunity for the Left, the Resistance to slam Trump, to engage the citizens in this resistance by appealing to their "feelings" not their reason.
It worked!
And it was done, and is a prime example of BAD FAITH!

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gabe
on November 14, 2020 at 10:51:52 am

Well, if you don;t believe me, why not listen to that Delphic Oracle, Tony Fauci:

"This] was the backdrop to yesterday’s program at the National Cathedral that featured the execrable Anthony Fauci.

Fauci, speaking on Thursday at Washington National Cathedral with other top health experts on the pandemic, noted that it is a bit unfair to compare the United States’ coronavirus response with other countries. The United States isn’t an island with five million people that can easily be shut down, he notes. So suppressing and controlling the virus is a lot more of a challenge.

“I was talking with my U.K. colleagues who are saying the U.K. is similar to where we are now, because each of our countries have that independent spirit,” he said on stage. “I can understand that, but NOW is the time to DO WHAT YOU ARE TOLD.” (caps mine, well maybe).

Who will deny that this typifies Progressives patronizing view of we deplorable citizens?

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gabe
on November 15, 2020 at 08:18:01 am

Shut up and obey!
"In Fauci we trust."
"E pluribus Fauci."

When I was a kid in an Italian neighborhood, some of my friends' dads worked for the Mafia. They did not wear masks, but they had Fauci's attitude. Our neighborhood was very safe.

What this country needs is a Fake Unelected President who will issue an Executive Order to "follow the science." After all, scientists gave the world eugenics, the atom bomb, abortion-on-demand, the answer to climate change, the China Virus, and the pathway to one-party rule.

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paladin
on November 15, 2020 at 15:48:59 pm

Hey, fugeddaboudit!

It appears that it is a *viral pathway" to dominion.

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gabe
on November 18, 2020 at 22:15:06 pm

Just saw this.
Love it.

Except for mine and a few dozen other non-Italian families, my neighborhood was pretty much all Italian and Catholic. Yet the priest at St. James was Fr. Walters. Go figure. We rented from Mr. Iaconis, who called me Tuffy: "Heyyy, Tuffy! Come ovah hiyah."
I grew up in the deep coal country of West Virginia, which is loaded with Italians who still celebrate Columbus Day. It's a BFD there. The mob was very powerful in my town. Our next-door neighbor, a mobster who controlled the beverage market, was shot 5-6 times one morning while in his driveway lifting his garage door. The adult son of the old man who cut my hair when I was a boy became City Manager. He ran afoul of the Mafia. His teenage son was found dead at the playground, hanging from the basketball rim with piano wire around his neck. My middle school friend's father ran the numbers racket for the town. Had a chauffer/bodyguard for his emerald green Chrysler New Yorker with tinted power windows (in the days when windows were not tinted.) He was still alive at the time we moved away.

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paladin
on November 15, 2020 at 11:56:36 am

False religion sucks away our Imago Dei in service to Holy Father Fauci, the mas(k)ochist.
https://wiseblooding.com/wp-content/uploads/2020/11/Maskism.jpg

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Renee Oelschlaeger
on November 24, 2020 at 15:07:35 pm

Beautifully said - great poem - I saved it and will pass it on.

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Cephera
on November 15, 2020 at 14:15:13 pm

Based on the last numbers I've seen, 741 per million population have died of Covid-19 in the U.S. That works out to 8 people per 10,000 population if my math is correct. So 9,992 haven't died. Of course there are many others who are physically impacted as a result of the disease. The vast majority for whom it is fatal, as I understand it, are the very elderly with comorbidities. It is then important to compare this with all other causes of death. For example, if people watched their weight, could that more than offset those number of fatalities in terms of allocating resources? Saving the people who died based on the side-effects of the lockdowns also makes this an important debate to be had. I read the headlines, and it sounds very scary. Of course every individual life is a tragedy. If saving lives is the goal, is the incredible cost of lockdowns proportional to this objective versus how such investments and efforts could be allocated? That the moral high ground is not with those advocating perfect safety appears to be the winning argument. This moral and prudential principle would seem to be the rallying point against fear in general as the author, as I understand him, suggests.

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Bob K.
on November 16, 2020 at 10:45:46 am

Before we declare our independence from Covid fear, I have a question, that I am hoping someone who is an expert in the area of immunology, in particular regarding hepcidin as an immune regulator, can answer.

Does it seem logical to use use “ a sequence of genetic RNA material produced in a lab that, when injected into your body, must invade your cells and hijack your cells’ protein-making machinery called ribosomes to produce the viral components that subsequently train your immune system to fight the virus,” when that sequence of genetic RNA material is programmed to make your cells produce the coronavirus’ infamous spike protein that gives the virus its crown-like appearance (corona is crown in Latin) for which it is named, if “there is a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates”?

https://www.jpost.com/health-science/could-an-mrna-vaccine-be-dangerous-in-the-long-term-649253

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N.D.
on November 16, 2020 at 17:00:50 pm

Following your comment, I did a little search.
My initial response to your query was, "Well, a standard vaccine enables the same immunological response."
But, that is not so. As you suggest, this vaccine (actually two of them) instead trigger the body to produce only the "Spikes" or crown and not the entire protein.
So what happens if:
a) Covid 3 has different spikes or no spikes at all
b) but it has the same protein
What is the expectation of a proper immunological response when the immune system may only recognize and be prepared to "fight" the spikes and not the protein.

Also, good question on hepcidin, the main regulator of iron levels in the body. Can this cause a immunological response to hepcidin and the consequent afflictions associated with too high levels of iron in the bloodstream?
One hopes that this was investigated by the researchers.

As for me, I have no intention of taking this vaccine. No, I am not an "anti-vaxer" but I view this over-hyped plague as nothing more than the Flu with political power and I don;t take flu shots either.

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gabe
on November 17, 2020 at 09:49:38 am

“Can this cause a immunological response to hepcidin and the consequent afflictions associated with too high levels of iron in the bloodstream?”

My concern is that the immunological response would result in an increase in hepcidin and thus inflammation and lower levels of oxygen in the blood.

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N.D.
on November 22, 2020 at 17:10:14 pm

The spike protein was chosen as the antigen to use in a vaccine because it's on the outside of the viral capsid. The antibodies that your body generates to the spike protein will both neutralize the virus (bind to the spike and block its association with the ACE-2 receptor, thereby preventing the virus from entering host cells) as well as activate innate immunity. Part of the reason the mRNA vaccines were able to move so quickly through early development and into phase III trials was that research into MERS/SARS spike proteins could be applied to SARS-CoV-2 proteins. If a different SARS-CoV emerges that is able to evade the antibodies produced in response to this SARS-CoV-2 spike antigen in the vaccines, the mRNA sequence could easily be tweaked to encode the antigen for this new virus and a new vaccine produced. Note that, while SARS-CoV-2 is being closely monitored, coronaviruses have a low mutation rate (especially compared to flu) and therefore it's unlikely that SARS-CoV-2 will mutate to the point that the vaccine will not be effective. I highly recommend Vincent Racaniello's free lectures and his TWiV podcasts for further virology information.

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L.C.
on November 23, 2020 at 13:33:41 pm

*adaptive immunity

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L.C.
on November 22, 2020 at 16:44:28 pm

Two answers as to why this is not a worry in the least: a) The vaccine antigen omits the cytoplasmic tail (S-2P is aa 1-1208 with 2P and cleavage site mutations, Wrapp et al. structure paper). b) Even if the vaccine construct included this sequence, note that it's the "cytoplasmic tail" of the spike - how would an antibodies produced in response to a vaccine bind an *intracellular* antigen?

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L.C.
on November 24, 2020 at 11:45:11 am

Does it work” by giving the body instructions to produce a protein which is present on the surface of the coronavirus”?
Does “the immune system then learns to recognise and produce antibodies against the protein”.

Imagine the damage that can be done if said protein is necessary because it serves to regulate iron in the blood.

“When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.”

Hepcidin is a peptide hormone produced primarily by the liver and secreted into the circulation. Its synthesis increases in response to iron and inflammation and decreases in response to erythropoiesis.

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N.D.
on November 24, 2020 at 12:08:08 pm

That should read:

Does it work” by giving the body instructions to produce a protein which is present on the surface of the coronavirus”?

Does “the immune system then learn to recognise and produce antibodies against the protein”?

If so, Imagine the damage that can be done if said protein is necessary because it serves to regulate iron in the blood.

“When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.”

“Hepcidin is a peptide hormone produced primarily by the liver and secreted into the circulation. Its synthesis increases in response to iron and inflammation and decreases in response to erythropoiesis.”

Since hepcidin regulation might end up being key to fighting other diseases, how does said RNA vaccine help regulate and balance hepcidin.

Finally, regarding first principles:

https://www.lifesitenews.com/news/former-pfizer-vp-no-need-for-vaccines-the-pandemic-is-effectively-overall

Does it make any sense to vaccinate those who are not at risk for developing a hyper immune response to Covid 19?

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N.D.
on November 25, 2020 at 05:34:26 am

My understanding is that you are broadly concerned about autoimmunity, i.e. antibodies erroneously recognize your own proteins and cause the immune system to attack your own body. At the end of this post I will come back to why mRNA vaccines are actually less dangerous in this regard. However, first let me explain that your specific concern about hepcidin is completely and utterly moot.

You are concerned that a very short portion of the spike protein is similar to hepcidin. Putting aside the role of hepcidin, let's first consider whether or not this portion of the spike protein will be in the vaccine. The sole research paper on this speculates that part of the cytoplasmic tail (the portion of the spike protein found on the inside of lipid membranes) shows some similarity in its amino acid sequence to hepcidin. Regardless of the strength of that claim, if that particular amino acid sequence is not present in the vaccine, then no antibodies could be produced to it and therefore, the vaccine contains zero risk of hepcidin autoimmunity.

So, does the vaccine contain this tiny portion of the spike protein? No. The spike protein is 1273 amino acids long. Papers on Moderna's vaccine indicate that they are using the 'Spike-2P (S-2P)' antigen. When I looked at the paper describing the S-2P antigen, it states that S-2P is amino acids 1-1208 of the spike protein. The cytoplasmic tail is amino acids ~1230-1273. Therefore, the protein antigen that is encoded by the vaccine mRNA lacks the very sequence you seem so worried about.

That mRNA encodes the instructions for proteins is a bedrock principle in molecular biology [it's literally named the Central Dogma of]. In fact, right now, your cells are producing lots of different mRNA that each encodes the different proteins that your cells need. mRNA has been likened to software - just as you can rerun the same computer code multiple times to reproduce the output of the code, each individual mRNA molecule is read multiple times to produce many copies of the protein it encodes. This is part of the beauty of newer vaccine technologies, including mRNA vaccines. Unlike putting in a dead version of the virus or getting infected naturally with the virus and therefore having your body exposed to multiple different viral proteins, mRNA vaccines make only one protein (S-2P, the slightly smaller version of the spike protein) and make lots of it. This increases the specificity of the immune response and should lower the risk of autoimmunity because there's only one foreign protein antigen.

To your final point, no test exists that can tell who is at risk of developing severe complications upon SARS-CoV-2 infection. There are attributes associated with worse disease - age is the clearest risk factor of course, some evidence exists that males tend to have worse disease outcomes than females, and there is a rapidly expanded pool of research into what specific kind of immune responses are associated with mild vs severe disease. However, there's no clear test that can be run that could separate people into "at risk for developing a hyper immune response" or not. Your link leads to 404, so I am unable to evaluate any of its claims.

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L.C.
on December 16, 2020 at 21:40:46 pm

After recently listening to a talk on the Moderna vaccine, it appears that I incorrectly assumed that the crystallization construct and the mRNA were exactly the same - the Moderna mRNA vaccine does use the full-length protein including the transmembrane domain. This fact does not invalidate the idea that (a) any worry about the spike protein and autoimmunity applies to both the actual virus and the vaccine, (b) furin cleavage sites present in both the viral spike protein and human hepcidin not imply any similarity of biological function between them or imply that antibodies would target both proteins and (c) any similarity in amino acid sequence is due to both hepcidin and the cytoplasmic tail of the spike protein having 8 cysteines. I did not initially further explain this since I felt this second reason (c) to discount your original hypothesis requires a fair amount of biological reasoning: Hepcidin is out in the extracellular environment, and those cysteines form disulfide bonds, giving hepcidin its characteristic 3-dimensional structure. Any auto-antibody towards hepcidin would therefore need to recognize that folded up structure, including the disulfide bonds. The cytoplasmic tail of the spike protein on the other hand sits near the cell membrane and possibly help stabilize the protein near the large hydrophobic surface (membrane). Any antigen generated from the cytoplasmic tail would not contain disulfide bonds since its the intracellular part of the protein. Even if the amino acid sequences were actually quite similar (as claimed), this conformational difference would make antigens unlikely to target both the cytoplasmic tail and hepcidin.

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L.C.
on November 17, 2020 at 10:28:27 am

And no, I am not an “anti-Vader”, just someone who recognizes that when it comes to vaccines, safety is paramount.

https://www.google.com/search?q=increase+in+hepcidin+in+covid+19&ie=UTF-8&oe=UTF-8&hl=en-us&client=safari

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N.D.
on November 17, 2020 at 10:47:44 am

Oops! That should read, I am not an “anti-Vaxer”, as safe vaccines have saved countless lives.

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N.D.
on November 24, 2020 at 12:23:26 pm

https://www.lifesitenews.com/news/california-bishop-warns-catholics-not-to-take-covid-vaccine-connected-in-any-way-to-aborted-babies

Every vaccine must be both safe and ethical, if it serves to affirm and sustain human life.

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N.D.
on November 26, 2020 at 01:16:56 am

https://www.google.com/search?q=why+is+there+an+increase+in+hepcidin+levels+in+severe+Covid++19+cases&ie=UTF-8&oe=UTF-8&hl=en-us&client=safari

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N.D.
on December 01, 2020 at 23:19:20 pm

Hi N.D.! I tried posting this comment earlier, but it isn't appearing. Furin is an extracellular protease - this means that it's a protein that functions like scissors to cut proteins into two pieces. Furin is an enzyme that cleaves any protein that contains a particular string of amino acids (a "cut here" marker). Furin is mainly found on the outside of cells in the extracellular space. Because it's an enzyme, furin cleaves many different protein targets (albumin, growth factors, matrix metalloproteinases [another kind of enzyme], hepcidin, pro-hormones, ...). Furin can also cleave viral proteins that stick out into the extracellular space (like the SARS-CoV-2 spike protein). Precisely as many of the articles you included state, the furin cleavage site in the extracellular domain of the spike protein increases the RBD's ability to bind ACE2.

Before continuing, I want to make sure that you are clear that the cytoplasmic tail of the spike is nowhere near the RBD or the furin cleavage site and that the cytoplamsic tail is not in the vaccine - if not, please let me know and I try to think of a clearer way to explain that again. I know biology can be dreadfully confusing about what is part of what. A protein is a string of amino acids that folds up into a 3D structure. A protein domain is a particular stretch (subset) of amino acids within a protein. Intracellular (inside the cellular membrane of a cell) and extracellular (the space between cells) are places where different proteins are found. Cytokines, antibodies, hormones, hepcidin, and the RBD of the spike are all extracellular while ribosomes (machines that translate mRNA into protein), ATP production, protein folding, viral replication, and many other processes all happen inside the cell. Two questions to always be aware of with biological questions are Where and When is X happening. Great primer on the immmune system and COVID: https://www.theatlantic.com/health/archive/2020/08/covid-19-immunity-is-the-pandemics-central-mystery/614956/ Best overall 'picture' of a cell: https://t.co/YERCmdIJXH?amp=1

Ok, so while it's true that furin cleaves both hepcidin and the spike protein, this does not imply that somehow the spike protein itself affects iron regulation. Furin just cleaves anything that has the "cut here" string of amino acids. Rather, immune responses lead to increased cytokines (such as IL-6) and therefore increased hepcidin/lower serum iron levels. Cytokines have effects on multiple different cell types in multiple different organs besides iron regulation in the liver (blood vessels, B and T cells, neutrophils, neurons, blood stem cells, .... ). In fact, from the abstract of the paper you've posted multiple times: "In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic MARKER of disease progression, or a key MODULATOR in disease pathogenesis [emphasis mine]." Iron dysregulation may certainly turn out to be a key driver COVID-19 disease severity. However, this modulation of disease severity occurs far AFTER exposure to the virus and AFTER the battle between the replicating virus and your immune system is well underway.

A vaccine is designed to induce a specific subset of immune responses. You need a bit of inflammation to alert your body to make antibodies [why vaccines can often give you a fever for a day or so]. But the immune responses to a vaccine stop there because the vaccine cannot replicate. Unlike the vaccine, the virus doesn't stop. The virus keeps replicating and can keep triggering immune responses and more and more inflammation. Therefore, a vaccine (in any form) is highly unlikely to give you the kind of runaway inflammation associated with COVID-19 severe disease. In particular, the mRNA vaccines are highly unlikely to contribute to a sustained inflammatory response [remember, there's no danger of hepcidin autoimmunity because the vaccine lacks that sequence]. Because mRNA is fairly rapidly degraded, the entire vaccine will vanish from your body, leaving behind only your trained adaptive immune system. Of course, immunology is complicated and the testing (which has been underway since March for the mRNA vaccines) in people is crucial. And while safety data from the mRNA trials is not yet fully available, the lack of adverse side effects worse than a fever in >70k study participants between the two is cause for optimism.

- Your friendly neighborhood biologist

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L.C.
on November 19, 2020 at 05:17:21 am

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774025/

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N.D.
on November 19, 2020 at 09:33:54 am

Is it possible that the addition of this cysteine rich peptide is what makes Covid 19 novel?

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N.D.
on November 25, 2020 at 12:12:59 pm

Nope. The one speculative paper asserting m the sequence similarly between the cytoplasmic tail and hepcidin shows that this small portion of the spike protein is present in SARS and MERS viruses and iirc also in related cold viruses.

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L.C.
on November 28, 2020 at 20:17:44 pm

So are you suggesting that the spike protein is similar or the same? What accounts for the spike of Hepcidin production leading to hypoxia in some who are exposed to Covid 19 cold virus versus others whose Hepcidin levels do not appear to be elevated? Is a vaccine necessary for the general public when it appears that it is the immune response due to elevated Hepcidin levels when exposed to Covid 19 that appears to be the real danger in regards to exposure to Covid 19?Have they tested the Hepcidin level of those persons involved in the Vaccine trial before and after receiving the vaccine to see whether or not the Hepcidin levels increase or decrease? Since too little or too much Hepcidin can result in disease, do we know whether the vaccine may change this delicate balance over time? Is there a better way to treat the increase in the protein Hepcidin?

For example:

https://academic.oup.com/jcem/article-abstract/105/4/e1056/5733667

Best regards,

Nancy

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on November 29, 2020 at 19:09:27 pm

I will only respond here to your first question on the spike protein: I'm unclear what comparison you are implying, so I will describe several. The SARS-CoV-2 spike protein has multiple parts (also called domains). The Receptor Binding Domain (RDB) on the extracellular portion of the SARS-CoV-2 protein is notably different from the RBD of MERS or SARS - this is the business end of the spike protein. The RBD domain of just over 200 amino acids is where the spike protein binds the host receptor ACE2, causing viral entry into a host cell. The increased affinity of the SARS-CoV-2 RBD for ACE2 over the RBD of SARS/MERS/related cold viruses is likely a large part of why SARS-CoV-2 is more infectious than SARS/MERS. For example, this increased affinity for ACE2 likely explains why it can replicate in the upper respiratory tract, potentially explaining why people are infectious [virus being emitted during exhaling] before presenting symptoms [virus attacking lower respiratory tract]. On the other hand, the cytoplasmic tail is a domain within the spike protein far from the RBD - in fact these domains are separated from each other by a lipid membrane since the spike protein is a transmembrane protein. This cytoplasmic part of the protein is virtually identical between SARS and SARS-CoV-2. There is one paper claiming similarity just between the cytoplasmic tail and Hepcidin. The paper is entirely speculative and, based on my training in molecular biology, I find the evidence presented as the basis for the similarity between the secreted, extracellular hormone hepcidin and the cytoplasmic tail to be quite weak. So in summary: parts of the spike protein are quite different between SARS-CoV-2, and SARS-family viruses (e.g. the RBD) while other parts are similar (e.g. the cytoplasmic tail). Since the cytoplasmic tail is nearly identical between SARS and SARS-CoV-2, this part of the protein is unlikely to be driving the differences seen in the diseases caused by these two viruses.

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L.C.
on November 29, 2020 at 20:35:22 pm

Iron regulation is one of many systemic processes that are disrupted during COVID-19 disease. Several papers show that hepcidin increases in severe COVID-19 cases and may be a good biomarker correlated with disease severity. However, it's one of *many* possible biomarkers for COVID-19 severity and one of ***many*** possible reasons for some people having no disease and some people having severe disease after SARS-CoV-2 infection. Immunology is not my particular area of expertise, however my background in molecular biology does allow me some understanding of SARS-CoV-2. The literature on hepcidin is pretty clear that inflammation causes an increase hepcidin (mainly through IL-6/STAT pathway). In severe COVID-19, it's unclear whether iron dysregulation just one of many processes going haywire downstream of severe inflammation or if it is directly contributing to disease severity. This will require lots more animal model work as well as clinical trials to figure out conclusively. Until then, it's a reasonable hypothesis among many reasonable hypotheses. There are several clinical trials registered looking at the effect of iron and IL-6 regulators on severe COVID-19 disease. Some of them however have been terminated because now steroids like dexamethasone are part of the standard of care. Since steroids decrease inflammation, they are likely to also decrease IL-6 levels and thus hepcidin levels.

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L.C.
on November 30, 2020 at 18:17:30 pm

https://science.thewire.in/the-sciences/coronavirus-spike-protein-ace2-furin-tropism/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264936/

It appears that iron regulation is a main if not the main systemic process that is disrupted during exposure to Covid 19, and that is precisely why I am concerned that a vaccine that can further disrupt iron regulation for those most vulnerable should be tested to determine whether the vaccine has the potential to cause a serious immune reaction that could be fatal for those who are susceptible to “persistent alterations of iron deregulation”.

The fact that those who are most vulnerable to a fatal response to Covid 19 have diseases that result in or are a result of “persisting alterations of iron metabolism”, most likely due to “an alteration in hepcidin expression, which is the key regulator of iron, is telling. Could the increase “affinity for ACE 2 be due to “the binding of the ACE2 receptor and fusion with cell membrane activated by Furin protease”?

https://www.biorxiv.org/content/10.1101/2020.04.18.047951v2

“The conversion of prohepcidin to hepcidin is mediated by the prohormone convertase Furin.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366646
https://ashpublications.org/blood/article/111/2/924/103758/Furin-mediated-release-of-soluble-hemojuvelin-a

L.C., based on your training in molecular biology, have you become familiar with hepcidin and it’s relationship to Furin?

Thank you for taking the time to address my concerns.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264936/

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N.D.
on November 29, 2020 at 17:55:57 pm

Godspeed to all who travel here!

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Nancy
on December 01, 2020 at 17:57:44 pm

Hi N.D. - your friendly neighborhood biologist here! Furin is an extracellular protease - this means that it's a protein that functions like scissors to cut proteins into two pieces. Furin is an enzyme that cleaves any protein that contains a particular string of a few amino acids (a "cut here" marker). Furin is mainly found on the outside of cells, in the extracellular space. Because it's an enzyme, furin cleaves many different protein targets (albumin, growth factors, matrix metalloproteinases, hepcidin, pro-hormones, ...). Furin can also cleave viral proteins (like the SARS-CoV-2 spike protein). Precisely as many of the articles you included state, the furin cleavage site in the extracellular domain of the spike protein increases the RBD's ability to bind ACE2. This presence of a "cut here" sequence is thought to be a major driver of the differences between SARS and SARS-CoV-2.

Before continuing, I want to make sure that you are clear that the cytoplasmic tail of the spike is nowhere near the RBD or the furin cleavage site and that the cytoplamsic tail is not in the vaccine - if not, please let me know and I try to think of a clearer way to explain that again. I know biology can be dreadfully confusing about what is part of what. Technically the intro to papers should cover what you need to know, but much of the time they don't provide nearly enough context. Lectures and textbook articles, as well as review articles, are great places to get some of that context. A protein is a string of amino acids that folds up into a 3D structure; a protein domain is a particular stretch of amino acids within a protein. Intracellular (inside the cellular membrane of a cell) and extracellular (the space between cells) are places where different proteins are found. Cytokines, antibodies, hormones, hepcidin, and the RBD of the spike are all extracellular while ribosomes (the machines that translate mRNA into protein), protein folding, viral replication and viral particle assembly happen inside the cell. Two questions to always be aware of with biological questions are Where and When is X happening. My favorite view of a cell: http://www.digizyme.com/cst_landscapes.html. A far clearer explanation of the immune system: https://www.theatlantic.com/health/archive/2020/08/covid-19-immunity-is-the-pandemics-central-mystery/614956/

Ok. So while it's true that furin cleaves both hepcidin and the spike protein, this does not imply that somehow the spike protein itself affects iron regulation. Furin just cleaves anything that has the "cut here" string of amino acids. Rather, the immune responses (innate immunity responses to viral ssRNA, T-cell, B-cell, inflammation, etc) due to the presence of viral particles can lead to increased cytokines (such as IL-6) and therefore increased hepcidin/lower serum iron levels. Inflammation triggered by cytokines has effects on multiple different cell types in many different organs besides iron regulation in the liver (blood vessels, B and T cells, neutrophils, neurons, blood stem cells, .... ). In fact, from the abstract of the paper you've posted multiple times: "In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic MARKER of disease progression, or a key MODULATOR in disease pathogenesis [emphasis mine]." Iron dysregulation may certainly turn out to be a key driver COVID-19 disease severity. However, this modulation of disease severity occurs far AFTER exposure to the virus and AFTER the battle between the replicating virus and your immune system is well underway.

A vaccine is designed to induce a specific subset of immune responses. You need a bit of inflammation to alert your body to make antibodies [why vaccines can often give you a fever for a day or so]. But the inflammation triggered by vaccines necessarily stops because the vaccine cannot replicate. Unlike the vaccine, the virus doesn't stop. The virus keeps replicating and can keep triggering immune responses and more and more inflammation. Therefore, a vaccine (in any form) is highly unlikely to give you the kind of runaway immune responses like that associated with severe COVID-19. In particular, the mRNA vaccines are highly unlikely to contribute to a sustained inflammatory response [remember, there's no danger of hepcidin autoimmunity because the vaccine lacks that sequence]. Because mRNA is fairly rapidly degraded, the entire vaccine will vanish from your body, leaving behind only your trained adaptive immune system. Of course biology and particularly immunology is extremely complicated with certain molecules acting in opposite ways in different contexts, so nothing is guaranteed. But, while safety data from the mRNA trials is not yet fully available, the lack of adverse side effects worse than a fever in >70k study participants between the two trials is cause for optimism.

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L.C.
on December 02, 2020 at 09:33:04 am

Thank you, L.C.. Is it possible that it is this difference that makes the immune reaction to Covid 19 so deadly for the vulnerable population, when you include the fact that “ as the population ages, increasing attention has become focused on the prevalence of anemia in elderly individuals. Anemia occurs in more than 10% of individuals who are older than the age of 65 years, and it increases to more than 50% in individuals who are older than the age of 80 years”?
https://www.ncbi.nlm.nih.gov › pmc
Anemia in the Elderly - NCBI - NIH

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N.D.
on December 02, 2020 at 15:35:08 pm

Anytime! I think it's a fairly reasonable hypothesis that anemia may be part of the reason older individuals tend to have more severe COVID-19, although I don't have enough background atm to truly evaluate it. Right now, other than sickle cell anemia, I'm not finding much information on people with pre-existing anemias who get COVID - hopefully as more and more data comes out, the hypothesis can be refined, refuted, or strengthened. However, lots of things change with age (T-cell responses are slower for example) and immune responses to a virus can throw lots of homeostatic processes out of whack, so while I would not be surprised to see anemias as one risk factor, I am inherently skeptical that it would be the main age-associated risk factor without more data.

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L.C.
on December 02, 2020 at 15:48:25 pm

Also, on the vaccine safety front, since there's positive news in that arena today with UK's approval - the designs and initial manufacture of the vaccines (esp the mRNA one) occurred back in February right after the genome sequence was available. Everything since then has been checking for safety and then for efficacy. On efficacy, I'm a bit surprised that the Moderna and Pfizer trials are only testing for asymptomatic infection post-hoc (seeing if trial participants have anti-N antibodies which could only come from viral infection and not the vaccine), so we'll have to wait to see if the vaccines actually reduced transmission of the virus. But having something that reduces severe disease is super awesome - there's really no antiviral better than our own adaptive immune systems!

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L.C.
on January 11, 2021 at 21:45:02 pm

Hi L.C.,
Just found this very interesting article which makes me wonder why they found the spike protein on the Covid 19 coronavirus to be novel. See page 5, where it becomes clear the spike on Covid 19 is not novel after all

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086990/

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N.D.
on January 12, 2021 at 18:03:19 pm

And these:

Overall, furin preactivation can facilitate SARS-CoV-2 to enter some types of cells (particularly those with low expressions of TMPRSS2 and/or lysosomal cathepsins) (Fig. 6A).

https://www.pnas.org/content/117/21/11727

https://www.rethinkanemiaofckd.com/more-than-epo-and-iron.html

https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008461

Which begs an answer to the question, how was the FURIN site added to SARS COV to become COVID 19, and does MERS have anything to do with it?

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N.D.
on January 12, 2021 at 18:12:55 pm

I may have left out this article:

https://jvi.asm.org/content/92/19/e00683-18

Thank you, L.C.

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N.D.
on December 01, 2020 at 18:15:51 pm

Hi N.D. - your friendly neighborhood biologist here! Furin is an extracellular protease - this means that it's a protein that functions like scissors to cut proteins into two pieces. Furin is an enzyme that cleaves any protein that contains a particular string of amino acids (a "cut here" marker). Furin is mainly found on the outside of cells in the extracellular space. Because it's an enzyme, furin cleaves many different protein targets (albumin, growth factors, matrix metalloproteinases [another kind of enzyme], hepcidin, pro-hormones, ...). Furin can also cleave viral proteins that stick out into the extracellular space (like the SARS-CoV-2 spike protein). Precisely as many of the articles you included state, the furin cleavage site in the extracellular domain of the spike protein increases the RBD's ability to bind ACE2.

Before continuing, I want to make sure that you are clear that the cytoplasmic tail of the spike is nowhere near the RBD or the furin cleavage site and that the cytoplamsic tail is not in the vaccine - if not, please let me know and I try to think of a clearer way to explain that again. I know biology can be dreadfully confusing about what is part of what. A protein is a string of amino acids that folds up into a 3D structure. A protein domain is a particular stretch (subset) of amino acids within a protein. Intracellular (inside the cellular membrane of a cell) and extracellular (the space between cells) are places where different proteins are found. Cytokines, antibodies, hormones, hepcidin, and the RBD of the spike are all extracellular while ribosomes (machines that translate mRNA into protein), ATP production, protein folding, viral replication, and many other processes all happen inside the cell. Two questions to always be aware of with biological questions are Where and When is X happening. Great primer on the immmune system and COVID: https://www.theatlantic.com/health/archive/2020/08/covid-19-immunity-is-the-pandemics-central-mystery/614956/ Best overall 'picture' of a cell: https://t.co/YERCmdIJXH?amp=1

Ok, so while it's true that furin cleaves both hepcidin and the spike protein, this does not imply that somehow the spike protein itself affects iron regulation. Furin just cleaves anything that has the "cut here" string of amino acids. Rather, immune responses lead to increased cytokines (such as IL-6) and therefore increased hepcidin/lower serum iron levels. Cytokines have effects on multiple different cell types in multiple different organs besides iron regulation in the liver (blood vessels, B and T cells, neutrophils, neurons, blood stem cells, .... ). In fact, from the abstract of the paper you've posted multiple times: "In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic MARKER of disease progression, or a key MODULATOR in disease pathogenesis [emphasis mine]." Iron dysregulation may certainly turn out to be a key driver COVID-19 disease severity. However, this modulation of disease severity occurs far AFTER exposure to the virus and AFTER the battle between the replicating virus and your immune system is well underway.

A vaccine is designed to induce a specific subset of immune responses. You need a bit of inflammation to alert your body to make antibodies [why vaccines can often give you a fever for a day or so]. But the immune responses to a vaccine stop there because the vaccine cannot replicate. Unlike the vaccine, the virus doesn't stop. The virus keeps replicating and can keep triggering immune responses and more and more inflammation. Therefore, a vaccine (in any form) is highly unlikely to give you the kind of runaway inflammation associated with COVID-19 severe disease. In particular, the mRNA vaccines are highly unlikely to contribute to a sustained inflammatory response [remember, there's no danger of hepcidin autoimmunity because the vaccine lacks that sequence]. Because mRNA is fairly rapidly degraded, the entire vaccine will vanish from your body, leaving behind only your trained adaptive immune system. Of course, immunology is complicated and the testing (which has been underway since March for the mRNA vaccines) in people is crucial. And while safety data from the mRNA trials is not yet fully available, the lack of adverse side effects worse than a fever in >70k study participants between the two is cause for optimism.

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L.C.
on December 05, 2020 at 16:41:17 pm

Hi L.C.,

Since it appears that, “This presence of a "cut here" sequence is thought to be a major driver of the differences between SARS and SARS-CoV-2”, it seems logical to assume that, because “the furin cleavage site in the extracellular domain of the spike protein increases the RBD's ability to bind ACE2”, this would explain why SARS-CoV-2 is more infectious than SARS.

We know that “Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease.”

https://academic.oup.com/ajcn/article/106/suppl_6/1559S/4823167

We also know that, “The finding that deadly bacterial and viral pathogens usurp the furin pathway to exert their virulence strongly argues for a strategy that targets furin for therapeutic intervention, even though such a strategy would have to consider that the very prevalence of furin might also create toxicity in the drugs that target it. Nevertheless, furin holds great promise as a key to solving both theoretical and practical questions in cell biology.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1964754/

Do we know whether, in fact, a vaccine is necessary for those who already have “anti- N antibodies”, which it seems logical to assume could be determined for those involved in the study, prior to their having received the vaccine?

Given the fact that, “The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade”, one cannot help but wonder where that cleavage site came from.

Do we know how a RNA vaccine will affect that cleavage site, that is essential in embryogenesis” but can be detrimental in some adults who are vulnerable to hypoxia?
Since too little or too much Hepcidin can result in disease, do we know whether the vaccine may change this delicate balance over time?

And finally, rather than vaccinate a whole people against a disease that many already are immune to, does it make sense to try to “Control the Systemic Iron Homeostasis by the Hemojuvelin-Hepcidin Axis ?

https://academic.oup.com/advances/article/1/1/38/4591552

Thank you once again for taking the time to address my concerns.

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N.D.
on December 07, 2020 at 11:52:20 am

And finally, is it possible that the SARS virus was manipulated in a lab by the addition of a cytoplasmic tail with cleavage site mutations, either for good or for ill? This, of course, would explain why from the beginning, the WHO knew that this virus would be detrimental to a certain vulnerable group of persons, the elderly and those who have compromised immune systems, while remaining mild for most of those who do not have a major underlying health condition such as “diabetes, hypertension, obesity, cardiovascular disease, kidney disease, or pulmonary disorders”.

First principles always matter if you want to get to get to the truth of the matter.

https://www.google.com/search?q=bats+with+hemochromatosis&ie=UTF-8&oe=UTF-8&hl=en-us&client=safari

https://www.google.com/search?q=furin+and+hemochromatosis&ie=UTF-8&oe=UTF-8&hl=en-us&client=safari

https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-018-1020-x

https://www.google.com/search?q=studies+on+improving+furin+cleavage+sites&ie=UTF-8&oe=UTF-8&hl=en-us&client=safari

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N.D.
on December 14, 2020 at 05:04:58 am

This will be my final response N.D. since I refuse to go anywhere near "the WHO purposefully made the virus" territory.

Regarding furin sites: Think of how many different things in your house have a perforated "Tear Here" line - everything from payroll check to a bag of chips. The fact that the object is torn apart can majorly change how it is used (I get to now cash my check or eat my chips), however the existence of "Tear Here" instructions doesn't imply any sort similarity in function of a paystub and a bag of chips. Besides, many other things also use "Tear here" or "cut here" lines (ketchup packets, Amazon packages, hot chocolate mixes, etc). So your question about "the mRNA vaccine affecting a cleavage site important in embryogenesis" is complete gooblygook - the equivalent of asking how a W2 tax form is going to affect a hot chocolate mix since they both require tearing. In other words, the mRNA produces a protein (spike protein) that does have furin cleavage site, and hepcidin also has an important furin cleavage site, but those two facts don't affect each other in any biologically meaningful way.

Think of catching the virus as your house catching on fire. Most fires are small stove-top flares that are immediately put out (people who have mild cold/flu-like symptoms), while others turn the entire structure to ash (people who have severe Covid-19 complications). Your worry about iron homeostasis is like worrying that a fire will cause water damage to important documents in your house. Is it true - likely. Is it a problem - sure. But is it the entire picture? No. Water damage to, say, your birth certificate, from sprinklers or from a fire hose is a secondary consequence of the fire - replacing your waterlogged birth certificate is just of one of many, many issues that will have to be dealt with as a consequence of the fire. Even if it were possible to protect your birth certificate inside a waterproof and fireproof box (e.g. a medicine that would guarantee iron homeostasis), that won't put out the rest of the fire (e.g. viral lung damage, kidney damage, heart damage, neuronal damage) or even prevent the fire in the first place. But there is something that can prevent the fire (virus) in the first place - a vaccine.

It's normal to be skeptical of a vaccine - why should I get jabbed and deal with a fever for a day when I'm otherwise healthy? In the long run, there are basically four outcomes: get the virus, get a vaccine, never breath near another human, or get plum lucky. The last two options are not sustainable longterm. This leaves getting the virus or getting the vaccine. As an aside, if you are immunocompromised, you rely on everyone else is getting the vaccine and protecting you via herd immunity [a further aside: herd immunity applies to vaccine-acquired immunity and has never been observed for naturally-acquired immunity]. A vaccine, by definition, gives you a tiny part of the virus - basically a "Most Wanted" poster so that your immune system can recognize and attack the virus faster next time you encounter it. Since the vaccine gives you just a little part of the virus, via first principles, the vaccine will be safer than the complete virus. Of course biology is complicated, so scientists actually test things to determine how well they work in addition to relying on first principles. We knew that mRNA vaccines would basically be SnapChats - the mRNA will generate a bunch of "Most Wanted" posters for the immune system and then disappear quickly, leaving only your immune memory. While in theory mRNA vaccines are amazing and safer than other vaccine formulations, I only believed it once I saw that (both) the Pfizer and Moderna vaccines passed efficacy and safety thresholds. Of course there is always further information to suss out (effect on viral transmission and final vaccine longterm safety), the data so far is truly remarkable. The graph with the blue-placebo and red-vaccine cumulative COVI-19 cases from Pfizer has been one of the few bright spots in a year in which over 300,000 Americans have died from COVID-19. Thousands of formerly healthy individuals will also have live with longterm complications from COVID-19 that are still not entirely clear. Remember, we only have a few more months of data on "longterm effects" of the virus than we do of the vaccine. And, any theoretical concern you have about the spike protein (including its relationship to hepcidin) applies equally, if not more so, to actually getting infecting with the virus because the spike protein is a crucial part of the virus. Given all that, yes, healthy people should absolutely get any approved vaccine.

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L.C.
on December 18, 2020 at 15:30:49 pm

L.C., From the beginning my concern has been that the elderly, the immune compromised, and those with severe co morbidities, when exposed to the novel Coronavirus, are most likely to have a fatal inflammatory response due to what may very well be the result of an imbalance in iron homeostasis, which is regulated by the hormone, hepcidin.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801113/

https://www.gao.gov/assets/720/710831.pdf

Here is a list of possible vaccines against Covid 19 from the above pdf, page 15

1. mRNA platform

mRNA -Encapsulated genetic instructions that allow vaccinated individuals to produce spike protein of SARS-CoV-2 (No vaccine using this technology has ever been licensed by FDA)

2. Replication-defective live-vector platform

Non-replicating virus that delivers genetic instructions to allow vaccinated individuals to produce spike protein of SARS-CoV-2. (No vaccine using this technology has ever been licensed by FDA)

3. Recombinant-subunit-adjuvanted protein platform

Fully -formed spike protein of SARS-Cov-2 delivered with adjuvant, which helps to stimulate immune system of vaccinated individuals. ( Example-Seasonal influenza vaccine licensed by FDA)

4. Attenuated replicating live-vector platform

Replicating virus that delivers genetic instructions to allow vaccinated individuals to produce spike protein of SARS-CoV-2. (Example- Ebola vaccine licensed by FDA)

“The public is told, he says, that with respect to these vaccines, the mRNA “will go into the cell and instruct the DNA to code a particular protein, which will then fight against the virus.”
Since these mRNA vaccines are novel, and thus a new type of vaccine, and , according to CDC, “ the mRNA from the vaccine, never enters the nucleus of the cell and does not affect or interact with a person’s DNA”, but rather mRNA vaccines “take advantage of the process that cells use to make proteins in order to trigger an immune response and build immunity to SARS-CoV-2”, why hasn’t the CDC revealed the particular protein that will be coded, least that particular protein can be both beneficial and harmful, and an excess or a shortage of that particular protein, could, in essence, cause a problematic immune response, putting someone at risk who would have had an appropriate immune response, had they not received the vaccine?
The fact that the particular protein targeted may be a protein involved in the regulation of hepcidin and thus iron regulation and homeostasis necessary for embryogenesis, for proper growth and development, as well as for various other biological functions in the body, such as respiratory functions and the transport of oxygen, fighting infection etc., and the fact that “the conversion of prohepcidin to hepcidin is mediated by the prohormone convertase furin, is of the utmost importance and precisely why it is important to know how an immune response to the particular protein targeted in the vaccine, will effect iron homeostasis immediately or in the future.

https://www.gao.gov/assets/720/710831.pdf

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N.D.
on December 20, 2020 at 20:29:49 pm

I don't believe I fully understand your concern: so let me see if I am able to restate it. N.D., your concern is that a vaccine (and particularly the mRNA one) will somehow reduce the amount of hepcidin in vaccinated people (via furin??), and therefore potentially worsen a future infection with SARS-CoV-2. Is this correct?

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L.C.
on January 06, 2021 at 03:20:07 am

I came across a really cool paper that looked at autoimmunity in COVID-19 disease patients against nearly all human extracellular proteins (including testing for autoantibodies against hepcidin, the HAMP gene product). While they don't explicitly state that the don't find hepcidin autoantibodies, they find strong evidence of autoantibodies targeting immune modulators in patients with severe COVID-19. The kind of large inflammatory response needed to generate these kinds of autoantibodies is found in severe and not mild COVID and has not been seen in any of the vaccine data. Here's a far better explanation: https://www.youtube.com/watch?v=RZMOC0q7Al8&feature=youtu.be

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L.C.
on January 13, 2021 at 14:40:46 pm

L.C.,

In regards to the video, https://www.youtube.com/watch?v=RZMOC0q7Al8&feature=youtu.be, Is the researcher suggesting that the Covid 19 vaccine is safe because it has been demonstrated to not result in the production of any autoantibodies? Is it possible that the presence of auto antibodies correspond with the level of hepcidin or that the body’s attack against a low grade infection can be taxing the natural Cortisol and Hypothamic-Pituitary-Adrenal Axis, resulting in hypoxia, inflammation, and an imbalance of iron,
the proper balance of which is necessary for the endocrine system to function properly?

We all have various microbes in our bodies. It is when “our immune system is weakened, and these microbes enter a normally sterile part of the body, that infection occurs”. There exists other types of pathogens that are not naturally occurring in our bodies, and can also cause an immune response, which can be deadly.

Certainly it would have made sense, given what is known about inflammation, and the role insufficient or excessive iron has been shown to play in disease and hypoxia, to consider hepcidin levels when testing the effectiveness of a Covid 19 vaccine, for those most vulnerable to having a serious and possibly deadly, reaction to Covid 19.

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N.D.
on January 16, 2021 at 05:10:28 am

While I really appreciate that this conversation is public, the formatting of these comments is abysmal and the pace of the conversation not conducive to understanding/a structured argument. If you like to talk further, I'd happy to continue this conversation and can be reached at lec ote at uchicago period edu (no spaces).

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L.C.
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