#VitaminDStopsCOVID - COVID-19, flu and sepsis are only serious problems because of the Vitamin D Pandemic, which can and must be fixed

Robin Whittle rw@firstpr.com.au  31 January 2021
Be sure to read the Disclaimer: about/ .

Please see Over 200 Scientists, Doctors, & Leading Authorities Call For Increased Vitamin D Use To Combat COVID-19https://vitamindforall.org/letter.html  Also, an anonymous meta-analysis of recent vitamin D COVID-19 observational and intervention trials: https://vdmeta.com .

Contents

Page
Description
Last update
2020-
about/
Purpose, contact and copyright details.  The Nutrition for Immune System Health email discussion list. The Open Letter Google Groups discussion list of Karl Pfleger and Gareth Davies. Disclaimer - I am not a doctor etc.
2020-11-16
#update-2021-01-31
Please read this before reading any other sections or pages
2021-01-31
01-supp/
My suggestions for how to calculate vitamin D supplementation quantities as a ratio of bodyweight, rather than using the traditional approach of age groups, where age is a proxy for weight. 

The story behind the US Institute of Medicine, in 2011, calculating the RDA for vitamin D3 to attain at least 20ng/ml 25OHD in 97.5% of the population as 600 IU, when the real figure is closer to 7000 IU.  Most doctors and D3 recommended intake committees are working as if the 600IU figure was true.

My proposed 25plusD3 dual 25OHD and bolus D3 suggestion for treating severe or potentially severe COVID-19 and influenza, and sepsis.  (Sepsis is always potentially deadly within hours.)
2020-12-12
01-supp/a-ratios/ How I derived these ratios from the work of Ekwaru et al. 2014.
2020-11-06
01-supp/b-grh/
Analysis of the results of the GrassRootsHealth vitamin D supplementation calculator, which works internally on ratio of bodyweight.
2020-11-05
02-autocrine/
An illustrated explanation of autocrine and paracrine signaling, with two examples from peer-reviewed articles.

Almost all of the functions of the vitamin D compounds involve autocrine signaling (inside a cell) and paracrine signaling (to nearby cells).   Yet few people understand this, and mistakenly think "vitamin D is a hormone" or some other mixed up idea such as circulating 1,25OHD (the hormonal function, for calcium-bone metabolism) somehow "regulating" immune responses.

Read this page and understand!   Then you will be able to understand the highly significant McGregor et al. article which describes exactly how lack of 25OHD in the lungs of patients with severe COVID-19 causes autocrine signaling in Th1 lymphocytes to fail - leaving them in the hyper-inflammatory state which causes severe COVID-19/
2020-12-21

Please also see my original and more extensive site: https://aminotheory.com/cv19/ and my Twitter outpost: https://twitter.com/RobinWhittle3 .


#update-2021-01-31

#update-2021-01-31 for aminotheory.com/cv19/ and VitaminDStopsCOVID.info

The domain name, based on Vitamin D Stops COVID has turned out to be overly-optimistic, considering new variants of the virus which are significantly more transmissible than those which were strongly suppressed in the UK summer of 2020.   More worryingly, researchers have evolved further mutations (without creating viruses with these mutations) which will be very much more transmissible than even the currently most transmissible variants: the independently evolved but otherwise identical South African and Brazilian variants, which are more transmissible than the recent "British" variant.

I will retain the domain name for now, but please read the following update: Vitamin D is vitally important, but I think vaccination and some masks and social distancing will play an important role in suppressing COVID-19 (hopefully not outright lockdowns and travel restrictions) for the next few years and perhaps indefinitely.   If we could suddenly get everyone, in most or all countries, up to 50ng/ml vitamin D blood levels, then this would make a huge difference, but is probably not enough on its own to render all other control measures unnecessary.   There's no prospect of this occurring in the next year or so, because the forces of resistance against such population-scale vitamin D supplementation remain very strong and because there is not yet sufficient global production capacity to supply this.


In mid- to late-2020 my sites https://aminotheory.com/cv19/ and https://VitaminDStopsCovid.info conveyed arguments including my view that the UK 2020 summer lull in COVID-19 transmission and severity was due primarily to increased solar UV-B skin exposure raising vitamin D (25OHD blood levels) of most people in the country sufficiently to, on average:

1 - Strengthen the direct immune responses to the virus, which are especially weak, on average, in winter and spring.  Low vitamin D causes autocrine (internal) signaling in immune and other cells to fail: https://vitamindstopscovid.info/02-autocrine/ .  So initial defenses were stronger in summer and autumn.

2 - Reduce the hyperinflammatory immune dysregulation (also caused by autocrine signaling failure in immune cells due to low blood vitamin D 25OHD levels), which causes some people to have severe, debilitating, lastingly harmful and sometimes deadly, severe COVID-19.  Low vitamin D is the most common, most important, easily correctable cause of this.  See also https://aminotheory.com/cv19/#helminthsgone for why, without intestinal parasites, and with considerable individual genetic variation, almost all humans (and domestic dogs and cats) have systematically overly-strong, self-destructive, inflammatory immune responses.

3 - Reduce the more thorough spread (with winter-spring low vitamin D levels) of the virus in the body and so overall symptom severity.  This summer increase in vitamin D levels across the UK population reduces the total number of viruses shed by each infected person, on average.   I regard this as the most important cause of reduced transmission, with UV-B inactivation of viruses outdoors a second factor.   I surveyed the research on UV-B seasonality (I have not had time to finalise this on a web page, but if you want a copy of the draft, please email me) and found strong results showing COVID-19 seasonality is driven primarily by UV-B radiation changes.  There was mixed research results and unconvincing arguments for the importance of outdoor high temperatures and/or humidity.  (These are of marginal importance, since in-building and in-vehicle conditions are generally maintained by heating and air conditioning to be the opposite of summer and winter extremes - and most close human contact occurs in vehicles and buildings.)

The high UV-B of summer-autumn has two possible mechanisms for suppressing COVID-19, influenza etc. transmission and severity: Firstly, high vitamin D levels, which are pervasive, last for months and profoundly affect immune responses.  Secondly, and I am sure much less importantly, UV-B inactivates viruses on surfaces and in aerosols, but only outside buildings and vehicles, since glass blocks UV-B.

Since, as best we know, UK average 25OHD levels were around 25ng/ml in summer, I argued that robust (e.g. 0.125mg 5000 IU D3 / day for 70kg adults: https://vitamindstopscovid.info/01-supp/ ) supplementation, which will raise average 25OHD levels to about 50ng/ml all year round, and so roughly double the peak summer UK average levels, would suppress COVID-19 transmission and severity much more substantially than in that UK summer (as with influenza) to the point of, as I wrote:

. . . there would be no need for lockdowns, social distancing, masks or vaccines.

However, I am no longer confident about this, primarily because of current and likely future mutations in the viral genome which significantly enhance its transmissiblity - and perhaps (it would not be surprising) the severity of symptoms.  The combination of three  mutations in a South African / Brazilian (the two evolved separately but are the same) variant is raising most concern in late January 2021:

The lethal triad: SARS-CoV-2 Spike, ACE2 and TMPRSS2. Mutations in host and pathogen may affect the course of pandemic
Matteo Calcagnile, Patricia Forgez, Marco Alifano, Pietro Alifano Preprint 2021-01-14
https://www.biorxiv.org/content/10.1101/2021.01.12.426365v1

Shin Jie Yong's 2021-01-30 research roundup at  https://shinjieyong.medium.com/

More detailed, and worrying, molecular-level, details can be found in this French - Israeli preprint (AKA not yet peer reviewed):



SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor
Jiri Zahradnik et al.  Preprint (2nd version) 2021-01-29
https://www.biorxiv.org/content/10.1101/2021.01.06.425392v3

Here are some key points - but remember that I am an electronic technician trying to understand and summarize bleeding edge virology: 
  • The researchers used yeast rather than viruses to evolve genetic variations on the SARS-CoV-2 spike protein Receptor Binding Domain (RBD the part of the protein which matches the ACE-2 receptor.  This automated process evolves genetic variants far faster (days weeks and maybe a month or two) than can occur in SARS-CoV-2 viruses in the wild (months and years).

  • They were primarily interested in finding novel structures which would bind very tightly to the ACE-2 receptor without upsetting its normal enzymatic function in the body, for the purpose of introducing such molecules as a drug, in necessarily low concentrations, to attach to most ACE-2 receptors and so prevent viruses from attaching to them and so gaining entry into cells.  This is a promising form of antiviral therapy.

  • The affinity of a particular RBD for the ACE-2 receptor (here ignoring considerable genetic variation in the ACE-2 structure) is expressed as the concentration required to bind to half of a population of such receptors.   The affinity of the normal (wild type, before South African / Brazilian mutations) viral spike protein RBD for the ACE-2 receptor is 1600pM (picomols concentration).  (This is really inverse affinity, since a higher affinity means a lower concentration of spike proteins with a particular RBD pattern will bind to 50% of the ACE-2 receptors.)

  • The (inverse, to my way of thinking) affinity of the "British" mutation RBD is 455pM, meaning that this RBD has a 1600 /  455 = 3.5 times the affinity of the WT (wild type) original SARS-CoV-2 RBD.  

  • The South African / Brazilian RBD (with the same, independently evolved, three - Triad, above -  mutations) has an (inverse) affinity of 126pM, and so an affinity 1600 / 126 = 12.7 times the affinity of the WT RBD, which was the main type of SARS-CoV-2 virus present in the UK in the summer of 2020.  The current prevalence of this strain, and its likely spread throughout the world, is the primary reason for me thinking that population average 50ng/ml vitamin D levels may not "stop" COVID-19, meaning very substantially suppress its transmission and severity, as much as I anticipated in late 2020.

  • The researchers' evolutionary system reliably produced variants with the same three mutations as the South African / Brazilian variant.  It also produced variants with further mutations which increased the binding affinity a lot more.  Their best mutation "RBD-62" produces and RBD with an (inverse) affinity of 2.5pM.  This RBD has an affinity for the ACE-2 receptor of 1600 / 2.5 = 640 times the affinity of the ordinary, wild-type (not counting British, South African or Brazilian variant) SARS-CoV-2 RBD.

    If a soluble form of this RBD was made, it would be a good drug to reduce SARS-CoV-2 infections, since (depending on its concentration, which could be quite low) such molecules will bind to most ACE-2 receptors and so prevent viruses from binding to them.

  • However . . . this research, which is perfectly legitimate (and does not involve making viruses with these genetic variations - they are not allowed to) shows the specific set of mutations which would give a SARS-CoV-2 virus a very much greater affinity RBD than even the South African / Brazilian variant.

    This, and other combinations of mutations they discovered show that there is tremendous scope for the various SARS-CoV-2 strains to evolve still higher affinity RBDs, and so become much more transmissible - since each virus has a higher chance of binding to an ACE-2 receptor.

    The 12.7 times higher affinity of the South African / Brazilian RBD does not translate directly into 12.7 times more transmissibility - however this might be measured - but the increased transmissibility is obviously significant, since these variants are spreading faster than the strains which lack this combination of mutations.   The exact effect of some mutations depends on the presence of others (epistatic), and may be affected by individual and racial genetic differences in the structure of the ACE-2 receptor.

    SARS-CoV-2 is evolving faster than anticipated.  There's no way of predicting how rapidly still higher affinity strains will evolve, but it is reasonable to assume that they will evolve in months or years, not decades.

    (Of course, with the information in this article, a person with suitable equipment and the very worst of intentions could produce a SARS-CoV-2 virus with these exact mutations and release it.)

    Blue boxes on these pages denote quotes from the aforementioned article, with my notes in [square brackets].

    This suggests that with the spread of the "British", "Brazilian", and "South African" variants, we project that the Q498R mutation will appear in the future, on top of these mutations. The synergism of Q498R with N501Y and E484K increases ACE2 binding by ~50-fold relative to WT [ordinary SARS-CoV-2 before the British or South African / Brazilian mutations, which have affinities 3.5 and 12.7 times that of WT].

    If anyone can find a qualified virologist who can attest that the above scenario is either exceedingly unlikely, or not cause for a very high level of alarm, please let me know!

    It seems reasonable to assume that these are the early days of SARS-CoV-2 and so the COVID-19 pandemic, with the viruses likely to evolve to be very much more transmissible, and likely cause more serious symptoms, due to being able to spread even when at much lower concentrations in the body than are required with today's variants.

  • There are other important characteristics of the RBD part of the spike protein apart from its affinity for the ACE-2 receptor.  One is its stability at higher temperatures.  The mutations mentioned in this summary are all no less stable than the WT RBD.

    Another is to what extent the changes in the RBD mean that neutralizing antibodies [WP] produced in the body by various methods are less likely to bind to a virus with these altered RBD sections of their spike protein.  My understanding of the text at the top of page 14 is that for this (yet to evolve in viruses) RBD-62 genetic pattern of RBD, over half of the tested antibodies (raised by infection and/or vaccination, I guess) were less able to attach to these spike proteins than they do with the current strains of SARS-CoV-2.   So this particular, exceedingly high binding affinity RBD genetic pattern, if it evolved in SARS-CoV-2 viruses, would have significant survival advantages by way of lower chance of being found by antibodies, in addition to the immense benefit provides the virus by way of its higher binding ACE-2 binding affinity.


Resistance to proper, robust, population-wide vitamin D3 supplementation remains very strong, in part because many MDs cannot imagine, and do not care to research, the profound importance of vitamin D levels being well above the low, to disastrously low (UK winter) levels they are accustomed to.   This is in part due to lack of understanding of autocrine signaling, and false ideas of vitamin D acting primarily or solely as a hormone.

It is also hard for MDs to accept that a lot of the chronic diseases they battle, with great complexity, effort and skill, would be very much less prevalent if everyone had proper levels of vitamin D and other nutrients.  (A gram of D3 every 22 years is all a 70kg adult needs to achieve these healthy levels, and a gram costs USD$2.50 ex-factory in 1kg lots.)

Nothing in this update detracts from the importance of raising everyone's 25OHD levels to, on average, 50ng/ml (125nmol/L) or so.  Its just that I now think the SARS-CoV-2 virus variants are mutating in ways which mean this disease will be a serious burden for all people, indefinitely, despite this.  However, the impact of COVID-19 will be very much less if we get the average levels to 50ng/ml than if we fail to do so, and leave them as they are, below 20ng/ml in many countries in winter, rising to the mid-20s or perhaps mid-30s if we are lucky in summer.


It is all the more important to have good vitamin D levels when being vaccinated for COVID-19.   This is well established with influenza vaccines, where stronger immune responses are illicited in people with higher vitamin D levels:

Effect of 25-hydroxyvitamin D status on serological response to influenza vaccine in prostate cancer patients
Manpreet K Chadha, Marwan Fakih, Josephia Muindi, Lili Tian, Terry Mashtare, Candace S Johnson, Donald Trump
Prostate 2010-09-01
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718551/

Baseline Serum Vitamin A and D Levels Determine Benefit of Oral Vitamin A&D Supplements to Humoral Immune Responses Following Pediatric Influenza Vaccination
Nehali Patel et al.  Viruses 2019-09-25
https://www.mdpi.com/1999-4915/11/10/907


Vaccines vary in their effectiveness and risks of serious ill-effects.  It is far too early to tell to what degree any one vaccine will really protect against COVID-19 infection, for all the strains of the virus in circulation now or in the future.   We don't know how long vaccine-induced immunity will last, or to what degree it is specific to particular strains of the virus.  There are concerns about lack of testing in frail older folks, with potentially poorer immune responses and higher risks of serious ill-effects, such as Bells Palsy: https://covid.us.org/2020/12/23/is-there-a-risk-of-bells-palsy-with-mrna-covid-19-vaccines/ .

The popular vision, driven by popular hope and the statements of politicians, is that once most people are vaccinated, life can return to normal.   There is no prospect of this being true, since the viral strains will continue to mutate, since immunity from vaccines and prior infections will fade, since vaccine effectiveness will vary with numerous personal characteristics - including especially age, obesity and low vitamin D levels.

Close to the equator, some countries are doing pretty well.  But people there tend to have dark skin and, wisely, avoid direct sunlight - so vitamin D levels can still be lower than required for proper immune function.

Far from the equator, seasonal variation in UV-B skin exposure will drive very strong seasonal patterns in COVID-19 transmission and severity.

Even if more than half the population of many countries are vaccinated by the end of 2021, the virus will still be transmitted, with increasing likelihood of variants which infect people with immunity to prior forms of the virus, either through prior infection or vaccine-induced immunity.  The vaccination programs put the virus under selection pressure to evolve in ways which avoid being detected by the immunity raised by current vaccines.  So this will be a global cat and mouse game between the virus variants and the vaccine manufacturers.

Moderate or severe COVID-19 can cause very long lasting problems - probably permanent loss of capacity - for quite a high proportion of people.   It is a serious disease, and people who minimise its importance, such as by quoting average ages of those killed by, or with, COVID-19, are avoiding the impact it has on many people in their twenties to fifties.  They are also avoiding the impact it has on children by triggering Kawasaki disease or Multiststem Inflammatory Syndrome: https://aminotheory.com/cv19/#2015-Stagi .

Even if governments decided to have their entire populations supplement D3 properly tomorrow, world production of pharma grade D3 would soon be overwhelmed if more than a few tens of millions of people adopted this.   D3 factories take years to build by ordinary means - and those running now operate 24 hours a day.  Governments should work together globally with an urgency normally only found in times of war to build new pharma-grade D3 factories.  In the meantime, we should direct some of the much greater animal feed grade D3 production for humans.

Omega 3 fatty acids should also be recommended to the population for substantial daily supplementation.  There are numerous health reasons for this, and now must urgently regarding COVID-19: Asher et al. https://www.plefa.com/article/S0952-3278(21)00013-2/  The trouble is people need grams of fish or algae oil a day, when they only need, on average 1/8000 of a gram of D3.   I can't imagine how global production could be ramped up to a few grams per day per person, which is what everyone needs.   B vitamins: the same story but the quantities are smaller than for omega-3 fatty acids, so production could be ramped up.  But all these are far more expensive than vitamin D, and vitamin D is surely the most important nutritional deficiency which needs to be fixed for reasons of general health and COVID-19 in particular.  Zinc - best to take 25mg or so a day as chelate.  Some people are sensitive to excess zinc, so more than this may be a problem.

In the coming months or years it seems likely that SARS-CoV-2 variants will become very much more transmissible than they are today.  Then, perhaps, vaccines would not be able to produce the very high concentrations of antibodies, to the various strains, which would be required to either prevent infection or seriously reduce the risk of severe symptoms.

This would leave us with the following options for avoiding severe symptoms, and reducing transmission to some extent:
  1. High, continual, doses of antiviral drugs for a substantial fraction, or most, of the population.  This would be extraordinarily expensive, difficult to ramp up to this massive scale, and would surely cause significant ill-effects. 

    There are quite a number of possible antiviral drugs and combinations of nutrient which directly reduce viral replication, so these should not be ruled out for vulnerable people, but this is not a solution to the whole problem.

  2. More mask, social distancing and lockdowns - we are already at our limit with these and the costs are extraordinarily high.   This is no way to live into the indefinite future.

  3. Nutrititional supplements to boost direct antiviral immune function and, most importantly, to greatly reduce the tendency of many or most people to having dysregulated, hyper-inflammatory, immune responses to SARS-CoV-2, influenza etc. 

    First and foremost this means population-scale vitamin D supplementation to attain average 25OHD levels of around 50ng/ml .  

    The costs and practicalities of other supplements are more challenging than D3 supplementation.   Boron is likely to be helpful, but it needs to be taken every day and many people do not recognise it as a nutrient.  Borax is banned in the EU, for no good reason.   Vitamin C is also a daily intake nutrient.   Various B vitamins are surely important.  Zinc needs to be taken once a day, and some people are sensitive to higher levels - but as far as I know 25mg a day is OK for adults.  (Zinc and other minerals have some interactions at the time of ingestion, so it can be complex to schedule when to have such nutrients.   Also, zinc as oxide is not as bioavailable as chelate.)

    Selenium may help too.

    Omega 3 fatty acids are surely beneficial but these are bulky and expensive, and it takes months, as far as I know, to alter the omega-3 to omega-6 ratio in the body's overall circulating, stored and in-membrane fatty acid makeup.
In short, very much increased SARS-CoV-2 transmissibility may make vitamin D and other nutrients the only long-term sustainable way we can cope with these viruses.   All the above nutritional supplements have broad, profound, health benefits, and are worth doing anyway even if there was no COVID-19 pandemic.


I worked unsustainably on these websites from March to December 2020.   I need to get back to paying work with electronic musical instruments.  I will try to mention the most significant developments.





My main current infographics:



This is UK-USA-Australia-deaths.png .  OurWorldInData graph.



Infographic for #VitaminDStopsCOVID


This is VitaminDStopsCOVID.png .


Links and other items regarding the infographic

2008 Call to D*Action: https://www.grassrootshealth.net/project/our-scientists/ .

Immunologic Effects of Vitamin D on Human Health and Disease: https://doi.org/10.3390/nu12072097 .

UK vitamin D levels: Fig. 1D of:  https://academic.oup.com/jpubhealth/article/42/3/451/5859581 .

UK COVID-19 hospitalisation graphs: https://coronavirus.data.gov.uk/details/healthcare .

Kawasaki disease and Multisystem Inflammatory Syndrome, frequently triggered in children and adolescents by COVID-19: https://sci-hub.se/10.1007/s10067-015-2970-6https://aminotheory.com/cv19/#2015-Stagi and rebelem.com/...kawasaki-disease/ .

Barbara Gilchrist 2008: Sun exposure and vitamin D sufficiency

Greater viral shedding with more severe symptoms: Fig 1 [annotated here] in  https://www.jci.org/articles/view/138759 .

My suggestion for vitamin D3 supplementation quantities as a ratio of bodyweight: 01-supp/ This includes links to research which shows that the 2010 Institute of Medicine vitamin D recommended intake levels, as relied upon to this day by many health authorities, was completely miscalculated.

Excellent video 2020-09-24 with Rufus Greenbaum, Michael Holick MD, Bill Grant PhD, Gareth Davies PhD and David Grimes MD.

Be sure to see https://VitaminDWiki.com .

For background on how we all got into this mess of almost universally inadequate vitamin D levels, despite it being a very safe and inexpensive nutrient - with tiny quantities such as 1/22 gram per year needed for repletion - please read Bill Grant's article:

Vitamin D acceptance delayed by Big Pharma following the Disinformation Playbook
William B. Grant  Orthomolecular Medicine News Service, 2018-10-01
http://orthomolecular.org/resources/omns/v14n22.shtml

Orthomolecular is an awkward term for a field in which nutrition is given greater prominence for disease prevention and perhaps cure than is common in Western medicine.

Introduction and elaboration upon the infographic

COVID-19 and influenza are only serious problems due to many people having weak and/or dysregulated immune responses - overly-inflammatory, cytokine storm responses which kill healthy cells and damage organs.   Sepsis is a condition in which a variety of infections - and sometimes burns - trigger extreme immune system dysregulation which damages organs. 

The biggest single cause of these weak and dysregulated immune responses is also the one which is most easily corrected: vitamin D deficiency

Inadequate zinc also drives COVID-19 severe symptoms.  25mg zinc, as chelate, every day is safe and will guard against deficiency in this important mineral, which is part of approximately 2000 enzymes and 750 gene-controlling transcription factors [Read et al. 2019] and which which reduces the ability of the SARS-CoV-2 virus to replicate its RNA.  [See these graphs of zinc and COVID-19 from Vogel-Gonzalez et al. 2020.]     

Omega 3 fatty acids, vitamin C and several of the vitamin B family are also important to good immune health, are frequently deficient, and can be easily and safely supplemented.

#d
Vitamin D refers primarily to three compounds which are essential for human health:

D3 cholecalciferol, [WP] which is produced from 7-dehydrocholesterol when the skin is exposed to short-wavelength 297 nanometre UVB light.   This can occur naturally with high elevation sunlight and bare skin - no sunscreen or glass.  There is very little D3 in food or multivitamins, so people who do not have substantial all-year-round UVB sun exposure need to take vitamin D3 supplements regularly.

D3 itself helps stabilize endothelial cells, which line our blood vessels. [Gibson et al. 2015]  COVID-19 and immune system destruction of these cells, particularly in the lungs, restricts the ability to breathe and causes the blood to become hypercoagulative.  This hypercoagulative state causes microembolisms and larger blood clots in all organs,  damage to the lungs, heart, brain, kidneys and liver and to death due to stroke and heart failure.


25 hydroxyvitaminD3 AKA 25(OH)D,  25OHD and calcifediol [WP] is produced in the liver, over several days, by an enzyme which attaches an oxygen-hydrogen hydroxyl group at the 25 position of D3. 
   


25OHD circulating in the bloodstream has a half-life of a month or two.  Higher 25OHD levels have a shorter half-life as a self-limiting degradation process kicks in.  Vitamin D blood tests report 25OHD levels as, for instance, 50ng/ml or 125nmol/L, which is one part in 20 million.  Circulating 25OHD supplies all cells in the body.  Many cell types consume 25OHD for their autocrine (internal) and paracrine (nearby cells) signaling systems.


Another enzyme can add a hydroxyl group to the 1 position of 25OHD, which converts it into 1,25dihydroxyvitaminD3, AKA 1,25OHD and calcitriol [WP] which has a half-life of a few hours. 

A small fraction of the circulating 25OHD is converted by this enzyme in the kidneys to a much lower level - around one part in 30 billion - of 1,25OHD which also circulates in the blood.  The exact blood level of 1,25OHD is tightly regulated by parathyroid hormone.  This is the only hormonal (long range signaling, via the bloodstream) function of vitamin D: to regulate calcium and bone metabolism.

All other known functions of vitamin D are in the autocrine and paracrine signaling systems of a large number of cell types, including especially those of the immune system.  Each type of cell responds to particular circumstances by converting 25OHD to 1,25OHD which activates vitamin D receptors [WP] inside the cell (autocrine) and which may diffuse to other nearby cells (paracrine) to alter their behaviour too.  In both cases, the activated receptor migrates to the nucleus and turns up the replication of multiple genes into messenger RNAs [WP], with each cell type upregulating different sets of genes.  These mRNAs instruct ribosomes [WP] to make particular proteins which cause the cell to respond properly to its conditions.  [Fuller explanation of autocrine and paracrine signaling.]

Researchers recently found that Th1 lymphocytes from the lungs of hospitalised COVID-19 patients failed to respond to their circumstances.  They are supposed to turn off their inflammatory cytokine [WP] production and instead produce an anti-inflammatory cytokine.  The sole reason their autocrine signaling systems were not working was that they did not have enough 25OHD. [McGregor et al. 2020

The critical role circulating 25OHD levels play in COVID-19 was further illustrated by the Cordoba trial [Castillo et al. 2020], in which just 0.532mg oral 25OHD calcifideol, raised circulating 250HD to over 100ng/ml (one part in 10 million) within a few hours [graph].  These Spanish-made Hidroferol capsules cost only one or two Euros each.  The supplementation group received another capsule on days 3, 7, 14, 21 etc.  Half the 26 patients in the control group needed intensive care and two of them (8%) died.  Of the 50 patients in the supplementation group, only one required intensive care and none died.

If all people with serious COVID-19 were treated as soon as possible, Cordoba-style, with 0.5mg calcifideol plus a 7.5mg or so loading dose of D3 (300,000IU), they would get better very much faster than most patients do today with conventional treatment, and probably with less need for corticosteroids.

Vitamin D is not strictly-speaking a vitamin, since we can make it ourselves if short wavelength ultraviolet UVB light strikes our skin.  However, this UVB light also damages DNA, and most people do not have access to sufficient UVB light all year round.   So for almost all people, vitamin D is an essential nutrient - not a mineral, but a vitamin.

Vitamin D's one hormonal role regulating calcium and bone metabolism is well known and it seems that many doctors still think of vitamin D as a hormone - or at least of 25OHD as the pro-hormone to the 1,25OHD hormone.  In recent decades researchers have discovered more about vitamin D's role in autocrine and paracrine signaling of many cell types.   Researchers have found that 25OHD levels of 40ng/ml (100nmol/L) or more are required so that these autocrine and paracrine signaling systems function properly. [Fabbri et al. 2020].


Traditionally living Maasai pastoralists and Hadzabe hunter gatherers in Africa average 46ng/ml [Luxwolda et al. 2012].  This is the best indication we have of the 25OHD levels of our African ancestors during the time when our present-day immune systems evolved.

Since 2008 [Call to D*Action] researchers and MDs have been advocating that everyone  supplement sufficient D3 to aim for 40 to 60ng/ml (100 to 150nmol/L) 25OHD.    A recent article confirms this:

Immunologic Effects of Vitamin D on Human Health and Disease
Nipith Charoenngam, Michael F. Holick 2020-07-15
Nutrients 2020, 12(7), 2097

https://doi.org/10.3390/nu12072097

You can see in the four wavy lines of the infographic above how the average 25HOD levels of white and Black, Asian and Ethnic Minority people in the UK vary throughout the year.  These averages are far lower then the 40 to 60ng/ml range researchers have known since 2008 is healthy.  Up to 100ng/ml is normal and healthy too.  Toxicity may become a concern for some people if their 25OHD levels exceed 150ng/ml (375ng/ml) - but this can only occur with far greater D3 intakes than is necessary to achieve healthy levels, as you can see from the way the 25OHD levels fail to rise so much for higher D3 intakes:



The above graph is adapted from Ekwaru et al. 2014.


This chart from Weishaar et al. 2013 indicates how low many people's vitamin D levels are today, compared to the healthy 40 to 60ng/ml range.  The right curve represents the distribution of 25OHD levels in the Luxwolda et al. African study.



There are various definitions of vitamin D deficiency, insufficiency etc.   A recent analysis of all available research by Karl Pfleger arrived at an estimate of 53% of the world's population having 25OHD levels below 20ng/ml (50nmol/L) and 83% below 30ng/ml (75nmol/L).  These two thresholds are still widely used to define deficiency, but the research of the last decade or so indicates we should be aiming for higher levels than to ensure the autocrine signaling systems of many cell types work properly.  This enables the cells to respond rapidly and fully to their changing conditions.

Another way of viewing the variation in 25OHD levels between individuals is this scatter plot of the levels of individual white women in the USA with no supplementary vitamin D3, and with 0.01mg (400IU), 0.02mg (800IU), 0.04mg (1600) and 0.06mg (2400IU) D3 a day:



Supplementing 0.125mg (5000IU) D3 a day will, after several months, raise the 25OHD vitamin D levels of 70kg (154lb) adults to, on average 50ng/ml (125nmol/L). [Ekwaru et al. 2014 and their graph, above.]   It is fine to take D3 in larger amounts, once a week or so.

This is only 45 milligrams of vitamin D3 a year.  To give some idea of this, 0.045 grams is the mass of a piece of office paper 42mm (1.65") square.  Pharmaceutical grade D3 costs about USD$2.50 a gram ex-factory, so this is 13 US cents per year.   0.125mg is the mass of a 2.2mm square piece of office paper.  IU means International Unit, 1/40,000,000th of a gram of D3. One IU of D3 is sufficient for a 10 gram mouse for a day, and for a 70kg human to maintain about 50ng/ml 25OHD for 17 seconds.   IU (International Units) is a silly unit of measurement.  The large numbers involved make some people concerned they are taking excessive amounts of D3.

If all, or almost all, people supplement with sufficient D3 to raise the average blood levels to 50ng/ml, all year round, this will greatly reduce or eliminate the weakened and dysregulated (overly-aggressive, hyper-inflammatory, self-destructive) immune responses which cause severe symptoms and high rates of viral shedding of influenza and COVID-19.   Likewise, the incidence of the gross immune dysregulatory disorder, sepsis [WP], will be greatly reduced.  Numerous other health benefits will result from ending the Vitamin D Deficiency Pandemic.

Further explanation, including regarding reduced viral shedding, is on the 01-supp/ page.


The causes of weak and/or deregulated immune system responses

Here are some important points about the common human proclivity for weak and/or dysregulated immune responses in humans.  These may also apply to companion and agricultural animals who lack proper nutrition and/or UVB exposure and/or who no longer have the helminths which infested the digestive tracts of their wild ancestors.
  1. SARS-CoV-2 (the virus which causes the COVID-19 disease) and influenza are only a significant problem for humanity because a large fraction of the population have weak and dysregulated immune responses, at least in winter.

  2. By far the most important, easily correctable, cause of these weak and dysregulated immune responses is inadequate vitamin D - due to inadequate supplementation if the person has not had sufficient UVB light exposure to synthesize sufficient D3 in their skin.

  3. Another major reason for our immune systems being poorly regulated, is that we now lack the intestinal worms (helmlinths [WP]) which infested our human and pre-human ancestors over the past tens of millions of years during which our immune systems evolved.  These helminths downmodulated some immune responses for their own protection, and our ancestors' immune systems evolved to be overly inflammatory ( overly-destructive) to counter this expected downmodulation which no longer exists for most humans today.  This is a tough problem to solve, but for most people these problems will not be significant once they have healthy vitamin D levels of 40ng/ml or more.  See my explanation https://aminotheory.com/cv19/#helminthsgone and https://helminthictherapywiki.org/wiki/index.php/Helminthic_Therapy_Wiki .   

  4. Other nutritional deficiencies drive weak and/or dysregulated immune responses.  One which is particularly important for COVID-19 is zinc, as previously mentioned.  Inadequate omega 3 fatty acids, B vitamins, magnesium and vitamin C are also widely recognised as common causes of immune system weakness and/or dysregulation.   Low boron intakes are also a likely cause of this, but most doctors have never heard of this as a nutrient and are unaware of the research which shows its importance in limiting chronic inflammation to reduce osteoporosis and arthritis.   See https://aminotheory.com/cv19/#08-boron .

  5. There are reasons to believe that excessive fructose lowers vitamin D levels, so this a nutritional excess which upsets the immune system.

  6. Fever is a healthy, early, response to viral infection and lowering it with drugs is widely regarded as a bad idea.  See the research I cite at: https://aminotheory.com/cv19/fever/
If this sounds too good to be true - 13 cents worth of vitamin D3 a year protecting an average weight adult from COVID-19 - then please read on and learn more about the immune system, COVID-19 and how low vitamin D levels drive the seasonal (winter and spring) spread of influenza and now COVID-19, with severe symptoms and high rates of viral shedding causing more people to become infected.



I am one of many people with no medical or nutritional training who are raising awareness of we must do to end the Vitamin D Deficiency Pandemic

Ordinarily electronic technicians wouldn't be meddling with the work of nutritionists and doctors - and these healthcare professionals wouldn't be messing with the work of electronic technicians.   Indeed they don't mess with our work, because electronic technicians are generally doing a good job.

Doctors have a huge range of responsibilities and must amass and maintain a vast body of knowledge and skills.   Unfortunately, for a number of reasons - including shortage of time and constant schmoozing by drug and vaccine companies - many doctors' understanding of nutrition has not kept pace with the best research.   The conventional approach of most members of the medical profession to vitamin D has for some decades been disastrously out of touch with reality.  

If nutritionists and doctors had been doing this part of their work well, then the populations of all countries would be supplementing D3 and, on average, have vitamin D levels (as measured by 25 hydroxyvitmainD3 - 25OHD) in the healthy 40 to 60ng/ml range, and sometimes higher - all year round

Then, influenza would cause little trouble and there would be no need for vaccines. 

Then, there would be little sepsis, which according to researchers from the Global Burden of Disease project, accounts for 20% of deaths worldwide. 

Then. SARS-CoV-2 would hardly spread and only very rarely harm or kill anyone.  So there would be no COVID-19 pandemic or the approximately equally harmful and deadly lockdowns, social distancing and economic and social devastation which has, so far, been governments' only response.

I am one of an increasing number of people, including doctors, nurses and a surprising number of physicists, electronic engineers/technicians, computer programmers etc. who have been working assiduously for years, and sometimes decades, researching and raising awareness of nutrition in general and of vitamin D in particular.   I figured out the critical role vitamin D deficiency plays in the COVID19 pandemic in late March - just by reading research articles.

People trust their doctors to advise them, and doctors trust panels of experts to advise them - because they generally cannot navigate the vast volumes of research to decide which articles  are the most important.  Doctors also rely on government guidelines, in part so they can work without unreasonable risk of being sued for malpractice.  

Yet many of these official guidelines are based on the work of the US Institute of Medicine, who in 2011 calculated an RDA (Recommended Daily Allowance) of vitamin D of 0.015mg (600 IU).   The real RDA (for the low 25OHD level of 20ng/ml) is about 0.175mg (7000 IU).  The IOM made a simple, but crucial, statistical error.   It seems likely that if they had not made this error, many people would now be supplementing with adequate quantities of vitamin D and there would be little trouble from influenza or COVID-19, all year round.  The IOM's error was identified in peer reviewed journal articles in 2014 and 2015.  No critiques of these articles have surfaced and it is reasonable to conclude that the IOM really did make this enormous mistake.   Yet the impact of this mistaken calculation continues with government recommended vitamin D supplemental intakes of 0.01mg (400 IU) and 0.015mg (600 IU) in many countries, which are less than a tenth of what is really needed.  (See the 01-supp/ page for links to these articles.)

If these advisory committees and the doctors who rely on them had been doing their work properly, we wouldn't be in the current disastrous predicament, and we physicists, IT people, technicians, engineers and lots of other non-medical people would not be working outside our fields, attempting to fix the disastrous failings in particular aspects of nutrition and medicine.

One such retired electronics engineer is Henry Lahore, in Washington State, who now collaborates on articles with leading vitamin D researchers and works tirelessly to document research into vitamin D and several other nutrients at:

https://vitamindwiki.com

Another person taking a keen interest in this field is AI PhD Karl Pfleger, with his Low Vitamin D Worsens COVID-19 Risk article, listing recent research:

https://agingbiotech.info/vitamindcovid19/

Gordon Shotwell, who trained in law and works as a data scientist, maintains a page of recent COVID-19 and vitamin D research:

https://vitamin-d-covid.shotwell.ca


Here is my adaptation of graphs from some recent observational research showing how low vitamin D levels are strongly associated with, and surely largely the cause of (rather than caused by) COVID-19 severe symptoms and death: https://doi.org/10.3390/nu12092757 .





#c

Table of planned contents

It will take me a while to complete these.  Please see my longer and less well organised pages at: https://aminotheory.com/cv19/ .

Page
Description and, if I have not created it yet, a link to a relevant  aminotheory.com section
Last update
2020-
about/
Purpose, contact and copyright details.  The Nutrition for Immune System Health email discussion list. The Open Letter Google Groups discussion list of Karl Pfleger and Gareth Davies. Disclaimer - I am not a doctor etc.
11-16
00-intro/
Introduction to vitamin D, the immune system and COVID-19. D3 cholecalciferol, 25OHD calcifediol and 1,25OHD calcitriol.

00-intro/a-defs/ The three main forms of vitamin D: D3 cholecalciferol, 25OHD calcifediol and 1,25OHD calcitriol.  How only 1,25OHD acts as a hormone - and then only when it is circulating in the bloodstream and cerebrospinal fluid.  Why a bolus (loading) dose of D3 is desirable for people who are ill with COVID-19 and why an initial, oral, dose of calcifediol is particularly beneficial, as was used in the Cordoba trial.

00-intro/b-infog1/ Full text, references and other notes for the above infographic.

00-intro/c-hist/
Brief history of vitamin D and how we got to this point, including the Institute of Medicines 2011 blunder of incorrectly calculating the D3 RDA to achieve 20ng/ml (50mol/L).

01-supp/
My suggestions for how to calculate vitamin D supplementation quantities as a ratio of bodyweight, rather than using the traditional approach of age groups, where age is a proxy for weight. 

The story behind the US Institute of Medicine, in 2011, calculating the RDA for vitamin D3 to attain at least 20ng/ml 25OHD in 97.5% of the population as 600 IU, when the real figure is closer to 7000 IU.  Most doctors and D3 recommended intake committees are working as if the 600IU figure was true.

My proposed 25plusD3 dual 25OHD and bolus D3 suggestion for treating severe or potentially severe COVID-19 and influenza, and sepsis.  (Sepsis is always potentially deadly within hours.)
11-19
01-supp/a-ratios/ How I derived these ratios from the work of Ekwaru et al. 2014.
11-06
01-supp/b-grh/
Analysis of the results of the GrassRootsHealth vitamin D supplementation calculator, which works internally on ratio of bodyweight.
11-05
01-supp/c-old/ Existing systems of D3 supplementation guidance, mainly based on IOM conclusions now known to be false.  Please see the 01-supp pages and:
https://sci-hub.se/10.1038/s41430-020-00706-3 .

01-supp/d-tox/
Vitamin D toxicity, sarcoidosis etc.
End of: https://aminotheory.com/cv19/d3/ .

02-autocrine/
An illustrated explanation of autocrine and paracrine signaling, with two examples from peer-reviewed articles.

Almost all of the functions of the vitamin D compounds involve autocrine signaling (inside a cell) and paracrine signaling (to nearby cells).   Yet few people understand this, and mistakenly think "vitamin D is a hormone" or some other mixed up idea such as circulating 1,25OHD (the hormonal function, for calcium-bone metabolism) somehow "regulating" immune responses.

Read this page and understand!   Then you will be able to understand the highly significant McGregor et al. article which describes exactly how lack of 25OHD in the lungs of patients with severe COVID-19 causes autocrine signaling in Th1 lymphocytes to fail - leaving them in the hyper-inflammatory state which causes severe COVID-19/
12-09
03-lr/
Latest research.
https://aminotheory.com/cv19/#lr
https://aminotheory.com/cv19/icu/

04-kd/
Kawasaki disease, Multisystem Inflammatory Syndrome etc. - extreme immune dysregulation causing vasculitis in babies, children and adolescents, triggered by an infection including especially COVID-19.
https://aminotheory.com/cv19/#2015-Stagi

05-logi/
Logistics of fixing the Vitamin D Deficiency Pandemic ASAP, considering that we don't have enough D3 factories to meet the new demand.  Building D3 factories ASAP and prioritising existing D3 for those most in need.

For now please refer to this excellent description of industrial production of vitamin D3 cholecalciferol by Arnold L. Hirsch in 2010 :  https://sci-hub.se/10.1016/B978-0-12-381978-9.10006-X

20 tonnes for humans and 77 tonnes (less pure, but probably fine for humans too) for agricultural animals.  For global vitamin D repletion we need a few hundred tonnes a year for humans.  Currently most of the vitamin D3 factories are in China and India.  These factories' current output is less than the requirements of the populations of these two countries, so other countries cannot rely on exports from China or India any time soon.











This was work in progress but is unlikely to be completed.  I need to earn a living.










© 2020 Robin Whittle   Daylesford, Victoria, Australia