Everyone needs at least 50 ng/mL 125nmol/L 25-hydroxyvitamin D for their immune system to function properly.  Without proper vitamin D3 supplementation, most people's 25-hydroxyvitamin D levels are 1/2 to 1/10th this - greatly raising the risk of severe symptoms from COVID-19, Kawasaki disease, Multisystem Inflammatory Syndrome and sepsis.

Robin Whittle  rw@firstpr.com.au  10 July  2022

I am an electronic technician and computer programmer - not a doctor.  Please read the research articles I cite and summarise and make your own decisions - or ask your doctor or other primary healthcare provider to read the the 00-evi/ page so they can learn about the most pertinent research before they advise you.

Please also see my articles at https://nutritionmatters.substack.com where comments can be made.
 

Contents

Page
Description
Last update
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
00-evi/  <<< <<< Please read this first.

This is a comprehensive discussion of the most pertinent research regarding vitamin D, the immune system, the need for at least 50 ng/mL 125 nmol/L 25-hydroxyvitamin D and the bodyweight ratio based amounts of vitamin D3 which should be taken to attain this in most people.

This is a  submission from Patrick W. Chambers (MD, retired, Hawaii) and myself to a UK government department's request for evidence regarding vitamin D, in May 2022.

<<< Please read the research articles cited in this submission.
2022-07-09
01-supp/
From December 2021 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. 

Most of the material in this page is covered better in 00-evi/.

2020-12-12
02-intracrine/
An illustrated explanation of intracrine and paracrine signaling, with two examples from peer-reviewed articles.   (This was previously in a page 02-autocrine, but intracrine is the proper term.)

Almost all of the functions of the vitamin D compounds involve intracrine 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 1,25(OH)2D (the hormonal function, for calcium-phosphate-bone metabolism) somehow "regulates" immune responses.

Read this page and understand!   Then you will be able to understand the highly significant Chauss et al. 2021 article which describes exactly how lack of 25(OH)D in the lungs of patients with severe COVID-19 causes intracrine signaling in Th1 lymphocytes to fail - leaving them in the hyper-inflammatory state which is probably the major cause of hypercoagulative blood and so severe COVID-19.
2022-05-15
03-not-orphan/
Most of the material in this page is covered better in 00-evi/.

In April 2021 the British Medical Journal published an article which described both Ivermectin and vitamin D as "orphan treatments" - as if they were useless, or at least not proven yet to be useful, and that some MDs used them despite all the evidence of them being ineffective.  Nothing could be further from the truth! 
2021-05-12
04-calcifediol/
In April 2021, DSM released a new non-prescription calcifediol product for online sales to customers in the USA and Canada: d.velop

This, together with a similar product Fortaro for Australian consumers, is the first widely available, affordable, source of pharma grade calcifediol.

Since these tablets are inexpensive and readily available they should be used for rapid repletion of blood vitamin D (circulating 25OHD) in emergency situations such as when a person has sepsis, Kawasaki Disease, Multisystem Inflammatory Syndrome and of course severe or potentially severe COVID-19.

Around 1 milligram of calcifediol, in a single oral dose, for 55 to 85kg body weight is all it takes to make a huge difference to outcomes in people suffering from COVID-19.  

All doctors should be aware of this, and should understand vitamin D intracrine / paracrine signaling for immune system cells, which can only work with good, ~50 ng/mL vitamin D blood levels.  1 milligram of calcifediol can attain this in a few hours, while even bolus D3 takes days or a week or so.
2021-12-21
05-mds/
Most of the material in this page is covered better in 00-evi/.

What every MD should know about Vitamin D and the Immune System.

2021-11-23
06-adv/
Advanced vitamin D topics - some people need much more D3 than normal, to suppress rheumatoid arthritis, multiple sclerosis, psoriasis, cluster headaches, migraine etc.; newly discovered vitamin D compounds; helminths, the immune system and severe COVID-19

This page links to articles concerning the Coimbra Protocol for higher than normal D3 intakes (with other nutrients) for reducing the incidence and severity of, or eliminating, inflammatory auto-immune diseases, including cluster headaches and migraine.
2022-05-26

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 50 ng/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 25 ng/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 50 ng/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):



#zahradnik

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 50 ng/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, 50 ng/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 50 ng/mL than if we fail to do so, and leave them as they are, below 20 ng/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 elicited 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 Multisystem 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. Nutritional 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 50 ng/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.



Another infographic

This chart from Weishaar et al. 2013 indicates how low many people's 25-hydroxyvitamin D levels are today, compared to the healthy 50  ng/mL or greater range.  The right curve represents the distribution of 25OHD levels in the Luxwolda et al. African study.




© 2020 to 2022  Robin Whittle   Daylesford, Victoria, Australia