Vitamin D is not a substitute for any vaccine — Deplatform Disease

  • Vitamin D is unnecessary.
    Vitamin D is an important hormone and plays critical roles in the regulation of calcium and phosphate metabolism. It is obviously necessary and claiming otherwise is ridiculous and not what I am doing.
  • Diet has no meaningful role in immunological function (this was the subject of an excellent recent review, as well as here).
    The interplay between diet and the immune system is a complex and exciting area in immunology and is the subject of much active research. However, this research is still in its infancy and we are far from being able to make definitive recommendations about dietary changes and a precise immunological effect in humans. Further complicating this are the intersections between this field and the examination of interactions between the microbiota and the immune system. The latter studies are often interesting and valuable but involve so many variables and often require such contrived models that external validity of the studies is an unrealistic claim; this field too, I would argue, is still in its infancy and a ways away from being able to use its findings to make clinical guidances (at least those more granular than “don’t overuse antibiotics”). Nonetheless, the research in these fields is valuable and should be done.
    Principally, the most valuable recommendation regarding diet and immunity is simply to ensure that adequate intake of all nutrients is achieved. The immune system is an extraordinarily complex network of molecules, cells, tissues, and organs and deficiency of any nutrient can potentially be harmful for its optimal function.
  • Vitamin D supplementation is harmful.
    You should consult with your care team before initiating any supplement. However, while vitamin D is fat-soluble and toxicity can be devastating, it is difficult to attain at reasonable doses of the substance, though in particular, it may be an issue in patients who have sarcoidosis or other granulomatous conditions. I do however think that vitamin D supplementation in most circumstances is a waste of money as it doesn’t do much and is often recommended for people who are not actually deficient.
  • Vitamin D deficiency is not necessary to correct.
    There is no good reason to be deficient in any nutrient (or hormone in this case). Physiologic levels of vitamin D are important for health maintenance. Any individual who has evidence of vitamin D deficiency should have it corrected. However, people should be realistic in the benefits associated with that correction.

What is Vitamin D?

Cell Biology and Mechanism of Action

Production, Absorption, Transport, Storage, and Metabolism

D2 vs D3

Vitamin D in Mineral Homeostasis

  1. Calcium ions enter at the apical surface of the intestinal epithelial cell through channel proteins like TRPV5 and TRPV6. Other protein channels are known to play a role here but it is not clear which specific ones.
  2. On entry into the intestinal epithelial cells, the free ions are bound up by calbindin-D9k, which shuttles the ions to the basolateral surface.
  3. The ions are released from the basolateral surface into the body via PMCA1b.
  • Osteoclasts are the major cells that break down bone, releasing calcium and phosphate from the bone mineral matrix into the blood, known as bone resorption. They are derived from monocytes and do not divide (some regard them as the tissue-resident macrophages of the bone). Mature osteoclasts have receptors for calcitonin, but not parathyroid hormone or vitamin D. To break down bone, osteoclasts bind a region and form an adhesive ring which makes contact with a specialized organelle known as a ruffled border, which is essentially a giant lysosome containing proteases like cathepsin K which break down the protein components of the bone and liberate free calcium.
  • Osteoblasts are the major bone-forming (known as bone mineralization) cell. They express receptors for both parathyroid hormone and vitamin D and can lay down matrix called osteoid that gets filled with hydroxyapatite. These cells also secrete large amounts of the alkaline phosphatase enzyme, which is required for bone mineralization. These cells are the major target for parathyroid hormone.
  • Osteoblasts that remain in the bone during the remodeling process become osteocytes. Osteocytes can regulate the functions of osteoblasts through secreted substances. Osteocytes are thought to play a role in the transfer of mineral from the interior of bone to the growth surfaces. A detailed review of osteocyte functions can be found here.

Extraskeletal Effects of Vitamin D

Immunological Effects of Vitamin D

The Controversies and Misconceptions of Optimal Levels

  • Manaseki-Holland 2010: This was a double-blind 1:1 RCT of 453 children in an inner‐city hospital in Kabul, diagnosed with non‐severe or severe pneumonia at the outpatient clinic. The study is well designed and its principal finding is a significantly lower risk of repeat episodes of pneumonia among the group receiving vitamin D, which looks real to me (45 % in the vitamin D group vs. 58% of the placebo group). Children were excluded from the study if they had evidence of rickets or were known to have received high-dose vitamin D supplementation within 3 months of the study. The randomization looks less than ideal to me but not unreasonable. The principal limitation of this study as I see it is that its subject population is very young children (mean age about 13 months) and it appears to be in a region where vitamin D deficiency is very prevalent which makes me concerned about the external validity of the study.
  • Camargo 2012: A cluster-randomized trial examining 247 Mongolian schoolchildren randomized to vitamin D-fortified milk vs. placebo comparing the incidence of acute respiratory infections as per parental report. One of the major things that jump out in this study is the mean vitamin D level of these patients was 7 ng/mL, which would be universally considered severely deficient. Another potential issue is that it relies on parental reporting which isn’t ideal as it’s subject to a number of biases, but this is mitigated by the randomization process of the trial. The benefit here does also seem real to me, but again, it’s the same problem of external validity: this level of deficiency in places like the US is very rare, and we aren’t principally concerned with schoolchildren in the case of COVID-19.
  • Laaksi 2010: DBPCT of 164 young, Finnish men who received vitamin D supplementation vs. placebo which compared the number of days absent from daily duty. There was a clear benefit for the supplementation group. However, these groups also had pretty significant vitamin D deficiency to start with (~8 ng/mL), so that’s not particularly surprising. The principle is true with vitamins: a health benefit is seen when true deficiency is corrected.
  • Bergman 2012: This is a very interesting study because it examines specifically patients who have diagnosed or possible occult immunological deficiency that predisposes to respiratory infection, and it also followed all 140 patients for 1 year, which is nice (we love a long prospective study). The levels of vitamin D at baseline between the groups are similar but under some classification schemes, the placebo group would be considered mildly/borderline deficient while the treatment group starts out at a level that is sufficient. The major difference was that antibiotic use was rarer in the treatment group than the placebo group, which accounted for the marginally significant result obtained. However, the confidence intervals for this estimate are very wide, which speaks to the study being underpowered as it only has 140 patients. Further, it involves such a specific group of patients that I don’t think it’s very generalizable.
  • Marchisio 2013: 116 children with a history of recurrent middle ear infections were randomized to vitamin D supplementation or placebo for 4 months and the frequency of middle ear infections were monitored for 6 months. The small sample size made randomization difficult, as the gender distribution between the groups is not super well-matched, the number of children that had a symptomatic allergy in the vitamin D group was lower at baseline, and the vitamin D group was also more likely to be breastfed for > 3 months. These differences aren’t huge though. Importantly, the vitamin D levels in both groups were similar and would be considered sufficient under the IOM ranges. Interestingly, the vitamin D levels in the placebo group declined quite a bit throughout the study to a level that would be considered deficient. Vitamin D didn’t seem to affect complicated middle ear infections much, but did show significant reduction in uncomplicated and overall showed a reduction that took about 40 days to manifest. These effects are pretty big though and this meta-analysis does note a relationship between vitamin D levels and otitis media. So I think this might actually possibly be a legitimate benefit for vitamin D supplementation, but middle ear infections are generally a pediatric issue.

Toxicity, Deficiency, and Supplementation

Vitamin D in COVID-19


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I write about vaccines here. You can find me on Twitter @enirenberg and at (where I publish the same content without a paywall)

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Edward Nirenberg

Edward Nirenberg

I write about vaccines here. You can find me on Twitter @enirenberg and at (where I publish the same content without a paywall)

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