Immune Stack
by David Archibald
2 April 2026
Tuned for antiviral efficacy and cognitive protection. In order of importance, the stack is:
Vitamin C Immunity antioxidant
Vitamin D Immune system regulation
Urolithin A Mitochondrial response
Zinc Improves interferon response
Quercetin Zinc ionophore and vitamin D receptor activator
Shiitake Innate immunity
Omega 3 Inflammation regulation
Magnesium Required for vitamin D activation
Vitamin C
One of the predecessor animals of humans lost the ability to make vitamin C in the Eocene, 40 to 60 million years ago. The world was a lot warmer then and most land areas were covered with rain forest. There was plenty of vitamin C available all year round in the fruit of the flowering plants that had evolved not long before. There were two evolutionary advantages for doing so. Firstly, producing that vitamin C at the rate of 20 mg/kilo of body weight/day would have taken 0.1% of resting body energy, which is a big enough advantage over time. Secondly, the antioxidant effect from the vitamin C produced by the liver is exactly offset by the oxidising effect of the hydrogen peroxide also produced in the liver in the making of the vitamin C.
While that vitamin C travels all over the body, the hydrogen peroxide has to be reduced by other antioxidants made in the liver. As the liver is only two percent of human body weight, this is a big load on the liver and would have resulted in higher rates of liver disease and failure. In animals that do make their own vitamin C, the production of antioxidant molecules by their reducing effect is roughly one third vitamin C, one third glutathione and one third uric acid. All glutathione production by the liver would have to go to offsetting the hydrogen peroxide resulting from making vitamin C. Not having to have the liver work so hard would have been a big driver for the mutation to lose the ability to make vitamin C.
So far, so good. Then Antarctica drifted over the South Pole, the Antarctic ice sheet appeared and the current ice age began. The world became colder and drier. There was no longer a year-round supply of vitamin C from fruit. The human range expanded to all the climatic zones. Most of humanity now lives with a chronic vitamin C deficiency. Though in places like Malaysia, there is a high rate of diabetes because people eat too much fruit.
We know how much vitamin C we need because of what other animals do. For mammals, that is shown in this graph:
Figure 1: Daily Vitamin C production in mg per kilo of body weight
In the carnivores and omnivores, vitamin C production is typically near 20 mg/kg of body weight/day. Dogs have a high level because of their high metabolic rate. As omnivores, humans need about 20 mg/kg of body weight/day. For a normal person of 70 kg, that equates to 1.4 grams — equivalent to three 500 mg tablets, assuming it all gets through to the bloodstream.
Ruminants need a lot of vitamin C to cope with all the oxidative stress from fermentation. Among the ruminants, vitamin C production is proportional to how bad the country the species can survive on. So, goats produce seven times as much as pigs. The non-ruminant herbivores have a normal sort of production rate. Other phyla also produce vitamin C. In the fishes, bony fish produce vitamin C. Fruit flies make their own vitamin C but crabs don’t.
The recommended daily allowance for vitamin C in Australia is 45 mg per day and we consume 110 mg per day on average. That is still less than 10% of what other omnivores use. Most of us are living our lives chronically vitamin C deficient. There is another effect we are missing out on due to our nonfunctional L-gulonolactone oxidase gene, the one that makes vitamin C. Production of vitamin C in animals reacts to stress. Infection can cause vitamin C production to increase two to five-fold, trauma can increase it three to six-fold, prolonged exertion can increase it two to four-fold, the increase due to heat stress can be up to three-fold, and crowding can increase it two-fold. So an infected 50 kg goat can produce up to 50 grams of vitamin C per day. Humans don’t get the benefit of this disease response.
This explains the effect seen in a 2020 study of the positive response of covid patients to N-acetyl cysteine (NAC) dosing. NAC is a strong anti-oxidant. Because humans live their lives chronically vitamin C-deficient, any anti-oxidant can fill the gap and produce a positive result. The US Federal Drug Administration attempted to ban NAC because they didn’t want anything to compete with the covid vaccines that were then coming.
Figure 2: Maximum daily Vitamin C production increase in response to stress
Most mammals have the ability to significantly increase vitamin D production in response to stressors such as trauma and disease. For each species, the lefthand column is the normal daily production and the righthand column is the maximum measured increase in response to stress. Given what happens in animals, it is advisable for humans to increase vitamin C consumption in response to disease. For a 70 kg person, a five-fold increase from the normal level of omnivores would be seven grams per day.
We have made some adaptations to now being chronically vitamin C deficient. Humans and other great apes have lost the uricase enzyme that degrades uric acid. Uric acid is a powerful extracellular antioxidant. At the high end of their concentration ranges, humans have seven times the concentration of uric acid in plasma as pigs do. This offsets about 40% of the effect of the loss of vitamin C in humans. But the effect is only in serum and uric acid does not support collagen synthesis or immune cell function. Taking up to 500 mg per day of vitamin C lowers the serum uric acid level by up to 20%.
Another human adaptation to low vitamin C levels is to concentrate it in white blood cells at 20 to 80 times the level in plasma. The brain also retains vitamin C, including during deficiency. Humans have evolved to waste almost no vitamin C, though this only works if there is an intake in the first place. In effect, humans rely heavily on secondary antioxidant systems because the primary system is missing.
All that is to provide background to the disease implications. Vitamin C is required, as in not optional, for collagen cross-linking in skin, blood vessels and joints, mitochondrial protection, immune surveillance, stem cell maintenance and suppressing cancers. Vitamin C has a big role in slowing aging by better connective tissue integrity, lower frailty and slower immune senescence. Aging in humans resembles chronic low-grade vitamin C deficiency.
Humans show rapid depletion of plasma vitamin C during infections with the concentration often falling into the scurvy range. This in turn causes capillary leaks and oxidative damage. The human vitamin C level in plasma is normally in the range of 40 to 60 µmoles per litre. During infection this falls to under 20 µmoles per litre. Scurvy starts at below 11 µmoles per litre. Relative to other animals, the human vitamin C level collapses rapidly under stress. In contrast, animals go from the 60 µmoles per litre baseline to up to 100 µmoles per litre under stress. That said, absorption of vitamin C drops sharply from oral dosing above four to 14 grams per day, depending on individual tolerance. Five grams per day will get you to about 90 µmoles per litre. Taking vitamin C intravenously bypasses the limits imposed by oral dosing.
One of the things that vitamin C does during infection is to protect mitochondria from oxidation. Many hypoxic disease states are vitamin C-sensitive, not oxygen-related per se. Animals that make their own vitamin C maintain mitochondrial output during infection or exertion. Humans fatigue faster and accumulate inflammatory byproducts.
With respect to viral infection, vitamin C enhances type 1 interferon production. This slows viral load early, before viral load peaks. N-acetyl cysteine (NAC), another strong antioxidant, likely works in the same way. Vitamin C also keeps iron bound to proteins with the result that less is available for viral proteins. It also limits viral oxidative signalling cascades, capping the replication rate. In summary, viruses replicate fastest in vitamin-C depleted cells. Animals respond to viral infections by increasing vitamin C synthesis; humans experience uncontrolled inflammatory amplification instead.
Vitamin C, vitamin D and zinc have complementary roles in controlling viral infections. Vitamin C acts within hours while vitamin D acts over days to weeks. Vitamin D controls gene transcription in making proteins, prevents immune overshoot, and reduces autoimmunity and inflammatory overshoot. Zinc is needed for making antiviral enzymes, inhibition of RNA replication, and increasing the function of the thymus. Zinc is quickly depleted during infection. Zinc works best when vitamin C keeps the oxidative state of cells stable. This is a simpler way of putting it:
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- Vitamin C responds quickly to a viral infection.
- Zinc slows viral replication.
- Vitamin D prevents the immune system from burning the house down.
- Mammals evolved to make vitamin C because timing matters.
- Humans lost the buffer of being able to increase vitamin C production in response to the stress load and pay for it under viral stress.
The normal blood concentration of vitamin C is 12 µg/ml. Cells of the immune system concentrate vitamin C within them at 20 to 80 times higher than the plasma level. So, vitamin C is important in a properly functioning immune system. Immune system impairment starts when the plasma vitamin C level falls below 8 µg/ml. Immune cells work by creating reactive-oxygen-species to kill pathogen cells. The role of vitamin C is to protect the immune cells during this oxidative burst.
With respect to cancer, a high proportion of chemotherapy drugs work by creating reactive-oxygen-species (ROS) in the mitochondria. This stresses the cancer cell so it sends signals to the cell surface to make more death receptors on the cell surface. Most antioxidants negate this effect to some extent. With vitamin C at high blood concentrations, which can only be achieved by intravenous injection, this inverts to create an anti-cancer effect. Cancers have a voracious appetite for glucose. Oxidised vitamin C looks similar to glucose to the transporter proteins that take glucose into cells. Once in the cancer cells, this overload of oxidised vitamin C creates ROS which damages it. As a cancer treatment, intravenous vitamin C is most effective in the types that have a low ability to break hydrogen peroxide into water and oxygen
The first dose in intravenous vitamin C treatment of cancer is usually 15 grams. This is to make sure that the body is not overloaded with necrotic cancer cells if too many of them die at the beginning of treatment. The next dose is 30 grams. Daily dose rates of up to 90 grams have been used. This is equivalent to what two 50 kg, infected goats might produce between them.
The history of vitamin C is instructive. Portuguese sailors were using citrus to ward off scurvy by the late 1400s. English surgeon John Woodall recommended lemon juice in 1617. The convincing medical case was the shipboard trial aboard HMS Salisbury in 1747 in which sailors given oranges and lemons recovered rapidly. Vitamin C was isolated in 1928 and chemically produced in 1933. A decade later, doctors started using large doses on normally intractable patients. A Dr Frederick Klenner practiced in Reidsville, North Carolina. At the height of the polio epidemic in 1949, when all young parents lived in the fear that their babies and young children would be the next victims, Klenner published that he had successfully cured 60 out of 60 polio patients who had presented to office or to the emergency room. None suffered permanent damage from polio.
Klenner demonstrated repeatedly that vitamin C appears to be the ideal agent for killing any infecting virus. He would often use daily doses of vitamin C on a patient that would be as much as 10,000 times more than the daily doses used in the many clinical studies in the literature.
Klenner and others successfully treated the following diseases and afflictions with large vitamin C doses: polio, viral hepatitis, measles, mumps, viral encephalitis, chickenpox, herpes, viral pneumonia, influenza, rabies, AIDS, common cold, diphtheria, pertussis, tetanus, tuberculosis, streptococcal infections, leprosy, typhoid fever, malaria, brucellosis, trichinosis, amoebic dysentery, bacillary dysentery, pseudomonas infections, rocky mountain spotted fever, staphylococcal infections, trypanosomal infections, mushroom poisoning, lead poisoning and many other toxic substances, snake bite, spider bite, arthritis and cancers.
Klenner preferred to administer large doses by intravenous drip, supplemented by oral dosing. When the case required it, he also injected large doses via syringe as fast as the patient could take it. Klenner developed the principle that the dose must match the disease severity and be given often enough.
The next major insight in using vitamin C was from Dr Robert Cathcart who practiced medicine near San Francisco in California. While well people normally have a bowel tolerance for oral vitamin C in the range of four to 15 grams daily, Cathcart noticed that bowel tolerance increased in response to the severity of disease and other stressors, including something as simple as exercise. In 1981, he published this table of responses based on his experience with patients:
Cathcart’s insights included that diseases acted like acute induced scurvy on the body and that, while lower doses provided some improvement in a patient’s condition, only doses close to bowel tolerance would overcome the disease. In most cases, vitamin C was the only treatment necessary to achieve that. Some patients taking more than 200 grams per day orally have been recorded.
What Klenner and Cathcart achieved two generations ago has been forgotten. In recent years a Dr Paul Marik formulated a sepsis cure which is 1.5 grams of vitamin C every six hours plus hydrocortisone, thiamine on top of normal treatment. His protocol failed to replicated in subsequent trials. With the knowledge of Klenner and Cathcart’s work, it is apparent that Marik’s vitamin C dose is less than a tenth of what is should be.
As to the practicalities of dosing, Klenner in his 1971 paper asserted that in order to bring about quick reversal of both infectious and toxic insult to the body, the initial vitamin C must be given intravenously, in doses ranging from 350 mg to 1,200 mg/kg of body weight. Vitamin C as sodium ascorbate or ascorbic acid is buffered to pH neutrality with sodium bicarbonate in sterile water. A final fluid volume of 500 cc, containing 50 grams of vitamin C, in the IV bottle or bag works well. Vitamin C has a solubility in water of 330 grams per litre.
Vitamin D
Vitamin D regulates several hundred genes related to immune response to pathogens and cancer. There is a negative correlation between the vitamin D level in the blood and the incidence of sepsis, viral infections, cancer and most other diseases. The main role of vitamin D is bone turnover. Once the vitamin D level in the blood falls below 40 ng/ml, the thyroid gland starts producing parathyroid hormone which takes over that role, freeing some vitamin D for more immediately vital roles. The average Australian blood level is 25 ng/ml so most Australians live their lives with a chronic vitamin D deficiency. The incidence of most diseases would halve at 50 ng/ml. There is increasing benefit up to at least 80 ng/ml. Getting there will take supplementing at between 5,000 IU and 10,000 IU of vitamin D per day, depending on weight.
Figure 3: Vitamin D levels
In the long evolutionary fight between multicellular life forms and viruses, the multicellular forms created antiviral protections and the viruses evolved right back. Thus some viruses have the ability to turn off vitamin D receptors within cells they have infected. Turning them back on requires a vitamin D receptor activator such as quercetin.
Urolithin A
Pomegranates contain a number of ellagitannins, including one called punicalagin which has a strong IC50 against NSP13 of covid of 0.1 µg/ml. Unfortunately, the ellagitannins have poor bioavailability and pass through to the colon almost unaltered. There the microbiota transform them into firstly ellagic acid and then urolithins, dominantly urolithin A which has a half life in the body of 17 hours.
Urolithin A has little direct antiviral effect but a number of indirect ones, starting with removal of damaged mitochondria. Other effects include suppression of inflammation and increasing ISG15 production. ISG15 is an enzyme produced by all cells to counter viruses that have entered the cell. One of the first things that covid does on entering a cell is to turn off ISG15 production. In total, urolithin A is a viral replication suppressor and inflammation modulator.
Zinc
Zinc is needed for making antiviral enzymes, inhibition of RNA replication, and increasing the function of the thymus. Zinc is quickly depleted during infection. Zinc works best when vitamin C keeps the oxidative state of cells stable.
The normal dose range is 25 to 50 mg of elemental zinc per day. For an antiviral effect during infection, this could rise to 100 mg per day. For longer term use of zinc supplements, copper should be added at a 1:10 copper to zinc ratio. So a 25 mg daily supplement of elemental zinc should come with 2.5 mg of copper. Otherwise there is a risk of copper depletion longer term.
To increase the zinc uptake by cells, zinc should be taken at the same time as quercetin. How that works is that quercetin is a zinc ionophore; it takes zinc out of the intercellular fluid and holds it in a ring structure in the molecule. Then the quercetin is absorbed into cells at up to 50 times the concentration of quercetin in the intercellular fluid. If each quercetin molecule is holding a zinc atom within it, then the zinc concentration in cells rises to 50 times the intercellular level.
Quercetin
Quercetin’s main role is to concentrate zinc into cells. It also is a vitamin D receptor activator. Beyond those two qualities, it has typical flavonoid antiviral and anti-cancer activity in the low microgram/ml range.
Shiitake
Three species of mushroom combine good antiviral activity with good anticancer efficacy: shiitake, reishi and turkey tail. These are the ones that are readily available commercially; there are plenty of others. Their efficacy comes by increasing immune function. Shiitake, for example, stimulates NK cells, T cells, macrophages and modulates cytokines. Cytokines are small signalling proteins including interleukins, interferons and chemokines. Treating an infection or cancer takes six grams per day; one gram per day is the sustaining dose.
Some people have reported curing their cancers by taking mushroom extracts alone. This means that increasing their immune function was enough to tip those cancers over into apoptosis (programmed cell death in which the cell contents are chopped up by enzymes to be carried off by the intercellular fluid).
Omega-3
Omega-3 fatty acids are made from long chains of carbon atoms. Alpha-linolenic acid (ALA) is sourced from plants and has 18 carbon atoms. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have 20 and 22 carbon atoms respectively. They are sourced from fatty fish. If there is sufficient EPA and DHA in the diet, ALA provides only a few, minor benefits. It is not worth chasing as an end in itself. Enough arrives in the diet in green vegetables.
The benefits of EPA and DHA consumption are such that it is well worthwhile attaining the optimum intake level. Getting to that level would mean either eating at least five fish meals a week or taking fish oil supplements. The ratio of EPA to DHA varies between types of fish, EPA and DHA have different roles in the body and even timing of supplementation makes a difference in how the body is affected.
Briefly, EPA is mainly a signalling molecule and DHA is a structural component of cell membranes. DHA is more important than EPA in pregnancy and infancy. EPA is more important for adults because adults already have DHA-saturated neural membranes.
The optimum daily intake of combined EPA and DHA is in the range of 20 to 30 mg per kilo of body weight. So a 100 kg person should consume at least two grams per day. Fatty fish such as sardines, herring and mackerel are about 2% omega-3 oils by weight. To get to the optimum intake through eating fatty fish of the right species requires consumption of an average of 100 grams per day. A fish oil supplement is an easier option.
People ingesting the right amount of the right types of omega-3 oils will live longer and look better while they are doing it. In the era of covid there are also some important effects which will preserve brain function. DHA reduces amyloid aggregation in the brain, improves synaptic density and is essential in hippocampal membranes. EPA reduces microglial overactivation, reduces the production of inflammatory proteins (IL-1β and TNF-α) that drive amyloid deposition and improve blood flow in the brain. There is also synergy with flavones such as quercetin and baicalein by omega-3 oils improving transport of these things across the blood-brain barrier.
Regarding timing, a high EPA content in an omega-3 dose can increase alertness in some people and might delay sleep for those affected. On the other hand, DHA improves slow-wave sleep and amyloid clearance. If you are up to taking two different types of omega-3 capsules on a daily basis, you could consider an EPA-dominant one in the morning and a DHA-dominant one in the evening.
The importance of omega-3 fatty acids is shown by this graph:
Figure 4: The Omega-3 Index shifts the Neutrophil to Lumphocyte Ratio to a healthier level
An elevated neutrophil to lymphocyte ratio is also a biomarker of cardiovascular disease and events, the severity of covid, mood disorders, cognitive impairment, cancer, periodontitis, rheumatoid arthritis, cancer, diabetic kidney disease and total mortality. As the graph shows, there is quite a strong correlation between the fatty acid content of red blood cell walls and immune system impairment.
Omega-3 supplementation is surprisingly beneficial. It is strange that, as animals, the last time we had a fish diet that would have supplied the amount of fish needed for our optimum omega-3 intake was in the Devonian period, some 400 million years ago, when we were fish eating other fish. The biochemical machinery to utilise a high fish diet has been persevered for a long time.
Magnesium
Magnesium is essential for vitamin D activation. It has a range of other properties in immunity, sleep and stress that make it worth taking.
Other
There are many other minor cofactors including selenium, iodine, lithium, boron, molybdenum, fermentation products and beyond which can be added to this foundational immune stack.
David Archibald is the author of The Anticancer Garden in Australia