Lactoferrin is an iron-binding protein naturally present in milk that has a number of properties that make it important for newborns, with antimicrobial properties being some of them. Lactoferrin from cows, or bovine lactoferrin, is commonly available as a supplement. Can it help with COVID-19?

My position, explained below, is that, although it does inhibit viral replication in a lab dish, it is most likely to help by lowering IL-6 when taken upon the first sign of illness. Choosing the right product, though, may be difficult, and whey protein might be the best approach for many people.

Lactoferrin Inhibits SARS-CoV-2 Replication In Vitro

In a preprint* released on May 13, pre-incubating kidney cells originally isolated from African green monkeys with various concentrations of bovine lactoferrin for one hour prior to viral exposure prevented the replication of SARS-CoV-2, the coronavirus that causes COVID-19, in a dose-dependent manner. 0.2 mg/mL lactoferrin cut viral replication approximately in half. 0.6 and 0.8 mg/mL each caused progressively greater reductions, and 1 mg/mL lactoferrin reduced it by 84.6%.

In human lung cancer cells, lactoferrin was also effective, but somewhat less consistent across concentrations and somewhat less potent. 0.2 mg/mL had no effect. 0.6 mg/mL reduced replication by 46%, but 0.8 mg/mL only reduced it by 24%. 1 mg/mL, however, reduced it the most, by 68.6%.

In each case, only the 1 mg/mL concentration was statistically significant. That means that, given the amount of random variation and the consistency and strength of the effect, only the effect of 1 mg/mL can be clearly distinguished from the effect of random chance.

Still, the more consistent dose-dependent effect in African green monkey kidney cells appears more reliable than the zig-zagging effectiveness in human lung cancer cells. Lactoferrin was also 23% more effective at 1 mg/mL in the African green monkey cells than in the human lung cancer cells.

On the one hand, that the effect generalizes across two cell types increases confidence that it will generalize to other cell types. On the other hand, that the consistency and strength varied considerably across the two cell types warrants caution about assuming it would be just as effective in other cell types.

Lastly, while 1 mg/mL is the most reliable and strongest concentration of lactoferrin used in this study, greater concentrations were not tested, so the maximally effective concentration was not found. The maximally effective concentration might be somewhat greater than 1 mg/mL.

Can Lactoferrin Reach 1 mg/mL in Human Tissues?

It is entirely unclear whether we can use lactoferrin supplements to reach 1 mg/mL in any human tissue.

In vitro modeling (in vitro means in a lab dish) suggests that the low pH of the stomach would degrade lactoferrin into fragments. The various fragments do retain some antimicrobial activity, but some fragments are antiviral toward some specific viruses and not others, and we do not know whether digested lactoferrin has any effect on SARS-CoV-2. Lactoferrin that is completely free of iron is degraded in the upper small intestine, although natural bovine lactoferrin has 15-20% of its iron-binding sites occupied, and the iron protects it from degradation in the GI tract.

Nevertheless, it is not clear even that natural iron-containing lactoferrin can be absorbed intact. One study measured the levels of bovine lactoferrin in human blood after dosing 200 or 600 mg/d of two different products for four weeks. One product was a natural 15% iron-saturated bovine lactoferrin, and the other product was Inferrin, which has its lactoferrin microencapsulated with Progel, a substance that shields lactoferrin from the low pH of the stomach. The supplements were taken once a day after breakfast, and the blood was taken before and after the four weeks, after an overnight fast. No bovine lactoferrin was found in the blood of any participant.

On the other hand, while I do not believe anyone has measured the half-life of bovine lactoferrin in humans, its half-life is 12.6 minutes in rats. A substance will be gone from the blood after 4-5 half-lives. That suggests that a dose would disappear from blood within 50-63 minutes of being absorbed. In the study mentioned above, blood measurements were taken roughly 24 hours after the last lactoferrin dose. As a result, it doesn’t actually refute the absorption of intact lactoferrin.

Further, the breakfast would enhance the low pH of the stomach and increase the degradation of the lactoferrin. Lactoferrin is usually recommended to be taken on an empty stomach to avoid this.

The bottom line, though, is that we don’t have any evidence about what dose of lactoferrin, if any, produces a consistent concentration of 1 mg/mL in any human tissue.

Lactoferrin Inhibits Interleukin-6 (IL-6)

Anemia of chronic disease, as discussed in this newsletter yesterday, is anemia driven by inflammation, where interleukin-6 (IL-6) prevents iron absorption and drives circulating iron into ferritin, preventing it from being available for hemoglobin synthesis.

In a non-randomized intervention trial, 90 pregnant women were given the choice of bovine lactoferrin or iron as ferrous sulfate. The lactoferrin was taken 100 mg twice a day before meals, yielding a daily dose of 200 mg. It was 20-30% saturated with iron, which corresponds to 70-84 micrograms of iron. The iron RDA for pregnant women is 27 milligrams per day, over 300 times the amount of iron present in the lactoferrin, so the lactoferrin was insignificant as a source of iron. By contrast, the ferrous sulfate provided 105 mg/d of iron.

The lactoferrin was just as effective as the ferrous sulfate at raising hemoglobin and more effective at raising serum iron, even though its content of iron was negligible. Ferrous sulfate did nothing to lower IL-6, whereas lactoferrin lowered IL-6.

In other words, ferrous sulfate provides more iron without impacting the underlying inflammation, while lactoferrin fixes the underlying inflammation and thereby fixes the dysregulation of iron metabolism causing the anemia.

In pregnant women with minor beta-thalassemia, serum IL-6 dropped 76% from 25 to 6 pg/mL.
In pregnant women with hereditary thrombophilia, serum IL-6 dropped 35% from 89 to 58 pg/mL.
In non-pregnant women with minor beta-thalassemia, serum IL-6 was almost cut in half, dropping from 24 to 13 pg/mL.
In non-pregnant women with hereditary thrombophilia, serum IL-6 dropped five-fold, from 45 to 9 pg/mL.

Since the study wasn’t randomized, it is essentially an observational study that doesn’t give us strong confirmation of cause-and-effect. Nevertheless, in all cases the IL-6 was unchanged in the women taking ferrous sulfate, lending confidence to the likelihood that lactoferrin reduces IL-6.

As discussed in this review, bovine lactoferrin suppresses the release of IL-6 from macrophages. This also adds confidence to the likelihood that it does so in humans, as it appears to have done in the women with anemia of chronic disease.

That review also reported original data in 525 pregnant women with anemia of chronic disease where IL-6 was cut in half, from 94 to 45 pg/mL.

Lactoferrin Has to Be Intact, and Maybe Iron-Saturated

Most commercially available lactoferrin supplements are apolactoferrin, which does not contain iron.

The lactoferrin used to lower IL-6 was hololactoferrin, which does contain iron. The specific product used in the main study reported above was Lattoglobina, which is sold from Italy, and has 20-30% of its iron-binding sites filled with iron, compared to 15-20% for most natural products prior to processing.

In the review mentioned above, the authors report 25 out of 550 pregnant women in whom IL-6 did not decline. The women in this study had used two different commercial products. The authors analyzed those products for intact lactoferrin. The 525 women for whom IL-6 declined were using a product with intact lactoferrin. The lactoferrin in the product the other 25 women were using was broken up into fragments. The company, unnamed, followed Good Manufacturing Practices (GMP) and had a certificate of analysis, so the authors concluded that these two signs are inadequate to judge whether the lactoferrin will be effective or intact.

Since most commercial products are apolactoferrin and none that I can find produce testing showing the lactoferrin is intact, it seems unreliable to use them to lower IL-6.

The most reliable way to get the right lactoferrin would be to order Lattoglobina from Italy.

I believe the next best thing is to use a high-quality low-temperature-processed whey protein. Whey protein is 0.35-2.0% lactoferrin. This suggests that 10-57 grams of whey protein would provide 200 mg of lactoferrin. Unfortunately, whey protein manufacturers do not seem to test and report their lactoferrin contents. The best approach might be to shoot for one or two 20-gram scoops of whey protein per day.

It should be noted that colostrum, while it is rich in lactoferrin, does not provide much lactoferrin when taken in the small doses of powder included in commercial supplements. For example, there is 57 times as much immunoglobulin in colostrum as there is lactoferrin. One capsule of Jarrow Colostrum Prime Life has 150 mg immunoglobulin, so probably has somewhere around 2.6 mg lactoferrin. Since colostrum capsules contain such little colostrum, they are an insignificant source of lactoferrin.

The Bottom Line

Lactoferrin inhibits SARS-CoV-2 replication in a lab dish, but it is not clear whether supplementing with it will increase the concentration in our tissues adequately to fight the virus when we are infected with it.

On the other hand, lactoferrin taken 200 mg/d in two divided doses on an empty stomach before meals may be effective at decreasing IL-6 and correcting the anemia of chronic disease that appears to accompany COVID-19.

The most reliable way to get the right type of lactoferrin is to order it from Italy.

The second best way is to take one or two scoops of a high-quality whey protein, or, if you find a company that tests and reports the lactoferrin content, whatever amount of whey protein provides 200 mg lactoferrin.

Commercial products marked as “apolactoferrin” might not be effective.

If this is to be effective, it is best used as a protocol at the first sign of sickness to prevent IL-6 from rising to dangerous levels. There are no randomized controlled trials showing this works. Rather, there is preliminary evidence suggesting it might work.

I was planning on updating The Food and Supplement Guide to the Coronavirus with a recommendation to use lactoferrin. However, due to the uncertainty around which products are and are not effective, I am currently withholding that recommendation. Still, I find the suggestions above to be harmless and possibly helpful.

Stay safe and healthy,
Chris

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Disclaimer

I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.

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*Footnotes

* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.

Lactoferrin, Whey Protein, and COVID-19