Vitamin A for Measles
Not a vaccine replacement
After being declared eliminated in 2000, the highly-contagious measles virus is now rearing its ugly head in the USA in a recent outbreak linked to declining rates of vaccination. In response to this outbreak, RFK Jr, our secretary of Health and Human Services, wrote a call to action in Fox News, with a rather timid language asking for parents to consider vaccines as well as an endorsement of updated CDC guidance on vitamin A as part of the therapeutic regiment for measles. I’m already seeing tons of (mis)information and confusing about measles being due to a poor diet, and that vitamin A can replace vaccination, so let’s unpack this one.
The story of measles and vitamin A is an offshoot of the story of childhood mortality in lower resource settings where there is substantial malnutrition. Researchers working in areas with endemic malnutrition noted decades ago that children with night blindness (nyctalopia) and Bitot’s spots, both ocular (eye) manifestations that occur with vitamin A deficiency, were associated with substantially increased mortality, particularly from infectious diseases. Prior to this work, there was significant doubt that vitamin A deficiency was a causal factor contributing to childhood mortality, given that it co-occurred with inadequate intake of calories/protein as well as infectious diseases. The relative specificity of the ocular manifestations for vitamin A deficiency strongly implicated it as a causal factor and spurred decades of animal models, epidemiological and clinical investigations into vitamin A intake/status’ relationship to immune function and mortality. In the modern era, vitamin A status is widely monitored in countries - through things like serum retinol, the circulating form of Vitamin A most closely linked to liver stores, as well as physical assessments that document ocular manifestations - and there are large successful supplementation programs that make a meaningful dent in childhood mortality. Unlike endless debates about nutrients/foods related to chronic diseases like atherosclerotic cardiovascular disease, the data here is relatively strong (though still a lot we don’t know!)
It is now well-appreciated that vitamin A deficiency impairs general immunity to an array of pathogens. Much of the reason vitamin A is essential for immune function is because vitamin A in the diet (either as a preformed retinol or a plant-based precursor that can be converted to retinol) is converted in cells to its active signaling form, retinoic acid, that binds its receptors and directly regulates the expression of essential genes. This signaling of retinoic acid and turning on of specific genes is critical for individual cell types of the immune system to achieve the correct cellular identity and perform their functions; retinoic acid influences a) epithelial cell differentiation, ensuring the integrity of the physical barriers that protect us from microorganisms in surfaces exposed to the outside world like lungs and GI tract); b) the activity of the adaptive immune system’s T- and B-cells, including the capacity to make antibodies; and c) ensuring the function of a variety of cell types in the innate immune system, including macrophages, neutrophils, dendritic cells and innate lymphoid cells. Vitamin A deficiency’s 3-pronged hit on immune function can leave the body unable to mount an appropriate immune defense to fight off an infection, unable to mount an appropriate memory response to the pathogen, and leave individuals suspectible to secondary infections (the degree to which each mechanism matters depends on the specific pathogen).
Given this critical role of vitamin A in maintaining a properly functioning immune system, there have unsurprisingly been a number of randomized controlled trials of vitamin A supplementation in predominantly low- and middle-income countries with high rates of vitamin A deficiency - these trials pretty consistently demonstrate significant improvements in mortality and the incidence of diarrhea (a common sign of enteric infections), and have led to the WHO giving strong recommendations to supplement vitamin A for infants and children in settings where vitamin A deficiency is common. (note: this is all the data behind vitamin A supplementation programs that USAID helped coordinate/implement that have now been cut :/)
With respect to measles, a role for vitamin A in its treatment was first suspected because the disease presented with ocular manifestations similar to vitamin A deficiency, including blindness. Serum retinol (the circulating form of vitamin A) has been consistently observed to be reduced in measles infection in developing countries, consistent with the clinical manifestations of the disease. Measles’ stress on circulating levels of vitamin A likely occurs through several non-specific mechanisms: 1) the acute phase response to infection results in reduced levels of hepatic protein synthesis and reductions in the binding protein complex (RBP4-TTR) that carries retinol/vitamin A in the blood and 2) there is considerable leakage of retinol and its binding protein into the urine and stool during infection (this is not a normally quantitatively significant route of retinol loss in healthy individuals). These stresses are likely to exacerbate and/or precipitate vitamin A deficiency in those with marginal intakes, and compromise immune function and have been the impetus for undertaking controlled interventions in this population. Data from 3 randomized controlled trials demonstrate that when vitamin A is supplemented at very high doses (2 doses of 200,000IU for children >1yr age and 100,000IU for infants), there is a significant 62% reduction in measles mortality. This evidence serves as the basis for WHO guidelines for treating measles that recommend supplementing with vitamin A.
This recommendation to supplement with vitamin A has some important caveats when considering it in the context of the current measles outbreak in the USA:
Nearly all studies were conducted in regions in Africa, in study populations where vitamin A deficiency is common. The relevance to countries with less vitamin A deficiency and less diarrheal disease is not clear.
The doses used here are very high, largely because vitamin A is a fat soluble vitamin that can be stored and mobilized. The units here are a bit weird but for reference the daily recommended intakes for children are 300-700 micrograms of retinol. The 200,000IU being used in measles treatment recommendations equates to 60,000micrograms (100-200X the daily recommended dose to maintain vitamin A levels in the body). I have to call this out because we are in the era of carnivore influencers selling people encapsulated beef liver extolling the benefits of vitamin A- despite liver being a rich source of vitamin A, it comes nowhere close to the doses we’re talking about here.
It’s critical to stress that we aren’t 100% sure how vitamin A is working to reduce risk of mortality in measles and that matters. It is probably working by helping to correct vitamin A deficiency and its associated impaired immunity, resulting in lower mortality. If this is the mechanism, vitamin A supplementation is unlikely to have much impact in developed nations where we have very low rates of vitamin A deficiency.
Other mechanisms may be at play, however. For example, the high dose supplementation could be having a drug-like effect we don’t yet understand. It might also be overriding a dip in supply of serum retinol that is essential for immunity acutely and independent of habitual intakes/body stores - indeed, the mechanisms we discussed above for measles impacting serum retinol are pretty nonspecific (e.g. reducing binding proteins during infection so serum levels are low) and we see this phenomena reflected in (the very limited data we have from) cohorts in the USA of children with measles where they present with low serum retinol during the active phase of infection (but levels return to normal during recovery). It’s possible, though speculative, that super high dose retinol is facilitating tissue supply during the acute stress of infection when normal mobilization from body stores are otherwise impaired. The only way to confirm this is to do a randomized controlled trials in individuals in the USA who have measles and see whether there is a benefit.
Unfortunately, we do not have such trials in the USA. In developed countries, we have one study from Japan (Kawasaki,1999, it's in Japanese but summarized in Cochrane reviews) reporting a reduction in cough duration in hospitalized patients with a 1 time dose of 100,000IU. An additional non-randomized study leveraging a shortage of vitamin A in Italy showed no difference in clinical course between patients with measles infection who received vitamin supplementation vs those who did not (not supportive of vitamin A’s potential in higher income countries with less vitamin A deficiency but not necessarily a nail in the coffin on its own). No real conclusions can be made from this limited literature about vitamin A supplementation’s efficacy in contexts where vitamin A deficiency is rare.
Despite this lack of domestic trial data, recommendations from the CDC and other groups, including the American Academy of Pediatrics and the National Foundation for Infectious Diseases (NFID), have echoed the WHO guidance - albeit the recommendations read a bit more conditional and acknowledge the uncertainty in relying on data from vitamin A deficiency endemic areas (something grading of the evidence would downgrade the certainty in a recommendation for due to ‘indirectness’) as well as assumption that the supplementation of vitamin A levels to offset the reduced serum retinol during the acute phase of the infection will be beneficial. NFID explicitly calls out the need for conducting trials in the USA setting to fill this evidence gap and make these guidelines more ‘evidence-based’.
Importantly, every group that recommends vitamin A supplementation (despite the lack of evidence) strongly clarifies that vaccination vs vitamin A is not an either or situation, and there is no data that vitamin A can replace vaccines. Indeed, measles vaccination is highly efficacious at reducing disease and mortality. For any folks arguing that vitamin A can replace vaccines, this is a highly dubious claim based on no data. I’ve seen some claims that high dose vitamin A supplementation can itself reduce the incidence of measles but the data that supports this claim is also in low- and middle-income countries targeting vitamin A deficiency, where correcting the vitamin A deficiency facilitates adequate antibody responses to vaccines and promote immunity - essentially, fixing the vitamin A deficiency can help vaccines do their thing, it’s not a direct effect of vitamin A on measles.
It should be noted that much of the enthusiasm around vitamin A assumes efficacy in the USA setting as well as low side effects. There is, however, concern that the very high doses of the fat-soluble vitamin A may have some toxicity. The data is limited, particularly in kids and fortunately doesn’t point to long-lasting side effects from acute high-dose ingestion (Gastrointestinal complaints are the most common from acute intakes of very high vitamin A doses). There are more serious side effects to chronic high dosing of vitamin A, especially in pregnant individuals where high levels can cause fetal malformations, so i’m hopeful that current vitamin A fanfare doesn’t lead to enthusiastic vitamin A supplementation at large. Any signs of toxicities will be something that clinicians employing vitamin A supplementation need to carefully monitor for, given the limited data we have employing these dosing regimens in individuals with higher vitamin A status at baseline.
A few other practical issues arise with vitamin A:
many pharmacies and physicians may not have ready access to vitamin A formulations or be familiar with how to administer vitamin A. Vitamin A supplements in the global health setting are commonly found as capsules ranging from 50,000-200,000 IU’s that can be cut open and their contents squeezed into a child’s mouth. Pharmacies will need to stock up on these formulations. Common over the counter supplements of vitamin A/retinol are 5000-25000IU typically, and would require having younger children ingest many capsules worth of a product (that may or may not be accurately labeled/stable). Clinicians should be discouraging patients and the public from trying to take vitamin A supplements at home to prevent or treat measles and seek out a qualified medical professional if they wish to employ high dose vitamin A supplementation as back to back doses for measles. If patients have concerns about their vitamin A intakes, they can consult with a knowledgeable dietitian. For those less familiar, there’s not a great lab that is a sensitive and specific marker of vitamin A status - serum retinol is maintained across a wide range of intakes, until you get either very low and it drops off, or achieve toxicity and it starts to rise. Otherwise, a simple serum values will not tell you whether you’re close to either end of the spectrum unfortunately so patients do need a dietary assessment to determine whether their intakes are potentially inadequate.
Measles outbreaks can occur in adolscenets as well as adults, where the data/dosing becomes even more uncertain. The wording of recommendations emphasizes children and its not clear whether existing guidance is relevant.
It’s worth its own post to unpack but I wanted to briefly call out RFK Jr’s enthusiasm for good nutrition in his Fox News piece as the ‘best defense’ against infectious illness. Stating that ‘good nutrition’ remains a ‘best defense’ to an American public that largely doesn’t suffer from protein-energy malnutrition and micronutrient deficiencies (the nutritional factors that impair immune function the most) is going pretty far beyond the data, and raises red flags when the same tone isn’t used to advocate for vaccination, which is overwhelmingly the best defense against infectious illnesses. Nutrition is important but we regularly see infections occur in well-nourished individuals and there are harms from this, especially in the case of measles where it wipes your immune system’s memory of other pathogens (“immune amnesia), exposing you to increased risk of other pathogens. We should be employing recommendations with the level of enthusiasm that the data supports, which means widely advocating for vaccination to reduce measles outbreaks, addressing malnutrition and improving food security at home and globally (cough USAID cough) and arguing for (and funding!) better trials to test potential treatments (like vitamin A supplementation).
