Madison Area Lyme Support Group

Editor’s note: This is part 2 of a three-part series on red meat allergy, a serious, lifestyle-limiting disorder that causes individuals to experience mild-to-life-threatening allergic symptoms several hours after eating red meat. Also known as “alpha-gal syndrome,” meat allergy has no cure — the only “treatment” is to avoid certain meats and animal products. Read part 1 of the series here.

Recent news reports on the recent rapid spread of alpha-gal syndrome (AGS), or red meat allergy, blamed the lone star tick. That’s because the tick’s saliva contains trace quantities of a sugar, alpha-gal, a known human irritant that many researchers and clinicians believe induces the dangerous allergic responses that are the hallmark of AGS.

But the lone star tick isn’t the only source of alpha-gal. One of many sugars that attach to meat proteins and other animal-derived products, alpha-gal also is used in the manufacture of foods, personal care products, medical devices and drugs — including vaccines.

The Centers for Disease Control and Prevention (CDC) provides an informative, but incomplete list of vaccine ingredients containing alpha-gal, whose chemical name is galactose-alpha-1,3-galactose.

The CDC’s list includes bovine serum albumin, a protein produced from cow’s blood; gelatin, made from the bones and connective tissues of cows and pigs; magnesium stearate from numerous animal sources including red-meat animals; and glycerin, sourced from both animals and plants.

These substances, known as excipients, are added to many types of drug formulations to protect the more active ingredients from chemical and environmental degradation.

The U.S. Food and Drug Administration (FDA) categorizes glycerin, stearate and gelatin as “generally recognized as safe” (GRAS), but that designation applies only to foods, not to injected substances.

Serum albumin, the most abundant protein in mammalian blood, is not on the GRAS list but is consumed by ingesting beef and dairy products. Albumin is also used in many drugs and in beauty and personal care products.

Bovine serum albumin is itself an allergic irritant that can, along with other milk proteins, induce cow’s milk protein allergy in susceptible individuals. This is not the same as lactose intolerance, which results from the inability to break down milk sugars.

The Johns Hopkins excipients in vaccines list is interesting for the sheer number and chemical diversity of additives found in vaccines. Just focusing on the four ingredients the CDC says “may contain” alpha-gal, one finds 11 vaccines use bovine or calf serum, three contain glycerin, three contain stearate and nine use gelatin as an ingredient.

Two vaccines list both stearate and glycerin. An additional 22 vaccines contain various bovine extracts.

So could vaccines — and not a tick bite — be the principal source of alpha-gal exposure leading to sensitization, and rarely, to symptomatic AGS?

That hinges on whether alpha-gal is actually present in one or more of the four vaccine components of interest mentioned above.

Do vaccines contain alpha-gal or not?

Of the questionable ingredients, bovine serum albumin would be the prime suspect, as it’s found in so many vaccines, is independently associated with allergic reactions, and because many related mammalian proteins readily link to alpha-gal.

But alpha-gal does not attach to albumin natively, so any alpha-gal present in preparations containing albumin must be an impurity carried over from the protein’s manufacturing process.

However, that is unlikely because of how albumin is manufactured. The process, especially for food and drug applications, almost always includes chromatography, a method that efficiently separates proteins from very small molecules like alpha-gal.

How about the other suspected ingredients?

As noted previously, the CDC warns that gelatin, another vaccine ingredient of interest, may contain alpha-gal. An AGS advocacy website echoes this concern.

According to the Johns Hopkins Institute for Vaccine Safety, nine vaccines contain gelatin in quantities up to 15 mg per dose. These include vaccines against rabies, influenza and measles/mumps/rubella.

Whether a product contains alpha-gal depends on how the gelatin was sourced. Alpha-gal has not been found in gelatin derived from fish, but its presence in cow-derived gelatin is well-established.

A 2021 study described cases of severe anaphylaxis in individuals receiving vaccines containing gelatin. The authors stated:

“Gelatin-containing vaccines should be administered with caution or avoided in patients with AGS because of their high potential to activate basophils indicating a risk for anaphylaxis.”

In living systems, glycerine (also called glycerol) is a carrier molecule that helps transport  fats and sugars throughout the body. Alpha-gal could be a side product of glycerin manufacture.

However, in contrast to the potential gelatin-alpha-gal connection, unbound alpha-gal and glycerin are similar enough chemically that some alpha-gal might sneak into the final product as an impurity.

A sugar closely related to alpha-gal attaches to glycerine — but this seems to occur only in plants.

Whether this sugar might also cause allergic reactions is unknown. But if it does, glycerine sourced from plants could pose a higher risk to individuals with alpha-gal sensitivity than similar products from cows.

Derived from stearic acid — biologically a fat — magnesium stearate is used in a variety of medicines, foods, and personal care products. Although stearic acid attaches to many other chemicals, it does not appear to combine with sugars.

The concern over magnesium stearate as a possible source of AGS is therefore limited to situations in which alpha-gal is a process impurity. Due to the chemical nature of both molecules, however, and how magnesium stearate is manufactured, this is practically impossible.

Table 1 summarizes these findings.

Table 1. Vaccine ingredients associated with exposure to alpha-gal, their sources, type of association, and the number of vaccines containing the ingredient

Note that “bovine extract” is a chemically undefined product that may include any number of suspicious ingredients, according to the FDA:

“Animal-derived products used in vaccine manufacture can include amino acids, glycerol, detergents, gelatin, enzymes and blood.

“Cow milk is a source of amino acids, and sugars such as galactose. Cow tallow derivatives used in vaccine manufacture include glycerol.

“Gelatin and some amino acids come from cow bones. Cow skeletal muscle is used to prepare broths used in certain complex media.”

Bovine extract is found in all four ingredients — albumin, stearate, gelatin and glycerin — that the CDC says contain alpha-gal.

Perhaps not alpha-gal at all, but similar sugars

Since so many individuals carry alpha-gal antibodies but so few get sick, the connection between alpha-gal sensitivity (based on a positive antibody test) and symptomatic allergy is at the very least mysterious.

But what if exposure to alpha-gal may not even be necessary for those antibodies to exist?

Many sugars trigger an allergic response, but sometimes the body confuses the original source of exposure with something else it encounters later on.

Sugars of one type that elicit a response to sugars of another type are known as “cross-reactive carbohydrate determinants.” Reactivity to alpha-gal, as measured by antibodies to this irritant, could therefore arise through exposure to a chemically similar sugar.

A study published in 2017 in the Journal of Allergy and Clinical Immunology noted that:

“Cross-reactive carbohydrate determinants (CCDs) in plants and insect venoms are a common cause of irrelevant positive test results during in vitro allergy diagnosis.

“We observed that some CCD-positive sera show nonspecific IgE binding even with CCD-free recombinant allergens when using the Phadia ImmunoCAP platform.”

In other words, an allergic reaction to some sugars could cause individuals to test positive for antibodies to totally different sugars. This study found that even cellulose, the main sugar-based structural component of wood, paper and many vegetables — and the “fiber” in many healthy foods — could elicit a false positive allergy test.

To summarize:

• A significant portion of the U.S. population carries antibodies to alpha-gal but only a tiny fraction develop AGS.
• A positive test for alpha-gal antibodies does not always mean a person has been exposed to alpha-gal.
• The prevalence of alpha-gal antibodies in the U.S. population (nearly one-third) makes it unlikely that the lone star tick is the sole cause of sensitization.
• Vaccines may be significant sources of initial alpha-gal exposure, sensitization and possibly of conversion from asymptomatic to full-blown AGS.
• Alpha gal sensitivity is possible even when someone has never been exposed to the sugar.

Part 3 of this series will examine data supporting these points, and investigate possible mechanisms underlying meat allergy.