Are there any immunizations that should be avoided in patients with allergy to alpha-gal?

Comment by InpharmD Researcher

As alpha-gal can be found in gelatin, alpha-gal allergic patients may react to gelatin-containing vaccines. Gelatin-containing vaccines in the United States include live, attenuated influenza (Flumist); measles, mumps, rubella (MMR II); measles, mumps, rubella, varicella (ProQuad); rabies (Rabavert); typhoid oral (Vivotif); varicella (Varivax); and yellow fever (YF-Vax), with higher content of gelatin and bovine calf serum noted in MMR and zoster vaccines. Safety measures (e.g., a priori skin testing, blood-specific IgE testing) may be considered to minimize the risk of potential vaccine-induced anaphylaxis in this cohort of patients.

Background

A 2021 experimental study aimed to investigate whether basophil activation tests (BATs) performed with gelatin-containing vaccines would yield positive results in patients with alpha-gal syndrome (AGS), potentially indicating a risk for anaphylaxis. The study included a total of 6 participants, consisting of two patients with confirmed AGS based on positive oral provocation tests (patients 1 and 2), two patients highly suspicious for AGS due to their history of anaphylaxis after exposure to alpha-gal-containing food products (patients 3 and 4), and two healthy controls without any previous medical history of allergies. None of the participants exhibited sensitization towards gelatin, indicated by serum immunoglobulin E (sIgE) levels <0.1 kU/L. Additionally, none of the participants had previously received varicella or varicella-zoster vaccinations, although all had contracted varicella infection during childhood. BATs were conducted using different dilutions of gelatin-containing vaccines, including attenuated varicella vaccine, measles, mumps, and rubella (MMR) live vaccine, and varicella-zoster vaccine. Due to the unavailability of certain vaccines, variations were observed in the specific types of vaccines used for testing across patients. Furthermore, additional BATs were performed using alpha-gal allergen at varying concentrations depending on the patient group. [1]

The findings revealed that patient 1 exhibited positive basophil activation for all tested vaccines, with the highest activation observed for the varicella-zoster vaccine at an undiluted concentration, showing a CD63 expression of 92.1%. Positive activation was also noted for varicella vaccine and MMR vaccine, with CD63 expressions of 87.3% and 88.7%, respectively. Patient 2 similarly demonstrated positive basophil activation for all vaccines, with the highest activation observed for varicella-zoster vaccine, with a CD63 expression of 51.3%. Patient 3, although only tested with MMR and varicella vaccines, also showcased positive basophil activation. Patient 4, who was tested with varicella vaccine and a non-gelatin MMR vaccine, exhibited basophil activation only with the varicella vaccine. Notably, healthy controls did not exhibit basophil activation for any tested vaccines. Additionally, basophil activation with alpha-gal allergen varied across patients, with different expressions observed at varying concentrations. Overall, these results suggested that patients with confirmed AGS exhibited strongly positive basophil activation in response to all tested gelatin-containing vaccines, while healthy controls and the non-gelatin vaccine remained negative. Although the clinical relevance of these findings is not definitively proven by BATs alone, the authors still advise caution when administering gelatin-containing vaccines to patients with AGS. [1]

A 2022 retrospective observational analysis evaluated the prevalence of IgE-mediated allergic reactions to alpha-gal containing vaccines. The Vaccine Adverse Event Reporting System (VAERS) database was used to analyze hypersensitivity reactions to the gelatin-containing vaccines, while physician surveys from an endemic area to the Lone Star Tick in New York were used to identify the incidence of allergic reactions observed in gelatin-containing vaccines in those with alpha-gal allergies. Gelatin-containing vaccines in the United States include live, attenuated influenza (Flumist), measles, mumps, rubella (MMR II), measles, mumps, rubella, varicella (ProQuad), rabies (Rabavert), typhoid oral (Vivotif), varicella (Varivax), and yellow fever (YF-Vax). While the VAERS database identified vaccine reactions, insufficient information prevented statistical analysis. Among the physicians surveyed with a patient population of over 650 individuals, only 2 cases of immediate IgE reaction to gelatin-continuing vaccines was observed. A 38-year old male patient with a history of suspected allergic reactions to meat and dairy experienced cough, chest, throat tightness, difficulty breathing and speaking within 40 minutes of receiving the MMR vaccine. Symptoms resolved after two doses of epinephrine. The emergency department collected alpha-gal IgE level which resulted in 57.4 kU/L. Another patient with a history of severe gastrointestinal symptoms daily and meat developed acute anaphylaxis following Varivax administration, and required treatment with epinephrine. Her alpha-gal IgE level was 10.5 kU/L. Results from this study did not support increased risk of IgE-mediated hypersensitivity reactions with gelatin-containing vaccines in alpha-gal sensitized patients. [2]

A 2022 abstract compared the incidence of hypersensitivity reactions to gelatin-containing vaccines in various locations via the VAERS database. The authors hypothesized that states endemic to the Lone Star Tick would have more patients sensitized to alpha-gal given the association between alpha-gal syndrome and the Lone Star tick bite. The results included 90 reactions to the MMR vaccine, 44 to Varivax and 34 to Zostavax; of which 49, 36, and 17 reactions were from the states endemic to the Lone Star Tick, respectively. When comparing reaction rates between endemic and non-endemic states, no statistical significance was found. This study’s findings did not correlate increased hypersensitivity reactions in states endemic to the Lone Star Tick and gelatin-containing vaccines were not found to have an increased risk of reaction in alpha-gal sensitive patients. [3]

References:

[1] Schmidle P, Mehlich J, Brockow K, Darsow U, Biedermann T, Eberlein B. Gelatin-Containing Vaccines for Varicella, Zoster, Measles, Mumps, and Rubella Induce Basophil Activation in Patients with Alpha-Gal Syndrome. Int Arch Allergy Immunol. 2021;182(8):716-722. doi:10.1159/000514263
[2] Zafar S. Hesitancy in administering gelatin-containing vaccines to alpha-gal sensitized patients. BJSTR. 2022;42(1).
[3] Zafar S, Wolff A, Schutzer S, McGintee E, Torre A. Are gelatin-containing vaccines safe to give in alpha-gal sensitized patients? Journal of Allergy and Clinical Immunology. 2022;149(2):AB99. doi: 10.1016/j.jaci.2021.12.348
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Are there any immunizations that should be avoided in patients with allergy to alpha-gal?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

 

Brief Summary of Relevant Case Reports 
Author, Year Case Presentation Study Author Conclusion

Pinson et al., 20151

A 58-year-old Caucasian male with alpha-Gal allergy, with a past medical history significant for multiple tick bites, was referred to the clinic to evaluate gelatin-containing vaccines. Initial serum-specific immunoglobulin testing was positive for alpha-Gal (6.01 kUA/L), beef (2.12 kUA/L), and pork (1.22 kUA/L) while negative for bovine gelatin (​<0.10 kUA/L), turkey (​<0.35 kUA/L), chicken (​<0.35 kUA/L), and cat dander (​<0.35 kUA/L). Initial allergy skin tests were positive for intradermal pork and beef, while gelatin and the live zoster vaccine skin tests were negative. Additionally, compared to atopic controls, immunoblot testing with patient serum was inconclusive. 

After obtaining informed consent, the patient was administered the live zoster vaccine in a single dose and observed for 30 minutes without any immediate reactions and no reported delayed reaction when contacted telephonically 24 hours later.

Gelatin content of vaccines
Vaccine Gelatin content
Influenza (Fluzone; Sanofi Pasteur) 250 mcg porcine gelatin per 0.5 mL dose
Influenza (Flumist, MedImmune Vaccines, Gaithersburg, MD) 2,000 mcg hydrolyzed porcine gelatin per 0.2 mL dose
Measles, mumps, rubella (ATTENUVAX, MERUVAXII, MMR II, MUMPSVAX; Merck, Whitehouse Station, NJ) 14,500 mcg hydrolyzed porcine gelatin per 0.5 mL dose
Measles, mumps, rubella, varicella (ProQuad; Merck) 11,000 mcg hydrolyzed porcine gelatin per 0.5 mL dose
Rabies (RabAvert; Novartis, Emeryville, CA) 12,000 mcg bovine gelatin per 1 mL dose
Typhoid vaccine live oral Ty21a (VIVOTIF; Berna, Coral Gables, FL) Bovine gelatin in capsule
Varicella (VARIVAX; Merck) 12,500 mcg hydrolyzed porcine gelatin per 0.5 mL dose
Yellow fever (YF-VAX; Sanofi Pasteur) 7,500 mcg porcine gelatin per 0.5 mL dose
Zoster (ZOSTAVAX; Merck) 15,580 mcg hydrolyzed porcine gelatin per 0.65 mL dose

Our patient, who tolerated a vaccine containing the highest gelatin content, is reassuring, but continued safety assessment of gelatin-containing vaccines for this patient cohort is recommended as multiple factors for this patient cohort influence the reaction risk.

Stone et al., 20172

A 68-year-old female patient with a medical history significant for recurrent delayed anaphylaxis after eating and a subsequent laboratory evaluation of elevated blood specific IgE (sIgE) to beef 10.5 kU/L, pork 10.4kU/L, and cow’s milk 2.90kU/L (reference for all <0.35 kU/L) presented to the emergency department due to anaphylactic reaction (dyspneic, flushed, with facial, oral, and uvular angioedema and bilateral conjunctival injections) upon 30 minutes of receiving a live attenuated herpes zoster vaccine containing the Oka VZV strain. 

One month after her episode of anaphylaxis, she was tested for alpha-gal allergy, with galactose-alpha-1,3-galactose sIgE 32.5 kU/L, beef sIgE 23.1 kU/L, lamb/mutton sIgE 12.2kU/L, and pork sIgE 17.1 kU/L. She was subsequently tested for allergy to gelatin, with porcine gelatin sIgE 1.84kU/L and bovine gelatin sIgE 0.15kU/L (reference range for all sIgE tests <0.35kU/L).

Subsequent testing of selected vaccines revealed the presence of alpha-gal allergen in MMR and zoster vaccines, which have in common a higher content of gelatin and content of bovine calf serum.

Reported Gelatin or Mammal Derived Product Content of Selected Vaccines
Vaccine Reported Gelatin Content of Vaccine Reported Type of Gelatin or Animal Derived Product
Zoster (Merck) 15,580 mcg per 0.65 mL dose Porcine Gelatin, Bovine Calf Serum
MMR (Merck) 14,500 mcg per 0.5 mL dose Bovine Gelatin, Bovine Calf Serum
Yellow Fever (Sanofi Pasteur) 7,500 mcg per 0.5 mL dose Gelatin, type not reported
Tetanus, Diptheria and acellular Pertussis (TDaP) (GSK) None Bovine Casein, Bovine Extract
Tetanus, Diptheria and acellular Pertussis (TDaP) (Sanofi Pasteur) None Bovine Casamino Acids

Alpha-gal allergy is an increasingly prevalent hypersensitivity syndrome in the Southeast US, as well as other parts of the world. Clinicians who manage it should be made aware of the risk of anaphylaxis to higher content gelatin-containing vaccines such as MMR and zoster vaccines, especially because of their parenteral delivery. While anaphylaxis from the zoster vaccine appears to be a low probability event, it has significant public health implications, and there is a need to determine on a population level how often patients who have anaphylaxis to higher gelatin content vaccines such as MMR and Zoster vaccine have an underlying alpha-gal allergy.

Stone et al., 20193

A 5-year-old male patient with a known alpha-gal allergy (alpha-gal sIgE of 8.19 kU/L, total IgE of 149 kU/L) experienced anaphylaxis 5 minutes after receiving routine vaccinations, including MMR, Varicella, and DTaP/IPV and was treated successfully in an emergency room setting. Subsequent, repeated sIgE testing revealed elevated sIgE levels of alpha-gal and various meats, suggesting the vaccines, which contain gelatin and potentially alpha-gal, triggered the reaction. Additionally, he demonstrated positive skin test responses to MMR vaccine, varicella vaccine, and porcine gelatin on undiluted pricks.

It is noted that both MMR and varicella vaccines contain large amounts of gelatin per dose when compared to other vaccines (14,500 mcg per 0.5 mL dose and 12,500 mcg per 0.5 mL dose, respectively). MMR, Varicella, and DTaP/IPV combination vaccines also contain bovine calf serum, quantity unreported.

This is the first case of vaccine-induced anaphylaxis in a pediatric patient that implicates alpha-gal allergy as another possible contributory mechanism. The co-presence of gelatin sIgE may indicate the context in which an alpha-gal allergic patient will react to vaccines, as not all alpha-gal allergic patients will react to gelatin-containing vaccines. Going forward, a priori skin testing and measurement of gelatin sIgE should be evaluated to determine if these tests can predict the safety of gelatin-containing vaccines in individual alpha-gal allergic patients.

Leong et al., 20234

A 16-year-old male with a red meat allergy had two separate reactions to vaccines. At one visit, he received hepatitis B, MCV, Tdap, and varicella vaccines, after which he developed diffuse pruritic hives and restlessness 3-4 hours later. 6 months later, he received the MMR vaccine and reacted similarly. Skin-prick-testing (SPT) was negative for beef, lamb, and pork; it was equivocal for gelatin. Serum IgE (kU/L) showed beef 0.95, pork 0.85, lamb 0.56, alpha-gal 2.12. Two months later, SPT was positive for gelatin, borderline to MMR and varicella vaccines. SPT and intradermal testing were negative for Tdap, MCV, and hepatitis B vaccines.

Our patient had evidence of IgE-mediated sensitization to both alpha-gal and gelatin. We suspected reactions to MMR and varicella vaccines, which contain gelatin. As alpha-gal can be found in gelatin, he may have reacted to alpha-gal within these gelatin-containing vaccines. Alpha-gal allergy should be considered in patients who react to gelatin-containing vaccines and who have also reacted to mammalian meat.
References:

[1] Pinson ML, Waibel KH. Safe administration of a gelatin-containing vaccine in an adult with galactose-α-1,3-galactose allergy. Vaccine. 2015;33(10):1231-1232. doi:10.1016/j.vaccine.2015.01.020
[2] Stone CA Jr, Hemler JA, Commins SP, et al. Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. J Allergy Clin Immunol. 2017;139(5):1710-1713.e2. doi:10.1016/j.jaci.2016.10.037
[3] Stone CA Jr, Commins SP, Choudhary S, et al. Anaphylaxis after vaccination in a pediatric patient: further implicating alpha-gal allergy. J Allergy Clin Immunol Pract. 2019;7(1):322-324.e2. doi:10.1016/j.jaip.2018.06.005
[4] Leong S, Lee J. Delayed diffuse hives after vaccines in adolescent with positive alpha-gal ige and gelatin skin test. Annals of Allergy, Asthma & Immunology. 2023;131(5):S110-S111.