To the Editor:
For the 2009 to 2010 influenza season, 34 manufacturers in 19 countries are manufacturing influenza vaccines. In the United States, there are 5 manufacturers producing 1 nasal and 5 injectable Food and Drug Administration (FDA)–approved seasonal influenza vaccines. These manufacturers are also producing 1 nasal and 4 injectable H1N1 (hemagglutinin 1, neuraminidase 1) monovalent vaccines. Because influenza vaccines are developed by inoculating embryonated chicken eggs with virus, the final product has always contained ovalbumin, which can pose a risk in children and adults with egg allergy. However, because manufacturers do not report final lot ovalbumin content, allergists are directed to start with skin prick and intradermal skin testing to the vaccine followed by either a 2-dose or a graded multidose vaccine administration protocol.
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However, these recommendations may be too conservative, because all but 1 manufacturer for the 2009 to 2010 FDA-approved influenza vaccines state a maximum ovalbumin content of ≤1 μg per dose (≤2 μg/mL), and improvements such as ultracentrifugation have resulted in lower ovalbumin content in vaccines like FluMist (MedImmune LLC, Gaithersburg, Md).2
Scientific product monograph. FluMist Influenza vaccine, live intranasal 2009-2010 formula. MedImmune LLC: September 2009. Available at: http://www.vaccines.mil/documents/1278FluMist_SPM_090909.pdf. Accessed November 18, 2009.
The goal of this study was to determine the ovalbumin content in available 2009 to 2010 influenza vaccines. Because manufacturers express the maximum ovalbumin content as micrograms per dose, and there are 3 possible doses (0.2 mL for the nasal vaccines or 0.25 mL or 0.50 mL for the injectable vaccines), we chose a single concentration description of micrograms per milliliter to compare better the ovalbumin content of the vaccines against the manufacturers' stated content. A commercial ovalbumin ELISA kit (Chicken Egg Ovalbumin; Alpha Diagnostic International, San Antonio, Tex) that has a sensitivity range of 0.5 to 4 ng/mL was used. The detailed methods are provided in this article's Methods section of the Online Repository at www.jacionline.org. These results are presented in Table I, Table II.
Table IOvalbumin content in FDA-approved 2009 to 2010 seasonal influenza vaccines
| Brand name | Manufacturer | Stated ovalbumin content | Lot no. | Actual ovalbumin content (μg/mL) |
|---|---|---|---|---|
| Alfuria | CSL Limited (Parkville, Victoria, Australia) | ≤2 μg/mL | 07049111A 01749211A 08049111A | 0.021 0.018 0.020 |
| Fluzone | Sanofi Pasteur (Swiftwater, Pa) | ≤10 μg/mL | U3167FA U3214AA UT3172AA U3176AA | 0.716 1.083 1.238 1.421 |
| FluMist | MedImmune, LLC | ≤1.2 μg/mL | 500685P 500693P | 0.007 0.001 |
| Fluarix | GlaxoSmithKline (Dresden, Germany) | ≤2 μg/mL | NP | NP |
| Flulaval | ID Biomedical Corp of Quebec (Quebec City, QC, Canada) | ≤2 μg/mL | NP | NP |
| Fluvirin | Novartis (Speke, Liverpool, UK) | ≤2 μg/mL | NP | NP |
NP, Not performed.
∗ Per manufacturer's package insert.
† Obtained by communication with manufacturer.
‡ Ovalbumin measured by ELISA.
Table IIOvalbumin content in FDA-approved 2009 to 2010 influenza A H1N1 monovalent vaccines
| Brand name | Manufacturer | Stated ovalbumin content | Lot no. | Actual ovalbumin content (μg/mL) |
|---|---|---|---|---|
| H1N1 monovalent | Novartis | ≤2 μg/mL | 100739 2P | 0.041 |
| H1N1 monovalent | Sanofi Pasteur | ≤10 μg/mL | UP010AA | 0.064 |
| H1N1 monovalent | MedImmune, LLC | ≤1.2 μg/mL | 500778P | 0.003 |
| H1N1 monovalent | CSL Limited | ≤2 μg/mL | NP | NP |
| H1N1 monovalent | ID Biomedical Corp of Quebec | ≤2 μg/mL | NP | NP |
NP, Not performed.
No specific brand names have been given by manufacturers for H1N1 monovalent vaccines approved for use in the United States.
∗ Per manufacturer's package insert.
† Obtained by communication with manufacturer.
‡ Ovalbumin measured by ELISA.
In our opinion, this information is clinically important for 3 reasons: (1) manufacturers do not report final lot ovalbumin content, (2) routine measurement of ovalbumin is labor-intensive and generally inaccessible by practicing allergists, and (3) knowing the ovalbumin content guides current vaccine administration protocols. For children and adults with egg allergy, 3 clinical courses are generally recommended: vaccine avoidance, vaccine skin testing with a 2-dose vaccine administration protocol, or vaccine skin testing with a multidose graded vaccine administration protocol.
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The 2-dose protocol (10% of the dose is given initially, and if there is no reaction in 30 minutes, the remaining 90% of the dose is given, with an additional observation period afterward) is based on a single study demonstrating the safety of this approach with vaccines containing no more than 1.2 μg/mL ovalbumin in 83 children and adults with egg allergy.
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The multistep (usually 4-6 injections) graded challenge for patients with positive vaccine skin test results has been successful, although it has not been compared directly with a 2-step or single-step challenge.4
A recent abstract described success using a multidose protocol in 58 patients with egg allergy with positive vaccine skin test results, with only minor reactions, although the specific ovalbumin content was not reported.5
Also, since 1997, a virosomal adjuvanted influenza vaccine, Inflexal V (Berna Biotech, Berna, Switzerland), that is approved in Europe contains less than 50 ng of ovalbumin per dose. A recent study demonstrated the safety of this vaccine, administered as a single dose, in 44 children with egg allergy.6
Our study found the actual ovalbumin content of the brands and lots of vaccines tested from manufacturers claiming a maximum ovalbumin content of 2 μg/mL was actually much lower than this level, specifically 0.001 to 0.007 μg/mL for the nasal vaccines and 0.018 to 0.41 μg/mL for the injectable vaccines. The ovalbumin content in the vaccines from the manufacturer claiming a maximal ovalbumin content of 10 μg/mL was also lower than the stated maximum (0.064-1.411 μg/mL) but higher than the vaccines from the other manufacturers. Some limitations to our study include the fact that not all available influenza vaccines or their respective lots were analyzed. For the seasonal influenza vaccine alone, 248 lots from 6 FDA-approved seasonal influenza vaccines have been released. Although some experts are concerned about the possibility of lot-to-lot variability, ranging from 1 to 42 μg/mL,
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current manufacturing standards and our analysis suggest very little lot-to-lot variability.The 2009 American Academy of Pediatrics Red Book recommends that anyone with systemic anaphylactic symptoms (generalized urticaria, hypotension, or manifestations of upper or lower airway obstruction) generally not receive the influenza vaccine, whereas the British Society of Allergy and Clinical Immunology recommends using only vaccines with a maximal egg content of 1.2 μg/mL in patients with egg allergy.
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The influenza vaccine administered to subjects with egg allergy in the 2-dose protocol described here had a maximum ovalbumin content of 1.2 μg/mL, and all subjects tolerated the entire dose. Thus, one should consider administering any vaccine containing less than this amount to subjects with egg allergy as a single dose, without previous vaccine skin testing.Methods
A commercial ovalbumin ELISA kit (Chicken Egg Ovalbumin; Alpha Diagnostic International, San Antonio, Tex) that has a sensitivity range of 0.5 to 4 ng/mL was used. Antibodies used in this kit are monospecific for ovalbumin and have no cross-reactivity to other egg proteins. A total of 1 mL of each vaccine lot was obtained to perform testing in triplicate. A total of 200 μL of a wash solution was added to each well of a 96-well plate that contained immobilized ovalbumin antibodies. After 10 minutes, the liquid was removed, and 100 μL of each vaccine was added to predetermined wells and incubated at room temperature for 1 hour. Wells were washed 4 times, and 100 μL antiovalbumin enzyme conjugate was added with a 30-minute incubation period. After 5 additional wash steps, 100 μL substrate was added with incubation for 15 minutes in the dark. Finally, a stop solution was added, and the OD at 450 nm was measured. A standardized curve (0.5-4 ng/mL; r2 = 0.97) was included for each plate. Vaccine dilutions ranged from 1:10 to 1:1000 to determine ovalbumin content by using the standardized curve.
References
- Current issues with influenza vaccination in egg allergy.J Allergy Clin Immunol. 2002; 110: 834-840
Scientific product monograph. FluMist Influenza vaccine, live intranasal 2009-2010 formula. MedImmune LLC: September 2009. Available at: http://www.vaccines.mil/documents/1278FluMist_SPM_090909.pdf. Accessed November 18, 2009.
- Safe administration of influenza vaccine to patients with egg allergy.J Pediatr. 1998; 133: 624-628
- Administration of egg-derived vaccines in patients.Ann Allergy. 1990; 64: 527-529
- Administration of influenza vaccine to pediatric patients with egg allergy.J Allergy Clin Immunol. 2009; 123 ([abstract]): S175
- Safe administration of an inactivated virosomal adjuvanted influenza vaccine in asthmatic children with egg allergy.Vaccine. 2008; 26: 4664-4668
- Joint Task Force on Practice Parameters. Adverse reactions to vaccines.Ann Allergy Asthma Immunol. 2009; 103: S1-S14
- Influenza.in: Pickering L.K. Baker C.J. Kimberlin D.W. Long S.S. Red Book: 2009 report of the Committee on Infectious Diseases. 28th ed. American Academy of Pediatrics, Elk Grove Village (IL)2009: 400-412
- BSACI Standards of Care Committee. Swine flu vaccination in patients with egg allergy.Clin Exp Allergy. 2009; 39: 1288-1290
Article info
Publication history
Published online: January 11, 2010
Footnotes
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army, the Department of the Air Force, or the Department of Defense.
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© 2010 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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- Ovalbumin content of influenza vaccinesJournal of Allergy and Clinical ImmunologyVol. 125Issue 6
