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  1. Science & Research (Biologics)

Improving Safety and Potency Testing of Allergen Extracts

Jay E. Slater, MD

Office of Vaccines Research and Review
Division of Bacterial, Parasitic, and Allergenic Products
Laboratory of Immunobiochemistry

Jay.Slater@fda.hhs.gov


Biosketch

Dr. Slater received his medical degree at Harvard Medical School, trained in Pediatrics at the Babies Hospital in New York (Columbia Presbyterian), and in Allergy-Immunology at NIAID/NIH. He is board certified in Pediatrics, Allergy Immunology and Diagnostic Laboratory Immunology, and licensed to practice medicine in Maryland and the District of Columbia.

After 12 years as an academic allergist immunologist at Children’s National Medical Center in Washington, DC, Dr. Slater became a Supervisory Medical Officer at the US Food and Drug Administration, first as Chief of the Laboratory of Immunobiochemistry, then as Deputy Director and finally Director of the Division of Bacterial, Parasitic and Allergenic Products.

Dr. Slater’s research interests have included natural rubber latex allergy, and the detailed characterization of non-standardized allergen extracts including German cockroach, mouse and fungal allergen extracts, among others, using proteomics, monoclonal antibodies and mass spectrometry. Dr. Slater has authored 36 research papers as first or senior author, in addition to 22 review articles and 12 book chapters.


General Overview

Allergen extracts are used in the United States to diagnose and treat allergic diseases. Skin tests containing these extracts determine the causes of allergies. "Allergy shots" containing them are used to reduce or eliminate allergic symptoms. As with all drugs and biologics, good quality controls are needed to ensure that allergen extracts are safe and effective. The goal of our research is to provide new tools and data that allow allergen extract manufacturers to maintain and improve the quality of these important products.

Our major area of focus involves the methods by which FDA and manufacturers measure the potency, or strength, of an allergen extract. Existing methods either measure a single, dominant protein in the extract, or determine the potency by measuring several undefined proteins as a group.

We expand on available methods for assessing complex allergen extracts to include mass spectrometry. This will allow precise determinations of specific proteins and their isoforms. We will focus on the insect German cockroach, the fungus Alternaria alternata, mouse urine and house dust mite. We have chosen these allergens because they can cause serious human allergic disease, and are biologically complex.

Allergen extracts are important tools for the diagnosis and treatment of allergic diseases, which are common, often disabling, and occasionally dangerous. The novel methods that we are developing will enhance the efficacy, safety and quality control of these critical products.


Scientific Overview

The potencies of allergen extracts are determined by several methods, based on the nature of the extracts. For some, for which there are only one or two known allergens, specific allergen testing can be performed (by ELISA or radial immunodiffusion assay, RID). For others, overall allergenicity testing is required, usually by competition ELISA. The existing competition ELISA is a sensitive and specific method of determining overall potency, but its performance characteristics for each component allergen is uncertain. When an individual allergen is removed from the extract, the polyvalent sera cannot reliably discern its absence (J Allergy Clin Immunol 2000;105:482-488; Clin Exp Allergy 2006; 36:525-530). Until each relevant allergen in a mixture is identified, regulators must ask manufacturers to measure overall potency. Once important allergens are determined, their measurement requires a change in technology that can be time-consuming and difficult.

The purpose of this research program is to develop assay strategies that will have the strengths of both the allergen-specific assays and the overall allergenicity assays, and that will allow manufacturers and regulators to determine the amounts of specific allergens in a mixture, as well as its overall allergenicity. Multiplex assays have been used with success for a variety of assays, such as detecting allergen-specific IgE and the amount of allergen in the environment. Following this approach, we designed a multiplex allergen extract potency assay (MAEPA), based on the expressions and production of numerous monoclonal antibodies against allergens in complex mixtures. In completed work, the MAEPA assay was optimized for cat hair and short ragweed pollen allergen extracts, and German cockroach allergen extracts.

In current work we are developing a mass spectrometry-based multiplex assay (so-called multiple reaction monitoring, MRM) to house dust mite, Alternaria alternata, and mouse urine allergen extracts. All of these allergens are associated with rhinoconjunctivitis and asthma; three of them (cockroach, Alternaria, and mouse) are currently non-standardized. The potential advantages of the MRM method over existing technologies (RID, ELISA) include greater accuracy and multiplexing. The advantage of MRM over MAEPA is quicker development time and easier transferability to manufacturers.


Publications

  1. Int Arch Allergy Immunol 2024 Jan 22 [Epub ahead of print]
    Vitellin/vitellogenin is an important allergen in German cockroach.
    Hadiwinarta C, Blank A, Somers J, Schal C, Bronzert C, Sharma K, Strader MB, Hamilton RG, Slater JE
  2. Int Arch Allergy Immunol 2024 Jan 22;1-6
    Vitellin/vitellogenin is an important allergen in German cockroach.
    Hadiwinarta C, Blank A, Somers J, Schal C, Bronzert C, Sharma K, Strader MB, Hamilton RG
  3. J Allergy Clin Immunol 2022 Mar;149(3):812-8
    A regulator's view on AIT clinical trials in the United States and Europe: why successful studies fail to support licensure.
    Bonertz A, Tripathi A, Zimmer J, Reeb C, Kaul S, Bridgewater J, Rabin RL, Slater JE, Vieths S
  4. Allergy 2021 Dec;76(12):3723-32
    Diversity and complexity of mouse allergens in urine, house dust, and allergen extracts assessed with an immuno-allergomic approach.
    Mindaye ST, Sun C, Esfahani SAZ, Matsui EC, Sheehan MJ, Rabin RL, Slater JE
  5. J Allergy Clin Immunol Pract 2020 Sep;8(8):2506-14
    The allergen: sources, extracts, and molecules for diagnosis of allergic disease.
    Goodman RE, Chapman MD, Slater JE
  6. Clin Exp Allergy 2020 Jun;50(6):741-51
    Measurement of German cockroach (GCr) allergens and their isoforms in allergen extracts with mass spectrometry.
    Mindaye ST, David NA, Esfahani SAZ, Schal C, Matsui EC, Ronald RL, Slater JE
  7. J Allergy Clin Immunol 2019 Oct;144(4):1140
    Regulation of allergen immunotherapy products in Europe and the United States.
    Rabin RL, Bridgewater J, Slater JE
  8. Allergy 2018 Apr;73(4):816-26
    Allergen manufacturing and quality aspects for allergen immunotherapy in Europe and the United States: an analysis from the EAACI AIT Guidelines Project.
    Bonertz A, Roberts G, Slater JE, Bridgewater J, Rabin RL, Hoefnagel M, Timon M, Pini C, Pfaar O, Sheikh A, Ryan D, Akdis C, Goldstein J, Poulsen LK, van Ree R, Rhyner C, Barber D, Palomares O, Pawankar R, Hamerlijnk D, Klimek L, Agache I, Angier E, Casale T, Fernandez-Rivas M, Halken S, Jutel M, Lau S, Pajno G, Sturm G, Varga EM, van Wijk RG, Bonini S, Muraro A, Vieths S
  9. Allergy 2018 Jan;73(1):64-76
    Challenges in the implementation of EAACI guidelines on allergen immunotherapy: a global perspective on the regulation of allergen products.
    Bonertz A, Roberts G, Hoefnagel M, Timon M, Slater J, Rabin R, Bridgewater J, Pini C, Pfaar O, Akdis C, Goldstein J, Poulsen LK, van Ree R, Rhyner C, Barber D, Palomares O, Sheikh A, Pawankar R, Hamerlijnk D, Klimek L, Agache I, Angier E, Casale T, Fernandez-Rivas M, Halken S, Jutel M, Lau S, Pajno G, Sturm G, Maria Varga E, van Wijk RG, Bonini S, Muraro A, Vieths S
  10. Clin Exp Allergy 2017 Dec;47(12):1661-70
    Accurate quantification of 5 German cockroach (GCr) allergens in complex extracts using multiple reaction monitoring mass spectrometry (MRM MS).
    Mindaye ST, Spiric J, David NA, Rabin RL, Slater JE
  11. PLoS One 2017 Aug 2;12(8):e0182260
    Cross-reaction between Formosan termite (Coptotermes formosanus) proteins and cockroach allergens.
    Mattison CP, Khurana T, Tarver MR, Florane CB, Grimm CC, Pakala SB, Cottone CB, Riegel C, Bren-Mattison Y, Slater JE
  12. Ann Allergy Asthma Immunol 2017 Aug;119(2):101-7
    Food allergen extracts to diagnose food-induced allergic diseases: how they are made.
    David NA, Penumarti A, Burks AW, Slater JE
  13. Ann Allergy Asthma Immunol 2016 May;116(5):440-446.e2
    The NPC2 protein: a novel dog allergen.
    Khurana T, Newman-Lindsay S, Young PR, Slater JE
  14. PLoS One 2015 Oct 7;10(10):e0140225
    Multiplex assay for protein profiling and potency measurement of German cockroach allergen extracts.
    Khurana T, Dobrovolskaia E, Shartouny JR, Slater JE

 

 

 
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