Jpn. J. Infect. Dis., 54, 167-180, 2001

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Review　

Quality Control of Diphtheria Tetanus Acellular Pertussis Combined (DTaP) Vaccines in Japan

Yoshinobu Horiuchi*, Motohide Takahashi¹, Toshifumi Konda¹, Masaki Ochiai, Akihiko Yamamoto, Michiyo Kataoka, Hiromi Toyoizumi and Yoshichika Arakawa¹

Department of Safety Research on Biologics and ¹Department of Bacterial and Blood Products, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama-shi, Tokyo 208-0011, Japan

(Received March 30, 2001. Accepted October 1, 2001)

CONTENTS:
1. Introduction
2. A brief history of Japanese acellular pertussis vaccine development
3. A new trend in the quality control of DTaP vaccines and its complications 
  3-1. Testing the consistency of products
  3-2. Accuracy of the results of clinical trials 
4. Quality control of DTaP vaccines in Japan
  4-1. Potency of the pertussis component
    4-1-1. Intracerebral (ic) challenge model
    4-1-2. Aerosol and intranasal (respiratory) challenge models
  4-2. Potency tests of diphtheria and tetanus components of 
       combined vaccines
    4-2-1. Effect of whole cell pertussis vaccine on the potency 
           test of tetanus or diphtheria toxoid
    4-2-2. Effect of adjuvant gel and animal model on the toxoid 
           potency test 
    4-2-3. Effect of the toxoiding process on the immunogenicity 
           and efficacy of adjuvant gel
    4-2-4. Establishing the clinical relevance of toxoid potency tests
    4-2-5. Other problems
    4-2-6. Antitoxin titration
  4-3. Toxicity
    4-3-1.Endotoxin
      4-3-1-1. The bacterial endotoxin test
      4-3-1-2. Clinical relevance of the endotoxin test
      4-3-1-3. Necessary cautions for substituting a test method 
    4-3-2. Lymphocytosis (or leukocytosis)-promoting (LP) activity 
    4-3-3. Histamine sensitizing (HS) activity
    4-3-4. Chinese hamster ovary (CHO) cell clustering test
5. Conclusion

SUMMARY: Diphtheria tetanus acellular pertussis combined (DTaP) vaccines have been successfully used in Japan by controlling their potencies and toxicities with animal models. In accordance with the recent practical introduction of DTaP vaccines of various formulations, a question has been raised in other nations as to the efficacy of a quality control system based on animal tests and standard preparations. The World Health Organization issued its guidelines on the production and quality control of acellular pertussis vaccines in 1998 along with the concept of quality control by ensuring that production lots were consistent with clinical trial lots, rather than by comparing them with standard preparations in traditional laboratory tests. However, because it is not feasible to evaluate the combined use of vaccines from different manufacturers in a clinical study, the alternative trend of quality control may give rise to a difficulty in rationalizing the practical immunizations to use vaccines of different brands in a mixed consequence. A standardized national regulation system to ensure the equivalence of approved products would be essential for such an immunization practice. The success of the Japanese DTaP vaccination suggests the possibility of an effective quality control of DTaP vaccines by means of standardized test systems.

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