WHO working group on standardisation and control of acellular pertussis vaccines--report of a meeting held on 16-17 March 2006, St. Albans, United Kingdom.

This report reflects the discussion and conclusions of a WHO group of experts from national regulatory authorities, national control laboratories, vaccine industry and other relevant institutions involved in standardisation and control of acellular pertussis vaccines, held on 16-17 March 2006, in St. Albans, UK. Following previous discussions (Bethesda, 2000; Ferney-Voltaire, 2003; Geneva, 2005) and collection of relevant data for quality control, on the one hand, and clinical evaluation of acellular pertussis vaccines, on the other, this meeting was intended to review the scientific basis for the revision of WHO guidelines adopted in 1996 [Guidelines for the production and control of the acellular pertussis component of monovalent or combined vaccines. In: WHO Expert Committee on Biological Standardisation. Forty-seventh report. Geneva, World Health Organisation, 1998 (WHO Technical Report Series, No. 878), Annex 2]. The discussion on animal protection models, immunogenicity and toxicity testing was focused on three main aspects: value of the assay for the purpose of licensing and/or lot release; validity criteria and potential optimisation of the assays. The group agreed that establishment of JNIH-3 as a potential International Standard (IS) for modified intra-cerebral challenge assay should be under consideration. It was suggested that the inclusion of a reference vaccine, such as JNIH-3 in the intra-nasal challenge model could improve the standardisation of this assay. It was proposed that the development of stable reference vaccines for immunogenicity testing should be encouraged. Further collection of the data from the countries with established lot release of acellular pertussis vaccines will be undertaken to prepare a solid basis for recommendations on toxicity tests. In the context of recommendations for clinical assessment of new vaccines, the group emphasised the importance of comparability studies with antigens that have already undergone efficacy trials in the past. The outline for the section on clinical evaluation of acellular pertussis vaccines was presented and after the consultation further additions were made. Post-marketing surveillance was recognised as an important part of overall vaccine evaluation and a unique opportunity to understand vaccine performance in the population and to establish a link with quality control.

ADP-ribosylation activity in pertussis vaccines and its relationship to the in vivo histamine-sensitisation test.

Pertussis toxin (PTx) is a major virulence factor produced by Bordetella pertussis. In its detoxified form (PTd), it is an important component of acellular pertussis vaccines although some residual PTx activity may likely be present because of the limitations of the detoxification processes used. Furthermore, different detoxification procedures have been shown to result in different amino acid side-chain modifications for the resulting PTd. The histamine-sensitisation test (HIST) in mice is currently used for the safety testing of these vaccines. However, an alternative test is needed because of large assay variability and ethical concerns. The ADP-ribosylation enzyme activity of PTx is thought to be the major factor responsible for the histamine-sensitising activity detected in vivo. In the present study, the ADP-ribosylation activity in different acellular pertussis-based combination vaccine formulations was measured and compared with reactivity in the HIST. The results indicated that different products showed differences in ADP-ribosylation activity and a level which would be significant in relation to the reactivity seen in the HIST could not be defined, except for vaccines that contain genetically detoxified PTx, which do not have enzymatic activity nor in vivo toxicity. Different detoxification procedures as well as formulation factors could contribute to this variation. Relying solely on the residual enzyme activity of PTx in vaccines containing chemically detoxified PTd may not fully reflect the in vivo reactivity observed by the HIST. Refinement of the in vitro test to include a step which monitors the B-subunit activity of PTx may provide a better correlation with the in vivo HIST.