Animal models in influenza vaccine testing.

Section on Safety of Medicines and Teratology, Centre for Biological Medicines and Medical Technology, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands.
Expert Review of Vaccines (Impact Factor: 4.22). 09/2008; 7(6):783-93. DOI: 10.1586/14760584.7.6.783
Source: PubMed

ABSTRACT The threat of a pandemic outbreak of influenza A H5N1 and H2N2 has brought attention to the development of new vaccines. Regulatory authorities require companies to provide data proving the effectiveness of vaccines, which cannot, however, be based on real efficacy data in humans. A weight-of-evidence approach may be used, based on evidence of protection in an appropriate animal model and the satisfaction of the surrogate end points in the clinical situation. In this review, we will discuss various animal species that can be infected with influenza. The main animals used for testing vaccines destined for human use are laboratory mice and ferrets and, to a lesser extent, macaques. We will focus particularly on these species.

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    ABSTRACT: Background Ferrets have long been used as a disease model for the study of influenza vaccines, but a more recent use has been for the study of human monoclonal antibodies directed against influenza viruses. Published data suggest that human antibodies are cleared unusually quickly from the ferret and that immune responses may be partially responsible. This immunogenicity increases variability within groups and may present an obstacle to long-term studies. Objective Our aim was to identify an antibody design with reduced immunogenicity and longer circulating half-life in ferrets. Methods The constant region coding sequences for ferret immunoglobulin G were cloned, and chimeric human/ferret antibodies were expressed and purified. Some of the chimeric antibodies included substitutions that have been shown to extend the half-life of human IgG antibodies. These chimeric antibodies were tested for binding to recombinant ferret FcRn receptor and then evaluated in pharmacokinetic studies in ferrets. ResultsA one-residue substitution in the ferret Fc domain, S252Y, was identified that increased binding affinity to the ferret neonatal receptor by 24-fold and extended half-life from 6527 to 206 +/- 28hours or similar to 9days. Ferrets dosed twice with this surrogate antibody showed no indications of an immune response. Conclusion Expressing the variable region of a candidate human therapeutic antibody with ferret constant regions containing the S252Y substitution can offer long half-life and limit immunogenicity.
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