Safety Of Alphavirus Vectors

The pathogenicity of the alphavirus family varies significantly, but the three most commonly used vectors, SFV, SIN, and VEE, are considered only mild pathogens (1). There are descriptions of some SFV-related epidemics of febrile illnesses in the Central Republic of Africa (48). The typical symptoms of the infected individuals were fever and persistent headache. Some SIN and SFV strains have additionally showed strong neurovirulence and pathogenicity in young mice.

However, most of the alphavirus vectors used so far are replication-deficient, which generates one cycle of infection and no further virus progeny production. Additional safety has been achieved by using attenuated alphavirus strains with a reduced virulence as the basis for vector construction. As homolog sequences are present in alphavirus expression and helper vectors, there is a slight chance of generating replication competent particles through homologous recombination. To prevent any amplification and spread of these particles, conditionally infectious particles can be produced from second generation helper vectors with point mutations (49). Applying a split-helper vector approach with separate helper vectors carrying the capsid and envelope protein genes has further enhanced the safety (50). For large-scale virus production and future good manufacturing practice (GMP) grade material for clinical trials the use of packaging cell lines developed for SFV and SIN vectors is highly recommended (51).

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