Principles underlying rational design of live attenuated influenza vaccines

Abstract

Despite recent innovative advances in molecular virology and the developments of vaccines, influenza virus remains a serious burden for human health. Vaccination has been considered a primary countermeasure for prevention of influenza infection. Live attenuated influenza vaccines (LAIVs) are particularly attracting attention as an effective strategy due to several advantages over inactivated vaccines. Cold-adaptation, as a classical means for attenuating viral virulence, has been successfully used for generating safe and effective donor strains of LAIVs against seasonal epidemics and occasional pandemics. Recently, the advent of reverse genetics technique expedited a variety of rational strategies to broaden the pool of LAIVs. Considering the breadth of antigenic diversity of influenza virus, the pool of LAIVs is likely to equip us with better options for controlling influenza pandemics. With a brief reflection on classical attenuating strategies used at the initial stage of development of LAIVs, especially on the principles underlying the development of cold-adapted LAIVs, we further discuss and outline other attenuation strategies especially with respect to the rationales for attenuation, and their practicality for mass production. Finally, we propose important considerations for a rational vaccine design, which will provide us with practical guidelines for improving the safety and effectiveness of LAIVs.

Keywords: Attenuation strategy; Cold-adaptation; Cross protection; Influenza live attenuated vaccine.

Fig. 1

Generation of reassortant live attenuated influenza vaccine (LAIV). LAIVs are made by genetic reassortment between attenuated donor strain and virulent circulating virus. Live vaccine virus consists of six internal genes derived from the attenuated donor strain and the surface genes, change to hematoglutinin and neuraminidase, from the virulent circulating virus. As a result, the vaccine demonstrates attenuated phenotype and carries desired antigen proteins.

Fig. 2

Reverse genetics approach for generating live attenuated influenza vaccines (LAIVs). Each of six internal genes of attenuated donor strain and two surface genes of circulating wild type virus is inserted into bidirectional expression and transcription plasmid. The eight plasmids are co-transfected into 293T cells, where viral RNAs and proteins are produced, ultimately resulting in the formation of desired vaccine virus particle. PB, polymerase basic; PA, polymerase acidic; HA, hematoglutinin NP, nucleoprotein; M, matrix protein; NS, nonstructural protein 1; NA, neuraminidase.

Fig. 3

Rational design of live attenuated vaccine. As the safety level of a live vaccine increases, the efficacy of the vaccine is likely to decrease due to the inefficient replication of the vaccine in host (A). Further, the attenuation of viral virulence is often achieved at the expanse of productivity of the vaccine because of the simultaneous loss of viral viability in production hosts (B). A rational vaccine design therefore should carefully consider these two aspects for the vaccine to be potentially practical for clinical use.