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.

Host Defense Mechanism-Based Rational Design of Live Vaccine

“…With the availability of reverse genetics of influenza virus [50], a variety of genetic methods of attenuation have been advanced as alternatives to the cold-adaptation, including the repressive modification of specific viral target such as NS1, HA, or M2 [51]–[53]. The design of clinically useful live influenza vaccine remains, however, a difficult task because the attenuation of virulence often compromises the vaccine growth in production hosts, thus limiting its practical use [54]. As a novel approach on attenuation of virulence at the post-translational level, the present strategy distinguishes itself from previous attenuation methods targeting transcription by microRNA [7] or translation by codon deoptimization [5] of viral genes.…”

Cross-Protective Immune Responses Elicited by Live Attenuated Influenza Vaccines

“…In this section, we discuss currently proposed mechanisms for the cross-reactivity of the CAIVs (Table 2) suggested in the references discussed above, which could be further extended to the cross-reactivity seen in other live attenuated vaccine strategies;66 however, with a varying degree of contribution of each factor depending on the attenuation tools employed.…”

An Oral Live Attenuated Vaccine Strategy against Severe Acute Respiratory Syndrome Coronavirus 2 (2019-nCoV)

“…The serially passaged virus would eventually be allowed to infect human intestinal cell line such as Hs 1.Int /HuTu 80/ Caco-2 after experimentally verifying the expression of ACE2, infectivity and viral replication (10). Alternatively, a genetic reassortment between attenuated donor Corona Virus strain and 2019-nCoV can be achieved (11). This strategy has the potential to provide an extended coverage to heterologous infections which is possibility with RNA viruses along the course of the epidemic due to inherent mutability and generation of hybrid viruses by genetic mixing with other wild viruses (11,15).…”