Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets.

Wang L1, Liu SY2, Chen HW3, Xu J4, Chapon M2, Zhang T4, Zhou F5, Wang YE2, Quanquin N2, Wang G5, Tian X6, He Z7, Liu L7, Yu W7, Sanchez DJ8, Liang Y9, Jiang T4, Modlin R10, Bloom BR11, Li Q7, Deng JC6, Zhou P5, Qin FX12, Cheng G13

Cell Host Microbe. 2017 Mar 8;21(3):334-343.

PMID: 28279345  DOI: 10.1016/j.chom.2017.02.007

Abstract
New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.