Development of a Recombinant Live Attenuated Influenza Vaccine Virus Expressing Pneumococcal Surface Antigen A as a Strategy for Combined Protection Against Influenza and Bacterial Coinfection Caused by Streptococcus pneumoniae

Abstract

Introduction Bacterial superinfection with Streptococcus pneumoniae following the influenza virus infection complicates the course of the disease and is a major cause of mortality during influenza virus epidemics. The effectiveness of licensed polysaccharide vaccines is limited by the serotypes included in the vaccine and possible immune tolerance during revaccination. Pneumococcal surface protein A (PspA), which includes conserved regions and has at least two functions in pathogen virulence, is considered a promising target for the development of new-generation vaccines, including gene-engineering constructions. Therefore, the development of an influenza virus vector-based vaccine expressing conserved bacterial proteins seems to be a promising strategy for designing combined vaccines against influenza and bacterial pathogens. Methods A recombinant live attenuated influenza virus (LAIV) expressing PspA fragment in a modified hemagglutinin was rescued on the A/Leningrad/134/17/57 (H2N2) backbone. This recombinant virus was assessed for its growth characteristics in vitro, as well as for its immunogenicity and protective capacity, using a mouse model of influenza-bacterial coinfection. Results The rescued recombinant LAIV/HA+PspA virus was genetically stable after sequential passaging in embryonated chicken eggs and possessed an attenuated phenotype similar to the classical LAIV strain. The LAIV/HA+PspA bivalent vaccine-induced IgG antibodies specific to both influenza virus and S. pneumoniae and provided complete protection of vaccinated mice against lethal influenza infection, as well as a 40% survival rate for lethal homologous and heterologous influenza infection complicated by concomitant bacterial infection with S. pneumoniae. Conclusion The presented design of a recombinant influenza virus carrying immunogenic fragments of a bacterial pathogen can be considered a promising strategy for the combined protection of vaccinated individuals against influenza and its bacterial complications, and further in-depth studies of such recombinant viruses in preclinical studies are warranted.