Recombinant live attenuated influenza virus expressing G protein fragment in a chimeric hemagglutinin molecule induces G-specific antibodies and confers protection against respiratory syncytial virus

Abstract

Abstract Respiratory syncytial virus (RSV) is one of the most important pathogens associated with significant morbidity and mortality in infants and the elderly. Live attenuated influenza vaccine (LAIV) is a licensed platform for vaccination in humans and known to induce broader immune responses locally and systemically. RSV G attachment proteins mediate virus binding to the target cells and contain a conserved central domain with neutralizing epitopes. Here, we generated recombinant LAIV based on the attenuated A/PR8/34 virus backbone, expressing a RSV G conserved domain in a chimeric hemagglutinin (HA) fusion molecule (HA-G). The attenuated phenotypes of chimeric HA-G LAIV were evident by restricted replication in the upper respiratory (nose) but not in the lower respiratory track lung tissues of the mice. Chimeric HA-G LAIV grew better at low temperature 33□. Prime and boost intranasal vaccination of mice with HA-G LAIV induced G-protein specific IgG and IgG2a (T helper type 1) isotype antibodies. Immunization of mice with chimeric HA-G LAIV showed significant increases in G-protein specific IgG and antibody-secreting cell responses in lung, bronchioalveolar fluid, bone marrow, and spleens after challenge. Vaccine-enhanced disease typically caused by inactivated-RSV vaccination was not observed in chimeric HA-G LAIV as analyzed by lung histopathology and infiltrating innate and adaptive immune cells after RSV challenge. Immunity of chimeric HA-G LAIV against influenza virus was not compromised. These results in this study suggest a novel approach of developing RSV vaccine candidates using LAIV, potentially dual vaccines conferring protection against both pathogens.