Recombinant Live Attenuated Influenza Virus Expressing Conserved G-Protein Domain in a Chimeric Hemagglutinin Molecule Induces G-Specific Antibodies and Confers Protection against Respiratory Syncytial Virus

Abstract

Respiratory syncytial virus (RSV) is one of the most important pathogens causing significant morbidity and mortality in infants and the elderly. Live attenuated influenza vaccine (LAIV) is a licensed vaccine platform in humans and it is known to induce broader immune responses. RSV G attachment proteins mediate virus binding to the target cells and they contain a conserved central domain with neutralizing epitopes. Here, we generated recombinant LAIV based on the attenuated A/Puerto Rico/8/1934 virus backbone, expressing an RSV conserved G-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 tract and low temperature growth characteristics. The immunization of mice with chimeric HA-G LAIV induced significant increases in G-protein specific IgG2a (T helper type 1) and IgG antibody-secreting cell responses in lung, bronchioalveolar fluid, bone marrow, and spleens after RSV challenge. Vaccine-enhanced disease that is typically caused by inactivated-RSV vaccination was not observed in chimeric HA-G LAIV as analyzed by lung histopathology. These results in this study suggest a new approach of developing an RSV vaccine candidate while using recombinant LAIV, potentially conferring protection against influenza virus and RSV.

Recent Progress in Recombinant Influenza Vaccine Development Toward Heterosubtypic Immune Response

“…Nonetheless, these internal antigens have several indirect utilities in vaccine development. Through plasmid-based reverse genetics, the proteins are used to regenerate RNA genomes from plasmid complementary DNA (viral rescue) during construction of RIVs in transfected cell lines ( 290 , 291 ). They also contribute to temperature sensitivity caused by mutations in PA, PB1, or PB2 in recombinant live attenuated avian influenza vaccine strains, which conferred protection in chickens ( 292 , 293 ).…”

Immune Prophylaxis Targeting the Respiratory Syncytial Virus (RSV) G Protein

“…As the G protein is important in virus attachment, infection, and immune modulation, it is proposed that anti-G protein mAb therapeutics is key in blocking infection and disease pathogenesis. Notably, several studies have shown that anti-G protein antibodies cross-neutralize RSV A and B strains, reduce indicators of RSV disease such as BAL cell numbers, improve antiviral cytokine and chemokine responses, attenuate pathogenic responses, and balance Th1/Th2 responses, and these immune responses correlate with improved lung pathology following RSV infection [ 21 , 30 , 48 , 78 , 79 ]. Additionally, anti-G protein mAbs have been shown to more effectively treat RSV disease compared to palivizumab, or an anti-F protein mAb in BALB/c mice [ 35 ].…”

Development of Nasal Vaccines and the Associated Challenges

“…This novel vaccine induces serum neutralizing antibodies comparable to the levels generated in the natural infection [ 154 , 155 ]. Recombinant attenuated influenza viruses expressing the structural domain of the RSV G protein reportedly induced robust IgA-specific immune responses and TRM T cell responses in the lung and bronchoalveolar fluid of mice, thereby protecting the mice from RSV attack [ 156 , 157 ]. Nasal immunization with HIV vaccine plus BCG or influenza virus-based vectors was reported to promote HIV-specific cellular and humoral immune responses in the airway and vagina of mice [ 158 ].…”