Protection against respiratory syncytial virus by inactivated influenza virus carrying a fusion protein neutralizing epitope in a chimeric hemagglutinin

Abstract

A desirable vaccine against respiratory syncytial virus (RSV) should induce neutralizing antibodies without eliciting abnormal T cell responses to avoid vaccine-enhanced pathology. In an approach to deliver RSV neutralizing epitopes without RSV-specific T cell antigens, we genetically engineered chimeric influenza virus expressing RSV F262-276 neutralizing epitopes in the globular head domain as a chimeric hemagglutinin (HA) protein. Immunization of mice with formalin-inactivated recombinant chimeric influenza/RSV F262-276 was able to induce RSV protective neutralizing antibodies and lower lung viral loads after challenge. Formalin-inactivated RSV immune mice showed high levels of pulmonary inflammatory cytokines, macrophages, IL-4-producing T cells, and extensive histopathology. However, RSV-specific T cell responses and enhancement of pulmonary histopathology were not observed after RSV infection of inactivated chimeric influenza/RSV F262-276. This study provides evidence that an inactivated vaccine platform of chimeric influenza/RSV virus can be developed into a safe RSV vaccine candidate without priming RSV-specific T cells and immunopathology.

Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus

“…The ability of both mice and humans to generate antibodies that have substantial cross-protection potential by targeting a conserved site I on GP38 also bodes well for developing GP38-inspired antigens for vaccine platforms. This could take the form of chimeric GP38s, GP38 cocktails, or GP38 mini proteins 47 , 48 .…”

Broad cross protection by recombinant live attenuated influenza H3N2 seasonal virus expressing conserved M2 extracellular domain in a chimeric hemagglutinin

“…The size of foreign epitopes or fragments to be inserted into the N-terminus of HA appears to be highly flexible as large as 246 residues while maintaining HA functional 39 . Whereas, recombinant influenza viruses containing only limited length of foreign epitopes less than 18 residues in the HA head domain could be rescued as for generating replication competent viruses 40 , 41 . The location of inserting foreign epitopes in HA molecules should be considered in the size of epitopes and routes of vaccination.…”

Cold‐adapted influenza‐vectored RSV vaccine protects BALB/c mice and cotton rats from RSV challenge

“…The LAIV vaccine platform based on reverse genetics allows the generation of genetically manipulated influenza viruses expressing foreign genes, such as RSV. [35][36][37][38] Intranasal immunization with LAIV mimics infections in the upper respiratory tract caused by influenza virus and elicits local and systemic immune responses, without causing lung disease. 39 Previous studies have shown that HA and NA of influenza virus have complementary activities.…”

“…Natural RSV infection does not elicit a long‐term immune response, such that infection can re‐occur throughout life. The LAIV vaccine platform based on reverse genetics allows the generation of genetically manipulated influenza viruses expressing foreign genes, such as RSV 35–38 . Intranasal immunization with LAIV mimics infections in the upper respiratory tract caused by influenza virus and elicits local and systemic immune responses, without causing lung disease 39 .…”