Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus

Abstract

Development of an influenza vaccine that provides broadly cross-protective immunity has been a scientific challenge for more than half a century. This study presents an approach to overcome strain-specific protection by supplementing conventional vaccines with virus-like particles (VLPs) containing the conserved M2 protein (M2 VLPs) in the absence of adjuvants. We demonstrate that an inactivated influenza vaccine supplemented with M2 VLPs prevents disease symptoms without showing weight loss and confers complete cross protection against lethal challenge with heterologous influenza A viruses including the 2009 H1N1 pandemic virus as well as heterosubtypic H3N2 and H5N1 influenza viruses. Cross-protective immunity was long-lived, for more than 7 mo. Immune sera from mice immunized with M2 VLP supplemented vaccine transferred cross protection to naive mice. Dendritic and macrophage cells were found to be important for this cross protection mediated by immune sera. The results provide evidence that supplementation of seasonal influenza vaccines with M2 VLPs is a promising approach for overcoming the limitation of strain-specific protection by current vaccines and developing a universal influenza A vaccine.

MyD88 Plays an Essential Role in Inducing B Cells Capable of Differentiating into Antibody-Secreting Cells after Vaccination

“…Mice were euthanized if their body weight loss exceeded the 25% IACUC endpoint to minimize suffering. To determine the protective efficacy of immune sera, immune sera from vaccinated mice were 4-fold diluted, mixed with a lethal dose of A/PR/8/34 virus (3 LD 50 ), and then used to infect naïve mice as described previously (34,35). Body weight changes and survival rates were monitored daily for 14 days.…”

Enhanced Influenza Virus-Like Particle Vaccines Containing the Extracellular Domain of Matrix Protein 2 and a Toll-Like Receptor Ligand

“…Nevertheless, some M2e-based vaccine candidates protected immunized mice from low-dose lethal virus challenge (8,10,15,16,39,42). Improved protection was also observed when an M2-based virus-like particle (VLP) antigen was used as a supplement to inactivated viral vaccines (36). Thus, M2e is considered a promising antigen for the development of a universal influenza vaccine.…”

“…3A shows that (42). Influenza virus-infected MDCK cells express high levels of M2 on the cell membrane and can be used to determine M2-specific antibody binding (36). Therefore, we further evaluated antibody binding to native M2 protein by an MDCK cell-based ELISA.…”

Roles of Major Histocompatibility Complex Class II in Inducing Protective Immune Responses to Influenza Vaccination

“…For in vivo infection, mice were anesthetized with isoflurane (Baxter, Deerfield, IL), intranasally challenged with A/PR8 virus (5ϫ 50% lethal dose [LD 50 ]) at 3 weeks after boost immunization and sacrificed at 4 days after challenge or monitored for 14 days for measuring body weights and survival rates to assess the protective efficacy of vaccination. For the serum protective efficacy, 6-to 7-week-old female naive BALB/c mice were infected with a lethal dose A/PR8 virus mixed with heat-inactivated sera (56°C for 30 min) from each of the indicated groups after incubation at room temperature for 30 min (36,37).…”