NOVEL VLP VACCINES FOR PANDEMIC INFLUENZA VIRUS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recurrent outbreaks of highly pathogenic avian influenza virus pose the threat of pandemic spread of lethal disease and make it a priority to develop safe and effective vaccines. Influenza virus-like particles (VLPs) have been suggested to be a promising vaccine approach. However, VLP-induced immune responses, and their roles in inducing memory immune responses and cross-protective immunity have not been investigated. In this study, we developed VLPs containing influenza A/PR8/34 (H1N1) hemagglutinin (HA) and matrix (M1) proteins, and investigated their immunogenicity, long-term cross-protective efficacy, and effects on lung pro-inflammatory cytokines in mice. Intranasal immunization with VLPs containing HA induced high serum and mucosal antibody titers, and neutralizing activity against PR8 as well as A/WSN/33 (H1N1) viruses. Mice immunized with VLPs containing HA showed little or no pro-inflammatory lung cytokines and were protected from a lethal challenge with mouse-adapted PR8 or WSN viruses even 5 months post-immunization. Influenza VLPs induced mucosal IgG and cellular immune responses, which were reactivated rapidly upon virus challenge. Long-lived antibody secreting cells were detected in the bone marrow of immunized mice. Immune sera when administered intranasally were able to confer 100% protection from a lethal challenge with PR8 or WSN, which provides further evidence that anti-HA antibodies are primarily responsible for preventing infection. Taken together, these results indicate that non-replicating influenza VLPs represent a promising strategy for the development of a safe and effective vaccine to control the spread of lethal influenza viruses.