Virus-like particles elicit enhanced immunity to influenza and provide the scaffolding for a novel vaccine platform

Abstract

We first show that the intranasal delivery of virus-like particles (VLPs), which bear no antigenic similarities to respiratory pathogens, prime the lungs to facilitate heightened and accelerated primary immune responses to high-dose influenza virus challenge. These responses were characterized by accelerated CD103 + and CD11b + dendritic cell trafficking to the local tracheobronchial lymph node (TBLN). Furthermore, both alveolar macrophages and dendritic cells of VLP-exposed mice processed both a model antigen, and influenza virus in the lungs and TBLNs significantly earlier than controls. Additionally, VLP-primed CD11c + cells that trafficked in a CCR2-dependent manner, and upregulated T cell co-stimulatory molecules were associated with enhanced viral clearance. Influenza-specific CD4 + T cell proliferation and activation were significantly accelerated in both inducible bronchus-associated lymphoid tissues (iBALT) and the TBLNs of VLP-exposed mice. Finally, pulmonary epithelial expression of the polymeric Ig receptor allowed for the enhanced luminal presence of anti-influenza antibody, and these responses were further supported by germinal center B cells and TFH cells in the lung. Thus, the exposure of the lungs to VLPs resulted in enhanced antigen processing abilities, causing accelerated influenza-specific primary immune responses in both the iBALT and TBLNs, which resulted in accelerated viral clearance. We next show that a model antigen, ovalbumin (OVA), can be chemically conjugated to the exterior of our VLP, the small heat-shock protein (sHsp). When conjugated OVA-sHsp was delivered intranasally to naive mice, the resulting immune response to OVA was accelerated and intensified, and OVA-specific IgG1 responses were apparent within 5 days after a single immunizing dose. If animals were pretreated with a disparate VLP, P22 (a non-replicative bacteriophage capsid), before OVA-sHsp conjugate immunization, OVA-specific IgG1 responses were apparent already by 4 days after a single immunizing dose of conjugate in OVA-naive mice. Additionally, the mice pretreated with P22 produced high titer mucosal IgA, and isotype-switched OVA-specific serum IgG. Thus, VLP-treatment elicited quick and intense antibody responses and these accelerated responses could similarly be induced to an antigen chemically conjugated to the sHsp VLP, demonstrating the utility of conjugating antigens to VLPs for pre-, or possibly post-exposure prophylaxis of lung, all without the need for adjuvant.