Abstract
Influenza virus M2 protein has a highly conserved ectodomain (M2e) as a cross-protective antigenic target. We investigated the antigenic and immunogenic properties of tandem repeat M2e (5xM2e) proteins and virus-like particles (5xM2e VLP) to better understand how VLP and protein platform vaccines induce innate and protective adaptive immune responses. Despite the high antigenic properties of 5xM2e proteins, the 5xM2e VLP was superior to 5xM2e proteins in inducing IgG2a isotype antibodies, T cell responses, plasma cells and germinal center B cells as well as in conferring cross protection. Mice primed with 5xM2e VLP were found to be highly responsive to 5xM2e protein boost, overcoming the low immunogenicity and protective efficacy of 5xM2e proteins. Immunogenic differences between VLPs and proteins in priming immune responses might be due to an intrinsic ability of 5xM2e VLP to stimulate dendritic cells secreting T helper type 1 (Th1) cytokines. We also found that 5xM2e VLP was effective in inducing inflammatory cytokines and chemokines, and in recruiting macrophages, monocytes, neutrophils, and CD11b+ dendritic cells at the injection site. Therefore, this study provides evidence that 5xM2e VLP is an effective vaccine platform, inducing cross-protection by stimulating innate and adaptive immune responses.
Highlights
Current influenza vaccines relying on immunity to the highly variable hemagglutinin (HA)antigen are not effective in providing protection against antigenic variants and potential pandemic strains
We reported the construction of virus-like particles (VLPs) vaccines containing a tandem repeat of M2e sequences (5xM2e) derived from human, swine, and avian origin influenza A viruses (5xM2e VLP), which could confer cross protection against H1, H3, and H5 subtype influenza viruses in the absence of adjuvants [23]
We found that 5xM2e VLP primed immune responses that were effectively boosted after subsequent vaccination with low immunogenic 5xM2e soluble proteins
Summary
Current influenza vaccines relying on immunity to the highly variable hemagglutinin (HA)antigen are not effective in providing protection against antigenic variants and potential pandemic strains. Current influenza vaccines relying on immunity to the highly variable hemagglutinin (HA). The influenza A virus M2 ion channel protein has a highly conserved extracellular domain of 23 residues (M2e) proximal to the membrane surface [1]. M2 itself is a very poor immunogen, probably due to the small extracellular domain of M2e, membrane proximity, and low levels of M2 on virions, as well as the Vaccines 2018, 6, 66; doi:10.3390/vaccines6040066 www.mdpi.com/journal/vaccines. It was reported that the route of vaccine delivery impacts on the protection induced by influenza A virus conserved antigens (M2e, NP, HA2) and on vaccine adverse effects, preferring the intramuscular route over the intradermal route in a pig model [4]. Recombinant nucleoprotein-M2e vaccines were more effective in conferring protection when mice were immunized intranasally compared to the subcutaneous route [5]
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