Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 14, Issue 19, Pages 21872-21885Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.2c01028
Keywords
flagellin; HBc; VLP; M2e; universal influenza vaccine; CpG 1018; cancer vaccine; CTL
Funding
- National Institutes of Health [AI139473, AI156510]
- URI MARC U*STAR grant from the National Institute of General Medical Sciences of the National Institutes of Health [T34GM131948]
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20GM103430]
- National Science Foundation (NSF) EPSCoR Cooperative Agreement [OIA-1655221]
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This study explored a hybrid flagellin/HBc VLP (FH VLP) platform to present heterologous antigens. The FH VLPs were found to be highly immunogenic, safe, and versatile for vaccine development, eliciting potent humoral and cellular immune responses and providing significant protection against multiple viral strains and challenges.
Hepatitis B core (HBc) virus-like particles (VLPs) and flagellin are highly immunogenic and widely explored vaccine delivery platforms. Yet, HBc VLPs mainly allow the insertion of relatively short antigenic epitopes into the immunodominant c/e1 loop without affecting VLP assembly, and flagellin-based vaccines carry the risk of inducing systemic adverse reactions. This study explored a hybrid flagellin/HBc VLP (FH VLP) platform to present heterologous antigens by replacing the surface-exposed D3 domain of flagellin. FH VLPs were prepared by the insertion of flagellin gene into the c/e1 loop of HBc, followed by E. coli expression, purification, and self-assembly into VLPs. Using the ectodomain of influenza matrix protein 2 (M2e) and ovalbumin (OVA) as models, we found that the D3 domain of flagellin could be replaced with four tandem copies of M2e or the cytotoxic T lymphocyte (CTL) epitope of OVA without interfering with the FH VLP assembly, while the insertion of four tandem copies of M2e into the c/e1 loop of HBc disrupted the VLP assembly. FH VLP-based M2e vaccine elicited potent anti-M2e antibody responses and conferred significant protection against multiple influenza A viral strains, while FljB- or HBc-based M2e vaccine failed to elicit significant protection. FH VLP-based OVA peptide vaccine elicited more potent CTL responses and protection against OVA-expressing lymphoma or melanoma challenges than FljB- or HBc-based OVA peptide vaccine. FH VLP-based vaccines showed a good systemic safety, while flagellin-based vaccines significantly increased serum interleukin 6 and tumor necrosis factor alpha levels and also rectal temperature at increased doses. We further found that the incorporation of a clinical CpG 1018 adjuvant could enhance the efficacy of FH VLP-based vaccines. Our data support FH VLPs to be a highly immunogenic, safe, and versatile platform for vaccine development to elicit potent humoral and cellular immune responses.
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