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Abstract
Therapeutics based on fusing a protein of interest to the IgG Fc domain have been enormously successful, though fewer studies have investigated the vaccine potential of IgG fusions. In this study, we systematically compared the key properties of seven different plant-made human IgG1 fusion vaccine candidates using Zika virus (ZIKV) envelope domain III (ZE3) as a model antigen. Complement protein C1q binding of the IgG fusions was enhanced by: 1) antigen fusion to the IgG N-terminus; 2) removal of the IgG light chain or Fab regions; 3) addition of hexamer-inducing mutations in the IgG Fc; 4) adding a self-binding epitope tag to create recombinant immune complexes (RIC); or 5) producing IgG fusions in plants that lack plant-specific β1,2-linked xylose and α1,3-linked fucose N-linked glycans. We also characterized the expression, solubility, and stability of the IgG fusions. By optimizing immune complex formation, a potently immunogenic vaccine candidate with improved solubility and high stability was produced at 1.5 mg IgG fusion per g leaf fresh weight. In mice, the IgG fusions elicited high titers of Zika-specific antibodies which neutralized ZIKV using only two doses without adjuvant, reaching up to 150-fold higher antibody titers than ZE3 antigen alone. We anticipate these findings will be broadly applicable to the creation of other vaccines and antibody-based therapeutics.
Highlights
Subunit vaccines consisting of recombinant protein antigens are very promising due to their safety, ease of production, and capacity to elicit targeted immune responses directed towards desired epitopes
The 6D8 antibody without Zika virus envelope domain III (ZE3) or epitope tag is referred to as construct “HL,” and the corresponding recombinant immune complex (RIC) with epitope tag but lacking ZE3 is referred to as “HLe.” Since C1q mediates immune complex uptake into antigen presenting cells and complementcoated immune complexes play a key role in activating and maintaining long-term immunity [7, 8, 36, 37], the constructs were analyzed for C1q binding
A small increase in C1q binding was noted with HLZ compared to HL (p < 0.05) (Figure 1B), suggesting low-level aggregation of the construct or slight favorable alteration of the C-terminal fragment of crystallization of IgG (Fc) conformation due to the ZE3 fusion
Summary
Subunit vaccines consisting of recombinant protein antigens are very promising due to their safety, ease of production, and capacity to elicit targeted immune responses directed towards desired epitopes. IgG3 mediates the strongest complement activation and Fc receptor binding, it has significantly reduced serum half-life, and most IgG-fusions vaccine strategies use human IgG1 [11]. In addition to these factors, the polymeric state of an antibody affects its immunological properties. In this study we built on recent advances in antibody engineering to design and explore a panel of modified IgG fusion vaccines carrying ZE3 as a model antigen These constructs contained modifications designed to alter their polymeric and C1q binding characteristics. We compared the C1q binding, expression, solubility, stability, and immunogenicity of the IgG fusions
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