Vaccine synergy with virus-like particle and immune complex platforms for delivery of human papillomavirus L2 antigen

Abstract

Diverse HPV subtypes are responsible for considerable disease burden worldwide, necessitating safe, cheap, and effective vaccines. The HPV minor capsid protein L2 is a promising candidate to create broadly protective HPV vaccines, though it is poorly immunogenic by itself. To create highly immunogenic and safe vaccine candidates targeting L2, we employed a plant-based recombinant protein expression system to produce two different vaccine candidates: L2 displayed on the surface of hepatitis B core (HBc) virus-like particles (VLPs) or L2 genetically fused to an immunoglobulin capable of forming recombinant immune complexes (RIC). Both vaccine candidates were potently immunogenic in mice, but were especially so when delivered together, generating very consistent and high antibody titers directed against HPV L2 (>1,000,000) that correlated with virus neutralization. These data indicate a novel immune response synergy upon co-delivery of VLP and RIC platforms, a strategy that can be adapted generally for many different antigens.

Codelivery of improved immune complex and virus-like particle vaccines containing Zika virus envelope domain III synergistically enhances immunogenicity

“…By inserting the antigen into only one of two tandemly-linked HBc gene copies, it is possible to lessen the problem of destabilization, leading to an increased capacity of HBc VLPs to display antigens [36]. In addition, HBc VLPs can be efficiently produced in a number of expression systems, including plants [24,36,53,54]. In this study, we found that ZE3 displayed on either heterodimeric HBc or C-terminally fused to HBc monomer produced fully formed and highly immunogenic VLPs with nearly indistinguishable immunogenic properties (Figs.…”

“…RIC and VLP leaf samples were homogenized in ice-cold, 1:2 w/v extraction buffer at pH 8.0 (100 mM Tris-HCl, 50 mM NaCl, 10 mM EDTA, 0.1% Triton, 50 mM sodium ascorbate, and 2 mM PMSF). The VLP purification via sucrose gradient centrifugation and the RIC purification via protein G column chromatography purification protocol was conducted as described in [24]. For the N-terminal ZE3, the extraction buffer used was at pH 9.5 instead of pH 8.0.…”

“…C1q binding was measured as previously described [24]. Mouse Zika E specific antibody titers were measured by ELISA.…”

“…We previously found synergistic enhancement of immunogenicity when RIC are codelivered with hepatitis B core antigen (HBc) VLP [24]. To generate HBc VLPs carrying ZE3 for codelivery with ZE3 N-RICs and C-RICs, the ZE3 antigen (K301 to T406) flanked by flexible linkers was inserted into the second of two tandemly-linked HBc gene copies.…”

“…However, simply mixing antibody and antigen often produces inconsistent results as monomeric antibody-bound antigen is unable to efficiently crosslink immune receptors [18,21]. To circumvent this problem, recombinant immune complexes (RIC), which consist of an antibody fused to its cognate antigen, have also been explored as a vaccine platform due to their ability to form large antigen-antibody complexes that mimic those found during natural infection [22][23][24][25][26]. This complex formation results in a number of benefits including direct activation of antigen presenting cells via crosslinked Fcc receptors, enhancement of antigen presentation to B-cells, effective stimulation of immune responses through high avidity C1q binding, and increased T-cell activation [26][27][28][29].…”