Advantages and Limitations of Integrated Flagellin Adjuvants for HIV-Based Nanoparticle B-Cell Vaccines

Abstract

The great advantage of virus-like particle (VLP) nano-vaccines is their structural identity to wild-type viruses, ensuring that antigen-specific B-cells encounter viral proteins in their natural conformation. “Wild-type” viral nanoparticles can be further genetically or biochemically functionalized with biomolecules (antigens and adjuvants). Flagellin is a potent inducer of innate immunity and it has demonstrated adjuvant effectiveness due to its affinity for toll-like receptor 5 (TLR5). In contrast to most TLR ligands, flagellin is a protein and can induce an immune response against itself. To avoid side-effects, we incorporated a less inflammatory and less immunogenic form of flagellin as an adjuvant into HIV-based nanoparticle B-cell-targeting vaccines that display either the HIV-1 envelope protein (Env) or a model antigen, hen egg lysozyme (HEL). While flagellin significantly enhanced HEL-specific IgG responses, anti-Env antibody responses were suppressed. We demonstrated that flagellin did not activate B-cells directly in vitro, but might compete for CD4+ T-cell help in vivo. Therefore, we hypothesize that in the context of VLP-based B-cell nano-vaccines, flagellin serves as an antigen itself and may outcompete a less immunogenic antigen with its antibody response. In contrast, in combination with a strong immunogen, the adjuvant activity of flagellin may dominate over its immunogenicity.

Calcium Phosphate Nanoparticle-Based Vaccines as a Platform for Improvement of HIV-1 Env Antibody Responses by Intrastructural Help

“…To analyze the induction of anti-Env antibody responses in vivo, we applied Env-CaP nanoparticles intramuscularly, as it was demonstrated to be the most appropriate way for the delivery of B- and T-cell antigens with CaP nanoparticles into draining lymphoid organs [13]. In contrast to the model antigen [13] in a highly reactive C3H mouse strain (as discussed in Reference [34]), Env-CaP nanoparticles at a dose of 10 µg of Env protein per immunization induced poor anti-Env antibody responses in Bl6 mice (Figure 4A, Env-CaP vs. naive).…”

CD4+ T Cells Induced by Tuberculosis Subunit Vaccine H1 Can Improve the HIV-1 Env Humoral Response by Intrastructural Help

“…In context of weak immunogens such as the HIV-1 Env glycoprotein, it has been previously described that antigenic competition can impair the Env antibody response induced by fusion proteins [ 65 , 66 ]. In contrast to fusion proteins of antigens and T H epitopes, the encapsulation of immunodominant peptides into VLPs offers the benefit of preventing the induction of peptide-specific antibodies ( Figure 3 B), while simultaneously improving BCR crosslinking by the antigen presented on the surface of the VLPs [ 67 , 68 , 69 ].…”

The Use of Nanobiotechnology in Immunology and Vaccination

“…The surface manipulation [ 54 , 55 ] and the use of detector molecules such as aptamers [ 56 ] are examples of targeting. Of course, each method has its advantages and limitations [ 57 ]. Another technology is bacterial outer membrane vesicles (OMVs)-based vaccines [ 58 ], presenting the antigenic stable chimeric fusion protein of the H1-type haemagglutinin (HA) of influenza A virus and the receptor-binding domain (RBD) of MERS-CoV (OMVs-H1/RBD).…”