Abstract
Incorporation of immunodominant T-helper epitopes of licensed vaccines into virus-like particles (VLP) allows to harness T-helper cells induced by the licensed vaccines to provide intrastructural help (ISH) for B-cell responses against the surface proteins of the VLPs. To explore whether ISH could also improve antibody responses to calcium phosphate (CaP) nanoparticle vaccines we loaded the nanoparticle core with a universal T-helper epitope of Tetanus toxoid (p30) and functionalized the surface of CaP nanoparticles with stabilized trimers of the HIV-1 envelope (Env) resulting in Env-CaP-p30 nanoparticles. In contrast to soluble Env trimers, Env containing CaP nanoparticles induced activation of naïve Env-specific B-cells in vitro. Mice previously vaccinated against Tetanus raised stronger humoral immune responses against Env after immunization with Env-CaP-p30 than mice not vaccinated against Tetanus. The enhancing effect of ISH on anti-Env antibody levels was not attended with increased Env-specific IFN-γ CD4 T-cell responses that otherwise may potentially influence the susceptibility to HIV-1 infection. Thus, CaP nanoparticles functionalized with stabilized HIV-1 Env trimers and heterologous T-helper epitopes are able to recruit heterologous T-helper cells induced by a licensed vaccine and improve anti-Env antibody responses by intrastructural help.
Highlights
The unique characteristic of HIV-1 to infect activated CD4 T-cells requires alternative vaccination strategies that differ from the classical approaches used [1]
Polyfunctional serum antibodies against envelope glycoprotein (Env) of HIV-1 correlate with spontaneous HIV-1 control by elite controllers [2] and appear to be crucial for vaccine-mediated protection against HIV-1 [3,4,5]
We demonstrated how T-helper cells induced by a licensed vaccine against Tetanus toxoid (TT) can be harnessed to provide help for Env-specific B-cells in mice immunized with HIV-1 virus-like particles (VLP) containing T-helper epitopes of TT [8]
Summary
The unique characteristic of HIV-1 to infect activated CD4 T-cells requires alternative vaccination strategies that differ from the classical approaches used [1]. In animal models, where CD4 T-cells were genetically non-reactive to the surface antigen of the CaP nanoparticles, incorporation of the p30 peptide, a promiscuous (universal) T-helper epitope from TT [14], overcame the lack of functionally active CD4 T-cell epitopes [13] These data indicate that CaP nanoparticle-based vaccines might be potentially used for improvement of HIV-Env antibody responses by the ISH approach. We designed CaP nanoparticles with stabilized HIV-1 Env trimers coupled to the surface and universal T-helper peptides of TT in the core These nanoparticles were used to demonstrate effects of ISH in mice previously immunized with a licensed vaccine against Tetanus toxoid
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