A Universal Plug-and-Display Vaccine Carrier Based on HBsAg VLP to Maximize Effective Antibody Response

Abstract

Development of effective malaria vaccines requires delivery platforms to enhance the immunogenicity and efficacy of the target antigens. This is particularly challenging for transmission-blocking malaria vaccines (TBVs), and specifically for those based on the Pfs25 antigen, that need to elicit very high antibody titers to stop the parasite development in the mosquito host and its transmission. Presenting antigens to the immune system on virus-like particles (VLPs) is an efficient way to improve the quantity and quality of the immune response generated. Here we introduce for the first time a new VLP vaccine platform, based on the well-established hepatitis B surface antigen (HBsAg) fused to the SpyCatcher protein, so that the antigen of interest, linked to the SpyTag peptide, can be easily displayed on it (Plug-and-Display technology). As little as 10% of the SpyCatcher::HBsAg VLPs decorated with Pfs25::SpyTag (molar ratio) induces a higher antibody response and transmission-reducing activity in mice compared to the soluble protein, with 50 and 90% of the VLP coupled to the antigen further enhancing the response. Importantly, using this carrier that is a vaccine antigen itself could be beneficial, as we show that anti-HBsAg IgG antibodies are induced without interfering with the Pfs25-specific immune response generated. Furthermore, pre-existing anti-HBsAg immunity does not affect the antigen-specific response to Pfs25::SpyTag-SpyCatcher::HBsAg, suggesting that these VLPs can have a broad use as a vaccine platform.

Incorporation of a Novel CD4+ Helper Epitope Identified from Aquifex aeolicus Enhances Humoral Responses Induced by DNA and Protein Vaccinations

“…As such, several studies have explored conjugation of these carbohydrate, peptide, or mini-protein vaccines to carrier proteins, including but not limited to KLH, tetanus toxin, and HbsAg. Induction of more potent antibody responses was observed in many cases ( Jin et al., 2017 ; Marini et al., 2019 ). However, this approach may undermine the core motivations behind domain minimization by introducing a host of immunodominant distracting surfaces that may skew induced humoral responses.…”

A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone

“…www.nature.com/scientificreports/ nanoparticle monomers [2][3][4] , chemical conjugation 5,6 , and a spontaneous intramolecular isopeptide bond formation with the SpyTag:SpyCatcher system 7,8 , and some of these nanoparticles are now entering clinical trials 2,9,10 . Another important factor to consider in viral immunogen design is glycosylation.…”

Covalent protein display on Hepatitis B core-like particles in plants through the in vivo use of the SpyTag/SpyCatcher system

“…The conjugation reaction can be induced in vitro by mixing two purified components or in vivo by co-expression of both conjugation partners in the same cell 33 . The SpyTag/SpyCatcher strategy has been successfully used to conjugate different antigens to VLPs derived from bacteriophage AP205 38 , HBV surface antigen 39 , potato virus X 40 or lentiviruses 41 . It has been employed as part of various vaccine design strategies with growing success 42,43 .…”