Abstract
This article summarizes developments attained in oral vaccine formulations based on the encapsulation of antigen proteins inside porous silica matrices. These vaccine vehicles show great efficacy in protecting the proteins from the harsh acidic stomach medium, allowing the Peyer's patches in the small intestine to be reached and consequently enhancing immunity. Focusing on the pioneering research conducted at the Butantan Institute in Brazil, the optimization of the antigen encapsulation yield is reported, as well as their distribution inside the meso- and macroporous network of the porous silica. As the development of vaccines requires proper inclusion of antigens in the antibody cells, X-ray crystallography is one of the most commonly used techniques to unveil the structure of antibody-combining sites with protein antigens. Thus structural characterization and modelling of pure antigen structures, showing different dimensions, as well as their complexes, such as silica with encapsulated hepatitis B virus-like particles and diphtheria anatoxin, were performed using small-angle X-ray scattering, X-ray absorption spectroscopy, X-ray phase contrast tomography, and neutron and X-ray imaging. By combining crystallography with dynamic light scattering and transmission electron microscopy, a clearer picture of the proposed vaccine complexes is shown. Additionally, the stability of the immunogenic complex at different pH values and temperatures was checked and the efficacy of the proposed oral immunogenic complex was demonstrated. The latter was obtained by comparing the antibodies in mice with variable high and low antibody responses.
Highlights
Subcutaneous vaccine administration is the most used protocol in immunization campaigns due to its highest degree of effectiveness
Small-angle X-ray scattering (SAXS) characterization of the pure antigens in phosphate buffer saline (PBS) solution showed that hepatitis B surface antigen (HBsAg) is a globular particle with mean diameter of 30 Æ 5 nm, larger than the silica mean pore diameter D = 10.4 Æ 0.6 nm, confirmed by DLS and TEM images (Rasmussen et al, 2019a)
The HBsAg particles are in the macroporous region of SBA15, and may close the entrance of the mesopore and cluster in PBS. diphtheria anatoxin (dANA), on the other hand, has dimensions similar to the mean diameter of the mesopore, taken from simulation of the SAXS results shown in Fig. 2 (Rasmussen et al, 2021), implying that the dANA is protected inside the Marcia Carvalho de Abreu Fantini et al Using crystallography to improve vaccines 13
Summary
Subcutaneous vaccine administration is the most used protocol in immunization campaigns due to its highest degree of effectiveness. Even though the administration of oral and nasal vaccination seems to be the most natural way, there is a major challenge that needs to be resolved: antigens must safely overcome the body’s barriers to generate antibodies and induce immunization (Goffin et al, 2019; Coria et al, 2019; Miao et al, 2019) This means that efficient and biosafe carriers must be developed The main concerns being the decrease of immunization when micrometric particles are used, since the administration is not continuous, and the fact that silica can be excreted (He et al, 2011; Mariano-Neto et al, 2014; Scaramuzzi et al, 2016) Despite such concerns, from 2006 to 2020 more than fifty papers, including extensive reviews (Mody et al, 2013; Zhao et al, 2014), reported on how these nanostructured porous materials are powerful candidates for new and optimized oral vaccines. The interest comes from the fact that diphtheria anatoxin (dANA) is much smaller, with a maximum length around 9 nm (Rasmussen et al, 2021), than HBsAg, a globular particle around 30 nm (Scaramuzzi et al, 2016), making dANA an excellent candidate for full encapsulation into SBA-15, as in principle it is small enough to enter the mesopores, having a mean mesopore diameter of around 10 nm
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