Reprogramming the adjuvant properties of aluminum oxyhydroxide with nanoparticle technology

Abstract

Aluminum salts, developed almost a century ago, remain the most commonly used adjuvant for licensed human vaccines. Compared to more recently developed vaccine adjuvants, aluminum adjuvants such as Alhydrogel are heterogeneous in nature, consisting of 1–10 micrometer-sized aggregates of nanoparticle aluminum oxyhydroxide fibers. To determine whether the particle size and aggregated state of aluminum oxyhydroxide affects its adjuvant activity, we developed a scalable, top-down process to produce stable nanoparticles (nanoalum) from the clinical adjuvant Alhydrogel by including poly(acrylic acid) (PAA) polymer as a stabilizing agent. Surprisingly, the PAA:nanoalum adjuvant elicited a robust TH1 immune response characterized by antigen-specific CD4+ T cells expressing IFN-γ and TNF, as well as high IgG2 titers, whereas the parent Alhydrogel and PAA elicited modest TH2 immunity characterized by IgG1 antibodies. ASC, NLRP3 and the IL-18R were all essential for TH1 induction, indicating an essential role of the inflammasome in this adjuvant’s activity. Compared to microparticle Alhydrogel this nanoalum adjuvant provided superior immunogenicity and increased protective efficacy against lethal influenza challenge. Therefore PAA:nanoalum represents a new class of alum adjuvant that preferentially enhances TH1 immunity to vaccine antigens. This adjuvant may be widely beneficial to vaccines for which TH1 immunity is important, including tuberculosis, pertussis, and malaria.

<p>Crystalline and Amorphous Preparation of Aluminum Hydroxide Nanoparticles Enhances Protective Antigen Domain 4 Specific Immunogenicity and Provides Protection Against Anthrax</p>

“…Previous studies on modified nanoscale preparation of the alum components have been shown to have potential advantages over the traditional form of alhydrogel. 14,[24][25][26] Recently it was shown by Orr et al 27 that stable nanoparticle preparation from the conventional adjuvant alhydrogel by including a poly(acrylic acid) (PAA) polymer elicited a more robust antigen-specific Th1 immune response than alhydrogel. 27 In an attempt to improve the adjuvant characteristics of traditional aluminum hydroxide compounds, in the present study, we have prepared crystalline and amorphous forms of AH nps and evaluated its physicochemical and immunomodulating potential by utilizing antigen D4 of Bacillus anthracis.…”

Covering Aluminum Oxide Nanoparticles with Biocompatible Materials to Efficiently Deliver Subunit Vaccines

“…Surprisingly, it was recently reported that injection of alum with a carefully optimized protocol and a precise vaccination time schedule, induced effective anti-tumor CTL responses showing non-specific tumor suppression [13]. These outcomes indicate that innovative strategies may remarkably improve adjuvanticity of alums and even enable the alum-adjuvanted vaccines to elicit both humoral and cellular immunity, suggesting the Al-based adjuvants of more potentials in boosting immunoresponse than those in practical use [14].…”

Aluminum Nanoparticles Acting as a Pulmonary Vaccine Adjuvant-Delivery System (VADS) Able to Safely Elicit Robust Systemic and Mucosal Immunity

“…3b). Also, minimizing alum into nanoparticles remarkably enhances the VADS traffic to the draining lymph nodes, wherein different types of functional cells have an enlarged chance to be stimulated by vaccines to orchestrate to improve immunological reactions contributing to elevated immunity [14,37,38].…”

“…As a result of this, researchers are now making efforts on reformulation of conventional alums to improve their adjuvanticity. In particular, it was found that engineering of alums into special nanostructures, with/without certain materials, such as phospholipid engendering the phospholipid bilayer-coated aluminum nanoparticles (PLANs) and poly(acrylic acid) generating nanorods, can remarkably reduce their local irritating activity while rendering them able to enhance cellular immune responses toward the carried Ags [34][35][36][37][38][39]. These outcomes inspire us to trial the feasibility of using aluminum nanoparticles (ANs) as a pulmonary VADS for delivering vaccines to elicit strong mucosal immunity against air-borne pathogens, such as SARS-CoV2 and MERS, that incline to infringe and disable human respiratory system.…”