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.Adjuvants: Nanoalum gives a boostAluminum salt-based adjuvants such as alhydrogel have been a mainstay of vaccines for decades. Christopher B. Fox and colleagues at the Infectious Disease Research Institute in Seattle, USA, investigate the effect adjuvant particle size has on experimental vaccine responses. Shearing conventional micrometer-scale alhyrodogel into nanoparticles is followed by rapid reaggregation; however, the authors show that addition of anionic polymer (PAA) prevents this and results in stable nanoparticles (PAA:nanoalum). Used as an adjuvant with either influenza or TB antigens triggers robust TH1 and IgG2a responses that are superior to alhydrogel even when the latter includes a Toll-like receptor 4 (TLR4) agonist. Interestingly, addition of TLR4 agonist to PAA:nanoalum actually impairs its adjuvanticity. PAA:nanoalum efficacy is nevertheless dependent on the NLRP3 inflammasome suggesting that this novel adjuvant somehow triggers this pathway through some as yet undefined route.