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.
Highlights
Development of new vaccine adjuvants has entered a golden age of research and development
PRR signaling induces production of developed in the 1920’s, aluminum salts are the most specific cytokines and chemokines that determine which immune commonly used human vaccine adjuvants, and are included in cells are recruited to the site of injection, and will shape vaccines for polio, hepatitis A and B, anthrax, pneumococcus, the adaptive responses
Alum adjuvants have of pathogens (e.g., LPS on gram-negative bacteria that triggers an extensive record of safe use, and they effectively augment TH2 TLR4 or dsRNA of certain virus families that triggers TLR3), cellular immunity and antibody titers
Summary
Development of new vaccine adjuvants has entered a golden age of research and development. AS04, a combination of the TLR4 agonist MPL and alum, was licensed as a component of vaccines against hepatitis B virus (HBV) and human papillomavirus, making it the first intentional inclusion of a TLR ligand in a licensed vaccine.[1,2] More recently AS01, a combination of MPL and the saponin QS21, and the TLR9 agonist CpG1018, have achieved licensure as components of herpes zoster and HBV vaccines, respectively. These new adjuvants that promote TH1 immunity are promising for vaccines against malaria, tuberculosis, and pertussis
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