Improving vaccine delivery using novel adjuvant systems

Abstract

ASO4, a novel adjuvant, contains aluminum hydroxide and monophosphoryl lipid (MPL) (500 mg aluminum hydroxide and 50 mg 3-O-desacyl-4' MPL A). Aluminum hydroxide is an adjuvant known to facilitate vaccine antigen delivery and transport to the draining lymph nodes by creating a 'depot' at the injection site. 2 Like all aluminum adjuvants, aluminum hydroxide helps improve immunogenicity of low molecular weight antigens, which could otherwise clear rapidly from the injection site or draining lymph nodes. 2 MPL, a non-toxic derivative of lipopolysaccharide, improves specific antibody and cell-mediated immune responses to vaccination. 4 With only minimal toxicity, 5 MPL enhances macrophage and B-and Tcell responses, as well as T-helper cell generation. 5,6 AS04 adjuvant has been shown to improve vaccine-induced immune responses in hepatitis B (HBV) and cervical cancer vaccines.In 2004, Boland et al. 7 described a randomized study where healthy subjects received two doses of HBV vaccine with ASO4 adjuvant or three doses of HBV vaccine with aluminum adjuvant. 7 After the first and second dose of ASO4, substantially more subjects were seropositive for anti-HBV antibodies than after the first and third dose of aluminum adjuvanted vaccine (Table 1). Thus, the ASO4 adjuvant provided the potential for an effective two dose HBV vaccine schedule. In addition, after two doses of ASO4 adjuvanted vaccine, geometric mean titers (GMT) were two times higher than those observed with the aluminum adjuvanted vaccine (7,832 mlU/ml vs 3,725 mlU/ml). No serious adverse events (SAEs) related to the vaccinations occurred, and the overall incidence of vaccine-related adverse events (AEs) (e.g., pain, redness and swelling around the injection site) was comparable between groups. 7 For patients undergoing haemodialysis, the Centers for Disease Control recommends stronger or increased doses of HBV vaccine to assure protective immunity. 8 A clinical trial comparing the immune responses of pre-haemodialysis and haemodialysis patients showed four doses of HBV vaccine was more effective with ASO4 adjuvant than with aluminum adjuvant (Table 1). 9 More patients achieved seroprotection at three months (p = 0.005) and remained seroprotected at 36 months with ASO4 adjuvanted vaccine than with aluminum adjuvanted vaccine (p = 0.03, Table 1). 9 At three and seven months post final dose, signficiantly more patients in the HBV-ASO4 adjuvant group had anti-HB concentrations >100 mlU/mL (p < 0.001 and p < 0.04, respectively), and a higher percentage retained these high anti-HB levels at 36 months

Matrix MTMadjuvanted virosomal H5N1 vaccine induces balanced Th1/Th2 CD4+T cell responses in man

“…14,23,29 In murine studies of adjuvanted influenza vaccines, Matrix-M™, induced significantly higher both Th1 and Th2 cytokine response than observed after AS03 or alum formulations. 29 GM-CSF production was also elicited upon influenza-stimulation in all Matrix M TM adjuvanted groups, GM-CSF has adjuvant properties 30 and the adjuvant effect of Matrix M TM could partly rely on induction of GM-CSF. Similar to the frequencies of influenza-specific CD4+ Th1 cells, 25 the concentrations of T helper cytokines in the supernatants from in vitro influenza stimulated cells peaked at day 21 and were not further increased by a second dose of vaccine.…”

MF59 Emulsion Is an Effective Delivery System for a Synthetic TLR4 Agonist (E6020)

“…The clinical evaluations of MPL demonstrated the efficacy of an attenuated TLR4 agonist as a vaccine adjuvant. Presently, two TLR4 agonist containing vaccines are approved for use in humans, namely Fendrix® for the prevention of hepatitis B and the cervical cancer vaccine Cervarix™ (19)(20)(21)34,35). In both cases MPL is formulated with a delivery system.…”

Vaccinomics and a New Paradigm for the Development of Preventive Vaccines Against Viral Infections

“…Examples include the implementation of new molecular adjuvants that utilize TLRs or cytoplasmic pattern recognition receptors (NOD proteins, RIG-I, MDA-5) and/or modulate critical innate pathways to increase the ability of the immune system to circumvent age-related immune restrictions (such as TLR agonists and ligands: CpGcontaining oligodeoxynucleotides, poly(I:C), imidazoquinoline compounds: R-848, monophosphoryl lipid A, bacterial flagellins, etc.) (Kornbluth and Stone, 2006;Pichichero, 2008;Rosenthal, 2006). Other strategies that may enhance vaccine immunogenicity/efficacy in the elderly include: increased doses of antigen, new adjuvants and delivery systems, novel mucosal vaccines, ''early prime-later boost'' immunizations, T cell rejuvenation therapies such as stem cell interventions, androgen blockade, IL-7 treatment, or manipulation of other key cytokines and/or costimulatory molecules (Brien et al, 2009;Rosenthal, 2006;Siegrist and Aspinall, 2009).…”