Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion

Abstract

AS03 is an Adjuvant System composed of α-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. In various nonclinical and clinical studies, high levels of antigen-specific antibodies were obtained after administration of an AS03-adjuvanted vaccine, permitting antigen-sparing strategies. AS03 has been shown to enhance the vaccine antigen-specific adaptive response by activating the innate immune system locally and by increasing antigen uptake and presentation in draining lymph nodes, a process that is modulated by the presence of α-tocopherol in AS03. In nonclinical models of the AS03-adjuvanted prepandemic H5N1 influenza vaccine, increased levels of anti-influenza antibody afforded protection against disease and against virus replication of influenza strains homologous and heterologous to the vaccine strain. By incorporating AS03 in the pandemic H1N1/2009 vaccine, vaccine immunogenicity was increased compared with nonadjuvanted H1N1 vaccines. High H1N1/2009/AS03 vaccine effectiveness was demonstrated in several assessments in multiple populations. Altogether, the nonclinical and clinical data illustrate the ability of AS03 to induce superior adaptive responses against the vaccine antigen, principally in terms of antibody levels and immune memory. In general, these results support the concept of Adjuvant Systems as a plausible approach to develop new effective vaccines.

Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults

“…The highest responses were observed in HiP-AS recipients, consistent with the reported effects of AS03 on CD4 ϩ cell responses (25). Th17 has been implicated in vaccine-induced immunity against a range of bacterial pathogens, including pneumococcal infections at mucosal sites (39).…”

“…AS03 has been shown to enhance the vaccine antigen-specific adaptive responses of several candidate vaccines and is included in licensed H1N1 and H5N1 pandemic influenza vaccines (25). The potential immune-enhancing effects of AS03 were assessed in view of the target population of elderly individuals, in whom immune responses to vaccination may be attenuated.…”

Preclinical evaluation of Vaxfectin®-adjuvanted Vero cell-derived seasonal split and pandemic whole virus influenza vaccines

“…1). While a variety of different adjuvant formulations have been clinically tested with H5N1, predominantly squalene-based oil-in-water adjuvants including MF-59, AS03 and AF01, [40][41][42] additional adjuvant formulations such as Vaxfectin ® should be developed because it is conceivable that even adjuvant supplies may be limited during a pandemic. In addition, potential safety issues observed for some adjuvant formulations in pandemic settings, most recently with the reported association of AS03-adjuvanted H1N1 vaccine and narcolepsy in children, 43 could restrict their annual usage with seasonal vaccines in normal healthy subjects.…”

Safety assessment of adjuvanted vaccines: Methodological considerations

“…9 These include oil-in-water emulsions, which are based on squalene, a naturally occurring oil; 12 virosomes, which are spherical phospholipid layers carrying antigen either bound to the surface or encapsulated within the lumen; 13 and adjuvant combinations (Adjuvant Systems, AS) such as AS01, AS03 and AS04, which contain several components specifically combined to enhance and modulate the immune responses. 14,15 Vaccines destined for use in humans contain carefully selected antigens that are frequently highly purified, as well as other components such as adjuvants, stabilizers, preservatives, and potentially residual trace substances (such as egg proteins, antibiotics, or formaldehyde) left over from the manufacturing process. Safety is rarely assessed specifically on these components alone because they are never administered individually in clinical practice.…”