Development of adjuvant-active nonionic block copolymers.

Nonionic block copolymers are surfactants synthesized using propylene oxide (PO) and ethylene oxide (EO) which are organized as 'blocks' of polyoxyethylene (POE) and polyoxypropylene (POP). These copolymers can be designed and synthesized using variable amounts of the PO and EO and with differential arrangement of the POP and POE blocks so that individual products have unique physicochemical properties. The copolymers that have been most thoroughly evaluated in vaccine research are linear with the polymer blocks organized as POE-POP-POE. Low molecular weight (MW) copolymers, 3-6 kDa, of this type have been used in oil-based emulsion formulations, whereas high-MW copolymers, >9 kDa, can be used in aqueous formulations. The adjuvant activity of nonionic block copolymers is influenced greatly by the size of the POP core block. As the size of this block is increased so is the adjuvant activity of the copolymer; peak activity is achieved using copolymers with POP cores that are 12-15 kDa. However, adjuvant activity is also affected by the amount of POE with low concentrations, 5-10%, being optimal. The type of immune responses produced is also influenced by the POE content. Copolymers with 10% POE preferentially augment Type 2 helper T-lymphocyte responses which support antibody responses, including mucosal antibody responses. Copolymers with <10% POE augment both Type 1 and Type 2 helper T-lymphocyte responses, which support a broader range of antibody responses and cellular immune responses. This property may allow for vaccines to be 'customized' by using adjuvant-active nonionic block copolymers that will augment the most appropriate types of immune responses.