Slow Delivery of Antigen and Adjuvant Plus A Delayed Boost for Unexpected Immunogenicity

Immunization methods are provided. The methods typically include administering the subject an effective amount of an antigen and adjuvant to induce an immune response against an antigen, the method including two or more of (i) slow prime delivery of antigen and/or adjuvant, a (ii) temporally delayed 2nd immunization, and (iii) a robust adjuvant. Element (i) can be or include temporally extended exposure of antigen, adjuvant, or preferably the combination thereof, such as one or more of repeated administrations, infusion optionally by osmotic pump and escalating dosing. Element (ii) can include administering one or more boost doses of antigen and/or adjuvant, for example between 11 and 35 weeks after the start of the prime administration. A preferred robust adjuvant (iii) is one including non-liposome, non-micelle particles formed of a lipid, an additional adjuvant such as a TLR4 agonist, a sterol, and a saponin.