Article quick-view

Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria infection and immunogenicity study.


 Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria infection (CHMI) and natural exposure. Immunization regimens including a delayed fractional third dose were assessed for potential increased protection against malaria and immunologic responses. In a Phase IIa, controlled, open-label, study of healthy malaria-naïve adults, 16 subjects vaccinated with a 0, 1, 2-month full dose regimen (012M) and 30 subjects with a 0, 1, 7-month regimen including a fractional third dose (Fx017M) underwent CHMI three weeks after last dose. Plasmablast heavy and light chain immunoglobulin mRNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated post-8 months (Clinical NCT01857869). 26/30 subjects in the Fx017M group (vaccine efficacy [VE] 86·7% [95% CI: 66·8, 94·6]; p<0·0001), and 10/16 in the 012M group (VE 62·5% [95% CI: 29·4, 80·1]; p=0·0009) were protected against infection and protection differed between schedules (log rank p=0·040). The fractional dose boosting increased antibody somatic hypermutation and avidity, and sustained high protection upon re-challenge. A delayed third fractional vaccine dose improved immunogenicity and protection against infection. RTS,S/AS01 immunization regimen optimization may lead to improved approaches against malaria.