Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study

J Infect Dis. 2016 Sep 1;214(5):762-71. doi: 10.1093/infdis/jiw237. Epub 2016 Jun 13.


Background: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses.

Methods: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months.

Results: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge.

Discussions: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria.

Clinical trials registration: NCT01857869.

Keywords: Plasmodium falciparum; RTS,S/AS01; controlled human malaria parasite infection; delayed fractional dose; efficacy; immunogenicity; malaria; safety; vaccine spacing.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Protozoan / biosynthesis
  • Antibodies, Protozoan / immunology
  • Antibody Affinity
  • Female
  • Humans
  • Immunization Schedule*
  • Immunoglobulin Heavy Chains / biosynthesis
  • Immunoglobulin Light Chains / biosynthesis
  • Malaria / prevention & control*
  • Malaria Vaccines / administration & dosage*
  • Malaria Vaccines / immunology*
  • Male
  • Middle Aged
  • Vaccines, Synthetic / administration & dosage*
  • Vaccines, Synthetic / immunology*
  • Young Adult


  • Antibodies, Protozoan
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Malaria Vaccines
  • RTS,S-AS01 vaccine
  • Vaccines, Synthetic

Associated data