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

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

Author information

  • 1Malaria Vaccine Branch Military Malaria Research Program Uniformed Services University of the Health Sciences, Bethesda, Maryland.
  • 2Clinical Trials Center, Translational Medicine Branch.
  • 3Experimental Therapeutics Branch Military Malaria Research Program.
  • 4Malaria Vaccine Branch Military Malaria Research Program.
  • 5Entomology Branch, Walter Reed Army Institute of Research, Silver Spring.
  • 6Uniformed Services University of the Health Sciences, Bethesda, Maryland.
  • 7GSK Vaccines, Rixensart, Belgium.
  • 8PATH Malaria Vaccine Initiative, Seattle, Washington.
  • 9Atreca, Redwood City, California.
  • 10Military Malaria Research Program.



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.


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.


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.


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.




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

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