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

Jason A. Regules*, Susan B. Cicatelli, Jason W. Bennett, Kristopher M. Paolino, Patrick S. Twomey, James E. Moon, April K. Kathcart, Kevin D. Hauns, Jack L. Komisar, Aziz N. Qabar, Silas A. Davidson, Sheetij Dutta, Matthew E. Griffith, Charles D. Magee, Mariusz Wojnarski, Jeffrey R. Livezey, Adrian T. Kress, Paige E. Waterman, Erik Jongert, Ulrike Wille-ReeceWayne Volkmuth, Daniel Emerling, William H. Robinson, Marc Lievens, Danielle Morelle, Cynthia K. Lee, Bebi Yassin-Rajkumar, Richard Weltzin, Joe Cohen, Robert M. Paris, Norman C. Waters, Ashley J. Birkett, David C. Kaslow, W. Ripley Ballou, Christian F. Ockenhouse, Johan Vekemans

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

155 Scopus citations


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.

Original languageEnglish
Pages (from-to)762-771
Number of pages10
JournalJournal of Infectious Diseases
Issue number5
StatePublished - 1 Sep 2016
Externally publishedYes


  • Controlled human malaria parasite infection
  • Delayed fractional dose
  • Efficacy
  • Immunogenicity
  • Malaria
  • Plasmodium falciparum
  • RTS S/AS01
  • Safety
  • Vaccine spacing


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