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

• Published in: The Journal of infectious diseases Vol. 214; no. 5; pp. 762 - 771
• Main Authors: Regules, Jason A., Cicatelli, Susan B., Bennett, Jason W., Paolino, Kristopher M., Twomey, Patrick S., Moon, James E., Kathcart, April K., Hauns, Kevin D., Komisar, Jack L., Qabar, Aziz N., Davidson, Silas A., Dutta, Sheetij, Griffith, Matthew E., Magee, Charles D., Wojnarski, Mariusz, Livezey, Jeffrey R., Kress, Adrian T., Waterman, Paige E., Jongert, Erik, Wille-Reece, Ulrike, Volkmuth, Wayne, Emerling, Daniel, Robinson, William H., Lievens, Marc, Morelle, Danielle, Lee, Cynthia K., Yassin-Rajkumar, Bebi, Weltzin, Richard, Cohen, Joe, Paris, Robert M., Waters, Norman C., Birkett, Ashley J., Kaslow, David C., Ballou, W. Ripley, Ockenhouse, Christian F., Vekemans, Johan
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2016
• Subjects: 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; PARASITES; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - immunology; Young Adult; Plasmodium falciparum; controlled human malaria parasite infection; vaccine spacing; safety; delayed fractional dose; malaria; efficacy; immunogenicity; RTS,S/AS01
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiw237

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 immunologie 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 (FxO17M), 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 FxO17M 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.