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


CONCLUSIONS
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.


BACKGROUND
NCT01857869.
Malaria Vaccine Branch Military Malaria Research Program Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Jason A
JA
Regules
Clinical Trials Center, Translational Medicine Branch.
Susan B
SB
Cicatelli
Malaria Vaccine Branch Military Malaria Research Program Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Jason W
JW
Bennett
Clinical Trials Center, Translational Medicine Branch.
Kristopher M
KM
Paolino
Experimental Therapeutics Branch Military Malaria Research Program.
Patrick S
PS
Twomey
Malaria Vaccine Branch Military Malaria Research Program.
James E
JE
Moon
Malaria Vaccine Branch Military Malaria Research Program.
April K
AK
Kathcart
Malaria Vaccine Branch Military Malaria Research Program.
Kevin D
KD
Hauns
Malaria Vaccine Branch Military Malaria Research Program.
Jack L
JL
Komisar
Malaria Vaccine Branch Military Malaria Research Program.
Aziz N
AN
Qabar
Entomology Branch, Walter Reed Army Institute of Research, Silver Spring.
Silas A
SA
Davidson
Malaria Vaccine Branch Military Malaria Research Program.
Sheetij
S
Dutta
Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Matthew E
ME
Griffith
Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Charles D
CD
Magee
Experimental Therapeutics Branch Military Malaria Research Program.
Mariusz
M
Wojnarski
Experimental Therapeutics Branch Military Malaria Research Program.
Jeffrey R
JR
Livezey
Experimental Therapeutics Branch Military Malaria Research Program.
Adrian T
AT
Kress
Clinical Trials Center, Translational Medicine Branch.
Paige E
PE
Waterman
GSK Vaccines, Rixensart, Belgium.
Erik
E
Jongert
PATH Malaria Vaccine Initiative, Seattle, Washington.
Ulrike
U
Wille-Reece
Atreca, Redwood City, California.
Wayne
W
Volkmuth
Atreca, Redwood City, California.
Daniel
D
Emerling
Atreca, Redwood City, California.
William H
WH
Robinson
GSK Vaccines, Rixensart, Belgium.
Marc
M
Lievens
GSK Vaccines, Rixensart, Belgium.
Danielle
D
Morelle
PATH Malaria Vaccine Initiative, Seattle, Washington.
Cynthia K
CK
Lee
PATH Malaria Vaccine Initiative, Seattle, Washington.
Bebi
B
Yassin-Rajkumar
PATH Malaria Vaccine Initiative, Seattle, Washington.
Richard
R
Weltzin
GSK Vaccines, Rixensart, Belgium.
Joe
J
Cohen
Military Malaria Research Program.
Robert M
RM
Paris
Malaria Vaccine Branch Military Malaria Research Program.
Norman C
NC
Waters
GSK Vaccines, Rixensart, Belgium.
Ashley J
AJ
Birkett
GSK Vaccines, Rixensart, Belgium.
David C
DC
Kaslow
GSK Vaccines, Rixensart, Belgium.
W Ripley
WR
Ballou
PATH Malaria Vaccine Initiative, Seattle, Washington.
Christian F
CF
Ockenhouse
GSK Vaccines, Rixensart, Belgium.
Johan
J
Vekemans
D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000276:immunology; D000915:Antibody Affinity; D005260:Female; D006801:Humans; D007115:Immunization Schedule; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D014614:Vaccines, Synthetic / Q000008:administration & dosage* / Q000276:immunology*; D055815:Young Adult
D000913:Antibodies, Protozoan; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D017780:Malaria Vaccines; C577001:RTS,S-AS01 vaccine; D014614:Vaccines, Synthetic
Plasmodium falciparum; RTS,S/AS01; controlled human malaria parasite infection; delayed fractional dose; efficacy; immunogenicity; malaria; safety; vaccine spacing