Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection.
BACKGROUND
To further increase the efficacy of malaria vaccine RTS,S/AS02A, we tested the RTS,S antigen formulated using the AS01B Adjuvant System (GlaxoSmithKline Biologicals).


METHODS
In a double-blind, randomized trial, 102 healthy volunteers were evenly allocated to receive RTS,S/AS01B or RTS,S/AS02A vaccine at months 0, 1, and 2 of the study, followed by malaria challenge. Protected vaccine recipients were rechallenged 5 months later.


RESULTS
RTS,S/AS01B and RTS,S/AS02A were well tolerated and were safe. The efficacy of RTS,S/AS01B and RTS,S/AS02A was 50% (95% confidence interval [CI], 32.9%-67.1%) and 32% (95% CI, 17.6%-47.6%), respectively. At the time of initial challenge, the RTS,S/AS01B group had greater circumsporozoite protein (CSP)-specific immune responses, including higher immunoglobulin (Ig) G titers, higher numbers of CSP-specific CD4(+) T cells expressing 2 activation markers (interleukin-2, interferon [IFN]-gamma, tumor necrosis factor-alpha, or CD40L), and more ex vivo IFN-gamma enzyme-linked immunospots (ELISPOTs) than did the RTS,S/AS02A group. Protected vaccine recipients had a higher CSP-specific IgG titer (geometric mean titer, 188 vs 73 mug/mL; P < .001), higher numbers of CSP-specific CD4(+) T cells per 10(6) CD4(+) T cells (median, 963 vs 308 CSP-specific CD4(+) T cells/10(6) CD4(+) T cells; P < .001), and higher numbers of ex vivo IFN-gamma ELISPOTs (mean, 212 vs 96 spots/million cells; P < .001). At rechallenge, 4 of 9 vaccine recipients in each group were still completely protected.


CONCLUSIONS
The RTS,S/AS01B malaria vaccine warrants comparative field trials with RTS,S/AS02A to determine the best formulation for the protection of children and infants. The association between complete protection and immune responses is a potential tool for further optimization of protection. Trial registration. ClinicalTrials.gov identifier NCT00075049.
Kester
Kent E
KE
Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910, USA. kent.kester@us.army.mil
Cummings
James F
JF
Ofori-Anyinam
Opokua
O
Ockenhouse
Christian F
CF
Krzych
Urszula
U
Moris
Philippe
P
Schwenk
Robert
R
Nielsen
Robin A
RA
Debebe
Zufan
Z
Pinelis
Evgeny
E
Juompan
Laure
L
Williams
Jack
J
Dowler
Megan
M
Stewart
V Ann
VA
Wirtz
Robert A
RA
Dubois
Marie-Claude
MC
Lievens
Marc
M
Cohen
Joe
J
Ballou
W Ripley
WR
Heppner
D Gray
DG
D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D003430:Cross-Sectional Studies; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D017780:Malaria Vaccines / Q000009:adverse effects / Q000276:immunology / Q000592:standards; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D009073:Mozambique / Q000453:epidemiology; D018512:Parasitemia; D010963:Plasmodium falciparum / Q000276:immunology*; D013997:Time Factors
D000913:Antibodies, Protozoan; D017780:Malaria Vaccines