Anti-CS antibody geometric mean titer (GMT) ratios (first group over second group) at 1 mo after the third vaccine dose (ATP cohort for immunogenicity) valueavalue for differences in GMT (ANOVA model, pooled variance); vs., vs. Anti-CS antibody avidity (as determined by ELISA using the chaotropic agent, ammonium thiocyanate, and expressed as the avidity index) was in the same range for the 3 groups at each time point (Fig.?2). Open in a separate window Physique?2. higher for RTS,S/AS compared with RTS,S/saline. Most grade 3 solicited adverse events (AEs) were of short duration and grade 3 solicited general AEs were infrequent in the 3 groups. No serious adverse events were reported. In conclusion, in comparison with non-adjuvanted RTS,S, both RTS,S/AS vaccines exhibited better CS-specific immune responses. The Hyodeoxycholic acid anti-CS antibody response was significantly higher with RTS,S/AS01 than with RTS,S/AS02. The adjuvanted vaccines had acceptable safety profiles. circumsporozoite (CS) protein fused to the hepatitis B surface antigen (HBs).3 Two adjuvant systems have been evaluated with the RTS,S antigen: AS02, which consists of an oil-in-water emulsion with monophosphoryl lipid A (MPL) and Molina, fraction 21 (QS21, Antigenics Inc., a wholly owned subsidiary of Agenus Inc., Lexington, MA, USA), as immunostimulants, and Hyodeoxycholic acid AS01, a related liposome-based adjuvant system that also contains MPL and QS21.3,4 Anti-CS antibody titers and, to a lesser extent, CS-specific CD4+ T cells elicited by RTS,S have been identified as immunological markers associated with protection.5-7 CS-specific CD4+ T cells induced by RTS,S Sfpi1 produce a mixture of cytokines, such as interleukin (IL)-2, tumor necrosis factor (TNF)-, and interferon (IFN)-.7-11 In phase 2 clinical trials of adults and children, the RTS,S/AS01 formulation had an improved immunogenicity profile, in terms of humoral and cell-mediated immune (CMI) responses, and an equally favorable safety profile as compared with RTS,S/AS02.11-14 The RTS,S/AS01 formulation was consequently selected for phase 3 development. First results from the ongoing phase 3 trial in Africa show the vaccine candidate provides significant protection against clinical and severe malaria in young children and infants.15,16 The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended to establish in small Hyodeoxycholic acid studies the effect of vaccine adjuvants on immune responses to the antigens with which they are combined.17 The present study was therefore designed to evaluate the humoral and CMI responses elicited by RTS, S/AS01 and RTS,S/AS02 as compared with non-adjuvanted RTS,S antigen. The study also evaluated antibody avidity against the CS repeat antigen. This trial was conducted in healthy, malaria-na?ve adults in order to control for factors associated with immune responses following malaria exposure. As subjects with pre-existing anti-HBs immunity may have improved immune responses against both HBs and CS when compared with HBs-na?ve subjects,14 for uniformity, only adults seroprotected for HBs at baseline were enrolled in the trial. Results Study population Hyodeoxycholic acid A total of 56 malaria-na?ve volunteers were screened of which 36 were randomized (1:1:1) to the vaccination groups (Fig.?1); all participants completed the study. Two Hyodeoxycholic acid were excluded from the according-to-protocol (ATP) cohort for immunogenicity because of incomplete vaccination. The demographic profile of participants was balanced across groups (Table?1). All participants were white (Caucasian/European heritage). Open in a separate window Physique?1. CONSORT diagram of study flow in phase II randomized, double-blind study of humoral and cell-mediated immune responses against 3 doses of RTS,S malaria vaccine formulated with AS01 (RTS,S/AS01) or AS02 (RTS,S/AS02) compared with 3 doses of RTS,S reconstituted with saline (RTS,S/saline). Table?1. Demographic characteristics (ATP cohort for immunogenicity) 0.0001, RTS,S/AS01 vs. RTS,S/saline; = 0.0011, RTS,S/AS02 vs. RTS,S/saline) (Table?3). Anti-CS GMTs were 13-fold and 6-fold higher for recipients of RTS,S/AS01 and RTS,S/AS02, respectively, than for recipients of RTS,S/saline. In the adjuvanted RTS,S groups, GMTs increased with subsequent doses (Table?2) and significantly higher responses (= 0.0135) were observed with RTS,S/AS01 than with RTS,S/AS02 (Table?3). Table?3. Anti-CS antibody geometric mean titer (GMT) ratios (first group over.