Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area

Abstract

Background: This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine.

Methodology: A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1ratio1ratio1) to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (Rabipur; Chiron Behring GmbH) at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3) solicited or unsolicited general (i.e. systemic) adverse events (AEs) during 7 days follow up after each vaccination.

Principal findings: Both candidate vaccines had a good safety profile and were well tolerated. One grade 3 systemic AE occurred within 7 days of vaccination (RTS,S/AS01B group). No unsolicited AEs or SAEs were related to vaccine. A marked increase in anti-CS antibody GMTs was observed post Dose 2 of both RTS,S/AS01B (31.6 EU/mL [95% CI: 23.9 to 41.6]) and RTS,S/AS02A (16.7 EU/mL [95% CI: 12.9 to 21.7]). A further increase was observed post Dose 3 in both the RTS,S/AS01B (41.4 EU/mL [95% CI: 31.7 to 54.2]) and RTS,S/AS02A (21.4 EU/mL [95% CI: 16.0 to 28.7]) groups. Anti-CS antibody GMTs were significantly greater with RTS,S/AS01B compared to RTS,S/AS02A at all time points post Dose 2 and Dose 3. Both candidate vaccines produced strong anti-HBs responses. Vaccine efficacy in the RTS,S/AS01B group was 29.5% (95% CI: -15.4 to 56.9, p = 0.164) and in the RTS,S/AS02A group 31.7% (95% CI: -11.6 to 58.2, p = 0.128).

Conclusions: Both candidate malaria vaccines were well tolerated over a 12 month surveillance period. A more favorable immunogenicity profile was observed with RTS,S/AS01B than with RTS,S/AS02A.

Trial registration: Clinicaltrials.gov NCT00197054.

Figure 1. CONSORT diagram for study participants.

176 failed eligibility criteria: 13 outside age range [18–35]; 9 not available for the whole study duration (12 months); 44 not free of obvious health problem (med history/clin exam); 14 female of childbearing potential not using adequate contraceptives; 8 confirmed or suspected HIV; 10 acute disease at time of enrolment; 27 acute or chronic clinically significant pulmonary, cardiovascular hepatic or renal functional abnormality; 6 ALT outside range; 15 hemoglobin outside range; 9 history of chronic alcohol/drug use; 21 other (including pregnant, administration of IG/blood products, sickle cell disease, HBsAg positive, other safety labs outside range, history of seizures, or allergic reactions, planned administration of non-study vaccine). Note: Underlying medical conditions were not detected at screening. ADI: active detection of infection. * These subjects did not complete ADI assessments, but were followed up for safety assessments and appear in the total of completed single-blind phase.

Figure 2. Study design overview.

ADI = active detection of infection. CS = circumsporozoite protein.

Figure 3. Anti-CS GMTs over time (ATP cohort for immunogenicity).

Note: bars represent 95% confidence intervals.

Figure 4. Vaccine Efficacy: reverse cumulative curve showing the time to infection with malaria by vaccine group (ATP cohort for efficacy).

Gr 1 = RTS,S/AS01B; Gr 2 = RTS,S/AS02A; Gr 3 = Rabies; Day 0 = 14 days post Dose 3; ADI = Active Detection of Infection.

Figure 5. Anti-CS GMTs during efficacy surveillance by infection status (ATP cohort for efficacy).