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

Mark E Polhemus, Shon A Remich, Bernhards R Ogutu, John N Waitumbi, Lucas Otieno, Stella Apollo, James F Cummings, Kent E Kester, Christian F Ockenhouse, Ann Stewart, Opokua Ofori-Anyinam, Isabelle Ramboer, Conor P Cahill, Marc Lievens, Marie-Claude Dubois, Marie-Ange Demoitie, Amanda Leach, Joe Cohen, W Ripley Ballou, D Gray Heppner Jr, Mark E Polhemus, Shon A Remich, Bernhards R Ogutu, John N Waitumbi, Lucas Otieno, Stella Apollo, James F Cummings, Kent E Kester, Christian F Ockenhouse, Ann Stewart, Opokua Ofori-Anyinam, Isabelle Ramboer, Conor P Cahill, Marc Lievens, Marie-Claude Dubois, Marie-Ange Demoitie, Amanda Leach, Joe Cohen, W Ripley Ballou, D Gray Heppner Jr

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.

Conflict of interest statement

Competing Interests: WRB, JC, AL, OO, ML, MCD,MAD, PM, IR and CC are currently employed by GSK Biologicals or were employed at the time the study was conducted. WRB, JC, AL, OO, and MCD hold shares in GlaxoSmithKline Biologicals. JC, WRB, VAS and DGH are all inventors on patents relating to malaria vaccines.

Figures

Figure 1. CONSORT diagram for study participants.
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.
Figure 2. Study design overview.
ADI = active detection of infection. CS = circumsporozoite protein.
Figure 3. Anti-CS GMTs over time (ATP…
Figure 3. Anti-CS GMTs over time (ATP cohort for immunogenicity).
Note: bars represent 95% confidence intervals.
Figure 4. Vaccine Efficacy: reverse cumulative curve…
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…
Figure 5. Anti-CS GMTs during efficacy surveillance by infection status (ATP cohort for efficacy).

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Source: PubMed

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