Safety and reactogenicity of an MSP-1 malaria vaccine candidate: A randomized phase Ib dose-escalation trial in Kenyan children

Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2: 1 fashion to receive either the test product or a comparator. Setting: The study was conducted in a rural population in Kombewa Division, western Kenya. Participants: Subjects were 135 children, aged 12-47 mo. Interventions: Subjects received 10, 25, or 50 mu g of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 mu L, respectively, of AS02A, or they received a comparator (Imovax(R) rabies vaccine). Outcome Measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 mu g of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 mu g of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F-3,F-1047 = 10.78, or F-3,F-995 = 11.22, p < 0.001); however, the comparison of 25 mu g and 50 mu g recipients indicated no significant difference (F-1,F-1047 = 0.05; p = 0.82). Conclusions: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 mu g doses was superior to that of the 10 mu g dose.