Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children

RTS,S/AS02A is a pre-erythrocytic malaria vaccine candidate in which a portion of the circumsporozoite surface protein (CSP) of Plasmodium falciparum is genetically linked to hepatitis B surface antigen (HBsAg) coexpressed in yeast with unfused HBsAg. The resulting particulate antigen is formulated with the adjuvant system AS02A. We have initiated the paediatric clinical development of this vaccine by conducting two sequential Phase I studies in children: a study in older children (6-11 years), followed by a second study in younger children (1-5 years). In each study, a double-blind, randomised controlled, staggered, dose-escalation design was used to evaluate 10 μg RTS,S dose (10 μg RTS,S in 0.1 mL AS02A), 25 μg dose (25 μg RTS,S in 0.25 mL AS02A) and finally a 50 μg dose (50 μg RTS,S in 0.5 mL AS02A) of the RTS,S/AS02A candidate malaria vaccine administered according to a 0-, 1- and 3-month vaccination schedule. Safety and reactogenicity were evaluated before moving to a higher dose level. The RTS,S/AS02A vaccine was safe at all dose levels, in both age groups. No serious adverse events related to vaccination were reported. The frequency of local Grade 3 symptoms was low but tended to increase with increasing dose level. Grade 3 general adverse events in the RTS,S/AS02A groups were infrequent and of short duration. The majority of local and general Grade 3 symptoms resolved or decreased in intensity within 48 h. The pattern and intensity of reactogenicity seen in these studies are similar to those of previous studies with RTS,S/AS02A. All doses were highly immunogenic for anti-CSP and anti-HBsAg antibodies. The pooled anti-CSP antibody data from the two studies showed that the 25 μg dose and 50 μg dose anti-CSP antibody response were similar at both dose levels. However, the immunogenicity of the 10 μg dose anti-CSP response was significantly lower than that of either the 50 μg or 25 μg dose. The 25 μg dose was selected for future studies of RTS,S/AS02A in paediatric populations. © 2005 Elsevier Ltd. All rights reserved.