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Abstract: 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 10μg RTS,S dose (10μg RTS,S in 0.1mL AS02A), 25μg dose (25μg RTS,S in 0.25mL AS02A) and finally a 50μg dose (50μg RTS,S in 0.5mL 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 48h. 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 25μg dose and 50μg dose anti-CSP antibody response were similar at both dose levels. However, the immunogenicity of the 10μg dose anti-CSP response was significantly lower than that of either the 50μg or 25μg dose. The 25μg dose was selected for future studies of RTS,S/AS02A in paediatric populations. [Copyright &y& Elsevier]

New-borns raise limited antibody responses to most T cell-dependent antigens but little is known about neonatal T lymphocyte responses to vaccines. In this study, we compared the immune response induced by the hepatitis B vaccine in new-borns and naı¨ve adults. Infants produced markedly higher serum anti-hepatitis B surface (HBs) antibody titres than adults. This was not associated with greater HBs Ag-specific Th2 cytokine responses but with lower primary IFN-γ responses. At 1 year, the infant memory response to HBs Ag was characterised by higher Th2 responses than those of adults. We conclude that neonatal antibody and T cell responses to hepatitis B vaccine differ from those induced in adults. [Copyright &y& Elsevier]