Safety of experimental malaria vaccine RTS,S/AS01
The Committee reviewed clinical safety data from phase I and phase II trials of the candidate malaria vaccine RTS,S/AS01 (GlaxoSmithKline Biologicals, Rixensart, Belgium). The designation “RT” refers to approximately 190 amino acids from the carboxy terminus of the Plasmodium falciparum circumsporozoite protein, and “S” refers to the hepatitis-B surface antigen. RTS,S virus-like particles form when the RTS malaria–hepatitis B fusion protein is co-expressed with S antigen alone in yeast cells (Saccharomyces cerevisiae). The adjuvant AS01 consists of liposomes plus MPL plus QS21. An earlier version of the RTS,S vaccine was adjuvanted with AS02 (an oil–water emulsion plus MPL plus QS21). The paediatric dose of RTS,S for the phase III trial is 25 µg using a 3-dose schedule delivered intramuscularly at the ages of 0 months, 1 month and 2 months. The current RTS,S/AS01 vaccine has completed phase II trials in children aged 5–17 months and also in trials using the Expanded Programme on Immunization (EPI) for children aged 6–14 weeks; multicentre phase III trials in infants and young children started in May 2009 in sub-Saharan Africa.
Phase II studies have shown consistent efficacy for the vaccine, and the Committee evaluated its safety in anticipation of licensure for the prevention of P. falciparum malaria in young children in regions where it is endemic. Safety parameters included reactogenicity observed during 7 days following vaccination and unsolicited symptoms recorded during 30 days after inoculation with doses 1, 2 and 3 in delivery schedules administered at 0 months, 1 month and 2 months and for schedules administered at 0 months, 1 month and 7 months. Comparator vaccines given for control were cell-culture rabies vaccine and pentavalent diphtheria–tetanus–whole-cell pertussis plus hepatitis B vaccine plus Haemophilus influenzae type b vaccine. A total of 1147 study participants (including 340 in the age range recommended by EPI) who received 2 or 3 doses of RTS,S/AS01 were evaluated. In general, injection-induced local inflammatory signs and systemic signs and symptoms occurring during the 7 days and 30 days following vaccination were similar between study and control vaccines. Of those receiving study vaccines, 2 children had convulsions, which were assessed as febrile. One sign – skin rash – appeared in excess (statistically significant) during the 7-day interval in study children, and further detailed description of the nature of the rash is necessary to assess its clinical significance. This observation is particularly important in view of the earlier observations of skin lesions (including urticaria and immunoglobulin E response characteristic of immediate-type hypersensitivity, which may lead to anaphylaxis) and delayed-type hypersensitivity detected by skin testing in a few participants who received other experimental malaria vaccines.3 These other malaria vaccines used different antigens (for example, linear circumsporozoite antigen in doses of 200–2000 µg) and different adjuvants (that is, not AS01 or AS02).
The Committee concluded that the RTS,S/AS01 vaccine has an acceptable safety profile, although data are available only on a relatively small number of children. During the course of presentations, the safety profile of the AS01 adjuvant was reviewed; this adjuvant is delivered with a number of experimental vaccines, mostly in adult volunteers during phase I studies. This review gave additional assurance of the safety of the vaccine under consideration.
3 Edelman R et al. Immediate-type hypersensitivity and other clinical reactions in volunteers immunized with a synthetic multi-antigen peptide vaccine (PfCS-MAP- 1NYU) to Plasmodium falciparum sporozoites. Vaccine, 2002, 21:269–280.