Table 1.

Lessons learned in terms of safety, immunogenicity, efficacy and trial methodology from malaria vaccine research over the last 5-10 years

Safety	Reactogenicity is higher with water-in-oil emulsions (e.g. ISA 720) when compared to marketed adjuvants (alhydrogel) or a marketed virosomal platform.
	Safety and reactogenicity in semi-immune populations living in endemic areas has not been higher than in naïve populations, and is often lower.
	Safety and reactogenicity in young children has not been worse than in adult populations
Immunogenicity	DNA alone is poorly immunogenic
	Oil in water emulsions (AS01, AS02) and water in oil emulsions (ISA 720, ISA51) are more immunogenic than alhydrogel for recombinant monomeric protein
	In general, there is little induction of CD8 cells in humans (with the exception of certain adenovirus containing regimens)
	In general, there has been little clinically significant interference between the malarial antigen and EPI vaccine antigens
Efficacy	Only RTS,S-based vaccines have repeatedly shown efficacy to reduce morbidity in endemic areas
	Highly polymorphic blood-stage antigens have tended to lead to allele-specific efficacy, but poor efficacy against the population of circulating strains
	Multiple episodes of malaria takes priority over time to first episode for public health assessment in clinical malaria vaccine trials.
Methodology	Demonstration of effect in in vitro studies (growth-inhibition assay in particular) or animal studies have not been shown to correlate well with efficacy results in the field
	Human challenge studies (Phase IIa trials) have been validated for the screening of pre-erythrocytic vaccines by the RTS,S results
	It is agreed that every Phase IIb/III vaccine trial design includes a commercialized vaccine that will benefit the control group as comparator and that any trial subject receives at least the standard package of preventive measures (LLIN and others) implemented in the country.
	Methodological and ethical issues would arise in testing of new malaria vaccines in the field if a licensed malaria vaccine had become a standard preventive measure in a given setting.
	Methodological and feasibility issues are arising to test new vaccines in the field because malaria morbidity is considerably decreasing in areas where trial sites are in place.
	There is as yet no formal trial design to assess the efficacy of sexual stage and mosquito antigen vaccines prior to large scale cluster randomized trials; specific baseline epidemiological studies are required for sample size calculations and trial design for possible Phase IIb trials in this area