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Abstract
BackgroundThe objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02A in children exposed to seasonal falciparum malaria.Methodology/Principal FindingsA Phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1) based on apical membrane antigen 1 (AMA1) from the 3D7 clone of P. falciparum, formulated in the Adjuvant System AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert®). One hundred healthy Malian children aged 1–6 years were recruited into 3 cohorts and randomized to receive either 10 µg FMP2.1 in 0.1 mL AS02A, or 25 µg FMP2.1 in 0.25 mL AS02A, or 50 µg FMP2.1 50 µg in 0.5 mL AS02A, or rabies vaccine. Three doses of vaccine were given at 0, 1 and 2 months, and children were followed for 1 year. Solicited symptoms were assessed for 7 days and unsolicited symptoms for 30 days after each vaccination. Serious adverse events were assessed throughout the study. Transient local pain and swelling were common and more frequent in all malaria vaccine dosage groups than in the comparator group, but were acceptable to parents of participants. Levels of anti-AMA1 antibodies measured by ELISA increased significantly (at least 100-fold compared to baseline) in all 3 malaria vaccine groups, and remained high during the year of follow up.Conclusion/SignificanceThe FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and induced high and sustained antibody levels in malaria-exposed children. This malaria vaccine is being evaluated in a Phase 2 efficacy trial in children at this site.Trial RegistrationClinicalTrials.gov NCT00358332 [NCT00358332]
Highlights
A safe and effective malaria vaccine would be a major addition to current malaria control tools and could reinforce hope for malaria eradication
The Plasmodium falciparum apical membrane antigen 1 (AMA1) is considered to be a promising antigen for blood stage vaccine development based on evidence that it plays a critical role during merozoite invasion of erythrocytes and that this function can be abrogated with inhibitory antibodies [1,2,3,4,5], and on sero-epidemiological studies showing association of anti-AMA1 antibodies with naturally acquired protection against malaria [6,7]
A vaccine that boosts levels of anti-AMA1 antibodies might reduce the risk that malaria infection will cause clinical disease, making AMA1 an attractive candidate for inclusion in a multi-stage, multi-antigen malaria vaccine [8]
Summary
A safe and effective malaria vaccine would be a major addition to current malaria control tools and could reinforce hope for malaria eradication. AMA1 is highly polymorphic–more than 300 unique AMA1 haplotypes have been identified worldwide and more than 200 at a single site in Mali [9] This extreme genetic diversity presumably results from balancing selection driven by host immunity. In vitro [10] and animal studies [4,11,12] have suggested the possibility of strain-specific immunity, raising concern that AMA1 vaccines based on one or a few alleles might not provide broad protection [13] Both in vitro [14] and molecular epidemiological [9,15] studies have suggested possible diversity-covering approaches to developing effective AMA1 vaccines. The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/ AS02A in children exposed to seasonal falciparum malaria
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