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Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

ABSTRACT: The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02(A) in children exposed to seasonal falciparum malaria.A 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/AS02(A) 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 AS02(A). 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 microg FMP2.1 in 0.1 mL AS02(A), or 25 microg FMP2.1 in 0.25 mL AS02(A), or 50 microg FMP2.1 50 microg in 0.5 mL AS02(A), 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.The FMP2.1/AS02(A) 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.ClinicalTrials.gov NCT00358332 [NCT00358332].

SUBMITTER: Thera MA

PROVIDER: S-EPMC2816207 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

Thera Mahamadou A MA Doumbo Ogobara K OK Coulibaly Drissa D Laurens Matthew B MB Kone Abdoulaye K AK Guindo Ando B AB Traore Karim K Sissoko Mady M Diallo Dapa A DA Diarra Issa I Kouriba Bourema B Daou Modibo M Dolo Amagana A Baby Mounirou M Sissoko Mahamadou S MS Sagara Issaka I Niangaly Amadou A Traore Idrissa I Olotu Ally A Godeaux Olivier O Leach Amanda A Dubois Marie-Claude MC Ballou W Ripley WR Cohen Joe J Thompson Darby D Dube Tina T Soisson Lorraine L Diggs Carter L CL Takala Shannon L SL Lyke Kirsten E KE House Brent B Lanar David E DE Dutta Sheetij S Heppner D Gray DG Plowe Christopher V CV

PloS one 20100204 2

<h4>Background</h4>The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02(A) in children exposed to seasonal falciparum malaria.<h4>Methodology/principal findings</h4>A 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/AS02(A) is a recombinant protein (FMP2.1) based on apical ...[more]

PMID: 20140214

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Project description:ObjectivesThe objectives were to evaluate the safety, reactogenicity, and allele-specific immunogenicity of the blood-stage malaria vaccine FMP1/AS02A in adults exposed to seasonal malaria and the impact of natural infection on vaccine-induced antibody levels.DesignWe conducted a randomized, double-blind, controlled phase I clinical trial.SettingBandiagara, Mali, West Africa, is a rural town with intense seasonal transmission of Plasmodium falciparum malaria.ParticipantsForty healthy, malaria-experienced Malian adults aged 18-55 y were enrolled.InterventionsThe FMP1/AS02A malaria vaccine is a 42-kDa recombinant protein based on the carboxy-terminal end of merozoite surface protein-1 (MSP-1(42)) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The control vaccine was a killed rabies virus vaccine (Imovax). Participants were randomized to receive either FMP1/AS02A or rabies vaccine at 0, 1, and 2 mo and were followed for 1 y.Outcome measuresSolicited and unsolicited adverse events and allele-specific antibody responses to recombinant MSP-1(42) and its subunits derived from P. falciparum strains homologous and heterologous to the 3D7 vaccine strain were measured.ResultsTransient local pain and swelling were more common in the malaria vaccine group than in the control group (11/20 versus 3/20 and 10/20 versus 6/20, respectively). MSP-1(42) antibody levels rose during the malaria transmission season in the control group, but were significantly higher in malaria vaccine recipients after the second immunization and remained higher after the third immunization relative both to baseline and to the control group. Immunization with the malaria vaccine was followed by significant increases in antibodies recognizing three diverse MSP-1(42) alleles and their subunits.ConclusionsFMP1/AS02A was well tolerated and highly immunogenic in adults exposed to intense seasonal malaria transmission and elicited immune responses to genetically diverse parasite clones. Anti-MSP-1(42) antibody levels followed a seasonal pattern that was significantly augmented and prolonged by the malaria vaccine.

Project description:The FMP2.1/AS02A candidate malaria vaccine was tested in a Phase 2 study in Mali. Based on results from the first eight months of follow-up, the vaccine appeared well-tolerated and immunogenic. It had no significant efficacy based on the primary endpoint, clinical malaria, but marginal efficacy against clinical malaria in secondary analyses, and high allele-specific efficacy. Extended follow-up was conducted to evaluate extended safety, immunogenicity and efficacy.A randomized, double-blinded trial of safety, immunogenicity and efficacy of the candidate Plasmodium falciparum apical membrane antigen 1 (AMA1) vaccine FMP2.1/AS02A was conducted in Bandiagara, Mali. Children aged 1-6 years were randomized in a 1?1 ratio to receive FMP2.1/AS02A or control rabies vaccine on days 0, 30 and 60. Using active and passive surveillance, clinical malaria and adverse events as well as antibodies against P. falciparum AMA1 were monitored for 24 months after the first vaccination, spanning two malaria seasons.400 children were enrolled. Serious adverse events occurred in nine participants in the FMP2.1/AS02A group and three in the control group; none was considered related to study vaccination. After two years, anti-AMA1 immune responses remained significantly higher in the FMP2.1/AS02A group than in the control group. For the entire 24-month follow-up period, vaccine efficacy was 7.6% (p?=?0.51) against first clinical malaria episodes and 9.9% (p?=?0.19) against all malaria episodes. For the final 16-month follow-up period, vaccine efficacy was 0.9% (p?=?0.98) against all malaria episodes. Allele-specific efficacy seen in the first malaria season did not extend into the second season of follow-up.Allele-specific vaccine efficacy was not sustained in the second malaria season, despite continued high levels of anti-AMA1 antibodies. This study presents an opportunity to evaluate correlates of partial protection against clinical malaria that waned during the second malaria season.Clinicaltrials.gov NCT00460525 NCT00460525.

Dataset Information

Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

Publications

Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

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