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Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial.

ABSTRACT: 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.

SUBMITTER: Laurens MB

PROVIDER: S-EPMC3832522 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial.

Laurens Matthew B MB Thera Mahamadou A MA Coulibaly Drissa D Ouattara Amed A Kone Abdoulaye K AK Guindo Ando B AB Traore Karim K Traore Idrissa I Kouriba Bourema B Diallo Dapa A DA Diarra Issa I Daou Modibo M Dolo Amagana A Tolo Youssouf Y Sissoko Mahamadou S MS Niangaly Amadou A Sissoko Mady M Takala-Harrison Shannon S Lyke Kirsten E KE Wu Yukun Y Blackwelder William C WC Godeaux Olivier O Vekemans Johan J Dubois Marie-Claude MC Ballou W Ripley WR Cohen Joe J Dube Tina T Soisson Lorraine L Diggs Carter L CL House Brent B Bennett Jason W JW Lanar David E DE Dutta Sheetij S Heppner D Gray DG Plowe Christopher V CV Doumbo Ogobara K OK

PloS one 20131118 11

<h4>Background</h4>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.<h4>Methods< ...[more]

PMID: 24260195

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Project description:ObjectivesTo assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients.MethodsSpatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets.ResultsPDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR.Discussion and conclusionThe stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

Project description:BackgroundOsgood-Schlatter disease (OSD), an apophyseal injury of the tibial tuberosity, affects up to 1 in 10 adolescents. This condition has previously been assumed to be innocuous and to self-resolve with limited intervention.PurposeTo investigate the 24-month prognosis of OSD and examine if ultrasound (US) classification is associated with outcomes.Study designCase series; Level of evidence, 4.MethodsThis study included a preregistered prospective cohort of 51 adolescents (aged 10-14 years) diagnosed with OSD who were evaluated for 24 months. The primary outcome at 24-month follow-up was whether participants continued to experience OSD-related knee pain. Baseline US scans were collected and characterized by OSD type (De Flaviis classification) as well as maturation of the tibial tuberosity. Secondary outcomes included sports participation, Knee injury and Osteoarthritis Outcome Score (KOOS) Sport/Recreation subscale, and health-related quality of life (European Quality of Life-5 Dimensions-Youth [EQ-5D-Y]). All participants were invited for re-examination by US at follow-up.ResultsA total of 51 patients preregistered for the study, with 90% (n = 46) available at follow-up. Of these 46 participants, 37% (n = 17) still reported knee pain due to OSD. In this subgroup, the median duration since symptom onset was 42 months (interquartile range, 38-51 months). More than 1 in 5 participants reported stopping sport due to knee pain, and those who continued to experience knee pain reported significantly worse KOOS Sport/Recreation scores at follow-up compared with patients with no knee pain (mean 74 [95% CI, 63-84] vs 91 [95% CI, 85-97]). Participants with continued OSD-related pain also had lower health-related quality of life (mean difference in EQ-5D-Y, 0.11 [95% CI, 0.06-0.13]). Higher De Flaviis classification at baseline was significantly associated with an increased risk of knee pain at 2 years. Diagnostic US at follow-up demonstrated primarily tendon changes (thickening, positive Doppler signal), as well as an ununited ossicle in 32% of participants who underwent US scanning at follow-up.ConclusionOver one-third of the study participants had knee pain at 2-year follow-up, which was associated with lower sports related function and health related quality of life. This questions the assumption that all patients with OSD experience quick recovery. Participants without any changes on imaging at baseline were less likely to report pain at follow-up.

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Dataset Information

Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial.

Publications

Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial.

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