The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Philip Bejon - One of the best experts on this subject based on the ideXlab platform.
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a seven year study on the effect of the pre erythrocytic Malaria Vaccine candidate rts s as01 e on blood stage immunity in young kenyan children
Wellcome Open Research, 2019Co-Authors: Francis M Ndungu, Kevin Marsh, Juliana Wambua, Patricia Njuguna, Jedidah Mwacharo, Chris Drakeley, Philip BejonAbstract:Background: RTS,S/AS01 E, the most advanced Malaria Vaccine confers partial immunity. The Vaccine-induced pre-erythrocytic immunity reduces exposure to blood-stage parasites, delaying acquisition of antibodies to blood-stage antigens. However, the duration of this effect is unknown. Methods: We measured, by enzyme-linked immunosorbent assay, IgG-antibodies to 4 Plasmodium falciparum blood-stage antigens (AMA1, MSP1 42, EBA175, and MSP3) on 314 children randomized to receive RTS,S/AS01 E or Rabies Vaccine at 5 - 17 months of age in a phase 2b trial in Kenya, and thereafter participated in a 7-year study of the duration of Vaccine immunity. Results: Antibody levels to MSP1 42, AMA1 and EBA175 were slightly lower among the RTS,S/AS01 E recipients, relative to the Rabies-control Vaccinees, during the first 48 months of surveillance. Irrespective of Vaccine arm, antibody levels to merozoite antigens were positively associated with the risk for Malaria. However, this was only apparent at high levels for EBA175 and AMA1 and was not evident after adjusting for heterogeneity in Malaria-exposure. Among children with asymptomatic parasitaemia, antibody levels were associated with reduced clinical Malaria. Conclusions: The reduction in levels of antibodies to blood-stage antigens induced by vaccination with RTS,S/AS01 E can last for several years. In absence of asymptomatic infection, anti-merozoite antibody levels were unreliable correlates of clinical immunity.
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a combined analysis of immunogenicity antibody kinetics and Vaccine efficacy from phase 2 trials of the rts s Malaria Vaccine
BMC Medicine, 2014Co-Authors: Michael T White, Ally Olotu, Philip Bejon, Jamie T Griffin, Kalifa Bojang, John Lusingu, Nahya Salim, Salim Abdulla, Nekoye OtsyulaAbstract:The RTS,S Malaria Vaccine is currently undergoing phase 3 trials. High Vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical Malaria.
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peripheral blood monocyte to lymphocyte ratio at study enrollment predicts efficacy of the rts s Malaria Vaccine analysis of pooled phase ii clinical trial data
BMC Medicine, 2013Co-Authors: George M Warimwe, Selidji T Agnandji, Adrian V S Hill, Ally Olotu, Philip Bejon, Helen A Fletcher, Kevin MarshAbstract:Background RTS,S is the most advanced candidate Malaria Vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical Malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa.
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effect of the pre erythrocytic candidate Malaria Vaccine rts s as01e on blood stage immunity in young children
The Journal of Infectious Diseases, 2011Co-Authors: Ally Olotu, Philip Bejon, John Lusingu, Johan Vekemans, Jackie Cook, Elke S Bergmannleitner, Jedidah Mwacharo, Patricia NjugunaAbstract:Background. RTS,S/AS01E is the lead candidate Malaria Vaccine and confers pre-erythrocytic immunity. Vaccination may therefore impact acquired immunity to blood-stage Malaria parasites after natural infection. Methods. We measured, by enzyme-linked immunosorbent assay, antibodies to 4 Plasmodium falciparum merozoite antigens (AMA-1, MSP-142, EBA-175, and MSP-3) and by growth inhibitory activity (GIA) using 2 parasite clones (FV0 and 3D7) at 4 times on 860 children who were randomized to receive with RTS,S/AS01E or a control Vaccine. Results. Antibody concentrations to AMA-1, EBA-175, and MSP-142 decreased with age during the first year of life, then increased to 32 months of age. Anti‐MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months. Vaccination with RTS,S/AS01Eresulted in modest reductions in AMA-1, EBA175, MSP-142, and MSP-3 antibody concentrations and no significant change in GIA. Increasing anti-merozoite antibody concentrations and GIA were prospectively associated with increased risk of clinical Malaria. Conclusions. Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces antimerozoite antigen antibody concentrations. However, in this study, these antibodies were not correlates of clinical immunity to Malaria. Instead, heterogeneous exposure led to confounded, positive associations between increasing antibody concentration and increasing risk of clinical Malaria.
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quantitative real time polymerase chain reaction for Malaria diagnosis and its use in Malaria Vaccine clinical trials
American Journal of Tropical Medicine and Hygiene, 2005Co-Authors: Laura Andrews, Philip Bejon, Rikke F Andersen, Daniel P Webster, Susanna Dunachie, Michael R Walther, Angela Huntcooke, Gillian Bergson, Frances Sanderson, Adrian V S HillAbstract:The demand for an effective Malaria Vaccine is high, with millions of people being affected by the disease every year. A large variety of potential Vaccines are under investigation worldwide, and when tested in clinical trials, researchers need to extract as much data as possible from every vaccinated and control volunteer. The use of quantitative real-time polymerase chain reaction (PCR), carried out in real-time during the clinical trials of Vaccines designed to act against the liver stage of the parasite's life cycle, provides more information than the gold standard method of microscopy alone and increases both safety and accuracy. PCR can detect Malaria parasites in the blood up to 5 days before experienced microscopists see parasites on blood films, with a sensitivity of 20 parasites/mL blood. This PCR method has so far been used to follow 137 Vaccinee and control volunteers in Phase IIa trials in Oxford and on 220 volunteer samples during a Phase IIb field trial in The Gambia.
Ally Olotu - One of the best experts on this subject based on the ideXlab platform.
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the equatoguinean Malaria Vaccine initiative from the launching of a clinical research platform to Malaria elimination planning in central west africa
American Journal of Tropical Medicine and Hygiene, 2020Co-Authors: Peter F Billingsley, Carl Maas, Ally Olotu, Christopher Schwabe, Guillermo A Garcia, Matilde Riloha Rivas, Dianna Hergott, Claudia DaubenbergerAbstract:Fifteen years of investment in Malaria control on Bioko Island, Equatorial Guinea (EG), dramatically reduced Malaria-associated morbidity and mortality, but the impact has plateaued. To progress toward elimination, EG is investing in the development of a Malaria Vaccine. We assessed the unique public-private partnership that has had such a significant impact on Malaria on Bioko Island and now added a major effort on Malaria Vaccine development. As part of a $79M commitment, the EG government (75%) and three American energy companies (25%) have invested since 2012 greater than $55M in the Equatoguinean Malaria Vaccine Initiative (EGMVI) to support clinical development of Sanaria® PfSPZ Vaccines. In turn, the Vaccine development program is building human capital and physical capacity. The EGMVI established regulatory and ethical oversight to ensure compliance with the International Conference on Harmonization and Good Clinical Practices for the first importation of investigational product, ethical approval, and conduct of a clinical trial in Equatoguinean history. The Equatoguinean Malaria Vaccine Initiative has completed three Vaccine trials in EG, two Vaccine trials in Tanzania, and a Malaria incidence study, and initiated preparations for a 2,100-volunter clinical trial. Personnel are training for advanced degrees abroad and have been trained in Good Clinical Practices and protocol-specific methods. A new facility has established the foundation for a national research institute. Biomedical research and development within this visionary, ambitious public-private partnership is fostering major improvements in EG. The EGMVI plans to use a Plasmodium falciparum sporozoite Vaccine alongside standard Malaria control interventions to eliminate Pf Malaria from Bioko, becoming a potential model for elimination campaigns elsewhere.
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seven year efficacy of rts s as01 Malaria Vaccine among young african children
The New England Journal of Medicine, 2016Co-Authors: Ally Olotu, Gregory Fegan, Juliana Wambua, George Nyangweso, Amanda J Leach, Marc Lievens, David C Kaslow, Patricia NjugunaAbstract:BackgroundThe candidate Malaria Vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules. MethodsWe conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 Vaccine or a rabies (control) Vaccine. The end point was clinical Malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the Malaria exposure of each child was estimated with the use of information on the prevalence of Malaria among residents within a 1-km radius of the child’s home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group. ResultsOver 7 years of follow-up, we identified 1002 episodes of clinical Malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes a...
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a combined analysis of immunogenicity antibody kinetics and Vaccine efficacy from phase 2 trials of the rts s Malaria Vaccine
BMC Medicine, 2014Co-Authors: Michael T White, Ally Olotu, Philip Bejon, Jamie T Griffin, Kalifa Bojang, John Lusingu, Nahya Salim, Salim Abdulla, Nekoye OtsyulaAbstract:The RTS,S Malaria Vaccine is currently undergoing phase 3 trials. High Vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical Malaria.
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peripheral blood monocyte to lymphocyte ratio at study enrollment predicts efficacy of the rts s Malaria Vaccine analysis of pooled phase ii clinical trial data
BMC Medicine, 2013Co-Authors: George M Warimwe, Selidji T Agnandji, Adrian V S Hill, Ally Olotu, Philip Bejon, Helen A Fletcher, Kevin MarshAbstract:Background RTS,S is the most advanced candidate Malaria Vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical Malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa.
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effect of the pre erythrocytic candidate Malaria Vaccine rts s as01e on blood stage immunity in young children
The Journal of Infectious Diseases, 2011Co-Authors: Ally Olotu, Philip Bejon, John Lusingu, Johan Vekemans, Jackie Cook, Elke S Bergmannleitner, Jedidah Mwacharo, Patricia NjugunaAbstract:Background. RTS,S/AS01E is the lead candidate Malaria Vaccine and confers pre-erythrocytic immunity. Vaccination may therefore impact acquired immunity to blood-stage Malaria parasites after natural infection. Methods. We measured, by enzyme-linked immunosorbent assay, antibodies to 4 Plasmodium falciparum merozoite antigens (AMA-1, MSP-142, EBA-175, and MSP-3) and by growth inhibitory activity (GIA) using 2 parasite clones (FV0 and 3D7) at 4 times on 860 children who were randomized to receive with RTS,S/AS01E or a control Vaccine. Results. Antibody concentrations to AMA-1, EBA-175, and MSP-142 decreased with age during the first year of life, then increased to 32 months of age. Anti‐MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months. Vaccination with RTS,S/AS01Eresulted in modest reductions in AMA-1, EBA175, MSP-142, and MSP-3 antibody concentrations and no significant change in GIA. Increasing anti-merozoite antibody concentrations and GIA were prospectively associated with increased risk of clinical Malaria. Conclusions. Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces antimerozoite antigen antibody concentrations. However, in this study, these antibodies were not correlates of clinical immunity to Malaria. Instead, heterogeneous exposure led to confounded, positive associations between increasing antibody concentration and increasing risk of clinical Malaria.
Carole A. Long - One of the best experts on this subject based on the ideXlab platform.
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Immunoscreening of Plasmodium falciparum proteins expressed in a wheat germ cell-free system reveals a novel Malaria Vaccine candidate
Scientific Reports, 2017Co-Authors: Masayuki Morita, Kazutoyo Miura, Eizo Takashima, Daisuke Ito, Amporn Thongkukiatkul, Ababacar Diouf, Rick M. Fairhurst, Mahamadou Diakite, Carole A. Long, Motomi ToriiAbstract:The number of Malaria Vaccine candidates in preclinical and clinical development is limited. To identify novel blood-stage Malaria Vaccine candidates, we constructed a library of 1,827 P. falciparum proteins prepared using the wheat germ cell-free system (WGCFS). Also, a high-throughput AlphaScreen procedure was developed to measure antibody reactivity to the recombinant products. Purified IgGs from residents in Malaria endemic areas have shown functional activity against blood-stage parasites as judged by an in vitro parasite Growth Inhibition Assay (GIA). Therefore, we evaluated the GIA activity of 51 plasma samples prepared from Malian adults living in a Malaria endemic area against the WGCFS library. Using the AlphaScreen-based immunoreactivity measurements, antibody reactivity against 3 proteins was positively associated with GIA activity. Since anti-LSA3-C responses showed the strongest correlation with GIA activity, this protein was investigated further. Anti-LSA3-C-specific antibody purified from Malian adult plasmas showed GIA activity, and expression of LSA3 in blood-stage parasites was confirmed by western blotting. Taken together, we identified LSA3 as a novel blood-stage Vaccine candidate, and we propose that this system will be useful for future Vaccine candidate discovery.
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overcoming antigenic diversity by enhancing the immunogenicity of conserved epitopes on the Malaria Vaccine candidate apical membrane antigen 1
PLOS Pathogens, 2013Co-Authors: Sheetij Dutta, Damien R Drew, Carole A. Long, Meng Shi, Lisa S Dlugosz, Diouf Ababacar, Yazmin I Rovira, Kathleen J Moch, Michael Foley, James G BeesonAbstract:Malaria Vaccine candidate Apical Membrane Antigen-1 (AMA1) induces protection, but only against parasite strains that are closely related to the Vaccine. Overcoming the AMA1 diversity problem will require an understanding of the structural basis of cross-strain invasion inhibition. A Vaccine containing four diverse allelic proteins 3D7, FVO, HB3 and W2mef (AMA1 Quadvax or QV) elicited polyclonal rabbit antibodies that similarly inhibited the invasion of four Vaccine and 22 non-Vaccine strains of P. falciparum. Comparing polyclonal anti-QV with antibodies against a strain-specific, monovalent, 3D7 AMA1 Vaccine revealed that QV induced higher levels of broadly inhibitory antibodies which were associated with increased conserved face and domain-3 responses and reduced domain-2 response. Inhibitory monoclonal antibodies (mAb) raised against the QV reacted with a novel cross-reactive epitope at the rim of the hydrophobic trough on domain-1; this epitope mapped to the conserved face of AMA1 and it encompassed the 1e-loop. MAbs binding to the 1e-loop region (1B10, 4E8 and 4E11) were ∼10-fold more potent than previously characterized AMA1-inhibitory mAbs and a mode of action of these 1e-loop mAbs was the inhibition of AMA1 binding to its ligand RON2. Unlike the epitope of a previously characterized 3D7-specific mAb, 1F9, the 1e-loop inhibitory epitope was partially conserved across strains. Another novel mAb, 1E10, which bound to domain-3, was broadly inhibitory and it blocked the proteolytic processing of AMA1. By itself mAb 1E10 was weakly inhibitory but it synergized with a previously characterized, strain-transcending mAb, 4G2, which binds close to the hydrophobic trough on the conserved face and inhibits RON2 binding to AMA1. Novel inhibition susceptible regions and epitopes, identified here, can form the basis for improving the antigenic breadth and inhibitory response of AMA1 Vaccines. Vaccination with a few diverse antigenic proteins could provide universal coverage by redirecting the immune response towards conserved epitopes.
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evidence for erythrocyte binding antigen 175 as a component of a ligand blocking blood stage Malaria Vaccine
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Lubin Jiang, Carole A. Long, Deepak Gaur, Hong Zhou, Louis H. MillerAbstract:The ligands that pathogens use to invade their target cells have often proven to be good targets for Vaccine development. However, Plasmodium falciparum has redundant ligands that mediate invasion of erythrocytes. The first requirement for the development of a successful ligand-blocking Malaria Vaccine is the demonstration that antibodies induced to each ligand can block the erythrocyte invasion of parasites with polymorphic sequences. Because of P. falciparum’s redundancy in erythrocyte invasion, each ligand needs to be studied under artificial conditions in which parasite invasion is restricted in its use of alternative pathways. Here we investigate the role of erythrocyte-binding antigen 175 (EBA-175), a parasite ligand that binds to sialic acid on glycophorin A, in the invasion of erythrocytes by 10 P. falciparum clones under conditions in which invasion is partially limited to the EBA-175–glycophorin A pathway, using chymotrypsin-treated erythrocytes. We show that the ability to invade erythrocytes for both sialic acid–independent and sialic acid–dependent pathways requires the EBA-175–glycophorin A pathway for erythrocyte invasion. Importantly, antibodies against region II of EBA-175 from the 3D7 clone blocked invasion of chymotrypsin-treated erythrocytes by >50% by all parasite clones studied, including those with multiple different mutations described in the literature. The one exception was FCR3, which had a similar sequence to 3D7 but only 30% inhibition of invasion of chymotrypsin-treated erythrocytes, indicating alternative pathways for invasion of chymotrypsin-treated erythrocytes. Our findings suggest that antibodies to region II of EBA-175, as one component of a ligand-blocking Malaria Vaccine, are largely unaffected by polymorphism in EBA-175.
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enhancement of functional antibody responses to ama1 c1 alhydrogel a plasmodium falciparum Malaria Vaccine with cpg oligodeoxynucleotide
Vaccine, 2006Co-Authors: Gregory E D Mullen, Hong Zhou, Heather L Davis, Birgitte Giersing, Olubunmi Ajosepopoola, Cheryl Kothe, Joan Aebig, Gelu Dobrescu, Allan Saul, Carole A. LongAbstract:Apical membrane antigen 1 (AMA1) has been shown to be a promising Malaria Vaccine candidate. The multiallelic AMA1-C1 Vaccine currently in Phase 1 trials in the US and Mali contains an equal mixture of the ectodomain portion of recombinant AMA1 from the FVO and 3D7 clones of Plasmodium falciparum, formulated on Alhydrogel. It is hoped that inclusion of a human-optimized CpG oligodeoxynucleotide (ODN) (CPG 7909) with our existing AMA1-C1/Alhydrogel Vaccine will lead to a higher concentration of functional AMA1-C1 antibodies. Preclinical studies were performed in mice, rats and guinea pigs to assess the safety, immunogenicity and functionality of the immune response to AMA1-C1 with Alhydrogel + CPG 7909 compared to antigen with Alhydrogel alone. Day 42 mean anti-AMA1 ELISA titer values derived from individual animals were compared between Alhydrogel and Alhydrogel + CPG 7909 groups at each antigen dose for each species. Sera from Alhydrogel + CPG 7909 groups displayed significantly higher antibody titers (P < 0.025) than their comparable Alhydrogel alone group. Mouse IgG isotype analysis showed that AMA1-C1/Alhydrogel induced a predominately Th2 type response while AMA1-C1/Alhydrogel + CPG 7909 gave a mixed Th1/Th2 type response. When tested for functional activity by in vitro inhibition of parasite invasion, IgG isolated from serum pools of AMA1-C1/Alhydrogel + CPG 7909 animals was more effective against both FVO and 3D7 parasites than an equal concentration of IgG from animals receiving Vaccines adjuvanted with Alhydrogel alone. These promising preclinical results have recently led to the start of a Phase 1 trial in the US.
Selidji T Agnandji - One of the best experts on this subject based on the ideXlab platform.
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the effect of immunization schedule with the Malaria Vaccine candidate rts s as01e on protective efficacy and anti circumsporozoite protein antibody avidity in african infants
Malaria Journal, 2015Co-Authors: Anthony Ajua, Selidji T Agnandji, Bertrand Lell, Nahya Salim, Marcel Tanner, Maximilian Mpina, Kwaku Poku Asante, Seth Owusuagyei, Grace MwangokaAbstract:Background The Malaria Vaccine RTS,S induces antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and the concentration of Immunoglobulin G (IgG) against the repeat region of CSP following vaccination is associated with protection from P. falciparum Malaria. So far, only the quantity of anti-CSP IgG has been measured and used to predict vaccination success, although quality (measured as avidity) of the antigen-antibody interaction shall be important since only a few sporozoites circulate for a short time after an infectious mosquito bite, likely requiring fast and strong binding.
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peripheral blood monocyte to lymphocyte ratio at study enrollment predicts efficacy of the rts s Malaria Vaccine analysis of pooled phase ii clinical trial data
BMC Medicine, 2013Co-Authors: George M Warimwe, Selidji T Agnandji, Adrian V S Hill, Ally Olotu, Philip Bejon, Helen A Fletcher, Kevin MarshAbstract:Background RTS,S is the most advanced candidate Malaria Vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical Malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa.
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A phase 3 trial of RTS,S/AS01 Malaria Vaccine in African infants
New England Journal of Medicine, 2012Co-Authors: Selidji T Agnandji, José Francisco Fernandes, Barbara Gaelle Nfono Ondo Methogo, Beatrice Peggy Abossolo, Anita L Kabwende, Ayola Akim Adegnika, Bertrand Lell, Saadou Issifou, Benjamin Mordmuller, Peter G KremsnerAbstract:BACKGROUND The candidate Malaria Vaccine RTS,S/AS01 reduced episodes of both clinical and severe Malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS We administered RTS,S/AS01 or a comparator Vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) Vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical Malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all Malaria episodes, Vaccine efficacy against severe Malaria, safety, and immunogenicity were also assessed. RESULTS The incidence of the first or only episode of clinical Malaria in the intention-to-treat population during the 14 months after the first dose of Vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a Vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe Malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS The RTS,S/AS01 Vaccine coadministered with EPI Vaccines provided modest protection against both clinical and severe Malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).
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safety and efficacy of the rts s as01e candidate Malaria Vaccine given with expanded programme on immunisation Vaccines 19 month follow up of a randomised open label phase 2 trial
Lancet Infectious Diseases, 2011Co-Authors: Kwaku Poku Asante, Solange Solmeheim Soulanoudjingar, Selidji T Agnandji, Salim Abdulla, John Lyimo, Johan Vekemans, Ruth Owusu, Mwanajaa ShomariAbstract:Summary Background The RTS,S/AS01 E candidate Malaria Vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01 E when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. Methods We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01 E candidate Malaria Vaccine given with EPI Vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6–10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B Vaccines, Haemophilus influenzae type b Vaccine, and oral polio Vaccine at study months 0, 1, and 2, and measles Vaccine and yellow fever Vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01 E at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and Malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. Findings 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01 E 0, 1, 2 month group (34%, 95% CI 27–41), 47 in the 0, 1, 7 month group (28%, 21–35), and 49 (29%, 22–36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01 E groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26–70; p=0·0012) against first Malaria episodes and 59% (36–74; p=0·0001) against all Malaria episodes. For the entire study period, (total vaccinated cohort) Vaccine efficacy against all Malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33–73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16–45; p=0·0003). 1 year after dose three, Vaccine efficacy against first Malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6–77·1], p Interpretation Vaccine efficacy was consistent with the target put forward by the WHO-sponsored Malaria Vaccine technology roadmap for a first-generation Malaria Vaccine. The 0, 1, 2 month Vaccine schedule has been selected for phase 3 candidate Vaccine assessment. Funding Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.
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First results of phase 3 trial of RTS,S/AS01 Malaria Vaccine in African children
New England Journal of Medicine, 2011Co-Authors: Selidji T Agnandji, José Francisco Fernandes, Barbara Gaelle Nfono Ondo Methogo, Solange Solmeheim Soulanoudjingar, Yannick Doucka, Beatrice Peggy Abossolo, Bertrand Lell, Arnaud Flamen, Cornelia Conzelmann, Benjamin MordmullerAbstract:BACKGROUND: An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate Malaria Vaccine RTS,S/AS01 is being conducted in seven African countries.\n\nMETHODS: From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-Malaria comparator Vaccine. The primary end point of the analysis was Vaccine efficacy against clinical Malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of Vaccine according to protocol. After 250 children had an episode of severe Malaria, we evaluated Vaccine efficacy against severe Malaria in both age categories.\n\nRESULTS: In the 14 months after the first dose of Vaccine, the incidence of first episodes of clinical Malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe Malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe Malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64).\n\nCONCLUSIONS: The RTS,S/AS01 Vaccine provided protection against both clinical and severe Malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).
Vasee S. Moorthy - One of the best experts on this subject based on the ideXlab platform.
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A review of Malaria Vaccine clinical projects based on the WHO rainbow table
Malaria Journal, 2012Co-Authors: Lauren Schwartz, Graham V Brown, Blaise Genton, Vasee S. MoorthyAbstract:Development and Phase 3 testing of the most advanced Malaria Vaccine, RTS,S/AS01, indicates that Malaria Vaccine R&D is moving into a new phase. Field trials of several research Malaria Vaccines have also confirmed that it is possible to impact the host-parasite relationship through Vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the Malaria community considers the potential role of a first-generation Malaria Vaccine in Malaria control efforts, it is an apposite time to carefully document terminated and ongoing Malaria Vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation Malaria Vaccines over the next 10 years. The most comprehensive resource of Malaria Vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of Malaria Vaccine projects to be published in the last several years is provided below.
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Experimental human challenge infections can accelerate clinical Malaria Vaccine development
Nature Reviews Immunology, 2011Co-Authors: Robert W Sauerwein, Meta Roestenberg, Vasee S. MoorthyAbstract:Malaria is one of the most frequently occurring infectious diseases worldwide, with almost 1 million deaths and an estimated 243 million clinical cases annually. Several candidate Malaria Vaccines have reached Phase IIb clinical trials, but results have often been disappointing. As an alternative to these Phase IIb field trials, the efficacy of candidate Malaria Vaccines can first be assessed through the deliberate exposure of participants to the bites of infectious mosquitoes (sporozoite challenge) or to an inoculum of blood-stage parasites (blood-stage challenge). With an increasing number of Malaria Vaccine candidates being developed, should human Malaria challenge models be more widely used to reduce cost and time investments? This article reviews previous experience with both the sporozoite and blood-stage human Malaria challenge models and provides future perspectives for these models in Malaria Vaccine development.
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Malaria Vaccine developments
Lancet, 2004Co-Authors: Vasee S. Moorthy, Michael F Good, Adrian V S HillAbstract:Large gains in the reduction of Malaria mortality in the early 20th century were lost in subsequent decades. Malaria now kills 2-3 million people yearly. Implementation of Malaria control technologies such as insecticide-treated bednets and chemotherapy could reduce mortality substantially, but an effective Malaria Vaccine is also needed. Advances in Vaccine technology and immunology are being used to develop Malaria subunit Vaccines. Novel approaches that might yield effective Vaccines for other diseases are being evaluated first in Malaria. We describe progress in Malaria Vaccine development in the past 5 years: reasons for cautious optimism, the type of Vaccine that might realistically be expected, and how the process could be hastened. Although exact predictions are not possible, if sufficient funding were mobilised, a deployable, effective Malaria Vaccine is a realistic medium-term to long-term goal.
