2021 |
|
Journal Articles |
|
Rafael Dal-Ré, Linda-Gail Bekker, Christian Gluud, Søren Holm, Vivekanand Jha, Gregory A Poland, Frits R Rosendaal, Brigitte Schwarzer-Daum, Esperanc ca Sevene, Halidou Tinto, Teck Chuan Voo, Nadarajah Sreeharan Ongoing and future COVID-19 vaccine clinical trials: challenges and opportunities (Journal Article) In: Lancet Infect. Dis., vol. 21, no. 11, pp. e342–e347, 2021, ISSN: 1474-4457 1473-3099, (Copyright © 2021 Elsevier Ltd. All rights reserved. PMID: 34019801 PMCID: PMC8131060). (Abstract | Links | BibTeX | Tags: Clinical Trials as Topic, COVID-19 Vaccines/administration & dosage/immunology, COVID-19/epidemiology/immunology/prevention & control/virology, Double-Blind Method, Humans, Immunogenicity, Pandemics/prevention & control, SARS-CoV-2/immunology, Vaccine) @article{Dal-Re2021-mr, Large-scale deployment of COVID-19 vaccines will seriously affect the ongoing phases 2 and 3 randomised placebo-controlled trials assessing SARS-CoV-2 vaccine candidates. The effect will be particularly acute in high-income countries where the entire adult or older population could be vaccinated by late 2021. Regrettably, only a small proportion of the population in many low-income and middle-income countries will have access to available vaccines. Sponsors of COVID-19 vaccine candidates currently in phase 2 or initiating phase 3 trials in 2021 should consider continuing the research in countries with limited affordability and availability of COVID-19 vaccines. Several ethical principles must be implemented to ensure the equitable, non-exploitative, and respectful conduct of trials in resource-poor settings. Once sufficient knowledge on the immunogenicity response to COVID-19 vaccines is acquired, non-inferiority immunogenicity trials-comparing the immune response of a vaccine candidate to that of an authorised vaccine-would probably be the most common trial design. Until then, placebo-controlled, double-blind, crossover trials will continue to play a role in the development of new vaccine candidates. WHO or the Council for International Organizations of Medical Sciences should define an ethical framework for the requirements and benefits for trial participants and host communities in resource-poor settings that should require commitment from all vaccine candidate sponsors from high-income countries. | |
Daniel Chandramohan, Issaka Zongo, Issaka Sagara, Matthew Cairns, Rakiswendé-Serge Yerbanga, Modibo Diarra, Frédéric Niki`ema, Amadou Tapily, Frédéric Sompougdou, Djibrilla Issiaka, Charles Zoungrana, Koualy Sanogo, Alassane Haro, Mahamadou Kaya, Abdoul-Aziz Sienou, Seydou Traore, Almahamoudou Mahamar, Ismaila Thera, Kalifa Diarra, Amagana Dolo, Irene Kuepfer, Paul Snell, Paul Milligan, Christian Ockenhouse, Opokua Ofori-Anyinam, Halidou Tinto, Abdoulaye Djimde, Jean-Bosco Ouédraogo, Alassane Dicko, Brian Greenwood Seasonal malaria vaccination with or without seasonal malaria chemoprevention (Journal Article) In: N. Engl. J. Med., vol. 385, no. 11, pp. 1005–1017, 2021, ISSN: 1533-4406 0028-4793, (Copyright © 2021 Massachusetts Medical Society. Place: United States PMID: 34432975). (Abstract | Links | BibTeX | Tags: Amodiaquine/therapeutic use, Antimalarials/adverse effects/therapeutic use, Burkina Faso/epidemiology, Chemoprevention, Combination, Combined Modality Therapy, Double-Blind Method, Drug Combinations, Drug Therapy, Falciparum/epidemiology/mortality/prevention & control, Febrile/etiology, Female, Hospitalization/statistics & numerical data, Humans, Infant, Malaria, Malaria Vaccines/administration & dosage/adverse effects, Male, Mali/epidemiology, Pyrimethamine/therapeutic use, Seasons, Seizures, Sulfadoxine/therapeutic use) @article{Chandramohan2021-qm, BACKGROUND: Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa. METHODS: We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes. RESULTS: We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01E (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01E (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively. CONCLUSIONS: Administration of RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.). | |
Yeka Adoke, Rella Zoleko-Manego, Serge Ouoba, Alfred B Tiono, Grace Kaguthi, Juv^encio Eduardo Bonzela, Tran Thanh Duong, Alain Nahum, Marielle Bouyou-Akotet, Bernhards Ogutu, Alphonse Ouedraogo, Fiona Macintyre, Andreas Jessel, Bart Laurijssens, Mohammed H Cherkaoui-Rbati, Cathy Cantalloube, Anne Claire Marrast, Rapha"el Bejuit, David White, Timothy N C Wells, Florian Wartha, Didier Leroy, Afizi Kibuuka, Ghyslain Mombo-Ngoma, Daouda Ouattara, Ir`ene Mugenya, Bui Quang Phuc, Francis Bohissou, Denise P Mawili-Mboumba, Fredrick Olewe, Issiaka Soulama, Halidou Tinto, FALCI Study Group In: Malar. J., vol. 20, no. 1, pp. 222, 2021, ISSN: 1475-2875, (PMID: 34011358 PMCID: PMC8135182). (Abstract | Links | BibTeX | Tags: Adamantane/administration & dosage/analogs & derivatives, Adolescent, Adult, Aged, Aminoquinolines/administration & dosage, Benin, Burkina Faso, C580Y, Child, Combination treatment, Double-Blind Method, Drug Combinations, Exposure–response, Falciparum/prevention & control, Female, Ferroquine, Ferrous Compounds/administration & dosage, Gabon, Humans, Infant, Kelch-13 mutation, Kenya, Malaria, Male, Metallocenes/administration & dosage, Middle Aged, Mozambique, Parasite clearance, Peroxides/administration & dosage, Pharmacokinetics/pharmacodynamics, Plasmodium falciparum/drug effects, Preschool, resistance, Uganda, Vietnam, Vomiting, Young Adult) @article{Adoke2021-el, BACKGROUND: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children $łeq$ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged $łeq$ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1. | |
Mehreen S Datoo, Magloire H Natama, Athanase Somé, Ousmane Traoré, Toussaint Rouamba, Duncan Bellamy, Prisca Yameogo, Daniel Valia, Moubarak Tegneri, Florence Ouedraogo, Rachidatou Soma, Seydou Sawadogo, Faizatou Sorgho, Karim Derra, Eli Rouamba, Benedict Orindi, Fernando Ramos Lopez, Amy Flaxman, Federica Cappuccini, Reshma Kailath, Sean Elias, Ekta Mukhopadhyay, Andres Noe, Matthew Cairns, Alison Lawrie, Rachel Roberts, Innocent Valéa, Hermann Sorgho, Nicola Williams, Gregory Glenn, Louis Fries, Jenny Reimer, Katie J Ewer, Umesh Shaligram, Adrian V S Hill, Halidou Tinto In: Lancet, vol. 397, no. 10287, pp. 1809–1818, 2021, ISSN: 1474-547X 0140-6736, (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. PMID: 33964223 PMCID: PMC8121760). (Abstract | Links | BibTeX | Tags: Adjuvants, Burkina Faso, Double-Blind Method, Falciparum/prevention & control, Female, Hepatitis B Surface Antigens, Humans, Immunogenicity, Immunologic/administration & dosage, Infant, Malaria, Malaria Vaccines/therapeutic use, Malaria/prevention & control, Male, Nanoparticles/administration & dosage, Proportional Hazards Models, Protozoan Proteins/immunology, Saponins/administration & dosage, Treatment Outcome, Vaccine, Vaccines, Virus-Like Particle/therapeutic use) @article{Datoo2021-dk, BACKGROUND: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy. METHODS: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 $mu$g R21 plus 25 $mu$g MM, group 2 received 5 $mu$g R21 plus 50 $mu$g MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. FINDINGS: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. INTERPRETATION: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. FUNDING: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre. |
Input your search keywords and press Enter.