@article{Dal-Re2021-mr,

title = {Ongoing and future COVID-19 vaccine clinical trials: challenges  and opportunities},

author = {Rafael Dal-R\'{e} and Linda-Gail Bekker and Christian Gluud and S\oren Holm and Vivekanand Jha and Gregory A Poland and Frits R Rosendaal and Brigitte Schwarzer-Daum and Esperanc ca Sevene and Halidou Tinto and Teck Chuan Voo and Nadarajah Sreeharan},

doi = {10.1016/S1473-3099(21)00263-2},

issn = {1474-4457 1473-3099},

year  = {2021},

date = {2021-11-01},

urldate = {2021-11-01},

journal = {Lancet Infect. Dis.},

volume = {21},

number = {11},

pages = {e342--e347},

abstract = {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.},

note = {Copyright © 2021 Elsevier Ltd. All rights reserved.

PMID: 34019801 

PMCID: PMC8131060},

keywords = {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},

pubstate = {published},

tppubtype = {article}

}

@article{Chandramohan2021-qm,

title = {Seasonal malaria vaccination with or without seasonal malaria  chemoprevention},

author = {Daniel Chandramohan and Issaka Zongo and Issaka Sagara and Matthew Cairns and Rakiswend\'{e}-Serge Yerbanga and Modibo Diarra and Fr\'{e}d\'{e}ric Niki`ema and Amadou Tapily and Fr\'{e}d\'{e}ric Sompougdou and Djibrilla Issiaka and Charles Zoungrana and Koualy Sanogo and Alassane Haro and Mahamadou Kaya and Abdoul-Aziz Sienou and Seydou Traore and Almahamoudou Mahamar and Ismaila Thera and Kalifa Diarra and Amagana Dolo and Irene Kuepfer and Paul Snell and Paul Milligan and Christian Ockenhouse and Opokua Ofori-Anyinam and Halidou Tinto and Abdoulaye Djimde and Jean-Bosco Ou\'{e}draogo and Alassane Dicko and Brian Greenwood},

doi = {10.1056/NEJMoa2026330},

issn = {1533-4406 0028-4793},

year  = {2021},

date = {2021-09-09},

urldate = {2021-09-09},

journal = {N. Engl. J. Med.},

volume = {385},

number = {11},

pages = {1005--1017},

publisher = {Massachusetts Medical Society},

abstract = {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.).},

note = {Copyright © 2021 Massachusetts Medical Society.

Place: United States

PMID: 34432975},

keywords = {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},

pubstate = {published},

tppubtype = {article}

}

@article{Adoke2021-el,

title = {A randomized, double-blind, phase 2b study to investigate the  efficacy, safety, tolerability and pharmacokinetics of a  single-dose regimen of ferroquine with artefenomel in adults and  children with uncomplicated Plasmodium falciparum malaria},

author = {Yeka Adoke and Rella Zoleko-Manego and Serge Ouoba and Alfred B Tiono and Grace Kaguthi and Juv^encio Eduardo Bonzela and Tran Thanh Duong and Alain Nahum and Marielle Bouyou-Akotet and Bernhards Ogutu and Alphonse Ouedraogo and Fiona Macintyre and Andreas Jessel and Bart Laurijssens and Mohammed H Cherkaoui-Rbati and Cathy Cantalloube and Anne Claire Marrast and Rapha"el Bejuit and David White and Timothy N C Wells and Florian Wartha and Didier Leroy and Afizi Kibuuka and Ghyslain Mombo-Ngoma and Daouda Ouattara and Ir`ene Mugenya and Bui Quang Phuc and Francis Bohissou and Denise P Mawili-Mboumba and Fredrick Olewe and Issiaka Soulama and Halidou Tinto and FALCI Study Group},

doi = {10.1186/s12936-021-03749-4},

issn = {1475-2875},

year  = {2021},

date = {2021-05-19},

urldate = {2021-05-19},

journal = {Malar. J.},

volume = {20},

number = {1},

pages = {222},

publisher = {Springer Science and Business Media LLC},

abstract = {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 $\leq$ 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 $\leq$ 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.},

note = {PMID: 34011358 

PMCID: PMC8135182},

keywords = {Adamantane/administration \& dosage/analogs \& derivatives, Adolescent, Adult, Aged, Aminoquinolines/administration \& dosage, Benin, Burkina Faso, C580Y, Child, Combination treatment, Double-Blind Method, Drug Combinations, Exposure\textendashresponse, 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},

pubstate = {published},

tppubtype = {article}

}

@article{Datoo2021-dk,

title = {Efficacy of a low-dose candidate malaria vaccine, R21 in  adjuvant Matrix-M, with seasonal administration to children in  Burkina Faso: a randomised controlled trial},

author = {Mehreen S Datoo and Magloire H Natama and Athanase Som\'{e} and Ousmane Traor\'{e} and Toussaint Rouamba and Duncan Bellamy and Prisca Yameogo and Daniel Valia and Moubarak Tegneri and Florence Ouedraogo and Rachidatou Soma and Seydou Sawadogo and Faizatou Sorgho and Karim Derra and Eli Rouamba and Benedict Orindi and Fernando Ramos Lopez and Amy Flaxman and Federica Cappuccini and Reshma Kailath and Sean Elias and Ekta Mukhopadhyay and Andres Noe and Matthew Cairns and Alison Lawrie and Rachel Roberts and Innocent Val\'{e}a and Hermann Sorgho and Nicola Williams and Gregory Glenn and Louis Fries and Jenny Reimer and Katie J Ewer and Umesh Shaligram and Adrian V S Hill and Halidou Tinto},

doi = {10.1016/S0140-6736(21)00943-0},

issn = {1474-547X 0140-6736},

year  = {2021},

date = {2021-05-15},

urldate = {2021-05-15},

journal = {Lancet},

volume = {397},

number = {10287},

pages = {1809--1818},

publisher = {Elsevier BV},

abstract = {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.},

note = {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},

keywords = {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},

pubstate = {published},

tppubtype = {article}

}