@article{nokey,

title = {Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with protection.},

author = {D\'{i}dac Maci\`{a} and Joseph J. Campo and Gemma Moncunill and Chenjerai Jairoce and Augusto J. Nhabomba and Maximilian Mpina and Hermann Sorgho and David Dosoo and Ousmane Traore and Kwadwo Asamoah Kusi and Nana Aba Williams and Amit Oberai and Arlo Randall and H\`{e}ctor Sanz and Clarissa Valim and Kwaku Poku Asante and Seth Owusu-Agyei and Halidou Tinto and Selidji Todagbe Agnandji and Simon Kariuki and Ben Gyan and Claudia Daubenberger and Benjamin Mordm\"{u}ller and Paula Petrone and Carlota Doba\~{n}o},

doi = {10.1172/jci.insight.158030},

issn = {2379-3708},

year  = {2022},

date = {2022-05-01},

urldate = {2022-05-01},

journal = {JCI insight},

volume = {7},

issue = {10},

abstract = {The RTS,S/AS01E vaccine targets the circumsporozoite protein (CSP) of the Plasmodium falciparum (P. falciparum) parasite. Protein microarrays were used to measure levels of IgG against 1000 P. falciparum antigens in 2138 infants (age 6-12 weeks) and children (age 5-17 months) from 6 African sites of the phase III trial, sampled before and at 4 longitudinal visits after vaccination. One month postvaccination, IgG responses to 17% of all probed antigens showed differences between RTS,S/AS01E and comparator vaccination groups, whereas no prevaccination differences were found. A small subset of antigens presented IgG levels reaching 4- to 8-fold increases in the RTS,S/AS01E group, comparable in magnitude to anti-CSP IgG levels (~11-fold increase). They were strongly cross-correlated and correlated with anti-CSP levels, waning similarly over time and reincreasing with the booster dose. Such an intriguing phenomenon may be due to cross-reactivity of anti-CSP antibodies with these antigens. RTS,S/AS01E vaccinees with strong off-target IgG responses had an estimated lower clinical malaria incidence after adjusting for age group, site, and postvaccination anti-CSP levels. RTS,S/AS01E-induced IgG may bind strongly not only to CSP, but also to unrelated malaria antigens, and this seems to either confer, or at least be a marker of, increased protection from clinical malaria.},

keywords = {*Adaptive immunity, *Antigen, *Epidemiology, *Immunology, *Infectious disease, *Malaria, *Malaria Vaccines, *Malaria/prevention \& control, Antibodies, Antigens, Child, Falciparum/prevention \& control, Humans, Immunoglobulin G, Infant, Protozoan, Vaccination},

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}

}