#RTS,S #malaria #vaccine pilot studies: addressing the #human #realities in large-scale clinical trials (Trials, abstract)

[Source: Trials, full page: (LINK). Abstract, edited.]

Commentary / Open Access / Open Peer Review

RTS,S malaria vaccine pilot studies: addressing the human realities in large-scale clinical trials

Machteld van den Berg, Bernhards Ogutu, Nelson K. Sewankambo, Nikola Biller-Andorno and Marcel Tanner

Trials, 201920:316 / DOI: https://doi.org/10.1186/s13063-019-3391-7

©  The Author(s). 2019

Received: 18 December 2018 – Accepted: 2 May 2019 – Published: 31 May 2019 – Open Peer Review reports

 

Abstract

A malaria vaccine as part of the integrated malaria control and elimination efforts will have a major impact on public health in sub-Sahara Africa. The first malaria vaccine, RTS,S, now enters pilot implementation in three African countries. These pilot implementation studies are being initiated in Kenya, Malawi, and Ghana to inform the broader roll-out recommendation. Based on the malaria vaccine clinical trial experiences, key ethical practices for effective clinical trial research in low-resource settings are described. For successful vaccine integration into malaria intervention programs, the relational dynamics between researchers and trial communities must be made explicit. Incorporating community values and returning to research practices that serve the intended benefactors are key strategies that address the human realities in large-scale clinical trials and pilot implementation, leading to positive public health outcomes.

Keywords: Malaria vaccine – Pilot studies – Low-resource settings – Community engagement – Ethics – Transnational clinical trials

Keywords: Malaria; Vaccines; Bioethics.

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#Arboviral #diseases and #malaria in #Australia, 2014–15: Annual report of the National Arbovirus and Malaria Advisory Committee (Commun Dis Intell (2018), abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Commun Dis Intell (2018). 2019 Apr 15;43. doi: 10.33321/cdi.2019.43.14.

Arboviral diseases and malaria in Australia, 2014–15: Annual report of the National Arbovirus and Malaria Advisory Committee

Knope K1, Doggett SL2, Jansen CC3, Johansen CA4,5, Kurucz N6, Feldman R7, Lynch SE8, Hobby MP9, Sly A10, Jardine A11, Bennett S3, Currie BJ12, the National Arbovirus and Malaria Advisory Committee.

Author information: 1 Zoonoses, Foodborne and Emerging Infectious Diseases Section, Health Protection Policy Branch, Office of Health Protection, Department of Health, Canberra, Australian Capital Territory; 2 Department of Medical Entomology, Pathology West, Institute for Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales; 3 Communicable Diseases Branch, Department of Health, Queensland Government, Herston, Qld 4006; 4 Arbovirus Surveillance and Research Laboratory, School of Pathology and Laboratory Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Nedlands, Western Australia. 5
As of July 2015: Division of Microbiology and Infectious Diseases, PathWest Laboratory Medicine WA, QEII Medical Centre, Western Australian Department of Health, Nedlands, Western Australia. 6 Medical Entomology, Centre for Disease Control, Health Protection Division, Northern Territory Department of Health, Royal Darwin Hospital, Casuarina, Northern Territory; 7 Communicable Disease Prevention and Control, Department of Health, Melbourne, Victoria; 8 Agriculture Victoria Research, AgriBio Centre for AgriBioscience, 5 Ring Road, Bundoora, Victoria, 3083, Australia; 9 Health Protection, Public Health, South Australian Department of Health, Adelaide, South Australia; 10 Department of Agriculture and Water Resources, Compliance Division, Eagle Farm, Queensland; 11 Medical Entomology, Environmental Health Directorate, Department of Health, Western Australia; 12 Royal Darwin Hospital Northern Territory; Menzies School of Health Research, Darwin, Northern Territory

 

Abstract

This report describes the epidemiology of mosquito-borne diseases of public health importance in Australia during the 2014–15 season (1 July 2014 to 30 June 2015) and includes data from human notifications, sentinel chicken, vector and virus surveillance programs. The National Notifiable Diseases Surveillance System received notifications for 12,849 cases of disease transmitted by mosquitoes during the 2014–15 season. The Australasian alphaviruses Barmah Forest virus and Ross River virus accounted for 83% (n=10,723) of notifications. However, over-diagnosis and possible false positive diagnostic test results for these two infections mean that the true burden of infection is likely overestimated, and as a consequence, revised case definitions were implemented from 1 January 2016. There were 151 notifications of imported chikungunya virus infection. There were 74 notifications of dengue virus infection acquired in Australia and 1,592 cases acquired overseas, with an additional 34 cases for which the place of acquisition was unknown. Imported cases of dengue were most frequently acquired in Indonesia (66%). There were 7 notifications of Zika virus infection. No cases of locally-acquired malaria were notified during the 2014–15 season, though there were 259 notifications of overseas-acquired malaria and one notification for which no information on the place of acquisition was supplied. Imported cases of malaria were most frequently acquired in southern and eastern Africa (23%) and Pacific Island countries (20%). In 2014–15, arbovirus and mosquito surveillance programs were conducted in most of the states and territories. Surveillance for exotic mosquitoes at international ports of entry continues to be a vital part of preventing the establishment of vectors of mosquito-borne diseases such as dengue to new areas of Australia. In 2014-15, there was a sharp increase in the number of exotic mosquitoes detected at the Australian border, with 36 separate exotic mosquito detections made, representing a 280% increase from the 2013-14 period where there were 13 exotic mosquito detections.

KEYWORDS: arbovirus; Barmah Forest virus; chikungunya; dengue; Zika; disease surveillance; epidemiology; flavivirus; Japanese encephalitis; West Nile virus; Kunjin virus; malaria; mosquito-borne disease; mosquitoes; Murray Valley encephalitis virus; Ross River virus; yellow fever; exotic mosquitoes

PMID: 30982295

Keywords: Arbovirus; Alphavirus; Flaviviru; Barmah forest virus; Chikungunya fever; Zika virus; WNV; Malaria; Australia.

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Efficacy and #risk of #harms of repeat #ivermectin mass drug administrations for control of #malaria (#RIMDAMAL): a cluster-randomised trial (Lancet, abstract)

[Source: The Lancet, full page: (LINK). Abstract, edited.]

Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial

Prof Brian D Foy, PhD., Haoues Alout, PhD, Jonathan A Seaman, BSc, Sangeeta Rao, PhD, Tereza Magalhaes, PhD, Martina Wade, BSc et al.

Open Access / Published: March 13, 2019 / DOI: https://doi.org/10.1016/S0140-6736(18)32321-3

 

Summary

Background

Ivermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms.

Methods

We invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150–200 μg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov, number NCT02509481.

Findings

Eight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 [49%] males and 1379 [51%] females; median age 15 years [IQR 6–34]), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference −0·49 [95% CI −0·79 to −0·21], p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events [3%] among 1447 participants in the intervention group vs 24 events [2%] among 1265 in the control group; risk ratio 1·63 [1·01 to 2·67]; risk difference 1·21 [0·04 to 2·38], p=0·060), and no adverse reactions were reported.

Interpretation

Frequently repeated mass administrations of ivermectin during the malaria transmission season can reduce malaria episodes among children without significantly increasing harms in the populace.

Funding

Bill & Melinda Gates Foundation.

Keywords: Malaria; Ivermectin.

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#Outcomes of controlled #human #malaria infection after #BCG #vaccination (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 20 February 2019

Outcomes of controlled human malaria infection after BCG vaccination

Jona Walk, L. Charlotte J. de Bree, Wouter Graumans, Rianne Stoter, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Karina Teelen, Cornelus C. Hermsen, Rob J. W. Arts, Marije C. Behet, Farid Keramati, Simone J. C. F. M. Moorlag, Annie S. P. Yang, Reinout van Crevel, Peter Aaby, Quirijn de Mast, André J. A. M. van der Ven, Christine Stabell Benn, Mihai G. Netea & Robert W. Sauerwein

Nature Communications, volume 10, Article number: 874 (2019)

 

Abstract

Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed ‘trained immunity’. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development.

Keywords: Malaria; BCG; Vaccines.

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#Predictive #analysis across spatial scales links #zoonotic #malaria to #deforestation (Proc Roy Soc B., abstract)

[Source: Proceedings of the Royal Society, Biological Sciences, full page: (LINK). Abstract, edited.]

Predictive analysis across spatial scales links zoonotic malaria to deforestation

Patrick M. Brock, Kimberly M. Fornace, Matthew J. Grigg, Nicholas M. Anstey,Timothy William, Jon Cox, Chris J. Drakeley, Heather M. Ferguson and Rowland R. Kao

Published: 16 January 2019 / DOI: https://doi.org/10.1098/rspb.2018.2351

 

Abstract

The complex transmission ecologies of vector-borne and zoonotic diseases pose challenges to their control, especially in changing landscapes. Human incidence of zoonotic malaria (Plasmodium knowlesi) is associated with deforestation although mechanisms are unknown. Here, a novel application of a method for predicting disease occurrence that combines machine learning and statistics is used to identify the key spatial scales that define the relationship between zoonotic malaria cases and environmental change. Using data from satellite imagery, a case–control study, and a cross-sectional survey, predictive models of household-level occurrence of P. knowlesiwere fitted with 16 variables summarized at 11 spatial scales simultaneously. The method identified a strong and well-defined peak of predictive influence of the proportion of cleared land within 1 km of households on P. knowlesi occurrence. Aspect (1 and 2 km), slope (0.5 km) and canopy regrowth (0.5 km) were important at small scales. By contrast, fragmentation of deforested areas influenced P. knowlesi occurrence probability most strongly at large scales (4 and 5 km). The identification of these spatial scales narrows the field of plausible mechanisms that connect land use change and P. knowlesi, allowing for the refinement of disease occurrence predictions and the design of spatially-targeted interventions.

Keywords: Malaria; Deforestation.

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#Preclinical evaluation of a P. berghei-based whole- #sporozoite #malaria #vaccine candidate (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 27 November 2018

Pre-clinical evaluation of a P. berghei-based whole-sporozoite malaria vaccine candidate

António M. Mendes, Isaie J. Reuling, Carolina M. Andrade, Thomas D. Otto, Marta Machado, Filipa Teixeira, Joana Pissarra, Nataniel Gonçalves-Rosa, Dolores Bonaparte, João Sinfrónio, Mandy Sanders, Chris J. Janse, Shahid M. Khan, Chris I. Newbold, Matthew Berriman, Cynthia K. Lee, Yimin Wu, Christian F. Ockenhouse, Robert W. Sauerwein & Miguel Prudêncio

npj Vaccines, volume 3, Article number: 54 (2018)

 

Abstract

Whole-sporozoite vaccination/immunization induces high levels of protective immunity in both rodent models of malaria and in humans. Recently, we generated a transgenic line of the rodent malaria parasite P. berghei (Pb) that expresses the P. falciparum (Pf) circumsporozoite protein (PfCS), and showed that this parasite line (PbVac) was capable of (1) infecting and developing in human hepatocytes but not in human erythrocytes, and (2) inducing neutralizing antibodies against the human Pf parasite. Here, we analyzed PbVac in detail and developed tools necessary for its use in clinical studies. A microbiological contaminant-free Master Cell Bank of PbVac parasites was generated through a process of cyclic propagation and clonal expansion in mice and mosquitoes and was genetically characterized. A highly sensitive qRT-PCR-based method was established that enables PbVac parasite detection and quantification at low parasite densities in vivo. This method was employed in a biodistribution study in a rabbit model, revealing that the parasite is only present at the site of administration and in the liver up to 48 h post infection and is no longer detectable at any site 10 days after administration. An extensive toxicology investigation carried out in rabbits further showed the absence of PbVac-related toxicity. In vivo drug sensitivity assays employing rodent models of infection showed that both the liver and the blood stage forms of PbVac were completely eliminated by Malarone® treatment. Collectively, our pre-clinical safety assessment demonstrates that PbVac possesses all characteristics necessary to advance into clinical evaluation.

Keywords: Malaria; Vaccines; Plasmodium berghei; Animal models.

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#Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking #vaccine against #Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults

Issaka Sagara, MD†, Sara A Healy, MD†, Mahamadoun H Assadou, MD, Erin E Gabriel, PhD, Mamady Kone, MD, Kourane Sissoko, MD, Intimbeye Tembine, MD, Merepen A Guindo, PharmD, M’Bouye Doucoure, BS, Karamoko Niaré, PharmD, Amagana Dolo, PharmD, Kelly M Rausch, MS, David L Narum, PhD, David L Jones, PhD, Nicholas J MacDonald, PhD, Daming Zhu, MS, Rathy Mohan, MS, Olga Muratova, MS, Ibrahima Baber, PhD, Mamadou B Coulibaly, PhD, Michael P Fay, PhD, Charles Anderson, PhD, Yimin Wu, PhD, Prof Sekou F Traore, PhD, Prof Ogobara K Doumbo, MD, Patrick E Duffy, MD

†Contributed equally

Published: 27 July 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30344-X

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Pfs25H-EPA is a protein-protein conjugate transmission-blocking vaccine against Plasmodium falciparum that is safe and induces functional antibodies in malaria-naive individuals. In this field trial, we assessed Pfs25H-EPA/Alhydrogel for safety and functional immunogenicity in Malian adults.

Methods

This double-blind, randomised, comparator-controlled, dose-escalation trial in Bancoumana, Mali, was done in two staggered phases, an initial pilot safety assessment and a subsequent main phase. Healthy village residents aged 18–45 years were eligible if they had normal laboratory results (including HIV, hepatitis B, hepatitis C tests) and had not received a previous malaria vaccine or recent immunosuppressive drugs, vaccines, or blood products. Participants in the pilot safety cohort and the main cohort were assigned (1:1) by block randomisation to a study vaccine group. Participants in the pilot safety cohort received two doses of Pfs25H-EPA/Alhydrogel 16 μg or Euvax B (comparator vaccine), and participants in the main cohort received Pfs25H-EPA/Alhydrogel 47 μg or comparator vaccine (Euvax B for the first, second, and third vaccinations and Menactra for the fourth vaccination). Participants and investigators were masked to group assignment, and randomisation codes in sealed envelopes held by a site pharmacist. Vials with study drug for injection were covered by opaque tape and labelled with a study identification number. Group assignments were unmasked at final study visit. The primary outcomes were safety and tolerability for all vaccinees. The secondary outcome measure was immunogenicity 14 days after vaccination in the per-protocol population, as confirmed by the presence of antibodies against Pfs25H measured by ELISA IgG and antibody functionality assessed by standard membrane feeding assays and by direct skin feeding assays. This trial is registered with ClinicalTrials.gov, number NCT01867463.

Findings

Between May 15, and Jun 16, 2013, 230 individuals were screened for eligibility. 20 individuals were enrolled in the pilot safety cohort; ten participants were assigned to receive Pfs25H-EPA/Alhydrogel 16 μg, and ten participants were assigned to receive comparator vaccine. 100 individuals were enrolled in the main cohort; 50 participants were assigned to receive Pfs25H-EPA/Alhydrogel 47 μg, and 50 participants were assigned to receive comparator vaccine. Compared with comparator vaccinees, Pfs25H vaccinees had more solicited adverse events (137 events vs 86 events; p=0·022) and treatment-related adverse events (191 events vs 126 events, p=0·034), but the number of other adverse events did not differ between study vaccine groups (792 vs 683). Pfs25H antibody titres increased with each dose, with a peak geometric mean of 422·3 ELISA units (95% CI 290–615) after the fourth dose, but decreased relatively rapidly thereafter, with a half-life of 42 days for anti-Pfs25H and 59 days for anti-EPA (median ratio of titres at day 600 to peak, 0·19 for anti-Pfs25H vs 0·29 for anti-EPA; p=0·009). Serum transmission-reducing activity was greater for Pfs25H than for comparator vaccine after the fourth vaccine dose (p<0·001) but not after the third dose (p=0·09). Repeated direct skin feeds were well tolerated, but the number of participants who infected at least one mosquito did not differ between Pfs25H and comparator vaccinees after the fourth dose (p=1, conditional exact).

Interpretation

Pfs25H-EPA/Alhydrogel was well tolerated and induced significant serum activity by standard membrane feeding assays but transmission blocking activity was not confirmed by weekly direct skin feed. This activity required four doses, and titres decreased rapidly after the fourth dose. Alternative antigens or combinations should be assessed to improve activity.

Funding

Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Keywords: Malaria; Plasmodium falciparum; Vaccines.

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