#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.

——

#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.

——

#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.

——

#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.

——

The effect of #chloroquine dose and #primaquine on #Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis (Lancet Infect Dis., abstract)

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

The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis

Robert J Commons, FRACP, Prof Julie A Simpson, PhD, Kamala Thriemer, PhD, Georgina S Humphreys, PhD, Tesfay Abreha, MPH, Sisay G Alemu, MSc, Arletta Añez, PhD, Prof Nicholas M Anstey, PhD, Ghulam R Awab, PhD, Prof J Kevin Baird, PhD, Bridget E Barber, PhD, Isabelle Borghini-Fuhrer, PhD, Cindy S Chu, MD, Umberto D’Alessandro, PhD, Prabin Dahal, MSc, André Daher, MD, Peter J de Vries, PhD, Annette Erhart, MD, Margarete S M Gomes, PhD, Lilia Gonzalez-Ceron, PhD, Matthew J Grigg, PhD, Aliehsan Heidari, PhD, Jimee Hwang, MD, Prof Piet A Kager, MD, Tsige Ketema, PhD, Wasif A Khan, MHS, Prof Marcus V G Lacerda, PhD, Toby Leslie, PhD, Benedikt Ley, PhD, Kartini Lidia, MSc, Prof Wuelton M Monteiro, PhD, Prof Francois Nosten, PhD, Prof Dhelio B Pereira, MD, Giao T Phan, PhD, Aung P Phyo, PhD, Prof Mark Rowland, PhD, Prof Kavitha Saravu, MD, Prof Carol H Sibley, PhD, André M Siqueira, PhD, Kasia Stepniewska, PhD, ProfInge Sutanto, PhD, Walter R J Taylor, MD, Prof Guy Thwaites, FRCP, Binh Q Tran, MD, Prof Hien T Tran, MD, Neena Valecha, MD, José Luiz F Vieira, PhD, Sonam Wangchuk, PhD, Timothy William, MRCP, Charles J Woodrow, PhD, Lina Zuluaga-Idarraga, PhD, Prof Philippe J Guerin, MD, Prof Nicholas J White, FRS, Prof Ric N Price, FRCP

Published: 19 July 2018 / Open Access  / DOI: https://doi.org/10.1016/S1473-3099(18)30348-7

© 2018 The Author(s). Published by Elsevier Ltd.

 

Summary

Background

Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings.

Methods

A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310.

Findings

Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001).

Interpretation

Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax.

Funding

Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

Keywords: Malaria; Plasmodium vivax; Chloroquine; Primaquine.

——

#Plasmodium-associated changes in #human #odor attract #mosquitoes (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Plasmodium-associated changes in human odor attract mosquitoes

Ailie Robinson, Annette O. Busula, Mirjam A. Voets, Khalid B. Beshir, John C. Caulfield, Stephen J. Powers, Niels O. Verhulst, Peter Winskill, Julian Muwanguzi, Michael A. Birkett, Renate C. Smallegange, Daniel K. Masiga, W. Richard Mukabana, Robert W. Sauerwein, Colin J. Sutherland, Teun Bousema, John A. Pickett, Willem Takken, James G. Logan and Jetske G. de Boer

PNAS April 16, 2018. 201721610; published ahead of print April 16, 2018. DOI: https://doi.org/10.1073/pnas.1721610115

Contributed by John A. Pickett, March 14, 2018 (sent for review December 13, 2017; reviewed by David L. Denlinger and Ana Rivero)

 

Significance

In vector-borne disease systems, there is mounting evidence that vertebrate hosts become more attractive to disease vectors during infection, yet in human malaria, the underlying mechanism has not been studied. We identified compounds, including aldehydes, that are produced in relatively greater amounts in the skin odor of individuals with malaria, thus demonstrating a basis for this phenomenon in the cues used during mosquito host location. By establishing the attractiveness of these compounds to malaria mosquito vectors in laboratory bioassays, we characterize a process by which Plasmodium infection of humans could lead to increased mosquito biting. These compounds may serve as biomarkers of malaria or be used to enhance the efficacy of chemical lures used to trap mosquitoes.

 

Abstract

Malaria parasites (Plasmodium) can change the attractiveness of their vertebrate hosts to Anopheles vectors, leading to a greater number of vector–host contacts and increased transmission. Indeed, naturally Plasmodium-infected children have been shown to attract more mosquitoes than parasite-free children. Here, we demonstrate Plasmodium-induced increases in the attractiveness of skin odor in Kenyan children and reveal quantitative differences in the production of specific odor components in infected vs. parasite-free individuals. We found the aldehydes heptanal, octanal, and nonanal to be produced in greater amounts by infected individuals and detected by mosquito antennae. In behavioral experiments, we demonstrated that these, and other, Plasmodium-induced aldehydes enhanced the attractiveness of a synthetic odor blend mimicking “healthy” human odor. Heptanal alone increased the attractiveness of “parasite-free” natural human odor. Should the increased production of these aldehydes by Plasmodium-infected humans lead to increased mosquito biting in a natural setting, this would likely affect the transmission of malaria.

malaria transmission – host attractiveness – parasite–vector–host interactions – aldehydes – disease biomarkers

 

Footnotes

1 To whom correspondence may be addressed. Email: Ailie.Robinson@lshtm.ac.uk, pickettj4@cardiff.ac.uk, James.Logan@lshtm.ac.uk, or J.deBoer@nioo.knaw.nl.

2 Present address: Department of Biological and Agricultural Sciences, Kaimosi Friends University College, Kaimosi, Kenya.

3 Present address: Institute of Parasitology, National Centre for Vector Entomology, University of Zurich, 8057 Zurich, Switzerland.

4 Present address: School of Chemistry, Cardiff University, Cardiff CF10 3AT, United Kingdom.

5 Present address: Netherlands Institute of Ecology, Wageningen 6708 PB, The Netherlands.

Author contributions: A.R., A.O.B., N.O.V., M.A.B., R.C.S., D.K.M., W.R.M., R.W.S., T.B., J.A.P., W.T., J.G.L., and J.G.d.B. designed research; A.R., A.O.B., M.A.V., J.C.C., J.M., J.A.P., and J.G.d.B. performed research; A.R., K.B.B., J.C.C., P.W., and J.G.d.B. contributed new reagents/analytic tools; A.R., A.O.B., K.B.B., J.C.C., S.J.P., N.O.V., P.W., C.J.S., T.B., W.T., J.G.L., and J.G.d.B. analyzed data; and A.R., T.B., J.A.P., W.T., J.G.L., and J.G.d.B. wrote the paper.

Reviewers: D.L.D., The Ohio State University; and A.R., French National Centre for Scientific Research (CNRS).

Conflict of interest statement: A.R., J.G.d.B., J.G.L., and W.T. are inventors on a patent application filed with the UK Intellectual Property Office (application no. 1805023.7).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1721610115/-/DCSupplemental. Published under the PNAS license.

Keywords: Malaria; Plasmodium spp.; Mosquitoes.

——-

Safety and #mosquitocidal efficacy of high-dose #ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated #malaria … (Lancet Infect Dis., abstract)

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

Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial

Menno R Smit, MD, Eric O Ochomo, PhD, Ghaith Aljayyoussi, PhD, Titus K Kwambai, MD, Bernard O Abong’o, MSc, Tao Chen, PhD, Teun Bousema, PhD, Hannah C Slater, PhD, David Waterhouse, MSc, Nabie M Bayoh, PhD, John E Gimnig, PhD, Aaron M Samuels, MD, Meghna R Desai, PhD, Penelope A Phillips-Howard, PhD, Simon K Kariuki, PhD, ProfDuolao Wang, PhD, Prof Steve A Ward, PhD, Prof Feiko O ter Kuile, PhD

Published: 27 March 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30163-4

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment.

Methods

We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18–50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.

Findings

Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93–2·65, p<0·0001; hazard ratio [HR] 6·32, 4·61–8·67, p<0·0001; ivermectin 300 μg/kg per day RR 2·18, 1·86–2·57, p<0·0001; HR 4·21, 3·06–5·79, p<0·0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 μg/kg per day RR 1·23, 1·01–1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01–1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.

Interpretation

Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination.

Funding

Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC).

Keywords: Malaria; Mosquitoes; Ivermectin.

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