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Luc E Coffeng, Cornelus C Hermsen, Robert W Sauerwein, Sake J de Vlas
Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize power calculations for CHMI-based malaria vaccine trials, we developed a novel non-linear statistical model for parasite kinetics as measured by qPCR, using data from mosquito-based CHMI experiments in 57 individuals...
January 2017: PLoS Computational Biology
Ruth O Payne, Paul M Griffin, James S McCarthy, Simon J Draper
Modern controlled human malaria infection (CHMI) clinical trials have almost entirely focussed on Plasmodium falciparum, providing a highly informative means to investigate host-pathogen interactions as well as assess potential new prophylactic and therapeutic interventions. However, in recent years, there has been renewed interest in Plasmodium vivax, with CHMI models developed by groups in Colombia, the USA, and Australia. This review summarizes the published experiences, and examines the advantages and disadvantages of the different models that initiate infection either by mosquito bite or using a blood-stage inoculum...
December 9, 2016: Trends in Parasitology
Susanne H Hodgson, David Llewellyn, Sarah E Silk, Kathryn H Milne, Sean C Elias, Kazutoyo Miura, Gathoni Kamuyu, Elizabeth A Juma, Charles Magiri, Alfred Muia, Jing Jin, Alexandra J Spencer, Rhea J Longley, Thomas Mercier, Laurent Decosterd, Carole A Long, Faith H Osier, Stephen L Hoffman, Bernhards Ogutu, Adrian V S Hill, Kevin Marsh, Simon J Draper
Background: The timing of infection is closely determined in controlled human malaria infection (CHMI) studies, and as such they provide a unique opportunity to dissect changes in immunological responses before and after a single infection. The first Kenyan Challenge Study (KCS) (Pan African Clinical Trial Registry: PACTR20121100033272) was performed in 2013 with the aim of establishing the CHMI model in Kenya. This study used aseptic, cryopreserved, attenuated Plasmodium falciparum sporozoites administered by needle and syringe (PfSPZ Challenge) and was the first to evaluate parasite dynamics post-CHMI in individuals with varying degrees of prior exposure to malaria...
2016: Frontiers in Microbiology
Myriam Arévalo-Herrera, Juan M Vásquez-Jiménez, Mary Lopez-Perez, Andrés F Vallejo, Andrés B Amado-Garavito, Nora Céspedes, Angélica Castellanos, Karen Molina, Johanna Trejos, José Oñate, Judith E Epstein, Thomas L Richie, Sócrates Herrera
BACKGROUND: Immunizing human volunteers by mosquito bite with radiation-attenuated Plasmodium falciparum sporozoites (RAS) results in high-level protection against infection. Only two volunteers have been similarly immunized with P. vivax (Pv) RAS, and both were protected. A phase 2 controlled clinical trial was conducted to assess the safety and protective efficacy of PvRAS immunization. METHODOLOGY/PRINCIPAL FINDINGS: A randomized, single-blinded trial was conducted...
October 2016: PLoS Neglected Tropical Diseases
Jona Walk, Remko Schats, Marijke C C Langenberg, Isaie J Reuling, Karina Teelen, Meta Roestenberg, Cornelus C Hermsen, Leo G Visser, Robert W Sauerwein
BACKGROUND: Controlled human malaria infection (CHMI) has become well-established in the evaluation of drugs and vaccines. Anti-malarial treatment is usually initiated when thick blood smears are positive by microscopy. This study explores the effects of using the more sensitive qPCR as the primary diagnostic test. METHODS: 1691 diagnostic blood samples were analysed by microscopy and qPCR from 115 volunteers (55 malaria naïve and 60 having received chemoprophylaxis and sporozoite immunization) who were challenged by five mosquitoes infected with Plasmodium falciparum sporozoites of the NF54 strain...
2016: Malaria Journal
Bradley W Hickey, Joanne M Lumsden, Sharina Reyes, Martha Sedegah, Michael R Hollingdale, Daniel A Freilich, Thomas C Luke, Yupin Charoenvit, Lucy M Goh, Mara P Berzins, Lolita Bebris, John B Sacci, Patricia De La Vega, Ruobing Wang, Harini Ganeshan, Esteban N Abot, Daniel J Carucci, Denise L Doolan, Gary T Brice, Anita Kumar, Joao Aguiar, Thomas B Nutman, Susan F Leitman, Stephen L Hoffman, Judith E Epstein, Thomas L Richie
BACKGROUND: In this phase 1 clinical trial, healthy adult, malaria-naïve subjects were immunized with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) by mosquito bite and then underwent controlled human malaria infection (CHMI). The PfRAS model for immunization against malaria had previously induced >90 % sterile protection against homologous CHMI. This study was to further explore the safety, tolerability and protective efficacy of the PfRAS model and to provide biological specimens to characterize protective immune responses and identify protective antigens in support of malaria vaccine development...
2016: Malaria Journal
Tommy Rampling, Katie J Ewer, Georgina Bowyer, Carly M Bliss, Nick J Edwards, Danny Wright, Ruth O Payne, Navin Venkatraman, Eoghan de Barra, Claudia M Snudden, Ian D Poulton, Hans de Graaf, Priya Sukhtankar, Rachel Roberts, Karen Ivinson, Rich Weltzin, Bebi-Yassin Rajkumar, Ulrike Wille-Reece, Cynthia K Lee, Christian F Ockenhouse, Robert E Sinden, Stephen Gerry, Alison M Lawrie, Johan Vekemans, Danielle Morelle, Marc Lievens, Ripley W Ballou, Graham S Cooke, Saul N Faust, Sarah Gilbert, Adrian V S Hill
BACKGROUND: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector...
September 1, 2016: Journal of Infectious Diseases
Anna Abacjew-Chmyłko, Dariusz Grzegorz Wydra, Hanna Olszewska
Niche, a newly described in the polish literature cesarean section complication, is defined as a triangular anechoic deficient of the uterine myometrium localized in the site of the scar after the incision of a typically performed low-transverse cesarean delivery. The aim of the paper is to provide an overview of the available literature on the diagnosis and symptoms of niche. Diagnostic evaluation of the niche comprises of visual diagnostic methods: transvaginal ultrasonography to localize the cesarean scar and contrast-enhanced sonography as the method of choice for measuring the depth of the niche, the residual myometrium thickness and the total myometrial thickness...
2016: Ginekologia Polska
Anna O Abacjew-Chmyłk, Łukasz Chmyłko, Dariusz Grzegorz Wydra, Hanna Olszewska, Paulina Kobiela, Katarzyna Ciach
BACKGROUND: Nulliparity is one of the most important reproductive risk factors for endometrial cancer. It is still discussed whether multiparity implies a more favorable course of the disease and higher overall survival rates. The aim of the study was to analyze the effect of parity on the overall survival of endometrial cancer patients in Poland. MATERIAL AND METHOD: A retrospective analysis of parity on survival rates was performed in 810 women treated surgically for endometrial cancer in a single referential center of gynecological oncology...
2016: Ginekologia Polska
Jason A Regules, Susan B Cicatelli, Jason W Bennett, Kristopher M Paolino, Patrick S Twomey, James E Moon, April K Kathcart, Kevin D Hauns, Jack L Komisar, Aziz N Qabar, Silas A Davidson, Sheetij Dutta, Matthew E Griffith, Charles D Magee, Mariusz Wojnarski, Jeffrey R Livezey, Adrian T Kress, Paige E Waterman, Erik Jongert, Ulrike Wille-Reece, Wayne Volkmuth, Daniel Emerling, William H Robinson, Marc Lievens, Danielle Morelle, Cynthia K Lee, Bebi Yassin-Rajkumar, Richard Weltzin, Joe Cohen, Robert M Paris, Norman C Waters, Ashley J Birkett, David C Kaslow, W Ripley Ballou, Christian F Ockenhouse, Johan Vekemans
BACKGROUND: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose...
September 1, 2016: Journal of Infectious Diseases
Andrew S Ishizuka, Kirsten E Lyke, Adam DeZure, Andrea A Berry, Thomas L Richie, Floreliz H Mendoza, Mary E Enama, Ingelise J Gordon, Lee-Jah Chang, Uzma N Sarwar, Kathryn L Zephir, LaSonji A Holman, Eric R James, Peter F Billingsley, Anusha Gunasekera, Sumana Chakravarty, Anita Manoj, MingLin Li, Adam J Ruben, Tao Li, Abraham G Eappen, Richard E Stafford, Natasha K C, Tooba Murshedkar, Hope DeCederfelt, Sarah H Plummer, Cynthia S Hendel, Laura Novik, Pamela J M Costner, Jamie G Saunders, Matthew B Laurens, Christopher V Plowe, Barbara Flynn, William R Whalen, J P Todd, Jay Noor, Srinivas Rao, Kailan Sierra-Davidson, Geoffrey M Lynn, Judith E Epstein, Margaret A Kemp, Gary A Fahle, Sebastian A Mikolajczak, Matthew Fishbaugher, Brandon K Sack, Stefan H I Kappe, Silas A Davidson, Lindsey S Garver, Niklas K Björkström, Martha C Nason, Barney S Graham, Mario Roederer, B Kim Lee Sim, Stephen L Hoffman, Julie E Ledgerwood, Robert A Seder
An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization...
June 2016: Nature Medicine
Jason W Bennett, Anjali Yadava, Donna Tosh, Jetsumon Sattabongkot, Jack Komisar, Lisa A Ware, William F McCarthy, Jessica J Cowden, Jason Regules, Michele D Spring, Kristopher Paolino, Joshua D Hartzell, James F Cummings, Thomas L Richie, Joanne Lumsden, Edwin Kamau, Jittawadee Murphy, Cynthia Lee, Falgunee Parekh, Ashley Birkett, Joe Cohen, W Ripley Ballou, Mark E Polhemus, Yannick F Vanloubbeeck, Johan Vekemans, Christian F Ockenhouse
BACKGROUND: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use...
February 2016: PLoS Neglected Tropical Diseases
Ruth O Payne, Kathryn H Milne, Sean C Elias, Nick J Edwards, Alexander D Douglas, Rebecca E Brown, Sarah E Silk, Sumi Biswas, Kazutoyo Miura, Rachel Roberts, Thomas W Rampling, Navin Venkatraman, Susanne H Hodgson, Geneviève M Labbé, Fenella D Halstead, Ian D Poulton, Fay L Nugent, Hans de Graaf, Priya Sukhtankar, Nicola C Williams, Christian F Ockenhouse, April K Kathcart, Aziz N Qabar, Norman C Waters, Lorraine A Soisson, Ashley J Birkett, Graham S Cooke, Saul N Faust, Colleen Woods, Karen Ivinson, James S McCarthy, Carter L Diggs, Johan Vekemans, Carole A Long, Adrian V S Hill, Alison M Lawrie, Sheetij Dutta, Simon J Draper
BACKGROUND: Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point...
June 1, 2016: Journal of Infectious Diseases
Anja Scholzen, Robert W Sauerwein
Controlled human malaria infections (CHMIs) are a powerful tool to assess the efficacy of drugs and/or vaccine candidates, but also to study anti-malarial immune responses at well-defined time points after infection. In this review, we discuss the insights that CHMI trials have provided into early immune activation and regulation during acute infection, and the capacity to induce and maintain immunological memory. Importantly, these studies show that a single infection is sufficient to induce long-lasting parasite-specific T- and B-cell memory responses, and suggest that blood-stage induced regulatory responses can limit inflammation both in ongoing and potentially future infections...
February 2016: Parasitology
Guido J H Bastiaens, Maurits P A van Meer, Anja Scholzen, Joshua M Obiero, Mansoureh Vatanshenassan, Tim van Grinsven, B Kim Lee Sim, Peter F Billingsley, Eric R James, Anusha Gunasekera, Else M Bijker, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Wouter Graumans, Cornelus C Hermsen, Quirijn de Mast, André J A M van der Ven, Stephen L Hoffman, Robert W Sauerwein
Immunization of volunteers under chloroquine prophylaxis by bites of Plasmodium falciparum sporozoite (PfSPZ)-infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in volunteers taking chloroquine (PfSPZ chemoprophylaxis vaccine [CVac]). Vaccine groups 1 and 3 received 3× monthly immunizations with 7.5 × 10(4) PfSPZ. Control groups 2 and 4 received normal saline. Groups 1 and 2 underwent CHMI (#1) by mosquito bite 60 days after the third immunization...
March 2016: American Journal of Tropical Medicine and Hygiene
Onil Bhattacharyya, Kathryn Mossman, John Ginther, Leigh Hayden, Raman Sohal, Jieun Cha, Ameya Bopardikar, John A MacDonald, Himanshu Parikh, Ilan Shahin, Anita McGahan, Will Mitchell
BACKGROUND: Many health service delivery models are adapting health services to meet rising demand and evolving health burdens in low- and middle-income countries. While innovative private sector models provide potential benefits to health care delivery, the evidence base on the characteristics and impact of such approaches is limited. We have developed a performance measurement framework that provides credible (relevant aspects of performance), feasible (available data), and comparable (across different organizations) metrics that can be obtained for private health services organizations that operate in resource-constrained settings...
2015: Globalization and Health
Kirsten E Lyke, Matthew B Laurens, Kathy Strauss, Matthew Adams, Peter F Billingsley, Eric James, Anita Manoj, Sumana Chakravarty, Christopher V Plowe, Ming Lin Li, Adam Ruben, Robert Edelman, Michael Green, Tina J Dube, B Kim Lee Sim, Stephen L Hoffman
Controlled human malaria infection (CHMI) is a powerful tool to evaluate malaria vaccine and prophylactic drug efficacy. Until recently CHMI was only carried out by the bite of infected mosquitoes. A parenteral method of CHMI would standardize Plasmodium falciparum sporozoite (PfSPZ) administration, eliminate the need for expensive challenge facility infrastructure, and allow for use of many P. falciparum strains. Recently, intradermal (ID) injection of aseptic, purified, cryopreserved PfSPZ was shown to induce P...
December 2015: American Journal of Tropical Medicine and Hygiene
Martha Sedegah, Michael R Hollingdale, Fouzia Farooq, Harini Ganeshan, Maria Belmonte, Jun Huang, Esteban Abot, Keith Limbach, Ilin Chuang, Cindy Tamminga, Judith E Epstein, Eileen Villasante
We have previously shown that a DNA-prime followed by an adenovirus-5 boost vaccine containing CSP and AMA1 (DNA/Ad) successfully protected 4 of 15 subjects to controlled human malaria infection (CHMI). However, the adenovirus-5 vaccine alone (AdCA) failed to induce protection despite eliciting cellular responses that were often higher than those induced by DNA/Ad. Here we determined the effect of CHMI on pre-CHMI cellular and antibody responses against CSP and AMA1 expressed as fold-changes in activities. Generally, in the DNA/Ad trial, CHMI caused pre-CHMI ELISpot IFN-γ and CD8+ T cell IFN-γ responses of the protected subjects to fall but among non-protected subjects, CHMI caused rises of pre-CHMI ELISpot IFN-γ but falls of CD8+ T cell IFN-γ responses...
2015: Human Vaccines & Immunotherapeutics
Gloria P Gómez-Pérez, Almudena Legarda, Jose Muñoz, B Kim Lee Sim, María Rosa Ballester, Carlota Dobaño, Gemma Moncunill, Joseph J Campo, Pau Cisteró, Alfons Jimenez, Diana Barrios, Benjamin Mordmüller, Josefina Pardos, Mireia Navarro, Cecilia Justino Zita, Carlos Arlindo Nhamuave, Alberto L García-Basteiro, Ariadna Sanz, Marta Aldea, Anita Manoj, Anusha Gunasekera, Peter F Billingsley, John J Aponte, Eric R James, Caterina Guinovart, Rosa M Antonijoan, Peter G Kremsner, Stephen L Hoffman, Pedro L Alonso
BACKGROUND: Controlled human malaria infection (CHMI) by mosquito bite is a powerful tool for evaluation of vaccines and drugs against Plasmodium falciparum malaria. However, only a small number of research centres have the facilities required to perform such studies. CHMI by needle and syringe could help to accelerate the development of anti-malaria interventions by enabling centres worldwide to employ CHMI. METHODS: An open-label CHMI study was performed with aseptic, purified, cryopreserved P...
August 7, 2015: Malaria Journal
Louise Marquart, Mark Baker, Peter O'Rourke, James S McCarthy
The ongoing development of new antimalarial drugs and the increasing use of controlled human malaria infection (CHMI) studies to investigate their activity in early-stage clinical trials require the development of methods to analyze their pharmacodynamic effect. This is especially so for studies where quantitative PCR (qPCR) is becoming the preferred method for assessing parasite clearance as the study endpoint. We report the development and validation of an analytic approach for qPCR-determined parasite clearance data...
July 2015: Antimicrobial Agents and Chemotherapy
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