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Protective immune responses against <i>Schistosoma mansoni</i> infection by immunization with functionally active gut-derived cysteine peptidases alone and in combination with glyceraldehyde 3-phosphate dehydrogenase

PLoS Neglected Tropical Diseases News - 27 March 2017 - 9:00pm

by Hatem Tallima, Jan Dvořák, Sahira Kareem, Marwa Abou El Dahab, Nada Abdel Aziz, John Pius Dalton, Rashika El Ridi

Background

Schistosomiasis, a severe disease caused by parasites of the genus Schistosoma, is prevalent in 74 countries, affecting more than 250 million people, particularly children. We have previously shown that the Schistosoma mansoni gut-derived cysteine peptidase, cathepsin B1 (SmCB1), administered without adjuvant, elicits protection (>60%) against challenge infection of S. mansoni or S. haematobium in outbred, CD-1 mice. Here we compare the immunogenicity and protective potential of another gut-derived cysteine peptidase, S. mansoni cathepsin L3 (SmCL3), alone, and in combination with SmCB1. We also examined whether protective responses could be boosted by including a third non-peptidase schistosome secreted molecule, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), with the two peptidases.

Methodology/Principal findings

While adjuvant-free SmCB1 and SmCL3 induced type 2 polarized responses in CD-1 outbred mice those elicited by SmCL3 were far weaker than those induced by SmCB1. Nevertheless, both cysteine peptidases evoked highly significant (P < 0.005) reduction in challenge worm burden (54–65%) as well as worm egg counts and viability. A combination of SmCL3 and SmCB1 did not induce significantly stronger immune responses or higher protection than that achieved using each peptidase alone. However, when the two peptidases were combined with SG3PDH the levels of protection against challenge S. mansoni infection reached 70–76% and were accompanied by highly significant (P < 0.005) decreases in worm egg counts and viability. Similarly, high levels of protection were achieved in hamsters immunized with the cysteine peptidase/SG3PDH-based vaccine.

Conclusions/Significance

Gut-derived cysteine peptidases are highly protective against schistosome challenge infection when administered subcutaneously without adjuvant to outbred CD-1 mice and hamsters, and can also act to enhance the efficacy of other schistosome antigens, such as SG3PDH. This cysteine peptidase-based vaccine should now be advanced to experiments in non-human primates and, if shown promise, progressed to Phase 1 safety trials in humans.

Water, Sanitation and Hygiene (WASH) and environmental risk factors for soil-transmitted helminth intensity of infection in Timor-Leste, using real time PCR

PLoS Neglected Tropical Diseases News - 27 March 2017 - 9:00pm

by Suzy J. Campbell, Susana V. Nery, Rebecca Wardell, Catherine A. D’Este, Darren J. Gray, James S. McCarthy, Rebecca J. Traub, Ross M. Andrews, Stacey Llewellyn, Andrew J. Vallely, Gail M. Williams, Archie C. A. Clements

Background

No investigations have been undertaken of risk factors for intensity of soil-transmitted helminth (STH) infection in Timor-Leste. This study provides the first analysis of risk factors for intensity of STH infection, as determined by quantitative PCR (qPCR), examining a broad range of water, sanitation and hygiene (WASH) and environmental factors, among communities in Manufahi District, Timor-Leste.

Methods

A baseline cross-sectional survey of 18 communities was undertaken as part of a cluster randomised controlled trial, with additional identically-collected data from six other communities. qPCR was used to assess STH infection from stool samples, and questionnaires administered to collect WASH, demographic, and socioeconomic data. Environmental information was obtained from open-access sources and linked to infection outcomes. Mixed-effects multinomial logistic regression was undertaken to assess risk factors for intensity of Necator americanus and Ascaris infection.

Results

2152 participants provided stool and questionnaire information for this analysis. In adjusted models incorporating WASH, demographic and environmental variables, environmental variables were generally associated with infection intensity for both N. americanus and Ascaris spp. Precipitation (in centimetres) was associated with increased risk of moderate-intensity (adjusted relative risk [ARR] 6.1; 95% confidence interval [CI] 1.9–19.3) and heavy-intensity (ARR 6.6; 95% CI 3.1–14.1) N. americanus infection, as was sandy-loam soil around households (moderate-intensity ARR 2.1; 95% CI 1.0–4.3; heavy-intensity ARR 2.7; 95% CI 1.6–4.5; compared to no infection). For Ascaris, alkaline soil around the household was associated with reduced risk of moderate-intensity infection (ARR 0.21; 95% CI 0.09–0.51), and heavy-intensity infection (ARR 0.04; 95% CI 0.01–0.25). Few WASH risk factors were significant.

Conclusion

In this high-prevalence setting, strong risk associations with environmental factors indicate that anthelmintic treatment alone will be insufficient to interrupt STH transmission, as conditions are favourable for ongoing environmental transmission. Integrated STH control strategies should be explored as a priority.

Rapid Surveillance for Vector Presence (RSVP): Development of a novel system for detecting <i>Aedes aegypti</i> and <i>Aedes albopictus</i>

PLoS Neglected Tropical Diseases News - 24 March 2017 - 9:00pm

by Brian L. Montgomery, Martin A. Shivas, Sonja Hall-Mendelin, Jim Edwards, Nicholas A. Hamilton, Cassie C. Jansen, Jamie L. McMahon, David Warrilow, Andrew F. van den Hurk

Background

The globally important Zika, dengue and chikungunya viruses are primarily transmitted by the invasive mosquitoes, Aedes aegypti and Aedes albopictus. In Australia, there is an increasing risk that these species may invade highly urbanized regions and trigger outbreaks. We describe the development of a Rapid Surveillance for Vector Presence (RSVP) system to expedite presence- absence surveys for both species.

Methodology/Principal findings

We developed a methodology that uses molecular assays to efficiently screen pooled ovitrap (egg trap) samples for traces of target species ribosomal RNA. Firstly, specific real-time reverse transcription-polymerase chain reaction (RT-PCR) assays were developed which detect a single Ae. aegypti or Ae. albopictus first instar larva in samples containing 4,999 and 999 non-target mosquitoes, respectively. ImageJ software was evaluated as an automated egg counting tool using ovitrap collections obtained from Brisbane, Australia. Qualitative assessment of ovistrips was required prior to automation because ImageJ did not differentiate between Aedes eggs and other objects or contaminants on 44.5% of ovistrips assessed, thus compromising the accuracy of egg counts. As a proof of concept, the RSVP was evaluated in Brisbane, Rockhampton and Goomeri, locations where Ae. aegypti is considered absent, present, and at the margin of its range, respectively. In Brisbane, Ae. aegypti was not detected in 25 pools formed from 477 ovitraps, comprising ≈ 54,300 eggs. In Rockhampton, Ae. aegypti was detected in 4/6 pools derived from 45 ovitraps, comprising ≈ 1,700 eggs. In Goomeri, Ae. aegypti was detected in 5/8 pools derived from 62 ovitraps, comprising ≈ 4,200 eggs.

Conclusions/Significance

RSVP can rapidly detect nucleic acids from low numbers of target species within large samples of endemic species aggregated from multiple ovitraps. This screening capability facilitates deployment of ovitrap configurations of varying spatial scales, from a single residential block to entire suburbs or towns. RSVP is a powerful tool for surveillance of invasive Aedes spp., validation of species eradication and quality assurance for vector control operations implemented during disease outbreaks.

Vector status of <i>Aedes</i> species determines geographical risk of autochthonous Zika virus establishment

PLoS Neglected Tropical Diseases News - 24 March 2017 - 9:00pm

by Lauren Gardner, Nan Chen, Sahotra Sarkar

Background

The 2015-16 Zika virus pandemic originating in Latin America led to predictions of a catastrophic global spread of the disease. Since the current outbreak began in Brazil in May 2015 local transmission of Zika has been reported in over 60 countries and territories, with over 750 thousand confirmed and suspected cases. As a result of its range expansion attention has focused on possible modes of transmission, of which the arthropod vector-based disease spread cycle involving Aedes species is believed to be the most important. Additional causes of concern are the emerging new links between Zika disease and Guillain-Barre Syndrome (GBS), and a once rare congenital disease, microcephaly.

Methodology/principal findings

Like dengue and chikungunya, the geographic establishment of Zika is thought to be limited by the occurrence of its principal vector mosquito species, Ae. aegypti and, possibly, Ae. albopictus. While Ae. albopictus populations are more widely established than those of Ae. aegypti, the relative competence of these species as a Zika vector is unknown. The analysis reported here presents a global risk model that considers the role of each vector species independently, and quantifies the potential spreading risk of Zika into new regions. Six scenarios are evaluated which vary in the weight assigned to Ae. albopictus as a possible spreading vector. The scenarios are bounded by the extreme assumptions that spread is driven by air travel and Ae. aegypti presence alone and spread driven equally by both species. For each scenario destination cities at highest risk of Zika outbreaks are prioritized, as are source cities in affected regions. Finally, intercontinental air travel routes that pose the highest risk for Zika spread are also ranked. The results are compared between scenarios.

Conclusions/significance

Results from the analysis reveal that if Ae. aegypti is the only competent Zika vector, then risk is geographically limited; in North America mainly to Florida and Texas. However, if Ae. albopictus proves to be a competent vector of Zika, which does not yet appear to be the case, then there is risk of local establishment in all American regions including Canada and Chile, much of Western Europe, Australia, New Zealand, as well as South and East Asia, with a substantial increase in risk to Asia due to the more recent local establishment of Zika in Singapore.

Dengue seroprevalence, seroconversion and risk factors in Dhaka, Bangladesh

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Parnali Dhar-Chowdhury, Kishor Kumar Paul, C. Emdad Haque, Shakhawat Hossain, L. Robbin Lindsay, Antonia Dibernardo, W. Abdullah Brooks, Michael A. Drebot

Background

Dengue virus (DENV) activity has been reported in Dhaka, Bangladesh since the early 1960s with the greatest burden of dengue fever and dengue hemorrhagic fever cases observed in 2000. Since this time, the intensity of dengue activity has varied from year to year, and its determining factors remained relatively unknown. In light of such gaps in knowledge, the main objectives of this study were to determine the magnitude of seroprevalence and seroconversion among the surveyed population, and establish the individual/household level risk factors for the presence of DENV antibodies among all age groups of target populations in the city of Dhaka.

Methodology/Principal findings

Considering the lack of fine scale investigations on the factors driving dengue activity in Bangladesh, a prospective cohort study involving serological surveys was undertaken with participant interviews and blood donation across the city of Dhaka in 2012. Study participants were recruited from 12 of 90 wards and blood samples were collected during both the pre-monsoon (n = 1125) and post-monsoon (n = 600) seasons of 2012. The findings revealed that the seroprevalence in all pre-monsoon samples was 80.0% (900/1125) while the seropositivity in the pre-monsoon samples that had paired post-monsoon samples was 83.3% (503/600). Of the 97 paired samples that were negative at the pre-monsoon time point, 56 were positive at the post-monsoon time point. This resulted in a seroprevalence of 93.2% (559/600) among individuals tested during the post-monsoon period. Seroprevalence trended higher with age with children exhibiting a lower seropositivity as compared to adults. Results from this study also indicated that DENV strains were the only flaviviruses circulating in Dhaka in 2012. A multivariate analysis revealed that age, possession of indoor potted plants, and types of mosquito control measures were significant factors associated with dengue seroprevalence; while attendance in public/mass gatherings, and use of mosquito control measures were significantly associated with DENV seroconversion after adjusting for all other variables.

Conclusions/Significance

Our study suggests that there is a high level of endemic dengue virus circulation in the city of Dhaka which has resulted in significant DENV seroprevalence among its residents. Seropositivity increased with age, however, a substantial proportion of children are at risk for DENV infections. Our serological analysis also documents considerable DENV seroconversions among study participants which indicates that a large proportion of the population in the city of Dhaka were newly exposed to DENV during the study period (pre-and post-monsoon 2012). High levels of seroconversion suggest that there was an intense circulation of DENV in 2012 and this may have resulted in a significant risk for viral associated illness. Findings of our study further indicated that home-based interventions, such as removing indoor potted plants and increased bed net use, in addition to vector control measures in public parks, would reduce exposure to DENV and further decrease risk of viral associated disease.

Interdisciplinary approach at the primary healthcare level for Bolivian immigrants with Chagas disease in the city of São Paulo

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Maria Aparecida Shikanai Yasuda, Camila Gonçalves Sátolo, Noemia Barbosa Carvalho, Magda Maya Atala, Rosario Quiroga Ferrufino, Ruth Moreira Leite, Célia Regina Furucho, Expedito Luna, Rubens Antonio Silva, Marcia Hage, Caroline Medeji Ramos de Oliveira, Felipe Delatorre Busser, Vera Lucia Teixeira de Freitas, Dalva Marli Valerio Wanderley, Luzia Martinelli, Sonia Regina Almeida, Pedro Albajar Viñas, Nivaldo Carneiro Jr.

Background/Methods

In a pioneering cross-sectional study among Bolivian immigrants in the city of São Paulo, Brazil, the epidemiological profile, clinical manifestations and morbidity of Chagas disease were described. The feasibility of the management of Chagas disease at primary healthcare clinics using a biomedical and psychosocial interdisciplinary approach was also tested. Previously, a Trypanosoma cruzi (T. cruzi) infection rate of 4.4% among 633 immigrants was reported. The samples were screened using two commercial enzyme-linked immunoassay (ELISA) tests generated with epimastigote antigens, and those with discrepant or seropositive results were analyzed by confirmatory tests: indirect immunofluorescence (IFI), TESA-blot and a commercial recombinant ELISA. PCR and blood cultures were performed in seropositive patients.

Results

The majority of the 28 seropositive patients were women, of whom 88.89% were of child-bearing age. The predominant clinical forms of Chagas disease were the indeterminate and atypical cardiac forms. Less than 50% received the recommended antiparasitic treatment of benznidazole. An interdisciplinary team was centered on primary healthcare physicians who applied guidelines for the management of patients. Infectologists, cardiologists, pediatricians and other specialists acted as reference professionals. Confirmatory serology and molecular biology tests, as well as echocardiography, Holter and other tests, were performed for the assessment of affected organs in secondary healthcare centers. The published high performance of two commercial ELISA tests was not confirmed.

Conclusion

An interdisciplinary approach including antiparasitic treatment is feasible at the primary healthcare level for the management of Chagas disease in Bolivian immigrants. The itinerant feature of immigration was associated with a lack of adherence to antiparasitic treatment and was considered a main challenge for the clinical management of this population. This approach is recommended for management of the infected population in endemic and nonendemic areas, although different strategies are needed depending on the severity of the disease and the structure of the healthcare system.

Immune response of rats vaccinated orally with various plant-expressed recombinant cysteine proteinase constructs when challenged with <i>Fasciola hepatica</i> metacercariae

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Malgorzata Kesik-Brodacka, Agnieszka Lipiec, Monika Kozak Ljunggren, Luiza Jedlina, Katarzyna Miedzinska, Magdalena Mikolajczak, Andrzej Plucienniczak, Andrzej B. Legocki, Halina Wedrychowicz

Background

Cysteine proteinases of Fasciola hepatica are important candidates for vaccine antigens because of their role in fluke biology and host-parasite relationships. In our previous experiments, we found that a recombinant cysteine proteinase cloned from adult F. hepatica (CPFhW) can protect rats against liver fluke infections when it is administered intramuscularly or intranasally in the form of cDNA. We also observed considerable protection upon challenge following mucosal vaccination with inclusion bodies containing recombinant CPFhW produced in Escherichia coli.In this study, we explore oral vaccination, which may be the desired method of delivery and is potentially capable of preventing infections at the site of helminth entry. To provide antigen encapsulation and to protect the vaccine antigen from degradation in the intestinal tract, transgenic plant-based systems are used.

Methodology

In the present study, we aimed to evaluate the protective ability of mucosal vaccinations of 12-week-old rats with CPFhW produced in a transgenic-plant-based system. To avoid inducing tolerance and to maximise the immune response induced by oral immunisation, we used the hepatitis B virus (HBV) core protein (HBcAg) as a carrier. Animals were immunised with two doses of the antigen and challenged with 25 or 30 metacercariae of F. hepatica.

Conclusions

We obtained substantial protection after oral administration of the plant-produced hybrids of CPFhW and HBcAg. The highest level of protection (65.4%) was observed in animals immunised with transgenic plants expressing the mature CPFhW enzyme flanked by Gly-rich linkers and inserted into c/e1 epitope of truncated HBcAg. The immunised rats showed clear IgG1 and IgM responses to CPFhW for 4 consecutive weeks after the challenge.

Performance of TcI/TcVI/TcII Chagas-Flow ATE-IgG2a for universal and genotype-specific serodiagnosis of <i>Trypanosoma cruzi</i> infection

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Glaucia Diniz Alessio, Fernanda Fortes de Araújo, Denise Fonseca Côrtes, Policarpo Ademar Sales Júnior, Daniela Cristina Lima, Matheus de Souza Gomes, Laurence Rodrigues do Amaral, Marcelo Antônio Pascoal Xavier, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Marta de Lana

Distinct Trypanosoma cruzi genotypes have been considered relevant for patient management and therapeutic response Chagas disease. However, typing strategies for genotype-specific serodiagnosis of Chagas disease are still unavailable and requires standardization for practical application. In this study, an innovative TcI/TcVI/TcII Chagas Flow ATE-IgG2a technique was developed with applicability for universal and genotype-specific diagnosis of T. cruzi infection. For this purpose, the reactivity of serum samples (percentage of positive fluorescent parasites-PPFP) obtained from mice chronically infected with TcI/Colombiana, TcVI/CL or TcII/Y strain as well as non-infected controls were determined using amastigote-AMA, trypomastigote-TRYPO and epimastigote-EPI in parallel batches of TcI, TcVI and TcII target antigens. Data demonstrated that “α-TcII-TRYPO/1:500, cut-off/PPFP = 20%” presented an excellent performance for universal diagnosis of T. cruzi infection (AUC = 1.0, Se and Sp = 100%). The combined set of attributes “α-TcI-TRYPO/1:4,000, cut-off/PPFP = 50%”, “α-TcII-AMA/1:1,000, cut-off/PPFP = 40%” and “α-TcVI-EPI/1:1,000, cut-off/PPFP = 45%” showed good performance to segregate infections with TcI/Colombiana, TcVI/CL or TcII/Y strain. Overall, hosts infected with TcI/Colombiana and TcII/Y strains displayed opposite patterns of reactivity with “α-TcI TRYPO” and “α-TcII AMA”. Hosts infected with TcVI/CL strain showed a typical interweaved distribution pattern. The method presented a good performance for genotype-specific diagnosis, with global accuracy of 69% when the population/prototype scenario include TcI, TcVI and TcII infections and 94% when comprise only TcI and TcII infections. This study also proposes a receiver operating reactivity panel, providing a feasible tool to classify serum samples from hosts infected with distinct T. cruzi genotypes, supporting the potential of this method for universal and genotype-specific diagnosis of T. cruzi infection.

The rise and fall of rabies in Japan: A quantitative history of rabies epidemics in Osaka Prefecture, 1914–1933

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Aiko Kurosawa, Kageaki Tojinbara, Hazumu Kadowaki, Katie Hampson, Akio Yamada, Kohei Makita

Japan has been free from rabies since the 1950s. However, during the early 1900s several large-scale epidemics spread throughout the country. Here we investigate the dynamics of these epidemics between 1914 and 1933 in Osaka Prefecture, using archival data including newspapers. The association between dog rabies cases and human population density was investigated using Mixed-effects models and epidemiological parameters such as the basic reproduction number (R0), the incubation and infectious period and the serial interval were estimated. A total of 4,632 animal rabies cases were reported, mainly in dogs (99.0%, 4,584 cases) during two epidemics from 1914 to 1921, and 1922 to 1933 respectively. The second epidemic was larger (3,705 cases) than the first (879 cases), but had a lower R0 (1.50 versus 2.42). The first epidemic was controlled through capture of stray dogs and tethering of pet dogs. Dog mass vaccination began in 1923, with campaigns to capture stray dogs. Rabies in Osaka Prefecture was finally eliminated in 1933. A total of 3,805 rabid dog-bite injuries, and 75 human deaths were reported. The relatively low incidence of human rabies, high ratio of post-exposure vaccines (PEP) and bite injuries by rabid dogs (minimum 6.2 to maximum 73.6, between 1924 and 1928), and a decline in the proportion of bite victims that developed hydrophobia over time (slope = -0.29, se = 3, p < 0.001), indicated that increased awareness and use of PEP might have prevented disease. Although significantly more dog rabies cases were detected at higher human population densities (slope = 0.66, se = 0.03, p < 0.01), there were fewer dog rabies cases detected per capita (slope = -0.34, se = 0.03, p < 0.01). We suggest that the combination of mass vaccination and restriction of dog movement enabled by strong legislation was key to eliminate rabies. Moreover, the prominent role of the media in both reporting rabies cases and efforts to control the disease likely contributed to promoting the successful participation required to achieve rabies elimination.

The relationship between entomological indicators of <i>Aedes aegypti</i> abundance and dengue virus infection

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Elizabeth A. Cromwell, Steven T. Stoddard, Christopher M. Barker, Annelies Van Rie, William B. Messer, Steven R. Meshnick, Amy C. Morrison, Thomas W. Scott

Routine entomological monitoring data are used to quantify the abundance of Ae. aegypti. The public health utility of these indicators is based on the assumption that greater mosquito abundance increases the risk of human DENV transmission, and therefore reducing exposure to the vector decreases incidence of infection. Entomological survey data from two longitudinal cohort studies in Iquitos, Peru, linked with 8,153 paired serological samples taken approximately six months apart were analyzed. Indicators of Ae. aegypti density were calculated from cross-sectional and longitudinal entomological data collected over a 12-month period for larval, pupal and adult Ae. aegypti. Log binomial models were used to estimate risk ratios (RR) to measure the association between Ae. aegypti abundance and the six-month risk of DENV seroconversion. RRs estimated using cross-sectional entomological data were compared to RRs estimated using longitudinal data. Higher cross-sectional Ae. aegypti densities were not associated with an increased risk of DENV seroconversion. Use of longitudinal entomological data resulted in RRs ranging from 1.01 (95% CI: 1.01, 1.02) to 1.30 (95% CI: 1.17, 1.46) for adult stage density estimates and RRs ranging from 1.21 (95% CI: 1.07, 1.37) to 1.75 (95% CI: 1.23, 2.5) for categorical immature indices. Ae. aegypti densities calculated from longitudinal entomological data were associated with DENV seroconversion, whereas those measured cross-sectionally were not. Ae. aegypti indicators calculated from cross-sectional surveillance, as is common practice, have limited public health utility in detecting areas or populations at high risk of DENV infection.

Zika: A scourge in urban slums

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Robert E. Snyder, Claire E. Boone, Claudete A. Araújo Cardoso, Fabio Aguiar-Alves, Felipe P. G. Neves, Lee W. Riley

Fifteen years of programme implementation for the elimination of Lymphatic Filariasis in Ghana: Impact of MDA on immunoparasitological indicators

PLoS Neglected Tropical Diseases News - 23 March 2017 - 9:00pm

by Nana-Kwadwo Biritwum, Dziedzom K. de Souza, Benjamin Marfo, Samuel Odoom, Bright Alomatu, Odame Asiedu, Abednego Yeboah, Tei E. Hervie, Ernest O. Mensah, Paul Yikpotey, Joseph B. Koroma, David Molyneux, Moses J. Bockarie, John O. Gyapong

Correction: Metformin exhibits preventive and therapeutic efficacy against experimental cystic echinococcosis

PLoS Neglected Tropical Diseases News - 22 March 2017 - 9:00pm

by Julia A. Loos, Valeria A. Dávila, Christian Rodriguez Rodrigues, Romina Petrigh, Jorge A. Zoppi, Fernando A. Crocenzi, Andrea C. Cumino

Using simulation to aid trial design: Ring-vaccination trials

PLoS Neglected Tropical Diseases News - 22 March 2017 - 9:00pm

by Matt David Thomas Hitchings, Rebecca Freeman Grais, Marc Lipsitch

Background

The 2014–6 West African Ebola epidemic highlights the need for rigorous, rapid clinical trial methods for vaccines. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination.

Methods and findings

We present a stochastic, compartmental model for a ring vaccination trial. After identification of an index case, a ring of contacts is recruited and either vaccinated immediately or after 21 days. The primary outcome of the trial is total vaccine effect, counting cases only from a pre-specified window in which the immediate arm is assumed to be fully protected and the delayed arm is not protected. Simulation results are used to calculate necessary sample size and estimated vaccine effect. Under baseline assumptions about vaccine properties, monthly incidence in unvaccinated rings and trial design, a standard sample-size calculation neglecting dynamic effects estimated that 7,100 participants would be needed to achieve 80% power to detect a difference in attack rate between arms, while incorporating dynamic considerations in the model increased the estimate to 8,900. This approach replaces assumptions about parameters at the ring level with assumptions about disease dynamics and vaccine characteristics at the individual level, so within this framework we were able to describe the sensitivity of the trial power and estimated effect to various parameters. We found that both of these quantities are sensitive to properties of the vaccine, to setting-specific parameters over which investigators have little control, and to parameters that are determined by the study design.

Conclusions

Incorporating simulation into the trial design process can improve robustness of sample size calculations. For this specific trial design, vaccine effectiveness depends on properties of the ring vaccination design and on the measurement window, as well as the epidemiologic setting.

H<sup>+</sup> channels in embryonic <i>Biomphalaria glabrata</i> cell membranes: Putative roles in snail host-schistosome interactions

PLoS Neglected Tropical Diseases News - 20 March 2017 - 9:00pm

by Brandon J. Wright, Utibe Bickham-Wright, Timothy P. Yoshino, Meyer B. Jackson

The human blood fluke Schistosoma mansoni causes intestinal schistosomiasis, a widespread neglected tropical disease. Infection of freshwater snails Biomphalaria spp. is an essential step in the transmission of S. mansoni to humans, although the physiological interactions between the parasite and its obligate snail host that determine success or failure are still poorly understood. In the present study, the B. glabrata embryonic (Bge) cell line, a widely used in vitro model for hemocyte-like activity, was used to investigate membrane properties, and assess the impact of larval transformation proteins (LTP) on identified ion channels. Whole-cell patch clamp recordings from Bge cells demonstrated that a Zn2+-sensitive H+ channel serves as the dominant plasma membrane conductance. Moreover, treatment of Bge cells with Zn2+ significantly inhibited an otherwise robust production of reactive oxygen species (ROS), thus implicating H+ channels in the regulation of this immune function. A heat-sensitive component of LTP appears to target H+ channels, enhancing Bge cell H+ current over 2-fold. Both Bge cells and B. glabrata hemocytes express mRNA encoding a hydrogen voltage-gated channel 1 (HVCN1)-like protein, although its function in hemocytes remains to be determined. This study is the first to identify and characterize an H+ channel in non-neuronal cells of freshwater molluscs. Importantly, the involvement of these channels in ROS production and their modulation by LTP suggest that these channels may function in immune defense responses against larval S. mansoni.

Evaluation of radiation sensitivity and mating performance of <i>Glossina brevipalpis</i> males

PLoS Neglected Tropical Diseases News - 17 March 2017 - 9:00pm

by Chantel J. de Beer, Percy Moyaba, Solomon N. B. Boikanyo, Daphney Majatladi, Hanano Yamada, Gert J. Venter, Marc J. B. Vreysen

Background

Area-wide integrated pest management strategies that include a sterile insect technique component have been successfully used to eradicate tsetse fly populations in the past. To ensure the success of the sterile insect technique, the released males must be adequately sterile and be able to compete with their native counterparts in the wild.

Methodology/Principal findings

In the present study the radiation sensitivity of colonised Glossina brevipalpis Newstead (Diptera; Glossinidae) males, treated either as adults or pupae, was assessed. The mating performance of the irradiated G. brevipalpis males was assessed in walk-in field cages. Glossina brevipalpis adults and pupae were highly sensitive to irradiation, and a dose of 40 Gy and 80 Gy induced 93% and 99% sterility respectively in untreated females that mated with males irradiated as adults. When 37 to 41 day old pupae were exposed to a dose of 40 Gy, more than 97% sterility was induced in untreated females that mated with males derived from irradiated pupae. Males treated as adults with a dose up to 80 Gy were able to compete successfully with untreated fertile males for untreated females in walk-in field cages.

Conclusions/Significance

The data emanating from this field cage study indicates that, sterile male flies derived from the colony of G. brevipalpis maintained at the Agricultural Research Council-Onderstepoort Veterinary Institute in South Africa are potential good candidates for a campaign that includes a sterile insect technique component. This would need to be confirmed by open field studies.

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in <i>Trypanosoma cruzi</i>

PLoS Neglected Tropical Diseases News - 17 March 2017 - 9:00pm

by Chantal Reigada, Edward A. Valera-Vera, Melisa Sayé, Andrea E. Errasti, Carla C. Avila, Mariana R. Miranda, Claudio A. Pereira

Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6–10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

Barriers to dog rabies vaccination during an urban rabies outbreak: Qualitative findings from Arequipa, Peru

PLoS Neglected Tropical Diseases News - 17 March 2017 - 9:00pm

by Ricardo Castillo-Neyra, Joanna Brown, Katty Borrini, Claudia Arevalo, Michael Z. Levy, Alison Buttenheim, Gabrielle C. Hunter, Victor Becerra, Jere Behrman, Valerie A. Paz-Soldan

Background

Canine rabies was reintroduced to the city of Arequipa, Peru in March 2015. The Ministry of Health has conducted a series of mass dog vaccination campaigns to contain the outbreak, but canine rabies virus transmission continues in Arequipa’s complex urban environment, putting the city’s 1 million inhabitants at risk of infection. The proximate driver of canine rabies in Arequipa is low dog vaccination coverage. Our objectives were to qualitatively assess barriers to and facilitators of rabies vaccination during mass campaigns, and to explore strategies to increase participation in future efforts.

Methodology/Principal findings

We conducted 8 focus groups (FG) in urban and peri-urban communities of Mariano Melgar district; each FG included both sexes, and campaign participants and non-participants. All FG were transcribed and then coded independently by two coders. Results were summarized using the Social Ecological Model. At the individual level, participants described not knowing enough about rabies and vaccination campaigns, mistrusting the campaign, and being unable to handle their dogs, particularly in peri-urban vs. urban areas. At the interpersonal level, we detected some social pressure to vaccinate dogs, as well as some disparaging of those who invest time and money in pet dogs. At the organizational level, participants found the campaign information to be insufficient and ill-timed, and campaign locations and personnel inadequate. At the community level, the influence of landscape and topography on accessibility to vaccination points was reported differently between participants from the urban and peri-urban areas. Poor security and impermanent housing materials in the peri-urban areas also drives higher prevalence of guard dog ownership for home protection; these dogs usually roam freely on the streets and are more difficult to handle and bring to the vaccination points.

Conclusions

A well-designed communication campaign could improve knowledge about canine rabies. Timely messages on where and when vaccination is occurring could increase dog owners’ perception of their own ability to bring their dogs to the vaccination points and be part of the campaign. Small changes in the implementation of the campaign at the vaccination points could increase the public’s trust and motivation. Location of vaccination points should take into account landscape and community concerns.

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