The role of research in viral disease eradication and elimination programs: Lessons for malaria eradication

By examining the role research has played in eradication or regional elimination initiatives for three viral diseases-smallpox, poliomyelitis, and measles-we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios. © 2011 Breman et al

Ecological Niche and Geographic Distribution of Human Monkeypox in Africa

Monkeypox virus, a zoonotic member of the genus Orthopoxviridae, can cause a severe, smallpox-like illness in humans. Monkeypox virus is thought to be endemic to forested areas of western and Central Africa. Considerably more is known about human monkeypox disease occurrence than about natural sylvatic cycles of this virus in non-human animal hosts. We use human monkeypox case data from Africa for 1970–2003 in an ecological niche modeling framework to construct predictive models of the ecological requirements and geographic distribution of monkeypox virus across West and Central Africa. Tests of internal predictive ability using different subsets of input data show the model to be highly robust and suggest that the distinct phylogenetic lineages of monkeypox in West Africa and Central Africa occupy similar ecological niches. High mean annual precipitation and low elevations were shown to be highly correlated with human monkeypox disease occurrence. The synthetic picture of the potential geographic distribution of human monkeypox in Africa resulting from this study should support ongoing epidemiologic and ecological studies, as well as help to guide public health intervention strategies to areas at highest risk for human monkeypox

Comparison of infant malaria incidence in districts of Maputo province, Mozambique

<p>Abstract</p> <p>Background</p> <p>Malaria is one of the principal health problems in Mozambique, representing 48% of total external consultations and 63% of paediatric hospital admissions in rural and general hospitals with 26.7% of total mortality. <it>Plasmodium falciparum </it>is responsible for 90% of all infections being also the species associated with most severe cases. The aim of this study was to identify zones of high malaria risk, showing their spatially and temporal pattern.</p> <p>Methods</p> <p>Space and time Poison model for the analysis of malaria data is proposed. This model allows for the inclusion of environmental factors: rainfall, temperature and humidity as predictor variables. Modelling and inference use the fully Bayesian approach via Markov Chain Monte Carlo (MCMC) simulation techniques. The methodology is applied to analyse paediatric data arising from districts of Maputo province, Mozambique, between 2007 and 2008.</p> <p>Results</p> <p>Malaria incidence risk is greater for children in districts of Manhiça, Matola and Magude. Rainfall and humidity are significant predictors of malaria incidence. The risk increased with rainfall (relative risk - RR: .006761, 95% interval: .001874, .01304), and humidity (RR: .049, 95% interval: .03048, .06531). Malaria incidence was found to be independent of temperature.</p> <p>Conclusions</p> <p>The model revealed a spatial and temporal pattern of malaria incidence. These patterns were found to exhibit a stable malaria transmission in most non-coastal districts. The findings may be useful for malaria control, planning and management.</p

Cross-protection between attenuated Plasmodium berghei and P. yoelii sporozoites

An attenuatedPlasmodium falciparum sporozoite (PfSPZ) vaccine is under development, in part, based on studies in mice withP. berghei. We usedP. berghei andP. yoelii to study vaccine-induced protection against challenge with a species of parasite different from the immunizing parasite in BALB/c mice. One-hundred percent of mice were protected against homologous challenge. Seventy-nine percent immunized with attenuatedP. berghei sporozoite (PbSPZ)(six experiments) were protected against challenge withP. yoelii sporozoite (PySPZ), and 63% immunized with attenuatedPySPZ(three experiments) were protected against challenge withPbSPZ. Antibodies in sera of immunized mice only recognized homologous sporozoites and could not have mediated protection against heterologous challenge. Immunization with attenuatedPySPZ orPbSPZ induced CD8+ T cell-dependent protection against heterologous challenge. Immunization with attenuatedPySPZ induced CD8+ T cell-dependent protection against homologous challenge. However, homologous protection induced by attenuatedPbSPZ was not dependent on CD8+ or CD4+ T cells, and depletion of both populations only reduced protection by 36%. Immunization of C57BL/10 mice withPbSPZ induced CD8+ T cell-dependent protection againstP. berghei, but no protection againstP. yoelii. The cross-protection data in BALB/c mice support testing a human vaccine based on attenuatedPfSPZ for its efficacy againstP. vivax

Patterns of malaria-related hospital admissions and mortality among Malawian children: an example of spatial modelling of hospital register data

BACKGROUND: Malaria is a leading cause of hospitalization and in-hospital mortality among children in Africa, yet, few studies have described the spatial distribution of the two outcomes. Here spatial regression models were applied, aimed at quantifying spatial variation and risk factors associated with malaria hospitalization and in-hospital mortality. METHODS: Paediatric ward register data from Zomba district, Malawi, between 2002 and 2003 were used, as a case study. Two spatial models were developed. The first was a Poisson model applied to analyse hospitalization and minimum mortality rates, with age and sex as covariates. The second was a logistic model applied to individual level data to analyse case-fatality rate, adjusting for individual covariates. RESULTS AND CONCLUSION: Rates of malaria hospitalization and in-hospital mortality decreased with age. Case fatality rate was associated with distance, age, wet season and increased if the patient was referred to the hospital. Furthermore, death rate was high on first day, followed by relatively low rate as length of hospital stay increased. Both outcomes showed substantial spatial heterogeneity, which may be attributed to the varying determinants of malaria risk, health services availability and accessibility, and health seeking behaviour. The increased risk of mortality of children referred from primary health facilities may imply inadequate care being available at the referring facility, or the referring facility are referring the more severe cases which are expected to have a higher case fatality rate. Improved prognosis as the length of hospital stay increased suggest that appropriate care when available can save lives. Reducing malaria burden may require integrated strategies encompassing availability of adequate care at primary facilities, introducing home or community case management as well as encouraging early referral, and reinforcing interventions to interrupt malaria transmission

Monkeypox Disease Transmission in an Experimental Setting: Prairie Dog Animal Model

Monkeypox virus (MPXV) is considered the most significant human public health threat in the genus Orthopoxvirus since the eradication of variola virus (the causative agent of smallpox). MPXV is a zoonotic agent endemic to forested areas of Central and Western Africa. In 2003, MPXV caused an outbreak in the United States due to the importation of infected African rodents, and subsequent sequential infection of North American prairie dogs (Cynomys ludovicianus) and humans. In previous studies, the prairie dog MPXV model has successfully shown to be very useful for understanding MPXV since the model emulates key characteristics of human monkeypox disease. In humans, percutaneous exposure to animals has been documented but the primary method of human-to-human MPXV transmission is postulated to be by respiratory route. Only a few animal model studies of MPXV transmission have been reported. Herein, we show that MPXV infected prairie dogs are able to transmit the virus to naive animals through multiple transmission routes. All secondarily exposed animals were infected with MPXV during the course of the study. Notably, animals secondarily exposed appeared to manifest more severe disease; however, the disease course was very similar to those of experimentally challenged animals including inappetence leading to weight loss, development of lesions, production of orthopoxvirus antibodies and shedding of similar levels or in some instances higher levels of MPXV from the oral cavity. Disease was transmitted via exposure to contaminated bedding, co-housing, or respiratory secretions/nasal mucous (we could not definitively say that transmission occurred via respiratory route exclusively). Future use of the model will allow us to evaluate infection control measures, vaccines and antiviral strategies to decrease disease transmission

Assessing the Effectiveness of a Community Intervention for Monkeypox Prevention in the Congo Basin

Human monkeypox is a potentially severe illness that begins with a high fever soon followed by the development of a smallpox-like rash. Both monkeypox and smallpox are caused by infection with viruses in the genus Orthopoxvirus. But smallpox, which only affected humans, has been eradicated, whereas monkeypox continues to occur when humans come into contact with infected animals. There are currently no drugs specifically available for the treatment of monkeypox, and the use of vaccines for prevention is limited due to safety concerns. Therefore, monkeypox prevention depends on diminishing human contact with infected animals and preventing person-to-person spread of the virus. The authors describe a film-based method for community outreach intended to increase monkeypox knowledge among residents of communities in the Republic of the Congo. Outreach was performed to ∼23,600 rural Congolese. The effectiveness of the outreach was evaluated using a sample of individuals who attended small-group sessions. The authors found that among the participants, the ability to recognize monkeypox symptoms and the willingness to take ill family members to the hospital was significantly increased after seeing the films. In contrast, the willingness to deter some high-risk behaviors, such as eating animal carcasses found in the forest, remained fundamentally unchanged

Identification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley rats

YesBackground: This study aims at characterizing the in vitro metabolism of cryptolepine using human and rat hepatocytes, identifying metabolites in rat plasma and urine after a single cryptolepine dose, and evaluating the single-dose oral and intravenous pharmacokinetics of cryptolepine in male Sprague Dawley (SD) rats. Methods: The in vitro metabolic profiles of cryptolepine were determined by LC-MS/MS following incubation with rat and human hepatocytes. The in vivo metabolic profile of cryptolepine was determined in plasma and urine samples from Sprague Dawley rats following single-dose oral administration of cryptolepine. Pharmacokinetic parameters of cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose intravenous and oral administration. Results: Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine and plasma of rats following oral administration of cryptolepine. Unchanged cryptolepine detected in urine was negligible. The Pharmacokinetic profile of cryptolepine showed a very high plasma clearance and volume of distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma exposure and oral bioavailability were low. Conclusions: Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive distribution with a moderate half-life.Funded by Novartis Pharma under the Next Generation Scientist Program