Interrupt Malaria Transmission Research Articles

Evaluation of combination vaccines targeting transmission of Plasmodium falciparum and P. vivax

Transmission-blocking vaccines interrupting malaria transmission within mosquitoes represent an ideal public health tool to eliminate malaria at the population level. Plasmodium falciparum and P. vivax account for more than 90% of the global malaria burden, co-endemic in many regions of the world. P25 and P48/45 are two leading candidates for both species and have shown promising transmission-blocking activity in preclinical and clinical studies. However, neither of these target antigens as individual vaccines has induced complete transmission inhibition in mosquitoes. In this study, we assessed immunogenicity of combination vaccines based on P25 and P48/45 using a DNA vaccine platform to broaden vaccine specificity against P. falciparum and P. vivax. Individual DNA vaccines encoding Pvs25, Pfs25, Pvs48/45 and Pfs48/45, as well as various combinations including (Pvs25 + Pvs48/45), (Pfs25 + Pfs48/45), (Pvs25 + Pfs25), and (Pvs48/45 + Pfs48/45), were evaluated in mice using in vivo electroporation. Potent antibody responses were induced in mice immunized with individual and combination DNA vaccines, and specific antibody responses were not compromised when combinations of DNA vaccines were evaluated against individual DNA vaccines. The anti-Pvs25 IgG from individual and combination groups revealed concentration-dependent transmission-reducing activity (TRA) in direct membrane feeding assays (DMFA) using blood from P. vivax-infected donors in Brazil and independently in ex vivo MFA using Pvs25-transgenic P. berghei. Similarly, anti-Pfs25 and anti-Pfs48/45 IgGs from mice immunized with Pfs25 and Pfs48/45 DNA vaccines individually and in various combinations revealed antibody dose-dependent TRA in standard membrane feeding assays (SMFA) using culture-derived P. falciparum gametocytes. However, antibodies induced by immunization with Pvs48/45 DNA vaccines were ineffective in DMFA and require further vaccine construct optimization, considering the possibility of induction of both transmission-blocking and transmission-enhancing antibodies revealed by competition ELISA. These studies provide a rationale for combining multiple antigens to simultaneously target transmission of malaria caused by P. falciparum and P. vivax.

Geospatial Mapping of Malaria in the Lowland Forest Ecological Zone of Ondo State, Nigeria

Purpose: This study analyzed the spatial and temporal patterns of malaria occurrence in Ondo state, Nigeria, and to identify the major factors influencing the disease transmission and control.
 Methodology: The research collects primary data from questionnaires administered to hospital staff and workers in areas with high malaria cases while secondary data were sourced from the State’s ministry of health malaria cases gazette. The data was sorted, processed, and analyzed using Microsoft Excel and ArcGIS 10.2 software to produce maps and graphs showing the malaria occurrence and trends in the study area.
 Findings: The study analyzed the malaria occurrence and trends in Ondo State, Nigeria, from 2011 to 2018, using questionnaires and secondary data. The result revealed that mosquito, blood group, poverty, and communicability were significant factors for malaria incidence (p < 0.001), while seasonality, time of day, and immunity status were non-significant (p > 0.05). Result shows that malaria could be transmitted from mother to child during childbirth (p=0.008), but mortality was non-significant in the three Local Government Areas (LGAs) studied (p = 0.166). In addition, malaria cases and attack rate declined significantly from 2015 to 2018, due to the improved health facilities and preventive measures implemented by the State government and health authorities 
 Unique contributor to theory, policy and practice: The study contributes to the existing knowledge and literature on malaria epidemiology and control in Nigeria, by providing a comprehensive and updated spatial and temporal analysis of the disease occurrence and factors in Ondo state. The study also provides useful recommendations for the state ministry of health and government to conduct further studies and develop strategies to interrupt malaria transmission in low susceptible settings, and to achieve the goal of malaria elimination in the state in line with global setting.

MRNA-LNP expressing PfCSP and Pfs25 vaccine candidates targeting infection and transmission of Plasmodium falciparum

Malaria is a deadly disease responsible for between 550,000 and 627,000 deaths annually. There is a pressing need to develop vaccines focused on malaria elimination. The complex lifecycle of Plasmodium falciparum provides opportunities not only to target the infectious sporozoite stage, introduced by anopheline mosquitoes, but also the sexual stages, which are ingested by mosquitoes during blood feeding, leading to parasite transmission. It is widely recognized that a vaccine targeting multiple stages would induce efficacious transmission reducing immunity. Technological advancements offer new vaccine platforms, such as mRNA-LNPs, which can be used to develop highly effective malarial vaccines. We evaluated the immunogenicity of two leading P. falciparum vaccine candidates, Pfs25 and PfCSP, delivered as mRNA-LNP vaccines. Both vaccines induced extremely potent immune responses when administered alone or in combination, which were superior to Pfs25 and PfCSP DNA vaccine formulations. Purified IgGs from Pfs25 mRNA-LNPs immunized mice were highly potent in reducing malaria transmission to mosquitoes. Additionally, mice after three and four immunizations with PfCSP mRNA-LNP provided evidence for varying degrees of protection against sporozoite challenge. The comparison of immune responses and stage-specific functional activity induced by each mRNA-LNP vaccine, administered alone or in combination, also supports the development of an effective combination vaccine without any risk of immune interference for targeting malaria parasites at various life cycle stages. A combination of vaccines targeting both the infective stage and sexual/midgut stages is expected to interrupt malaria transmission, which is critical for achieving elimination goals.

Anopheline diversity in urban and peri-urban malaria foci: comparison between alternative traps and seasonal effects in a city in the Western Brazilian Amazon

BackgroundContinuous vector surveillance and sustainable interventions are mandatory in order to prevent anopheline proliferation (or spread to new areas) and interrupt malaria transmission. Anopheline abundance and richness were evaluated in urban and peri-urban malaria foci at a medium-sized city in the Brazilian Amazon, comparing the protected human landing catch technique (PHLC) and alternative sampling methods over different seasonal periods. Additional information was assessed for female feeding behaviour and faunal composition.MethodsAnophelines were sampled bimonthly in four urban and peri-urban sites in the city of Porto Velho, state of Rondônia, Brazil. The average number of captured mosquitoes was compared between an PHLC (gold standard), a tent trap (Gazetrap), and a barrier screen by means of generalized linear mixed models (GLMM), which also included season and environment (peri-urban/urban) as predictors.ResultsOverall, 2962 Anopheles individuals belonging to 12 species and one complex were caught; Anopheles darlingi represented 86% of the individuals. More mosquitoes were captured in the peri-urban setting, and the urban setting was more diverse. The model estimates that significantly more anophelines were collected by PHLC than by the Screen method, and Gazetrap captured fewer individuals. However, the Screen technique yielded more blood-engorged females. The peak hours of biting activity were from 6 to 7 p.m. in urban areas and from 7 to 8 p.m. in peri-urban areas.ConclusionsAlthough peri-urban settings presented a greater abundance of anophelines, Shannon and Simpson diversities were higher in urban sites. Each technique proved to be useful, depending on the purpose: PHLC was more effective in capturing the highest anopheline densities, Gazetrap caught the greatest number of species, and the barrier screen technique captured more engorged individuals. There was no seasonal effect on Anopheles assemblage structure; however, a more diverse fauna was caught in the transitional season. Biting activity was more intense from 6 to 8 p.m., with a predominance of An. darlingi.

Monoclonal antibodies for reducing malaria transmission

In 2020, 241 million malaria cases and 627 000 deaths were reported globally by WHO, 95% of which occurred in sub-Saharan Africa. 1 WHOWorld malaria report 2021. World Health Organization, Geneva2021 Google Scholar The maintenance of the malaria parasite within humans is reliant on the transmission of the gametocyte stage from infected humans to female Anopheles vectors during blood feeding. Gametocytes develop in humans through formation and maturation in five morphologically recognisable stages. 2 Bousema T Drakeley C Determinants of malaria transmission at the population level. Cold Spring Harb Perspect Med. 2017; 7a025510 Crossref PubMed Scopus (21) Google Scholar Early-stage gametocytes are sequestered and only mature stage V gametocytes circulate in peripheral blood. Once ingested by mosquitoes, the fusion of gametes results in the formation of zygotes that develops further into motile ookinetes and oocysts. The oocysts release sporozoites that render the mosquito infectious. To date, no effective broad treatments or preventative immune-based interventions are available to interrupt malaria transmission. Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adultsTB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season. Full-Text PDF Open Access

CRISPR/Cas9 mediates efficient site-specific mutagenesis of the odorant receptor co-receptor (Orco) in the malaria vector Anopheles sinensis.

Anopheles sinensis is the most widely distributed mosquito species and is the main transmitter of Plasmodium vivax malaria in China. Most previous research has focused on the mechanistic understanding of biological processes in An. sinensis and novel ways of interrupting malaria transmission. However, the development of functional genomics and genetics-based vector control strategies against An. sinensis remain limited because of insufficient site-specific genome editing tools. We report the first successful application of the CRISPR/Cas9 mediated knock-in for highly efficient, site-specific mutagenesis in An. sinensis. The EGFP marker gene driven by the 3 × P3 promoter was precisely integrated into the odorant receptor co-receptor (Orco) by direct injections of Cas9 protein, double-stranded DNA donor, and Orco-gRNA. We achieved a mutation rate of 3.77%, similar to rates in other mosquito species. Precise knock-in at the intended locus was confirmed by polymerase chain reaction (PCR) amplification and sequencing. The Orco mutation severely impaired mosquito sensitivity to some odors and their ability to locate and discriminate a human host. Orco was confirmed as a key mediator of multiple olfactory-driven behaviors in the An. sinensis life cycle, highlighting the importance of Orco as a key molecular target for malaria control. The results also demonstrated that CRISPR/Cas9 was a simple and highly efficient genome editing technique for An. sinensis and could be used to develop genetic control tools for this vector. © 2022 Society of Chemical Industry.

Supporting countries to achieve their malaria elimination goals: the WHO E-2020 initiative

BackgroundMalaria causes more than 200 million cases of illness and 400,000 deaths each year across 90 countries. The World Health Organization (WHO) set a goal for 35 countries to eliminate malaria by 2030, with an intermediate milestone of 10 countries by 2020. In 2017, the WHO established the Elimination-2020 (E-2020) initiative to help countries achieve their malaria elimination goals and included 21 countries with the potential to eliminate malaria by 2020.MethodsAcross its three levels of activity (country, region and global), the WHO developed normative and implementation guidance on strategies and activities to eliminate malaria; provided technical support and subnational operational assistance; convened national malaria programme managers at three global meetings to share innovations and best practices; advised countries on strengthening their strategy to prevent re-establishment and preparing for WHO malaria certification; and contributed to maintaining momentum towards elimination through periodic evaluations, monitoring and oversight of progress in the E-2020 countries. Changes in the number of indigenous cases in E-2020 countries between 2016 and 2020 are reported, along with the number of countries that eliminated malaria and received WHO certification.ResultsThe median number of indigenous cases in the E-2020 countries declined from 165.5 (interquartile range [IQR] 14.25–563.75) in 2016 to 78 (IQR 0–356) in 2020; 12 (57%) countries reported reductions in indigenous cases over that period, of which 7 (33%) interrupted malaria transmission and maintained a malaria-free status through 2020 and 4 (19%) were certified malaria-free by the WHO. Two countries experienced outbreaks of malaria in 2020 and 2021 attributed, in part, to the COVID-19 pandemic.ConclusionsAlthough the E-2020 countries contributed to the achievement of the 2020 global elimination milestone, the initiative highlights the difficulties countries face to interrupt malaria transmission, even when numbers of cases are very low. The 2025 global elimination milestone is now approaching, and the lessons learned, experience gained, and updated guidance developed during the E-2020 initiative will help serve the countries seeking to eliminate malaria by 2025.

Factors Contributing to Community None Acceptance for Indoor Residual Spraying (IRS) for Malaria prevention in Chipushi Area of Mpika, Zambia

Indoor residual spraying (IRS) is one of the primary vector control interventions for reducing and interrupting malaria transmission. In recent years, however, it has received relatively little attention. Just like it is the case in the 17 villages of the Chipushi area of Mpika district in Muchinga province, Zambia. In community work, among the things that attracted my attention are the non-acceptance and perceived negative attitudes towards acceptance for indoor residual spraying. The purpose of this study was to analyze and establish the factors that contribute to none acceptance for Indoor Residual Spraying (IRS) in the Chipushi area of Mpika, Zambia. None acceptance, in this case, refers to a widespread negative response to having indoor residual spraying performed in people’s homes at the community level. Simple random sampling was used to come up with the study population. And after executing the study through the questionnaire and semi-structured interviews on the 97 respondents, findings revealed that 12 (12.4%) respondents believed that chemicals used in IRS increase mosquitoes and bed bugs instead of controlling them. Other 22 (22.7%) never believed IRS could reduce the incidence of malaria. 18 (18.6%) respondents avoided being in-convenience by the spray operators and health personnel. 10 (10.3%) respondents don’t want to be seen how wrecked their houses are or fear of being embarrassed due to lack of sanity in their homes. Similarly, 17 (17.5%) respondents believed that by the culture, they could not allow strangers to expose their privacy in their homes. Surprisingly 26 (26.8%) respondents never just wanted to participate in spray operations. Keywords: Community, Households, Indoor Residual Spraying, Malaria elimination, Prevention.

Predicting the public health impact of a malaria transmission-blocking vaccine

Transmission-blocking vaccines that interrupt malaria transmission from humans to mosquitoes are being tested in early clinical trials. The activity of such a vaccine is commonly evaluated using membrane-feeding assays. Understanding the field efficacy of such a vaccine requires knowledge of how heavily infected wild, naturally blood-fed mosquitoes are, as this indicates how difficult it will be to block transmission. Here we use data on naturally infected mosquitoes collected in Burkina Faso to translate the laboratory-estimated activity into an estimated activity in the field. A transmission dynamics model is then utilised to predict a transmission-blocking vaccine’s public health impact alongside existing interventions. The model suggests that school-aged children are an attractive population to target for vaccination. Benefits of vaccination are distributed across the population, averting the greatest number of cases in younger children. Utilising a transmission-blocking vaccine alongside existing interventions could have a substantial impact against malaria.

Malaria is a cause of iron deficiency in African children.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n =7,453), but not among individuals living in malaria-free areas (n =3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.

Fenitrothion Bio-Efficacy on Different Intradomicile Surface Types Against Anopheles (Nyssorhynchus) Albimanus in the Main Malaria Endemic Regions of Panama

Background: The use of intradomicile residual insecticide on a large scale is a proven and efficacious intervention against malaria mosquito vectors. The objective of the study was determined the bio-efficacy and resistance of fenitrothion insecticide against the mosquito An. (Nyssorhynchus.) albimanus Wiedemann . Methods: This study included seven communities located in different endemic regions where fenitrothion is used to control An. (Nys.) albimanus populations. The test of bio-efficacy and susceptibility were conducted following the WHO standard bioassay methodology. Results: The average percent mortality of An. (Nys.) albimanus exposed to fenitrothion in the seven communities tested were 96% and 92% for the first two months. This bio-efficacy was maintained until the fifth month with 81% mortality in communities with high IRS coverage. Anopheles (Nys.) albimanus was susceptible to the organophosphate insecticides fenitrothion and malathion, as well as to carbamate propoxur but resistant to pirimiphos-methyl and chlorpyrifos. Conclusion: This study demonstrates that fenitrothion maintains an elevated insecticide residuality and toxic effect on different types of surfaces until the fifth month post-application. Furthermore, An. (Nys.) albimanus remains highly susceptible to this insecticide, providing a high degree of protection against mosquito bites inside households, and interrupting malaria transmission in places with high IRS coverage and where the mosquito is still susceptible to fenitrothion application.

Will More of the Same Achieve Malaria Elimination? Results from an Integrated Macroeconomic Epidemiological Demographic Model.

.Historic levels of funding have reduced the global burden of malaria in recent years. Questions remain, however, as to whether scaling up interventions, in parallel with economic growth, has made malaria elimination more likely today than previously. The consequences of “trying but failing” to eliminate malaria are also uncertain. Reduced malaria exposure decreases the acquisition of semi-immunity during childhood, a necessary phase of the immunological transition that occurs on the pathway to malaria elimination. During this transitional period, the risk of malaria resurgence increases as proportionately more individuals across all age-groups are less able to manage infections by immune response alone. We developed a robust model that integrates the effects of malaria transmission, demography, and macroeconomics in the context of Plasmodium falciparum malaria within a hyperendemic environment. We analyzed the potential for existing interventions, alongside economic development, to achieve malaria elimination. Simulation results indicate that a 2% increase in future economic growth will increase the US$5.1 billion cumulative economic burden of malaria in Ghana to US$7.2 billion, although increasing regional insecticide-treated net coverage rates by 25% will lower malaria reproduction numbers by just 9%, reduce population-wide morbidity by −0.1%, and reduce prevalence from 54% to 46% by 2034. As scaling up current malaria control tools, combined with economic growth, will be insufficient to interrupt malaria transmission in Ghana, high levels of malaria control should be maintained and investment in research and development should be increased to maintain the gains of the past decade and to minimize the risk of resurgence, as transmission drops.

Moving towards malaria elimination in southern Mozambique: Cost and cost-effectiveness of mass drug administration combined with intensified malaria control.

As new combinations of interventions aiming at interrupting malaria transmission are under evaluation, understanding the associated economic costs and benefits is critical for decision-making. This study assessed the economic cost and cost-effectiveness of the Magude project, a malaria elimination initiative implemented in a district in southern Mozambique (i.e. Magude) between August 2015-June 2018. This project piloted a combination of two mass drug administration (MDA) rounds per year for two consecutive years, annual rounds of universal indoor residual spraying (IRS) and a strengthened surveillance and response system on the back of universal long-lasting insecticide treated net (LLIN) coverage and routine case management implemented by the National Malaria Control Program (NMCP). Although local transmission was not interrupted, the project achieved large reductions in the burden of malaria in the target district. We collected weekly economic data, estimated costs from the project implementer perspective and assessed the incremental cost-effectiveness ratio (ICER) associated with the Magude project as compared to routine malaria control activities, the counterfactual. We estimated disability-adjusted life years (DALYs) for malaria cases and deaths and assessed the variation of the ICER over time to capture the marginal costs and effectiveness associated with subsequent phases of project implementation. We used deterministic and probabilistic sensitivity analyses to account for uncertainty and built an alternative scenario by assuming the implementation of the interventions from a governmental perspective. Economic costs are provided in constant US$2015. After three years, the Magude project averted a total of 3,171 DALYs at an incremental cost of $2.89 million and an average yearly cost of $20.7 per targeted person. At an average cost of $19.4 per person treated per MDA round, the social mobilization and distribution of door-to-door MDA contributed to 53% of overall resources employed, with personnel and logistics being the main cost drivers. The ICER improved over time as a result of decreasing costs and improved effectiveness. The overall ICER was $987 (CI95% 968-1,006) per DALY averted, which is below the standard cost-effectiveness (CE) threshold of $1,404/DALY averted, three times the gross domestic product (GDP) per capita of Mozambique, but above the threshold of interventions considered highly cost-effective (one time the GDP per capita or $468/DALY averted) and above the recently suggested thresholds based on the health opportunity cost ($537 purchasing power parity/ DALY averted). A significantly lower ICER was obtained in the implementation scenario from a governmental perspective ($441/DALY averted). Despite the initial high costs and volume of resources associated with its implementation, MDA in combination with other existing malaria control interventions, can be a cost-effective strategy to drastically reduce transmission in areas of low to moderate transmission in sub-Saharan Africa. However, further studies are needed to understand the capacity of the health system and financial affordability to scale up such strategies at regional or national level.

To screen or not to screen: an interactive framework for comparing costs of mass malaria treatment interventions

BackgroundMass drug administration and mass-screen-and-treat interventions have been used to interrupt malaria transmission and reduce burden in sub-Saharan Africa. Determining which strategy will reduce costs is an important challenge for implementers; however, model-based simulations and field studies have yet to develop consensus guidelines. Moreover, there is often no way for decision-makers to directly interact with these data and/or models, incorporate local knowledge and expertise, and re-fit parameters to guide their specific goals.MethodsWe propose a general framework for comparing costs associated with mass drug administrations and mass screen and treat based on the possible outcomes of each intervention and the costs associated with each outcome. We then used publicly available data from six countries in western Africa to develop spatial-explicit probabilistic models to estimate intervention costs based on baseline malaria prevalence, diagnostic performance, and sociodemographic factors (age and urbanicity). In addition to comparing specific scenarios, we also develop interactive web applications which allow managers to select data sources and model parameters, and directly input their own cost values.ResultsThe regional-level models revealed substantial spatial heterogeneity in malaria prevalence and diagnostic test sensitivity and specificity, indicating that a “one-size-fits-all” approach is unlikely to maximize resource allocation. For instance, urban communities in Burkina Faso typically had lower prevalence rates compared to rural communities (0.151 versus 0.383, respectively) as well as lower diagnostic sensitivity (0.699 versus 0.862, respectively); however, there was still substantial regional variation. Adjusting the cost associated with false negative diagnostic results to included additional costs, such as delayed treated and potential lost wages, undermined the overall costs associated with MSAT.ConclusionsThe observed spatial variability and dependence on specified cost values support not only the need for location-specific intervention approaches but also the need to move beyond standard modeling approaches and towards interactive tools which allow implementers to engage directly with data and models. We believe that the framework demonstrated in this article will help connect modeling efforts and stakeholders in order to promote data-driven decision-making for the effective management of malaria, as well as other diseases.

From malaria control to elimination within a decade: lessons learned from Timor Leste, a newly independent country

BackgroundTimor Leste has made remarkable progress from malaria control to malaria elimination in a span of 10 years during which organized malaria control efforts were instituted. The good practices and possible factors that have contributed to the remarkable transition from malaria control to elimination in a newly independent country devastated by civil unrest which left the entire administrative structure including the health sector in a disrupted non-functional state are highlighted.MethodsData from the National Malaria Control Programme were reviewed. A literature search was carried out using the key words “malaria”, “Timor Leste”, “East Timor”, and “malaria control” and “malaria elimination”. All relevant manuscripts and reports that were identified in the search were reviewed. Key personnel of the NMCP, WHO and the GFATM involved in the project were interviewed.ResultsWith the setting up of the National Malaria Control Programme just after independence in 2003 with two officers, the programme expanded over the years and strategic malaria control activities in an organized manner commenced in 2009 with funding from the Global Fund to fight AIDS, Tuberculosis and Malaria. The incidence of malaria declined dramatically from 223,002 cases in 2006 with the last indigenous case being reported in June 2017. The decline in malaria was associated with strategic application of key evidence-based interventions taking into account the burden of disease, characteristics of vectors, and stratification of risk areas ensuring universal access to malaria prevention, and quality assured diagnostic tools and effective anti-malarial medicines at point of care, intensified surveillance, monitoring and evaluation, and capacity building, including training of staff, with adequate programme funding. The programme was provided with technical expertise and sustained political commitment that ensured uninterrupted implementation of interventions based on national strategic plans. The incorporation of the malaria control programme within an evolving health system helped the transition from malaria control to malaria elimination.ConclusionUniversal access to quality assured malaria diagnosis and treatment and focussed vector control, implemented throughout the country in an organized manner with adequate funding and political commitment were key to the successful interruption of malaria transmission in the country. All the practices or factors listed did not work in isolation but rather synergistically in an integrated manner. Malaria elimination is possible even in tropical areas of South and Southeast Asia.

Identification, molecular characterization and expression of aminopeptidase N-1 (APN-1) from Anopheles stephensi in SF9 cell line as a candidate molecule for developing a vaccine that interrupt malaria transmission

BackgroundAccording to the World Health Organization reports, billions of people around the world are at risk for malaria disease and it is important to consider the preventive strategies for protecting the people that are living in high risk areas. One of the main reasons of disease survival is diversity of vectors and parasites in different malaria regions that have their specific features, behaviour and biology. Therefore, specific regional strategies are necessary for successful control of malaria. One of the tools that needs to be developed for elimination and prevention of reintroduction of malaria is a vaccine that interrupt malaria transmission (VIMTs). VIMT is a broad concept that should be adjusted to the biological characteristics of the disease in each region. One type of VIMT is a vector-based vaccine that affects the sexual stage of Plasmodium life cycle. According to recent studies, the aminopeptidase N-1 of Anopheles gambiae (AgAPN-1) is as a potent vector-based VIMT with considerable inhibition activity against the sexual stage of Plasmodium parasite.MethodsSystems for rapid amplification of cDNA ends (3ʹ-RACE) and genome walking methods were used for sequence determination of apn-1 gene from Anopheles stephensi and distinct bioinformatics software were used for structural analysis. AsAPN-1 was expressed in Spodoptera frugiperda (Sf9) insect cell line using the baculovirus expression system. Recombinant AsAPN-1 was purified under the hybrid condition and its biological activity was assayed.ResultsAsapn-1 gene and its coded protein from An. stephensi were characterized for the first time in this study. Subsequently, the structural features and immunological properties of its coded protein were evaluated by in silico approaches. Enzymatic activity of the recombinant AsAPN-1, which was expressed in Sf9 insect cell line, was equal to 6 unit/μl.ConclusionsResults of this study revealed that AsAPN-1 is very similar to its counterpart in An. gambiae. In silico evaluation and fundamental data which are necessary for its evaluation as a VIMT-based vaccine in the next steps were acquired in this study and those could be useful for research groups that study on malaria vaccine for countries that An. stephensi is the main malaria vector there.

Intracluster correlation coefficients in the Greater Mekong Subregion for sample size calculations of cluster randomized malaria trials

BackgroundSample size calculations for cluster randomized trials are a recognized methodological challenge for malaria research in pre-elimination settings. Positively correlated responses from the participants in the same cluster are a key feature in the estimated sample size required for a cluster randomized trial. The degree of correlation is measured by the intracluster correlation coefficient (ICC) where a higher coefficient suggests a closer correlation hence less heterogeneity within clusters but more heterogeneity between clusters.MethodsData on uPCR-detected Plasmodium falciparum and Plasmodium vivax infections from a recent cluster randomized trial which aimed at interrupting malaria transmission through mass drug administrations were used to calculate the ICCs for prevalence and incidence of Plasmodium infections. The trial was conducted in four countries in the Greater Mekong Subregion, Laos, Myanmar, Vietnam and Cambodia. Exact and simulation approaches were used to estimate ICC values for both the prevalence and the incidence of parasitaemia. In addition, the latent variable approach to estimate ICCs for the prevalence was utilized.ResultsThe ICCs for prevalence ranged between 0.001 and 0.082 for all countries. The ICC from the combined 16 villages in the Greater Mekong Subregion were 0.26 and 0.21 for P. falciparum and P. vivax respectively. The ICCs for incidence of parasitaemia ranged between 0.002 and 0.075 for Myanmar, Cambodia and Vietnam. There were very high ICCs for incidence in the range of 0.701 to 0.806 in Laos during follow-up.ConclusionICC estimates can help researchers when designing malaria cluster randomized trials. A high variability in ICCs and hence sample size requirements between study sites was observed. Realistic sample size estimates for cluster randomized malaria trials in the Greater Mekong Subregion have to assume high between cluster heterogeneity and ICCs. This work focused on uPCR-detected infections; there remains a need to develop more ICC references for trials designed around prevalence and incidence of clinical outcomes. Adequately powered trials are critical to estimate the benefit of interventions to malaria in a reliable and reproducible fashion.Trial registration: ClinicalTrials.govNCT01872702. Registered 7 June 2013. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT01872702

Investigating the drivers of the spatio-temporal patterns of genetic differences between Plasmodium falciparum malaria infections in Kilifi County, Kenya

Knowledge of how malaria infections spread locally is important both for the design of targeted interventions aiming to interrupt malaria transmission and the design of trials to assess the interventions. A previous analysis of 1602 genotyped Plasmodium falciparum parasites in Kilifi, Kenya collected over 12 years found an interaction between time and geographic distance: the mean number of single nucleotide polymorphism (SNP) differences was lower for pairs of infections which were both a shorter time interval and shorter geographic distance apart. We determine whether the empiric pattern could be reproduced by a simple model, and what mean geographic distances between parent and offspring infections and hypotheses about genotype-specific immunity or a limit on the number of infections would be consistent with the data. We developed an individual-based stochastic simulation model of households, people and infections. We parameterized the model for the total number of infections, and population and household density observed in Kilifi. The acquisition of new infections, mutation, recombination, geographic location and clearance were included. We fit the model to the observed numbers of SNP differences between pairs of parasite genotypes. The patterns observed in the empiric data could be reproduced. Although we cannot rule out genotype-specific immunity or a limit on the number of infections per individual, they are not necessary to account for the observed patterns. The mean geographic distance between parent and offspring malaria infections for the base model was 0.4 km (95% CI 0.24, 1.20), for a distribution with 58% of distances shorter than the mean. Very short mean distances did not fit well, but mixtures of distributions were also consistent with the data. For a pathogen which undergoes meiosis in a setting with moderate transmission and a low coverage of infections, analytic methods are limited but an individual-based model can be used with genotyping data to estimate parameter values and investigate hypotheses about underlying processes.

Long-distance transmission patterns modelled from SNP barcodes of Plasmodium falciparum infections in The Gambia

Malaria has declined significantly in The Gambia and determining transmission dynamics of Plasmodium falciparum can help targeting control interventions towards elimination. This can be inferred from genetic similarity between parasite isolates from different sites and timepoints. Here, we imposed a P. falciparum life cycle time on a genetic distance likelihood model to determine transmission paths from a 54 SNP barcode of 355 isolates. Samples were collected monthly during the 2013 malaria season from six pairs of villages spanning 300 km from western to eastern Gambia. There was spatial and temporal hierarchy in pairwise genetic relatedness, with the most similar barcodes from isolates within the same households and village. Constrained by travel data, the model detected 60 directional transmission events, with 27% paths linking persons from different regions. We identified 13 infected individuals (4.2% of those genotyped) responsible for 2 to 8 subsequent infections within their communities. These super-infectors were mostly from high transmission villages. When considering paths between isolates from the most distant regions (west vs east) and travel history, there were 3 transmission paths from eastern to western Gambia, all at the peak (October) of the malaria transmission season. No paths with known travel originated from the extreme west to east. Although more than half of all paths were within-village, parasite flow from east to west may contribute to maintain transmission in western Gambia, where malaria transmission is already low. Therefore, interrupting malaria transmission in western Gambia would require targeting eastern Gambia, where malaria prevalence is substantially higher, with intensified malaria interventions.

Malaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity.

The development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.