疟疾疫苗研究进展及前景

疟疾肆虐,对全球公共卫生健康提出了严峻的挑战,疫苗作为一个关键性的预防策略,为消除疟疾提供了新的机遇。随着现代科技的高速发展,科学家们针对疟疾疫苗的研究正如火如荼进行着,其中红细胞前期疟疾疫苗、红细胞内期疟疾疫苗、传播阻断疫苗以及多抗原、多表位重组疟疾疫苗和多阶段融合蛋白疟疾疫苗等的相关研究已取得了重大进展。虽目前尚未有任何一种疟疾疫苗获得上市许可,未来作为可以拯救生命的优质、高效的抗疟疫苗或将成为根除疟疾不可替代的工具。     

Severity of imported falciparum malaria: effect of taking antimalarial prophylaxis.

OBJECTIVE--To investigate the effects of antimalarial chemoprophylaxis and other variables on the severity of falciparum malaria. DESIGN--Review of consecutive malaria cases between 1987 and 1991. SETTING--The Hospital for Tropical Diseases, London. SUBJECTS--250 consecutive cases of mild and 51 consecutive cases of severe falciparum malaria. RESULTS--Prophylaxis was taken in 52.4% (131/250) of the cases of mild malaria and 21.6% (11/51) of cases of severe malaria. Severe malaria was more common in white patients than in those of African origin and was also seen more commonly in people returning from central, southern, and east Africa than in those returning from west Africa. Patients with severe malaria presented sooner than patients with mild malaria. CONCLUSIONS--Prior chemoprophylaxis led to a reduction in the severity of falciparum malaria. Ethnic origin, time to presentation, and sex were also associated with the severity of malaria.     

No Difference in the Incidence of Malaria in Human-Landing Mosquito Catch Collectors and Non-Collectors in a Senegalese Village with Endemic Malaria

BackgroundThe human landing catches is the gold standard method used to study the vectors of malaria and to estimate their aggressiveness. However, this method has raised safety concerns due to a possible increased risk of malaria or other mosquito-borne diseases among the mosquito collectors. The aim of this study was to evaluate the incidence of malaria attacks among mosquito collectors and to compare these results with those of non-collectors in a Senegalese village.MethodsFrom July 1990 to December 2011, a longitudinal malaria study involving mosquito collectors and non-collectors was performed in Dielmo village, Senegal. During the study period, 4 drugs were successively used to treat clinical malaria, and long-lasting insecticide-treated nets were offered to all villagers in July 2008. No malaria chemoprophylaxis was given to mosquito collectors. Incidence of uncomplicated clinical malaria and asymptomatic malaria infection were analyzed among these two groups while controlling for confounding factors associated with malaria risk in random effects negative binomial and logistic regression models, respectively.ResultsA total of 3,812 person-trimester observations of 199 adults at least 15 years of age were analyzed. Clinical malaria attacks accounted for 6.3% both in collectors and non-collectors, and asymptomatic malaria infections accounted for 21% and 20% in collectors and non-collectors, respectively. A non-significant lower risk of malaria was observed in the collector group in comparison with the non-collector group after adjusting for other risk factors of malaria and endemicity level (Clinical malaria: adjusted incidence rate ratio = 0.89; 95% confidence interval = 0.65-1.22; p= 0.47).ConclusionBeing a mosquito collector in Dielmo was not significantly associated with an increased risk of malaria both under holoendemic, mesoendemic and hypoendemic conditions of malaria epidemiology. This result supports the view that HLC, the most accurate method for evaluating malaria transmission, may be used without health concerns in Dielmo.     

Evaluating experimental cerebral malaria using oxidative stress indicator OKD48 mice

Cerebral malaria is a fatal complication of malaria. Conventional methods for evaluating experimental cerebral malaria have several drawbacks. Therefore, we aimed to develop an easy-to-use method for evaluating experimental cerebral malaria using OKD48 (Keap1-dependent Oxidative stress Detector, No-48-luciferase) mice to evaluate oxidative stress. OKD48 mice infected with Plasmodium berghei ANKA strain (PbA) suffered from experimental cerebral malaria and oxidative stress was successfully detected in the brains of living OKD48 mice developing experimental cerebral malaria. Oxidative stress in the brain was dependent on the development of experimental cerebral malaria, as prevention of experimental cerebral malaria did not elicit oxidative stress. We provide a novel evaluation method for experimental cerebral malaria using oxidative stress indicator OKD48 mice.     

Hot topic or hot air? Climate change and malaria resurgence in East African highlands

Climate has a significant impact on malaria incidence and we have predicted that forecast climate changes might cause some modifications to the present global distribution of malaria close to its present boundaries. However, it is quite another matter to attribute recent resurgences of malaria in the highlands of East Africa to climate change. Analyses of malaria time-series at such sites have shown that malaria incidence has increased in the absence of co-varying changes in climate. We find the widespread increase in resistance of the malaria parasite to drugs and the decrease in vector control activities to be more likely driving forces behind the malaria resurgence.     

What can the residents of malaria endemic countries do to protect themselves against malaria?

The incidence of malaria may vary substantially between adjacent communities and within an individual community, even in areas of high malaria transmission. Analysis of the factors responsible for these local variations in the incidence of malaria may identify potential control measures. Factors shown to be associated with local protection against malaria in some situations include house position, house design, the use of insect repellents and mechanical barriers such as bednets and curtains. The efficacy of insecticide treated nets and curtains in preventing mortality and morbidity from malaria, at least in the short-term, has been demonstrated convincingly. However, other measures of personal protection have not been evaluated in large trials which have clinical malaria as their endpoint. Such trials are needed to see if new malaria control tools can be identified that will assist current international efforts to improve malaria control, especially in Africa. The millions of non-immune travellers who visit malaria endemic areas each year need to protect themselves against malaria and the ways in which they can do this most effectively have been studied extensively. However, less attention has been paid to the local population of malaria endemic areas. What steps can they adopt to provide personal protection against malaria and how effective are these measures? Clues to which measures might be effective can come from study of the reasons for local variations in the incidence of malaria.     

Prevalence of Malaria in Pregnant Women in Lagos, South-West Nigeria

Prevalence rates reported for malaria in pregnancy in Nigeria vary considerably. The accuracy of results of malaria diagnosis is dependent on training, experience, and motivation of the microscopist as well as the laboratory facility available. Results of training programmes on malaria microscopy have shown low levels of sensitivity and specificity of those involved in malaria diagnosis routinely and for research. This study was done to ascertain the true prevalence of malaria in pregnancy in Lagos, South-West Nigeria. A total of 1,084 pregnant women were recruited into this study. Blood smears stained with Giemsa were used for malaria diagnosis by light microscopy. Malaria infection during pregnancy presents mostly as asymptomatic infection. The prevalence of malaria in this population was 7.7% (95% confidence interval; 6.2-9.4%). Factors identified to increase the risk of malaria infection include young maternal age (< 20 years), and gravidity (primigravida). In conclusion, this study exposes the over-diagnosis of malaria in pregnancy and the need for training and retraining of laboratory staffs as well as establishing the malaria diagnosis quality assurance programme to ensure the accuracy of malaria microscopy results at all levels.     

Affinity Proteomics Reveals Elevated Muscle Proteins in Plasma of Children with Cerebral Malaria

Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.     

Malaria vaccines: triumphs or tribulations?

A safe and effective malaria vaccine will greatly facilitate efforts to control the global spread of malaria. This paper discusses the conceptual framework for developing malaria vaccines and some of the difficulties that the various approaches face. It emphasizes the role of pre-erythrocytic malaria vaccines, which are designed to protect against malaria infection, rather than simply prevent clinical disease. It describes recent encouraging results in human subjects with the RTS,S vaccine, a promising pre-erythrocytic malaria vaccine candidate.     

Systems immunology of human malaria

Plasmodium falciparum malaria remains a global public health threat. Optimism that a highly effective malaria vaccine can be developed stems in part from the observation that humans can acquire immunity to malaria through experimental and natural P. falciparum infection. Recent advances in systems immunology could accelerate efforts to unravel the mechanisms of acquired immunity to malaria. Here, we review the tools of systems immunology, their current limitations in the context of human malaria research, and the human 'models' of malaria immunity to which these tools can be applied.     

The contribution of Plasmodium chabaudi to our understanding of malaria

Malaria kills close to a million people every year, mostly children under the age of five. In the drive towards the development of an effective vaccine and new chemotherapeutic targets for malaria, field-based studies on human malaria infection and laboratory-based studies using animal models of malaria offer complementary opportunities to further our understanding of the mechanisms behind malaria infection and pathology. We outline here the parallels between the Plasmodium chabaudi mouse model of malaria and human malaria. We will highlight the contribution of P. chabaudi to our understanding of malaria in particular, how the immune response in malaria infection is initiated and regulated, its role in pathology, and how immunological memory is maintained. We will also discuss areas where new tools have opened up potential areas of exploration using this invaluable model system.     

Combining community case management and intermittent preventive treatment for malaria

Employment of members of the community to treat malaria is a promising approach to the management of this infection in areas where access to treatment is difficult. Intermittent preventive treatment (IPT) of malaria has recently been shown to be a highly effective way of reducing morbidity from malaria in children living in areas of seasonal malaria transmission, and it can be delivered efficiently by community volunteers. Therefore, we suggest that in areas where malaria transmission is seasonal, and IPT an appropriate malaria intervention in children, community volunteers could be employed to deliver IPT during the peak malaria-transmission season and also to provide community case management during this period and during the rest of the year when occasional cases of malaria continue to occur.     

Estimating individual exposure to malaria using local prevalence of malaria infection in the field

Background

Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level.

Method and Findings

We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1₁₄₂ were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual''s malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1₁₄₂ antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66–0.73), 0.71 (95%CI: 0.69–0.73) and 0.82 (95%CI: 0.80–0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1₁₄₂ antibody levels provided an AUC of 0.83 (95%CI: 0.79–0.88).

Conclusion

We have proposed an approach to estimating the intensity of an individual''s malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria.     

Investigation of host candidate malaria-associated risk/protective SNPs in a Brazilian Amazonian population

The Brazilian Amazon is a hypo-endemic malaria region with nearly 300,000 cases each year. A variety of genetic polymorphisms, particularly in erythrocyte receptors and immune response related genes, have been described to be associated with susceptibility and resistance to malaria. In order to identify polymorphisms that might be associated with malaria clinical outcomes in a Brazilian Amazonian population, sixty-four human single nucleotide polymorphisms in 37 genes were analyzed using a Sequenom massARRAY iPLEX platform. A total of 648 individuals from two malaria endemic areas were studied, including 535 malaria cases (113 individuals with clinical mild malaria, 122 individuals with asymptomatic infection and 300 individuals with history of previous mild malaria) and 113 health controls with no history of malaria. The data revealed significant associations (p<0.003) between one SNP in the IL10 gene (rs1800896) and one SNP in the TLR4 gene (rs4986790) with reduced risk for clinical malaria, one SNP in the IRF1 gene (rs2706384) with increased risk for clinical malaria, one SNP in the LTA gene (rs909253) with protection from clinical malaria and one SNP in the TNF gene (RS1800750) associated with susceptibility to clinical malaria. Also, a new association was found between a SNP in the CTL4 gene (rs2242665), located at the major histocompatibility complex III region, and reduced risk for clinical malaria. This study represents the first association study from an Amazonian population involving a large number of host genetic polymorphisms with susceptibility or resistance to Plasmodium infection and malaria outcomes. Further studies should include a larger number of individuals, refined parameters and a fine-scale map obtained through DNA sequencing to increase the knowledge of the Amazonian population genetic diversity.     

Age-Specific Malaria Mortality Rates in the KEMRI/CDC Health and Demographic Surveillance System in Western Kenya, 2003–2010

Recent global malaria burden modeling efforts have produced significantly different estimates, particularly in adult malaria mortality. To measure malaria control progress, accurate malaria burden estimates across age groups are necessary. We determined age-specific malaria mortality rates in western Kenya to compare with recent global estimates. We collected data from 148,000 persons in a health and demographic surveillance system from 2003–2010. Standardized verbal autopsies were conducted for all deaths; probable cause of death was assigned using the InterVA-4 model. Annual malaria mortality rates per 1,000 person-years were generated by age group. Trends were analyzed using Poisson regression. From 2003–2010, in children <5 years the malaria mortality rate decreased from 13.2 to 3.7 per 1,000 person-years; the declines were greatest in the first three years of life. In children 5–14 years, the malaria mortality rate remained stable at 0.5 per 1,000 person-years. In persons ≥15 years, the malaria mortality rate decreased from 1.5 to 0.4 per 1,000 person-years. The malaria mortality rates in young children and persons aged ≥15 years decreased dramatically from 2003–2010 in western Kenya, but rates in older children have not declined. Sharp declines in some age groups likely reflect the national scale up of malaria control interventions and rapid expansion of HIV prevention services. These data highlight the importance of age-specific malaria mortality ascertainment and support current strategies to include all age groups in malaria control interventions.     

Unstable vivax malaria in Korea

Korean vivax malaria had been prevalent for longtime throughout the country with low endemicity. As a result of the Korean war (1950-1953), malaria became epidemic. In 1959-1969 when the National Malaria Eradication Service (NMES) was implemented, malaria rates declined, with low endemicity in the south-west and south plain areas and high endemic foci in north Kyongsangbuk-do (province) and north and east Kyonggi-do. NMES activities greatly contributed in accelerating the control and later eradication of malaria. The Republic of Korea (South Korea) was designated malaria free in 1979. However, malaria re-emerged in 1993 and an outbreak occurred in north Kyonggi-do and north-west Kangwon-do (in and/or near the Demilitarized Zone, DMZ), bordering North Korea. It has been postulated that most of the malaria cases resulted from bites of sporozoite-infected females of An. sinensis dispersed from North Korea across the DMZ. Judging from epidemiological and socio-ecological factors, vivax malaria would not be possible to be endemic in South Korea. Historical data show that vivax malaria in Korea is a typical unstable malaria. Epidemics may occur when environmental, socio-economical, and/or political factors change in favor to malaria transmission, and when such factors change to normal conditions malaria rates become low and may disappear. Passive case detection is a most feasible and recommendable control measure against the unstable vivax malaria in Korea in cost-effect point of view.     

Malaria in India: Challenges and opportunities

India contributes about 70% of malaria in the South East Asian Region of WHO. Although annually India reports about two million cases and 1000 deaths attributable to malaria, there is an increasing trend in the proportion of Plasmodium falciparum as the agent. There exists heterogeneity and variability in the risk of malaria transmission between and within the states of the country as many ecotypes/paradigms of malaria have been recognized. The pattern of clinical presentation of severe malaria has also changed and while multi-organ failure is more frequently observed in falciparum malaria, there are reports of vivax malaria presenting with severe manifestations. The high burden populations are ethnic tribes living in the forested pockets of the states like Orissa, Jharkhand, Madhya Pradesh, Chhattisgarh and the North Eastern states which contribute bulk of morbidity and mortality due to malaria in the country. Drug resistance, insecticide resistance, lack of knowledge of actual disease burden along with new paradigms of malaria pose a challenge for malaria control in the country. Considering the existing gaps in reported and estimated morbidity and mortality, need for estimation of true burden of malaria has been stressed. Administrative, financial, technical and operational challenges faced by the national programme have been elucidated. Approaches and priorities that may be helpful in tackling serious issues confronting malaria programme have been outlined.     

Malaria Prevalence,Spatial Clustering and Risk Factors in a Low Endemic Area of Eastern Rwanda: A Cross Sectional Study

Background

Rwanda reported significant reductions in malaria burden following scale up of control intervention from 2005 to 2010. This study sought to; measure malaria prevalence, describe spatial malaria clustering and investigate for malaria risk factors among health-centre-presumed malaria cases and their household members in Eastern Rwanda.

Methods

A two-stage health centre and household-based survey was conducted in Ruhuha sector, Eastern Rwanda from April to October 2011. At the health centre, data, including malaria diagnosis and individual level malaria risk factors, was collected. At households of these Index cases, a follow-up survey, including malaria screening for all household members and collecting household level malaria risk factor data, was conducted.

Results

Malaria prevalence among health centre attendees was 22.8%. At the household level, 90 households (out of 520) had at least one malaria-infected member and the overall malaria prevalence for the 2634 household members screened was 5.1%. Among health centre attendees, the age group 5–15 years was significantly associated with an increased malaria risk and a reported ownership of ≥4 bednets was significantly associated with a reduced malaria risk. At the household level, age groups 5–15 and >15 years and being associated with a malaria positive index case were associated with an increased malaria risk, while an observed ownership of ≥4 bednets was associated with a malaria risk-protective effect. Significant spatial malaria clustering among household cases with clusters located close to water- based agro-ecosystems was observed.

Conclusions

Malaria prevalence was significantly higher among health centre attendees and their household members in an area with significant household spatial malaria clustering. Circle surveillance involving passive case finding at health centres and proactive case detection in households can be a powerful tool for identifying household level malaria burden, risk factors and clustering.     

Predictive score of uncomplicated falciparum malaria patients turning to severe malaria

In acute uncomplicated falciparum malaria, there is a continuum from mild to severe malaria. However, no mathematical system is available to predict uncomplicated falciparum malaria patients turning to severe malaria. This study aimed to devise a simple and reliable model of Malaria Severity Prognostic Score (MSPS). The study was performed in adult patients with acute uncomplicated falciparum malaria admitted to the Bangkok Hospital for Tropical Diseases between 2000 and 2005. Total 38 initial clinical parameters were identified to predict the usual recovery or deterioration to severe malaria. The stepwise multiple discriminant analysis was performed to get a linear discriminant equation. The results showed that 4.3% of study patients turned to severe malaria. The MSPS = 4.38 (schizontemia) + 1.62 (gametocytemia) + 1.17 (dehydration) + 0.14 (overweight by body mass index; BMI) + 0.05 (initial pulse rate) + 0.04 (duration of fever before admission) - 0.50 (past history of malaria in last 1 year) - 0.48 (initial serum albumin) - 5.66. Based on the validation study in other malaria patients, the sensitivity and specificity were 88.8% and 88.4%, respectively. We conclude that the MSPS is a simple screening tool for predicting uncomplicated falciparum malaria patients turning to severe malaria. However, the MSPS may need revalidation in different geographical areas before utilized at specific places.