Mapping the global extent of malaria in 2005

Guidelines for travellers on malaria chemoprophylaxis, the altitude limits of dominant vector species, climate suitability for malaria transmission and human population density thresholds have been used to map the crude spatial limits of Plasmodium falciparum and Plasmodium vivax transmission on a global scale. These maps suggest that 2.510 and 2.596 billion people were at possible risk of transmission of P. falciparum and P. vivax, respectively, in 2005. Globally, 75 per cent of humans who are exposed to P. falciparum risk live in only ten countries.     

Getting down to malarial nuts and bolts: the interaction between Plasmodium vivax merozoites and their host erythrocytes

Of the four Plasmodium species that routinely cause malaria in humans, Plasmodium falciparum is responsible for the majority of malaria mortality and consequently gets most of the headlines. Outside Africa, however, more malaria cases are caused by its distant cousin Plasmodium vivax, resulting in a daunting morbidity and economic burden for countries across Asia and the Americas. Plasmodium life cycles are complex, but the symptoms and pathology of malaria occur during the blood phase, when merozoites recognize and invade erythrocytes, initiating a developmental programme that culminates in lysis of the erythrocyte and release of multiple daughter merozoites. P. vivax merozoites are dependent on a single host cell receptor for erythrocyte invasion, the Duffy antigen receptor for chemokines, and humans that do not express this receptor on the surface of their erythrocytes are immune to P. vivax infection. This essential receptor-ligand interaction is addressed from both the host and parasite side in two papers in this issue of Molecular Microbiology, with important implications for plans to develop a P. vivax vaccine.     

An update on the search for a Plasmodium vivax vaccine

Although Plasmodium falciparum is the leading cause of morbidity and mortality due to malaria worldwide, nearly 2.5 billion people, mostly outside Africa, are also at risk from malaria caused by Plasmodium vivax infection. Currently, almost all efforts to develop a malaria vaccine have focused on P. falciparum. For example, there are 23 P. falciparum vaccine candidates undergoing advanced clinical studies and only two P. vivax vaccine candidates being tested in preliminary (Phase I) clinical trials, with few others being assessed in preclinical studies. More investment and a greater effort toward the development of P. vivax vaccine components for a multi-species vaccine are required. This is mainly because of the wide geographical coexistence of both parasite species but also because of increasing drug resistance, recent observations of severe and lethal P. vivax cases and relapsing parasite behaviour. Availability of the P. vivax genome has contributed to antigen discovery but new means to test vaccines in future trials remain to be designed.     

Platform for Plasmodium vivax vaccine discovery and development

Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80-100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development.     

Contemporaneous and successive mixed Plasmodium falciparum and Plasmodium vivax infections are associated with Ascaris lumbricoides: an immunomodulating effect?

Following an investigation suggesting a protective role for Ascaris against cerebral malaria, possibly through immunomodulation, we examined whether Ascaris had any impact on mixed Plasmodium falciparum and Plasmodium vivax infections. We studied a cross section of 928 patient files between 1991 and 1999. Forty patients had contemporaneous mixed infections and 40 patients had P. falciparum infections, followed by P. vivax infections. There was a significant association between Ascaris infection and risk of having both contemporaneous or successive mixed P. falciparum and P. vivax infections (adjusted odds ratios respectively 6 [2-18] P = 0.001 and 3.6 [1.2-11.1] P = 0.02). There was a positive linear trend between the burden of Ascaris and the risk of mixed infections P < 0.0001. These results suggested the possibility that pre-existing Ascaris infection may increase tolerance of the host to different Plasmodium spp., thus facilitating their coexistence.     

Review of pyronaridine anti-malarial properties and product characteristics

ABSTRACT: Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other antimalarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax(R) and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.     

Cross-reactivity studies of an anti-Plasmodium vivax apical membrane antigen 1 monoclonal antibody: binding and structural characterisation

Apical membrane antigen 1 (AMA1) has an important, but as yet uncharacterised, role in host cell invasion by the malaria parasite, Plasmodium. The protein, which is quite conserved between Plasmodium species, comprises an ectoplasmic region, a single transmembrane segment and a small cytoplasmic domain. The ectoplasmic region, which can induce protective immunity in animal models of human malaria, is a leading vaccine candidate that has entered clinical trials. The monoclonal antibody F8.12.19, raised against the recombinant ectoplasmic region of AMA1 from Plasmodium vivax, cross-reacts with homologues from Plasmodium knowlesi, Plasmodium cynomolgi, Plasmodium berghei and Plasmodium falciparum, as shown by immunofluorescence assays on mature schizonts. The binding of F8.12.19 to recombinant AMA1 from both P. vivax and P. falciparum was measured by surface plasmon resonance, revealing an apparent affinity constant that is about 100-fold weaker for the cross-reacting antigen when compared to the cognate antigen. Crystal structure analysis of Fab F8.12.19 complexed to AMA1 from P. vivax and P. falciparum shows that the monoclonal antibody recognises a discontinuous epitope located on domain III of the ectoplasmic region, the major component being a loop containing a cystine knot. The structures provide a basis for understanding the cross-reactivity. Antibody contacts are made mainly to main-chain and invariant side-chain atoms of AMA1; contact antigen residues that differ in sequence are located at the periphery of the antigen-binding site and can be accommodated at the interface between the two components of the complex. The implications for AMA1 vaccine development are discussed.     

Serological investigations in retrospective diagnosis of malaria.

Sera were obtained in 415 known cases of malaria (88 residents, 327 immigrants) at different times after diagnosis. Three antigens were used in the indirect fluorscence antibody test to detect antibodies to either Plasmodium falciparum or P vivax. Results in residents and immigrants were analysed separately. Most residents had detectable antibodies within one week after an attack, which began to wane after a month. The strongest reactions were obtained in cases of falciparum malaria with the homologous antigen and in cases of vivax malaria with P fieldi. The overall pattern of results was the same in the immigrants but the proportions positive for malaria antibodies, mean titres, persistence of antibodies, and the cross-reaction were usually greater. Testing for malaria antibodies is probably of value in the retrospective differential diagnosis of malaria in patients who have not been exposed to malaria before but must be interpreted with caution in others.     

Severe disease in children hospitalized with a diagnosis of Plasmodium vivax in south-eastern Pakistan

ABSTRACT: BACKGROUND: Infection by Plasmodium vivax has been considered rarely threatening to life, but recent studies challenge this notion. This study documented the frequency and character of severe illness in paediatric patients admitted to a hospital in south-eastern Pakistan with a laboratory-confirmed diagnosis of vivax malaria. METHODS: An observational study of all 180 paediatric patients admitted with any diagnosis of malaria during 2010 was conducted: 128 P. vivax; 48 Plasmodium falciparum; and four mixed infections of these species. Patients were classified as having severe illness with any of the following indicators: Glascow coma scale <11; >2 convulsions; haemoglobin <5g/dL; thrombocytes <50,000/mL; blood glucose <45mg%; >70 breaths/min; or intravenous antimalarial therapy. Additionally, 64 patients with a diagnosis of vivax malaria were treated during 2009, and the 21 of these having severe illness were included in analyses of the frequency and character of severe illness with that diagnosis. RESULTS: During 2010, 39 (31%) or 37 (77%) patients with a diagnosis of P. vivax or P. falciparum were classified as having severe disease. Including the 2009 records of 64 patients having vivax malaria, a total of 60 (31%) patients with severe illness and a diagnosis of P. vivax were available. Altered mental status (Glascow coma scale score <11; or >2 convulsions) dominated at 54% of the 83 indicators of severe illness manifest among the patients with vivax malaria, as was true among the 37 children with a diagnosis of falciparum malaria and being severely ill; 58% of the 72 indicators of severe disease documented among them. No statistically significant difference appeared in frequencies of any other severe disease indicators between patients diagnosed with vivax or falciparum malaria. Despite such similarities, a diagnosis of falciparum malaria nonetheless came with 3.8-fold (95% CI = 1.8- 8.1) higher risk of presenting with severe illness, and 8.0-fold (95% CI = 2.1-31) greater likelihood of presenting with three or more severe disease indicators. Two patients did not survive hospitalization, one each with a diagnosis of falciparum or vivax malaria. CONCLUSIONS: Vivax malaria caused a substantial burden of potentially life-threatening morbidity on a paediatric ward in a hospital in south-eastern Pakistan.     

Neglect of Plasmodium vivax malaria

Plasmodium vivax infects 130-435 million of the 2.6 billion people living at risk of infection. Recent studies suggest that vivax malaria can become lethal in a similar way to severe falciparum malaria. First-line therapies remain unchanged after 50 years. Despite evidence of failing chloroquine efficacy, little work has assessed the problem or explored alternative therapies. Primaquine treatment, the only therapeutic option against relapse, might also be failing. No licensed primary chemoprophylactic agent protects travelers from relapse. Misdiagnosis of species now affects clinical decisions resulting in inadequate therapy for P. falciparum and P. vivax. All of these factors demonstrate the lack of research on P. vivax.     

Correlates of HIV and malaria co-infection in Southern India

ABSTRACT: BACKGROUND: Malaria and HIV co-infection adversely impact the outcome of both diseases and previous studies have mostly focused on falciparum malaria. Plasmodium vivax contributes to almost half of the malaria cases in India, but the disease burden of HIV and P. vivax co-infection is unclear. METHODS: HIV-infected subjects (n=460) were randomly selected from the 4,611 individuals seen at a Voluntary Counseling and Testing Center in Chennai, India between Jan 2 to Dec 31 2008. Malaria testing was performed on stored plasma samples by both nested PCR using both genus-specific and species-specific primers and immunochromatography-based rapid diagnostic test for detecting antibodies against both Plasmodium falciparum and P. vivax. RESULTS: Recent malaria co-infection, defined by the presence of antibodies, was detected in 9.8% (45/460) participants. Plasmodium vivax accounted for majority of the infections (60%) followed by P. falciparum (27%) and mixed infections (13%). Individuals with HIV and malaria co-infection were more likely to be men (p=0.01). Between those with and without malaria, there was no difference in age (p=0.14), CD4+ T-cell counts (p=0.19) or proportion CD4+ T-cell below 200/mL (p=0.51). CONCLUSIONS: Retrospective testing of stored plasma samples for malaria antibodies can facilitate identification of populations with high rates of co-infection, and in this southern India HIVinfected cohort there was a considerable burden of malaria co-infection, predominantly due to P. vivax. However, the rate of P. falciparum infection was more than 6-fold higher among HIV-infected individuals than what would be expected in the general population in the region. Interestingly, individuals co-infected with malaria and HIV were not more likely to be immunosuppressed than individuals with HIV infection alone.     

Plasmodium vivax in India

Four Plasmodium species cause malaria in humans: Plasmodium vivax is the most widespread and results in pronounced morbidity. India (population >1 billion) is a major contributor to the burden of vivax malaria. With a resurgence in interest concerning the neglected burden of vivax malaria and the completion of the P. vivax genome, it is timely to review what is known concerning P. vivax in India. The P. vivax population is highly diverse in terms of relapse patterns, drug response and clinical profiles, and highly genetically variable according to studies of antigen genes, isoenzyme markers and microsatellites. The unique epidemiology of malaria in India, where P. vivax predominates over Plasmodium falciparum, renders this location ideal for studying the dynamics of co-infection.     

Cross-reactive anti-PfCLAG9 antibodies in the sera of asymptomatic parasite carriers of Plasmodium vivax

The PfCLAG9 has been extensively studied because their immunogenicity. Thereby, the gene product is important for therapeutics interventions and a potential vaccine candidate. Antibodies against synthetic peptides corresponding to selected sequences of the Plasmodium falciparum antigen PfCLAG9 were found in sera of falciparum malaria patients from Rondônia, in the Brazilian Amazon. Much higher antibody titres were found in semi-immune and immune asymptomatic parasite carriers than in subjects suffering clinical infections, corroborating original findings in Papua Guinea. However, sera of Plasmodium vivax patients from the same Amazon area, in particular from asymptomatic vivax parasite carriers, reacted strongly with the same peptides. Bioinformatic analyses revealed regions of similarity between P. falciparum Pfclag9 and the P. vivax ortholog Pvclag7. Indirect fluorescent microscopy analysis showed that antibodies against PfCLAG9 peptides elicited in BALB/c mice react with human red blood cells (RBCs) infected with both P. falciparum and P. vivax parasites. The patterns of reactivity on the surface of the parasitised RBCs are very similar. The present observations support previous findings that PfCLAG9 may be a target of protective immune responses and raises the possibility that the cross reactive antibodies to PvCLAG7 in mixed infections play a role in regulate the fate of Plasmodium mixed infections.     

Plasmodium vivax: parasitemia determination by real-time quantitative PCR in Aotus monkeys

Plasmodium vivax and Plasmodium falciparum are the two prevalent human malaria species. A Colombian P. vivax wild strain has been adapted in Aotus nancymaae monkeys for use in further biological and immunological studies. We present data validating a real-time PCR assay quantifying P. vivax parasitemia, using the small subunit ribosomal RNA genes as an amplification target. P. vivax species-specific primers were designed on the 18S ribosomal gene V8 region, for amplifying both asexual and sporozoite ssrRNA genes. The assay detects amplification products bound to fluorescent SYBR-Green I dye using Perkin-Elmer GeneAmp-5700-SDS. Linear range standard curves from 6 DNA concentration logs (+0.99 correlation coefficients) were obtained. Standard curves were constructed using a plasmid containing target gene for real-time PCR amplification. This P. vivax specific assay is very sensitive, having a three parasite detection limit, and is reproducible and accurate. It involves a "closed-tube" PCR, avoids time-consuming post-PCR manipulation, and decreases potential PCR contamination.     

Radical curative efficacy of five-day regimen of primaquine for treatment of Plasmodium vivax malaria in India

For over 4 decades the antimalarial program in India has been prescribing a 5-day primaquine regimen as an antirelapse therapy to treat Plasmodium vivax malaria. In view of conflicting reports on the effectiveness of this regimen in the Indian subcontinent, and the varying prevalence of P. vivax in various ecosystems in India, the antirelapse efficacy of this regimen was evaluated in Orissa, a malaria endemic state in eastern India where P. falciparum predominates. In 723 cases of P. vivax infection treated with chloroquine alone and followed up weekly for 1 yr, the prevalence of recurrence of parasitaemia with fever was 8.6%. Among another 759 P. vivax cases treated with chloroquine and a 5-day regimen of primaquine at 15 mg/day (adult dose), the recurrence of infection was 6.5%. The difference in recurrence was not significant (P = 0.53). It is important to note that in a great majority of cases of P. vivax in this area, infection did not recur even without treatment with primaquine. This finding, that the use of the 5-day primaquine regimen with chloroquine had no significant advantage over the use of chloroquine alone, undermines the rationale of using primaquine as an antirelapse drug in forested areas with a high prevalence of P. falciparum.     

Identification and characterisation of the Plasmodium vivax rhoptry-associated protein 2

Plasmodium vivax is currently the most widespread of the four parasite species causing malaria in humans around the world. It causes more than 75 million clinical episodes per year, mainly on the Asian and American continents. Identifying new antigens to be further tested as anti-P. vivax vaccine candidates has been greatly hampered by the difficulty of maintaining this parasite cultured in vitro. Taking into account that one of the most promising vaccine candidates against Plasmodium falciparum is the rhoptry-associated protein 2, we have identified the P. falciparum rhoptry-associated protein 2 homologue in P. vivax in the present study. This protein has 400 residues, having an N-terminal 21 amino-acid stretch compatible with a signal peptide and, as occurs with its falciparum homologue, it lacks repeat sequences. The protein is expressed in asexual stage P. vivax parasites and polyclonal sera raised against this protein recognised a 46 kDa band in parasite lysate in a Western blot assay.     

Characterizing the spatial and temporal variation of malaria incidence in Bangladesh, 2007

ABSTRACT: BACKGROUND: Malaria remains a significant health problem in Bangladesh affecting 13 of 64 districts. The risk of malaria is variable across the endemic areas and throughout the year. A better understanding of the spatial and temporal patterns in malaria risk and the determinants driving the variation are crucial for the appropriate targeting of interventions under the National Malaria Control and Prevention Programme. METHODS: Numbers of Plasmodium falciparum and Plasmodium vivax malaria cases reported by month in 2007, across the 70 endemic thanas (sub-districts) in Bangladesh, were assembled from health centre surveillance reports. Bayesian Poisson regression models of incidence were constructed, with fixed effects for monthly rainfall, maximum temperature and elevation, and random effects for thanas, with a conditional autoregressive prior spatial structure. RESULTS: The annual incidence of reported cases was 34.0 and 9.6 cases/10,000 population for P. falciparum and P. vivax respectively and the population of the 70 malaria-endemic thanas was approximately 13.5 million in 2007. Incidence of reported cases for both types of malaria was highest in the mountainous south-east of the country (the Chittagong Hill Tracts). Models revealed statistically significant positive associations between the incidence of reported P. vivax and P. falciparum cases and rainfall and maximum temperature. CONCLUSIONS: The risk of P. falciparum and P. vivax was spatially variable across the endemic thanas of Bangladesh and also highly seasonal, suggesting that interventions should be targeted and timed according to the risk profile of the endemic areas. Rainfall, temperature and elevation are major factors driving the spatiotemporal patterns of malaria in Bangladesh.     

A case of symptomatic splenic infarction in vivax malaria

Splenic infarction is a rare complication in malaria cases, and is caused primarily by Plasmodium falciparum. Recently in South Korea, only P. vivax has prevailed since 1993. Although the probability that symptomatic splenic infarction may occur in vivax malaria cases is considered relatively high, there have never been any case reports describing the occurrence of symptomatic splenic infarction in cases of vivax malaria. A 34-year-old man presented with fever that had persisted for 5 days. P. vivax infection was verified using a peripheral blood smear, and chloroquine was utilized to treat the fever successfully. Six days later, the patient developed pain in the left upper abdomen, which was diagnosed as splenic infarction by computed tomography.