Protective Efficacy of Plasmodium vivax Radiation-Attenuated Sporozoites in Colombian Volunteers: A Randomized Controlled Trial.

BACKGROUND: Immunizing human volunteers by mosquito bite with radiation-attenuated Plasmodium falciparum sporozoites (RAS) results in high-level protection against infection. Only two volunteers have been similarly immunized with P. vivax (Pv) RAS, and both were protected. A phase 2 controlled clinical trial was conducted to assess the safety and protective efficacy of PvRAS immunization. METHODOLOGY/PRINCIPAL FINDINGS: A randomized, single-blinded trial was conducted. Duffy positive (Fy+; Pv susceptible) individuals were enrolled: 14 received bites from irradiated (150 ± 10 cGy) Pv-infected Anopheles mosquitoes (RAS) and 7 from non-irradiated non-infected mosquitoes (Ctl). An additional group of seven Fy- (Pv refractory) volunteers was immunized with bites from non-irradiated Pv-infected mosquitoes. A total of seven immunizations were carried out at mean intervals of nine weeks. Eight weeks after last immunization, a controlled human malaria infection (CHMI) with non-irradiated Pv-infected mosquitoes was performed. Nineteen volunteers completed seven immunizations (12 RAS, 2 Ctl, and 5 Fy-) and received a CHMI. Five of 12 (42%) RAS volunteers were protected (receiving a median of 434 infective bites) compared with 0/2 Ctl. None of the Fy- volunteers developed infection by the seventh immunization or after CHMI. All non-protected volunteers developed symptoms 8-13 days after CHMI with a mean pre-patent period of 12.8 days. No serious adverse events related to the immunizations were observed. Specific IgG1 anti-PvCS response was associated with protection. CONCLUSION: Immunization with PvRAS was safe, immunogenic, and induced sterile immunity in 42% of the Fy+ volunteers. Moreover, Fy- volunteers were refractory to Pv malaria. TRIAL REGISTRATION: Identifier: NCT01082341.

Killer cell immunoglobulin-like receptor (KIR) gene diversity in a population naturally exposed to malaria in Porto Velho, Northern Brazil.

Killer cell immunoglobulin-like receptors (KIR) are expressed mainly in natural killer cells and specifically recognize human leukocyte antigen (HLA) class I molecules. The repertoire of KIR genes and KIR-HLA pairs is known to play a key role in the susceptibilities to and the outcomes of several diseases, including malaria. The aim of this study was to investigate the distribution of KIR genes, KIR genotypes and KIR-HLA pair combinations in a population naturally exposed to malaria from Brazilian Amazon. All 16 KIR genes investigated were present in the studied population. Overall, 46 KIR genotypes were defined. The two most common genotypes in the Porto Velho communities, genotypes 1 and 2, were present at similar frequencies as in the Americas. Principal component analysis based on the frequencies of the KIR genes placed the Porto Velho population closer to the Venezuela Mestizos, USA California hispanic and Brazil Paraná Mixed in terms of KIR gene frequencies. This analysis highlights the multi-ethnic profile of the Porto Velho population. Most of the individuals were found to have at least one inhibitory KIR-HLA pair. Seventy-five KIR-HLA pair combinations were identified. The KIR-2DL2/3_HLA-C1, KIR3DL1_HLA-Bw4 and KIR2DL1_HLA-C2 pairs were the most common. There was no association between KIR genes, KIR genotypes or KIR-HLA pair combinations and malaria susceptibility in the studied population. This is the first report on the distribution of KIR and known HLA ligands in the Porto Velho population. Taken together, these results should provide baseline information that will be relevant to population evolutionary history, malaria and other diseases studies in populations of the Brazilian Amazon.

[The factors associated with noncompliance with antimalarial treatment in Ecuadorian patients]. / Factores asociados con el incumplimiento del tratamiento antipalúdico en pacientes ecuatorianos.

A total of 249 persons living in the northwest part of Ecuador with a clinical diagnosis of malaria confirmed by thick blood films were treated with chloroquine and primaquine according to the therapeutical system in force in the National Service for Eradication of Malaria. New clinical assessment and thick blood film were applied after 4 days in P. falciparum (n = 120) cases and after 8 days in P. vivax (n = 129) cases; patients were questioned about the compliance or non-compliance with the treatment, and the reasons for their acting in either way were studied. EPI-INFO 6.04 and SPSS PC 7.0 packages served to process the information: "kind adjustment test" (bondad de ajuste) abd factorial analysis of correspondences were used. The patient who daily took his/her pills for the number of days indicated, at the established intervals and at the right time was defined as a patient complying with the drug therapy. For every 3 patients complying with treatment, there were 2 who did not; non-compliance was not significantly related to age, sex, educational level, ethnic group, urban or rural setting or level of income, but learning about seriousness of the infection did help to compliance with the therapy. The reasons for non-compliance were mainly associated with drugs (side effects/reluctancy to take drugs), with the fact of forgetting to take them and of "getting cured quickly". The profile of the patient who did not comply with treatment corresponded to male, teenager, mixed race, poor and rural setting.

[Increase of malaria among migrants in Amsterdam-Zuidoost]. / Toename van malaria bij migranten in Amsterdam-Zuidoost.

In a general practice in Amsterdam Southeast in 1998 a delayed first attack of Plasmodium ovale infection was diagnosed in a 13-year-old girl from Ghana, malaria tropica with a low parasitaemia index in a 43-year-old Ghanaian man and a 8-year-old Ghanaian girl, and Plasmodium vivax infection in a 44-year-old Surinam woman. The Ghanaian patients had visited their native country, the Surinam woman had contracted the infection during a visit to India. All patients responded well to antimalaria medication. These patients were among a total of 6 patients of non-Dutch origin diagnosed with malaria in 1998 in this general practice. Four patients had not taken any prophylactic drug and two had not used the drugs properly. A relative increase of malaria in immigrants has been seen in the Netherlands and elsewhere in Europe in recent years. Underestimation of the risks and lack of knowledge of malaria and of the changing epidemiology make people of ethnic minorities travel without taking appropriate precautions. New, creative ways of communication and information will have to be explored to reach these migrant communities.

Increase of malaria among migrants in Amsterdam-Zuidoost

In a general practice in Amsterdam SouthEast in 1998 a delayed first attack of Plasmodium ovale infection was diagnosed in a 13-year-old-girl from Ghana, malaria tropica with a low parasitaemia index in a 43-year-old Ghanaian man and a 8-year-old Ghanaian girl, and a Plasmodium vivax infection in a 44-year-old Surinam woman. The Ghanaian patients had visited their native country, the Surinam woman had contracted the infection during a visit to India. All patients responded well to antimalaria medication. These patients were among a total of 6 patients of non-Dutch origin diagnosed with malaria in 1998 in this general practice. Four patients had not taken any prophylactic drug and two had not used the drugs properly. A relative increase of malaria in immigrants has been seen in the Netherlands and elsewhere in Europe in recent years. Underestimation of the risks and lack of knowledge of malaria and of the changing epidemiology make people of ethnic minorities travel without taking appropriate precautions. New, creative ways of communication and information will have to be explored to reach these migrant communities. (AU)

A novel mutation in the coding sequence of the FY*B allele of the Duffy chemokine receptor gene is associated with an altered erythrocyte phenotype.

The Duffy blood group system is of clinical and biological significance. Antibodies to Duffy antigens are responsible for some cases of transfusion incompatibility and newborn hemolytic disease. The Duffy protein is a receptor for the Plasmodium vivax erythrocyte-binding protein and is also a receptor for various chemokines (thus renamed Duffy Antigen Receptor for Chemokines [DARC]). The two Duffy polymorphic antigens, Fya and Fyb (coded by the FY*A and FY*B alleles), are present on erythrocyte membranes. The Fy(a-b-) phenotype is the predominant one in populations of black people and also occurs in other populations, including some non-Ashkenazi Jewish groups. The Fy(a-b-) phenotype has been associated with a mutation in the FY*B promoter at the GATA box that abolishes the expression of erythrocyte Duffy protein. We describe here a novel mutation, present in the FY*B coding sequence (271C --> T), that is associated with some Fy(b-) phenotypes among non-Ashkenazi Jews and among Brazilian blacks. The mutation is present in Fy(b-) individuals, who have wild-type FY*B GATA and carry the previously described 304G --> A substitution. The 271C --> T and 304G --> A can be identified by restriction enzyme-generated restriction fragment length polymorphisms. The 271C --> T substitution represents a considerable change in chemical nature (Arg91 --> Cys), one which may affect the antigenic determinants of DARC, and thus be of clinical significance. The mutation may have implications for some physiological roles of DARC and be of interest in malaria research and in studies of population genetics.

Pattern of malaria imported by foreign residents under active survey.

An active of imported malaria was carried out on 1432 foreign residents entering Czechoslovakia between 1986-1989. The survey group consisted of adult aged 18-35 years who arrived from malaria endemic regions. Of 660 people surveyed who were from regions of Africa south of the Sahara, 10% were positive for Plasmodium falciparum. Whereas, those arriving from South East Asia had a relatively low prevalence of malaria (2.6%), predominantly P. vivax. Of the 10% of cases testing positive for P. falciparum, 85% had less than 10,000 asexual stages/microliters of blood and 75% were asymptomatic carriers. By contrast, 93.8% of P. vivax/ovale infections were diagnosed because of the onset of symptoms. Both the frequency of seropositivity and the geometrical mean reciprocal titre (IgG), using P. falciparum antigen, were higher in those people arriving from Africa (79% and 1,307) compared with those arriving from S.E. Asia (44.4% and 628). Malaria was confirmed, by blood smear examination, in only 23.8% of the seropositive cohort. There was a positive correlation between the percentage of P. falciparum-positive blood smears and the level of antibody titre. There was no correlation between serum reactivity and level of parasitaemia.