RESUMO
A non-human primate model for the induction of protective immunity against the pre-erythrocytic stages of Plasmodium vivax malaria using radiation-attenuated P. vivax sporozoites may help to characterize protective immune mechanisms and identify novel malaria vaccine candidates. Immune responses and protective efficacy induced by vaccination with irradiated P. vivax sporozoites were evaluated in malaria-naive Aotus monkeys. Three groups of six monkeys received two, five, or ten intravenous inoculations, respectively, of 100,000 irradiated P. vivax sporozoites; control groups received either 10 doses of uninfected salivary gland extract or no inoculations. Immunization resulted in the production low levels of antibodies that specifically recognized P. vivax sporozoites and the circumsporozoite protein. Additionally, immunization induced low levels of antigen-specific IFN-γ responses. Intravenous challenge with viable sporozoites resulted in partial protection in a dose-dependent manner. These findings suggest that the Aotus monkey model may be able to play a role in preclinical development of P. vivax pre-erythrocytic stage vaccines.
Assuntos
Vacinas Antimaláricas/imunologia , Malária Vivax/prevenção & controle , Plasmodium vivax/imunologia , Esporozoítos/imunologia , Esporozoítos/efeitos da radiação , Animais , Anticorpos Antiprotozoários/sangue , Especificidade de Anticorpos , Aotidae , Feminino , Imunofluorescência , Interferon gama/biossíntese , Leucócitos Mononucleares/imunologia , Masculino , Plasmodium vivax/efeitos da radiação , Proteínas de Protozoários/imunologiaRESUMO
BACKGROUND: Polymorphism of the Duffy Antigen Receptor for Chemokines (DARC) is associated with susceptibility to and the severity of Plasmodium vivax malaria in humans. P. vivax uses DARC to invade erythrocytes. Individuals lacking DARC are 'resistant' to P. vivax erythrocytic infection. However, susceptibility to P. vivax in DARC+ individuals is reported to vary between specific DARC genotypes. We hypothesized that the natural acquisition of antibodies to P. vivax blood stages may vary with the host genotype and the level of DARC expression. Furthermore, high parasitemia has been reported to effect the acquisition of immunity against pre-erythrocytic parasites. We investigated the correlation between host DARC genotypes and the frequency and magnitude of antibodies against P. vivax erythrocytic stage antigens. METHODOLOGY/FINDINGS: We assessed the frequencies and magnitudes of antibody responses against P. vivax and P. falciparum sporozoite and erythrocytic antigens in Colombian donors from malaria-endemic regions. The frequency and level of naturally-acquired antibodies against the P. vivax erythrocytic antigens merozoite surface protein 1 (PvMSP1) and Duffy binding protein (PvDBP) varied with the host DARC genotypes. Donors with one negative allele (FY*B/FY*Bnull and FY*A/FY*Bnull) were more likely to have anti-PvMSP1 and anti-PvDBP antibodies than those with two positive alleles (FY*B/FY*B and FY*A/FY*B). The lower IgG3 and IgG1 components of the total IgG response may account for the decreased responses to P. vivax erythrocytic antigens with FY*A/FY*B and FY*B/FY*B genotypes. No such association was detected with P. falciparum erythrocytic antigens, which does not use DARC for erythrocyte invasion. CONCLUSION/SIGNIFICANCE: Individuals with higher DARC expression, which is associated with higher susceptibility to P. vivax infection, exhibited low frequencies and magnitudes of P. vivax blood-stage specific antibody responses. This may indicate that one of the primary mechanisms by which P. vivax evades host immunity is through DARC indirectly down-regulating humoral responses against erythrocytic invasion and development.
Assuntos
Anticorpos Antiprotozoários/imunologia , Sistema do Grupo Sanguíneo Duffy/genética , Malária Vivax/imunologia , Plasmodium falciparum/imunologia , Plasmodium vivax/imunologia , Receptores de Superfície Celular/genética , Animais , Antígenos de Protozoários/imunologia , Ensaio de Imunoadsorção Enzimática , Genótipo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Proteína 1 de Superfície de Merozoito/imunologia , Plasmodium vivax/patogenicidade , Proteínas de Protozoários/imunologia , Receptores de Superfície Celular/imunologiaRESUMO
Primaquine is the only available drug for preventing relapse of malaria, and confusion surrounds its use. This review examines the wide range of clinical applications of primaquine described in the medical literature between 1946 and 2004. The risk of relapse of Plasmodium vivax malaria without primaquine therapy ranged from 5% to 80% or more, depending largely upon geographic location. Supervision of therapy profoundly impacts the risk of relapse, and almost all reports of malaria resistant to primaquine are associated with lack of such supervision. We nonetheless suspect that there is widespread resistance to the standard course of primaquine therapy, which is 15 mg primaquine base daily for 14 days. Clinical evidence confirms that a course of 15 mg daily for just 5 days, a regimen widely used in areas where malaria is endemic, has no discernible efficacy. This review supports a recommendation for a regimen of 0.5 mg/kg primaquine daily for 14 days, on the basis of superior efficacy and good tolerability and safety in nonpregnant persons without glucose-6-phosphate dehydrogenase deficiency.
Assuntos
Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Primaquina/uso terapêutico , Animais , Antimaláricos/efeitos adversos , Resistência a Medicamentos , Humanos , Malária/parasitologia , Plasmodium/efeitos dos fármacos , Plasmodium/fisiologia , Primaquina/efeitos adversosRESUMO
An expanding risk and range of endemic malaria threatens travelers. Primaquine is an old drug recently demonstrated to offer effective prophylaxis. Clinical trials conducted in Indonesia, Kenya, and Colombia showed that a primaquine base (30 mg per day) had protective efficacy against Plasmodium falciparum and Plasmodium vivax of 85%-93%. Among 339 children (age, >8 years) and adults taking this regimen for 12-52 weeks, there was no greater risk of adverse symptomatic events among primaquine users than among recipients of placebo in double-blind studies. Among 151 subjects evaluated after 20 or 52 weeks of daily primaquine therapy, methemoglobinemia was found to be mild (<13%; typically <6%) and transient (duration, <2 weeks). We consider primaquine base (0.5 mg/kg per day consumed with food) to be safe, well-tolerated, and effective prophylaxis against malaria for nonpregnant persons and those with normal glucose-6-phosphate dehydrogenase levels. Primaquine's major advantage over most drugs for chemoprophylaxis is that it does not have to be taken before entering or beyond 3 days after leaving a malarious area.