Individual Plasmodium vivax msp1 variants within polyclonal P. vivax infections display different propensities for relapse.
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ABSTRACT:
SUBMITTER: Lin JT
PROVIDER: S-EPMC3318509 | biostudies-literature | 2012 Apr
REPOSITORIES: biostudies-literature
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Individual Plasmodium vivax msp1 variants within polyclonal P. vivax infections display different propensities for relapse.
Lin Jessica T JT Juliano Jonathan J JJ Kharabora Oksana O Sem Rithy R Lin Feng-Chang FC Muth Sinuon S Ménard Didier D Wongsrichanalai Chansuda C Rogers William O WO Meshnick Steven R SR
Journal of clinical microbiology 20120111 4
Using a newly developed Plasmodium vivax merozoite surface protein 1 gene (Pvmsp1) heteroduplex tracking assay, we genotyped 107 P. vivax infections in individuals from Cambodia, 45 of whom developed recurrent parasitemia within 42 days. The majority of isolates were polyclonal, but recurrent parasitemias displayed fewer variants compared to initial parasitemias. Two Pvmsp1 gene variants occurred more frequently in the initial genotypes of those who developed recurrent parasitemia, representing ...[more]
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Project description:Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission.A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse.Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas.The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.
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Project description:BackgroundThe distributions of incubation and relapse periods are key components of infectious disease models for the malaria parasite Plasmodium vivax; however, detailed distributions based upon experimental data are lacking.MethodsUsing a range of historical, experimental mosquito-transmitted human infections, Bayesian estimation with non-informative priors was used to determine parametric distributions that can be readily implemented for the incubation period and time-to-first relapse in P. vivax infections, including global subregions by parasite source. These analyses were complemented with a pooled analysis of observational human infection data with infections that included malaria chemoprophylaxis and long-latencies. The epidemiological impact of these distributional assumptions was explored using stochastic epidemic simulations at a fixed reproductive number while varying the underlying distribution of incubation periods.ResultsUsing the Deviance Information Criteria to compare parameterizations, experimental incubation periods are most closely modeled with a shifted log-logistic distribution; a log-logistic mixture is the best fit for incubations in observational studies. The mixture Gompertz distribution was the best fit for experimental times-to-relapse among the tested parameterizations, with some variation by geographic subregions. Simulations suggest underlying distributional assumptions have critically important impacts on both the time-scale and total case counts within epidemics.ConclusionsThese results suggest that the exponential and gamma distributions commonly used for modeling incubation periods and relapse times inadequately capture the complexity in the distributions of event times in P. vivax malaria infections. In future models, log-logistic and Gompertz distributions should be utilized for general incubation periods and relapse times respectively, and region-specific distributions should be considered to accurately model and predict the epidemiology of this important human pathogen.
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Project description:From 2003 through 2009, 687 of 2885 patients (23.8%) treated for Plasmodium falciparum malaria in clinical studies in Myanmar or on the Thailand-Myanmar border had recurrent Plasmodium vivax malaria within 63 days, compared with 18 of 429 patients (4.2%) from 2010 onward (risk ratio [RR], 0.176; 95% confidence interval, .112-.278; P < .0001). Corresponding data from 42 days of follow-up revealed that 820 of 3883 patients (21.1%) had recurrent P. vivax malaria before 2010, compared with 22 of 886 (2.5%) from 2010 onward (RR, 0.117; 95% CI, .077-.177; P < .0001). This 6-fold reduction suggests a recent decline in P. vivax transmission intensity and, thus, a substantial reduction in the proportion of individuals harboring hypnozoites.
| S-EPMC6548896 | biostudies-literature
Project description:The diversity of MSP1 in both Plasmodium falciparum and P. vivax is presumed be associated to parasite immune evasion. In this study, we assessed genetic diversity of the most variable domain of vaccine candidate N-terminal PvMSP1 (Block 2) in field isolates of Manaus. Forty-seven blood samples the polymorphism of PvMSP1 Block 2 generates four fragment sizes. In twenty-eight of them, sequencing indicated seven haplotypes of PvMSP1 Block 2 circulating among field isolates. Evidence of striking exchanges was observed with two stretches flanking the repeat region and two predicted recombination sites were described. Single nucleotide polymorphisms determined with concurrent infections per patient indicated that nonsynonymous substitutions occurred preferentially in the repeat-rich regions which also were predicted as B-cell epitopes. The comprehensive understanding of the genetic diversity of the promising Block 2 associated with clinical immunity and a reduced risk of infection by Plasmodium vivax would be important for the rationale of malaria vaccine designs.
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Project description:BackgroundTafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure."MethodsWe performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin.ResultsA protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96).ConclusionsAmong patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).
| S-EPMC6657225 | biostudies-literature
Project description:BackgroundTreatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax.MethodsThis multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia.ResultsIn the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention.ConclusionsSingle-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).
| S-EPMC6657226 | biostudies-literature