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Despite recent progress toward elimination, persisting malaria transmission in the Americas continues to pose a risk for infection to 120 million persons (1). The Amazon Basin, spanning 9 countries of [...]

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Gamma (P.1) variant emerged in November 2020 and drove the second wave of coronavirus disease (COVID-19) in Brazil. Emergence of this [...]

Background Malarial infections are often missed by microscopy, and most parasite carriers are asymptomatic in low-endemicity settings. Whether parasite detectability and its ability to elicit symptoms change as transmission declines remains unclear. Methods We performed a prospective panel survey with repeated measurements on the same participants over 12 months to investigate whether Plasmodium vivax detectability by microscopy and risk of symptoms upon infection varied during a community-wide larviciding intervention in the Amazon basin of Brazil that markedly reduced vector density. We screened 1096 to 1400 residents in the intervention site for malaria by microscopy and quantitative TaqMan assays at baseline and twice during intervention. Results We found that more P vivax infections than expected from their parasite densities measured by TaqMan assays were missed by microscopy as transmission decreased. At lower transmission, study participants appeared to tolerate higher P vivax loads without developing symptoms. We hypothesize that changes in the ratio between circulating parasites and those that accumulate in the bone marrow and spleen, by avoiding peripheral blood microscopy detection, account for decreased parasite detectability and lower risk of symptoms under low transmission. Conclusions P vivax infections are more likely to be subpatent and remain asymptomatic as malaria transmission decreases. [ABSTRACT FROM AUTHOR]

Background Immunity after dengue virus (DENV) infection has been suggested to cross-protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality. Methods We tested whether serologically proven prior DENV infection diagnosed in September–October 2019, before the coronavirus disease 2019 (COVID-19) pandemic, reduced the risk of SARS-CoV-2 infection and clinically apparent COVID-19 over the next 13 months in a population-based cohort in Amazonian Brazil. Mixed-effects multiple logistic regression analysis was used to identify predictors of infection and disease, adjusting for potential individual and household-level confounders. Virus genomes from 14 local SARS-CoV-2 isolates were obtained using whole-genome sequencing. Results Anti-DENV immunoglobulin G (IgG) was found in 37.0% of 1285 cohort participants (95% confidence interval [CI]: 34.3% to 39.7%) in 2019, with 10.4 (95% CI: 6.7–15.5) seroconversion events per 100 person-years during the follow-up. In 2020, 35.2% of the participants (95% CI: 32.6% to 37.8%) had anti-SARS-CoV-2 IgG and 57.1% of the 448 SARS-CoV-2 seropositives (95% CI: 52.4% to 61.8%) reported clinical manifestations at the time of infection. Participants aged >60 years were twice more likely to have symptomatic COVID-19 than children under 5 years. Locally circulating SARS-CoV-2 isolates were assigned to the B.1.1.33 lineage. Contrary to the cross-protection hypothesis, prior DENV infection was associated with twice the risk of clinically apparent COVID-19 upon SARS-CoV-2 infection, with P values between.025 and.039 after adjustment for identified confounders. Conclusions Higher risk of clinically apparent COVID-19 among individuals with prior dengue has important public health implications for communities sequentially exposed to DENV and SARS-CoV-2 epidemics. [ABSTRACT FROM AUTHOR]

Background: The population history of Plasmodium simium, which causes malaria in sylvatic Neotropical monkeys and humans along the Atlantic Coast of Brazil, remains disputed. Genetically diverse P vivax populations from various sources, including the lineages that founded the species P simium, are thought to have arrived in the Americas in separate migratory waves.Methods: We use population genomic approaches to investigate the origin and evolution of P simium.Results: We find a minimal genome-level differentiation between P simium and present-day New World P vivax isolates, consistent with their common geographic origin and subsequent divergence on this continent. The meagre genetic diversity in P simium samples from humans and monkeys implies a recent transfer from humans to non-human primates - a unique example of malaria as a reverse zoonosis of public health significance. Likely genomic signatures of P simium adaptation to new hosts include the deletion of >40% of a key erythrocyte invasion ligand, PvRBP2a, which may have favored more efficient simian host cell infection.Conclusions: New World P vivax lineages that switched from humans to platyrrhine monkeys founded the P simium population that infects nonhuman primates and feeds sustained human malaria transmission in the outskirts of major cities. [ABSTRACT FROM AUTHOR]

Malaria in the Amazon is often perceived as an exclusively rural disease, but transmission has been increasingly documented within and near urban centers. Here we explore patterns and causes of urban-to-rural mobility, which places travelers at risk of malaria in Mâncio Lima, the main malaria hotspot in northwestern Brazil. We also analyze rural-to-urban mobility caused by malaria treatment seeking, which poses an additional risk of infection to urban residents. We show that the rural localities most frequently visited by urban residents–typically farming settlements in the vicinity of the town–are those with the most intense malaria transmission and also the most frequent source localities of imported malaria cases diagnosed in the town. The most mobile urban residents are typically poor males 16 to 60-years old from multi-sited households who lack a formal job. Highly mobile residents represent a priority target for more intensive and effective malaria control interventions, that cannot be readily delivered to the entire community, in this and similar urbanized endemic settings across the Amazon. [ABSTRACT FROM AUTHOR]

Background: Plasmodium vivax is a neglected human malaria parasite that causes significant morbidity in the Americas, the Middle East, Asia, and the Western Pacific. Population genomic approaches remain little explored to map local and regional transmission pathways of P. vivax across the main endemic sites in the Americas, where great progress has been made towards malaria elimination over the past decades. Methodology/Principal findings: We analyze 38 patient-derived P. vivax genome sequences from Mâncio Lima (ML)–the Amazonian malaria hotspot next to the Brazil-Peru border—and 24 sequences from two other sites in Acre State, Brazil, a country that contributes 23% of malaria cases in the Americas. We show that the P. vivax population of ML is genetically diverse (π = 4.7 × 10−4), with a high polymorphism particularly in genes encoding proteins putatively involved in red blood cell invasion. Paradoxically, however, parasites display strong genome-wide linkage disequilibrium, being fragmented into discrete lineages that are remarkably stable across time and space, with only occasional recombination between them. Using identity-by-descent approaches, we identified a large cluster of closely related sequences that comprises 16 of 38 genomes sampled in ML over 26 months. Importantly, we found significant ancestry sharing between parasites at a large geographic distance, consistent with substantial gene flow between regional P. vivax populations. Conclusions/Significance: We have characterized the sustained expansion of highly inbred P. vivax lineages in a malaria hotspot that can seed regional transmission. Potential source populations in hotspots represent a priority target for malaria elimination in the Amazon. Authors' summary: Plasmodium vivax is the geographically most widespread human malaria parasite and causes 80% of the malaria burden in the Americas. Here we use whole-genome sequencing to explore levels of parasite relatedness and infer P. vivax transmission networks in the upper Juruá Valley, the main transmission hotspot in Amazonian Brazil. We characterize a genetically diverse population that displays significant linkage disequilibrium, consistent with the local circulation of highly inbred but genetically distant parasite lineages. Noteworthy, these discrete lineages remain stable over time and share recent ancestry with parasites at a large geographic distance. These results illustrate the power of genomic epidemiology approaches to map potential source parasite populations and prioritize areas for targeted control interventions to eliminate residual P. vivax transmission in the Amazon and similar endemic settings worldwide. [ABSTRACT FROM AUTHOR]

Background: The Americas were the last continent colonized by humans carrying malaria parasites. Plasmodium falciparum from the New World shows very little genetic diversity and greater linkage disequilibrium, compared with its African counterparts, and is clearly subdivided into local, highly divergent populations. However, limited available data have revealed extensive genetic diversity in American populations of another major human malaria parasite, P. vivax. Methods: We used an improved sample preparation strategy and next-generation sequencing to characterize 9 high-quality P. vivax genome sequences from northwestern Brazil. These new data were compared with publicly available sequences from recently sampled clinical P. vivax isolates from Brazil (BRA, total n = 11 sequences), Peru (PER, n = 23), Colombia (COL, n = 31), and Mexico (MEX, n = 19). Principal findings/Conclusions: We found that New World populations of P. vivax are as diverse (nucleotide diversity π between 5.2 × 10−4 and 6.2 × 10−4) as P. vivax populations from Southeast Asia, where malaria transmission is substantially more intense. They display several non-synonymous nucleotide substitutions (some of them previously undescribed) in genes known or suspected to be involved in antimalarial drug resistance, such as dhfr, dhps, mdr1, mrp1, and mrp-2, but not in the chloroquine resistance transporter ortholog (crt-o) gene. Moreover, P. vivax in the Americas is much less geographically substructured than local P. falciparum populations, with relatively little between-population genome-wide differentiation (pairwise FST values ranging between 0.025 and 0.092). Finally, P. vivax populations show a rapid decline in linkage disequilibrium with increasing distance between pairs of polymorphic sites, consistent with very frequent outcrossing. We hypothesize that the high diversity of present-day P. vivax lineages in the Americas originated from successive migratory waves and subsequent admixture between parasite lineages from geographically diverse sites. Further genome-wide analyses are required to test the demographic scenario suggested by our data. [ABSTRACT FROM AUTHOR]

Plasmodium vivax is the geographically most widespread human malaria parasite. To analyze patterns of microsatellite diversity and population structure across countries of different transmission intensity, genotyping data from 11 microsatellite markers was either generated or compiled from 841 isolates from four continents collected in 1999–2008. Diversity was highest in South-East Asia (mean allelic richness 10.0–12.8), intermediate in the South Pacific (8.1–9.9) Madagascar and Sudan (7.9–8.4), and lowest in South America and Central Asia (5.5–7.2). A reduced panel of only 3 markers was sufficient to identify approx. 90% of all haplotypes in South Pacific, African and SE-Asian populations, but only 60–80% in Latin American populations, suggesting that typing of 2–6 markers, depending on the level of endemicity, is sufficient for epidemiological studies. Clustering analysis showed distinct clusters in Peru and Brazil, but little sub-structuring was observed within Africa, SE-Asia or the South Pacific. Isolates from Uzbekistan were exceptional, as a near-clonal parasite population was observed that was clearly separated from all other populations (FST>0.2). Outside Central Asia FST values were highest (0.11–0.16) between South American and all other populations, and lowest (0.04–0.07) between populations from South-East Asia and the South Pacific. These comparisons between P. vivax populations from four continents indicated that not only transmission intensity, but also geographical isolation affect diversity and population structure. However, the high effective population size results in slow changes of these parameters. This persistency must be taken into account when assessing the impact of control programs on the genetic structure of parasite populations. Author Summary: Plasmodium vivax is the predominant malaria parasite in Latin America, Asia and the South Pacific. Different factors are expected to shape diversity and population structure across continents, e.g. transmission intensity which is much lower in South America as compared to Southeast-Asia and the South Pacific, or geographical isolation of P. vivax populations in the South Pacific. We have compiled data from 841 isolates from South and Central America, Africa, Central Asia, Southeast-Asia and the South Pacific typed with a panel of 11 microsatellite markers. Diversity was highest in Southeast-Asia, where transmission is intermediate-high and migration of infected hosts is high, and lowest in South America and Central Asia where malaria transmission is low and focal. Reducing the panel of microsatellites showed that 2–6 markers are sufficient for genotyping for most drug trials and epidemiological studies, as these markers can identify >90% of all haplotypes. Parasites clustered according to continental origin, with high population differentiation between South American and Central Asian populations and the other populations, and lowest differences between Southeast-Asia and the South Pacific. Current attempts to reduce malaria transmission might change this pattern, but only after transmission is reduced for an extended period of time. [ABSTRACT FROM AUTHOR]

Highlights: [•] Plasmodium vivax was hypothesized to be genetically more diverse than Plasmodium falciparum. [•] We found more microsatellite diversity in P. vivax than in P. falciparum from Cambodia. [•] These findings may reflect differences in population biology or genome plasticity between species. [ABSTRACT FROM AUTHOR]

Background: The population history of Plasmodium simium, which causes malaria in sylvatic Neotropical monkeys and humans along the Atlantic Coast of Brazil, remains disputed. Genetically diverse P vivax populations from various sources, including the lineages that founded the species P simium, are thought to have arrived in the Americas in separate migratory waves., Methods: We use population genomic approaches to investigate the origin and evolution of P simium., Results: We find a minimal genome-level differentiation between P simium and present-day New World P vivax isolates, consistent with their common geographic origin and subsequent divergence on this continent. The meagre genetic diversity in P simium samples from humans and monkeys implies a recent transfer from humans to non-human primates - a unique example of malaria as a reverse zoonosis of public health significance. Likely genomic signatures of P simium adaptation to new hosts include the deletion of >40% of a key erythrocyte invasion ligand, PvRBP2a, which may have favored more efficient simian host cell infection., Conclusions: New World P vivax lineages that switched from humans to platyrrhine monkeys founded the P simium population that infects nonhuman primates and feeds sustained human malaria transmission in the outskirts of major cities., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: This population-based open cohort study aims to investigate biological and sociodemographic drivers of malaria transmission in the main urban hotspot of Amazonian Brazil., Participants: Nearly 20% of the households in the northwestern town of Mâncio Lima were randomly selected and 2690 participants were enrolled since April 2018. Sociodemographic, housing quality, occupational, behavioural and morbidity information and travel histories were collected during consecutive study visits. Blood samples from participants>3 months old were used for malaria diagnosis and human genetic studies; samples from participants with laboratory-confirmed malaria have been cryopreserved for genetic and phenotypic characterisation of parasites. Serology was introduced in 2020 to measure the prevalence and longevity of SARS-CoV-2 IgG antibodies., Findings to Date: Malaria prevalence rates were low (up to 1.0% for Plasmodium vivax and 0.6% for P. falciparum ) during five consecutive cross-sectional surveys between April-May 2018 and October-November 2020; 63% of infections diagnosed by microscopy were asymptomatic. Malaria risk is heterogeneously distributed, with 20% study participants contributing 86% of the overall burden of P. vivax infection. Adult males are at greatest risk of infection and human mobility across the urban-rural interface may contribute to sustained malaria transmission. Local P. vivax parasites are genetically diverse and fragmented into discrete inbred lineages that remain stable across space and time., Future Plans: Two follow-up visits, with similar study protocols, are planned in 2021. We aim to identify high-risk individuals that fuel onwards malaria transmission and represent a priority target for more intensive and effective control interventions., Trial Registration Number: NCT03689036., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus but not in the main malaria hot spots across the Amazon Basin of Brazil, where CQ is routinely coadministered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (arm 1) or concomitant (arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in arm 1 subjects, who had PQ administered only at the end of the 28-day follow-up. We found adequate clinical and parasitological responses in all subjects assigned to arm 2. However, 2.2% of arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo In contrast, ex vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ coadministration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g., CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax -infected populations. (This study has been registered at ClinicalTrials.gov under identifier NCT02691910.)., (Copyright © 2019 American Society for Microbiology.)

We examined the mitogenomes of a large global collection of human malaria parasites to explore how and when Plasmodium falciparum and P. vivax entered the Americas. We found evidence of a significant contribution of African and South Asian lineages to present-day New World malaria parasites with additional P. vivax lineages appearing to originate from Melanesia that were putatively carried by the Australasian peoples who contributed genes to Native Americans. Importantly, mitochondrial lineages of the P. vivax-like species P. simium are shared by platyrrhine monkeys and humans in the Atlantic Forest ecosystem, but not across the Amazon, which most likely resulted from one or a few recent human-to-monkey transfers. While enslaved Africans were likely the main carriers of P. falciparum mitochondrial lineages into the Americas after the conquest, additional parasites carried by Australasian peoples in pre-Columbian times may have contributed to the extensive diversity of extant local populations of P. vivax.

Background: The Americas were the last continent colonized by humans carrying malaria parasites. Plasmodium falciparum from the New World shows very little genetic diversity and greater linkage disequilibrium, compared with its African counterparts, and is clearly subdivided into local, highly divergent populations. However, limited available data have revealed extensive genetic diversity in American populations of another major human malaria parasite, P. vivax., Methods: We used an improved sample preparation strategy and next-generation sequencing to characterize 9 high-quality P. vivax genome sequences from northwestern Brazil. These new data were compared with publicly available sequences from recently sampled clinical P. vivax isolates from Brazil (BRA, total n = 11 sequences), Peru (PER, n = 23), Colombia (COL, n = 31), and Mexico (MEX, n = 19)., Principal Findings/conclusions: We found that New World populations of P. vivax are as diverse (nucleotide diversity π between 5.2 × 10-4 and 6.2 × 10-4) as P. vivax populations from Southeast Asia, where malaria transmission is substantially more intense. They display several non-synonymous nucleotide substitutions (some of them previously undescribed) in genes known or suspected to be involved in antimalarial drug resistance, such as dhfr, dhps, mdr1, mrp1, and mrp-2, but not in the chloroquine resistance transporter ortholog (crt-o) gene. Moreover, P. vivax in the Americas is much less geographically substructured than local P. falciparum populations, with relatively little between-population genome-wide differentiation (pairwise FST values ranging between 0.025 and 0.092). Finally, P. vivax populations show a rapid decline in linkage disequilibrium with increasing distance between pairs of polymorphic sites, consistent with very frequent outcrossing. We hypothesize that the high diversity of present-day P. vivax lineages in the Americas originated from successive migratory waves and subsequent admixture between parasite lineages from geographically diverse sites. Further genome-wide analyses are required to test the demographic scenario suggested by our data.