Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. METHODS: We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. RESULTS: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. CONCLUSIONS: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04346628.

The escalating tuberculosis crisis in central and South American prisons.

In the past decade, tuberculosis incidence has declined in much of the world, but has risen in central and South America. It is not yet clear what is driving this reversal of progress in tuberculosis control. Since 2000, the incarcerated population in central and South America has grown by 206%, the greatest increase in the world. Over the same period, notified tuberculosis cases among the incarcerated population (hereinafter termed persons deprived of their liberty [PDL], following the Inter-American Commission on Human Rights) have risen by 269%. In both central and South America, the rise of disease among PDL more than offsets tuberculosis control gains in the general population. Tuberculosis is increasingly concentrated among PDL; currently, 11% of all notified tuberculosis cases in central and South America occur among PDL who comprise less than 1% of the population. The extraordinarily high risk of acquiring tuberculosis within prisons creates a health and human rights crisis for PDL that also undermines wider tuberculosis control efforts. Controlling tuberculosis in this region will require countries to take urgent measures to prioritise the health of PDL.

Local and Travel-Associated Transmission of Tuberculosis at Central Western Border of Brazil, 2014-2017.

International migrants are at heightened risk for tuberculosis (TB) disease. Intensified incarceration at international borders may compound population-wide TB risk. However, few studies have investigated the contributions of migration, local transmission, or prisons in driving incident TB at international borders. We conducted prospective population-based genomic surveillance in 3 cities along Brazil's central western border from 2014-2017. Although most isolates (89/132; 67%) fell within genomic transmission clusters, genetically unique isolates disproportionately occurred among participants with recent international travel (17/42; 40.5%), suggesting that both local transmission and migration contribute to incident TB. Isolates from 40 participants with and 76 without an incarceration history clustered together throughout a maximum-likelihood phylogeny, indicating the close interrelatedness of prison and community epidemics. Our findings highlight the need for ongoing surveillance to control continued introductions of TB and reduce the disproportionate burden of TB in prisons at Brazil's international borders.

All-cause and cause-specific mortality during and following incarceration in Brazil: A retrospective cohort study.

BACKGROUND: Mortality during and after incarceration is poorly understood in low- and middle-income countries (LMICs). The need to address this knowledge gap is especially urgent in South America, which has the fastest growing prison population in the world. In Brazil, insufficient data have precluded our understanding of all-cause and cause-specific mortality during and after incarceration. METHODS AND FINDINGS: We linked incarceration and mortality databases for the Brazilian state of Mato Grosso do Sul to obtain a retrospective cohort of 114,751 individuals with recent incarceration. Between January 1, 2009 and December 31, 2018, we identified 3,127 deaths of individuals with recent incarceration (705 in detention and 2,422 following release). We analyzed age-standardized, all-cause, and cause-specific mortality rates among individuals detained in different facility types and following release, compared to non-incarcerated residents. We additionally modeled mortality rates over time during and after incarceration for all causes of death, violence, or suicide. Deaths in custody were 2.2 times the number reported by the national prison administration (n = 317). Incarcerated men and boys experienced elevated mortality, compared with the non-incarcerated population, due to increased risk of death from violence, suicide, and communicable diseases, with the highest standardized incidence rate ratio (IRR) in semi-open prisons (2.4; 95% confidence interval [CI]: 2.0 to 2.8), police stations (3.1; 95% CI: 2.5 to 3.9), and youth detention (8.1; 95% CI: 5.9 to 10.8). Incarcerated women experienced increased mortality from suicide (IRR = 6.0, 95% CI: 1.2 to 17.7) and communicable diseases (IRR = 2.5, 95% CI: 1.1 to 5.0). Following release from prison, mortality was markedly elevated for men (IRR = 3.0; 95% CI: 2.8 to 3.1) and women (IRR = 2.4; 95% CI: 2.1 to 2.9). The risk of violent death and suicide was highest immediately post-release and declined over time; however, all-cause mortality remained elevated 8 years post-release. The limitations of this study include inability to establish causality, uncertain reliability of data during incarceration, and underestimation of mortality rates due to imperfect database linkage. CONCLUSIONS: Incarcerated individuals in Brazil experienced increased mortality from violence, suicide, and communicable diseases. Mortality was heightened following release for all leading causes of death, with particularly high risk of early violent death and elevated all-cause mortality up to 8 years post-release. These disparities may have been underrecognized in Brazil due to underreporting and insufficient data.

Correction: Colonization of the tsetse fly midgut with commensal Kosakonia cowanii Zambiae inhibits trypanosome infection establishment.

[This corrects the article DOI: 10.1371/journal.ppat.1007470.].

Colonization of the tsetse fly midgut with commensal Kosakonia cowanii Zambiae inhibits trypanosome infection establishment.

Tsetse flies (Glossina spp.) vector pathogenic trypanosomes (Trypanosoma spp.) in sub-Saharan Africa. These parasites cause human and animal African trypanosomiases, which are debilitating diseases that inflict an enormous socio-economic burden on inhabitants of endemic regions. Current disease control strategies rely primarily on treating infected animals and reducing tsetse population densities. However, relevant programs are costly, labor intensive and difficult to sustain. As such, novel strategies aimed at reducing tsetse vector competence require development. Herein we investigated whether Kosakonia cowanii Zambiae (Kco_Z), which confers Anopheles gambiae with resistance to Plasmodium, is able to colonize tsetse and induce a trypanosome refractory phenotype in the fly. Kco_Z established stable infections in tsetse's gut and exhibited no adverse effect on the fly's survival. Flies with established Kco_Z infections in their gut were significantly more refractory to infection with two distinct trypanosome species (T. congolense, 6% infection; T. brucei, 32% infection) than were age-matched flies that did not house the exogenous bacterium (T. congolense, 36% infected; T. brucei, 70% infected). Additionally, 52% of Kco_Z colonized tsetse survived infection with entomopathogenic Serratia marcescens, compared with only 9% of their wild-type counterparts. These parasite and pathogen refractory phenotypes result from the fact that Kco_Z acidifies tsetse's midgut environment, which inhibits trypanosome and Serratia growth and thus infection establishment. Finally, we determined that Kco_Z infection does not impact the fecundity of male or female tsetse, nor the ability of male flies to compete with their wild-type counterparts for mates. We propose that Kco_Z could be used as one component of an integrated strategy aimed at reducing the ability of tsetse to transmit pathogenic trypanosomes.

Host Specialisation, Immune Cross-Reaction and the Composition of Communities of Co-circulating Borrelia Strains.

We use mathematical modelling to examine how microbial strain communities are structured by the host specialisation traits and antigenic relationships of their members. The model is quite general and broadly applicable, but we focus on Borrelia burgdorferi, the Lyme disease bacterium, transmitted by ticks to mice and birds. In this system, host specialisation driven by the evasion of innate immunity has been linked to multiple niche polymorphism, while antigenic differentiation driven by the evasion of adaptive immunity has been linked to negative frequency dependence. Our model is composed of two host species, one vector, and multiple co-circulating pathogen strains that vary in their host specificity and their antigenic distances from one another. We explore the conditions required to maintain pathogen diversity. We show that the combination of host specificity and antigenic differentiation creates an intricate niche structure. Unequivocal rules that relate the stability of a strain community directly to the trait composition of its members are elusive. However, broad patterns are evident. When antigenic differentiation is weak, stable communities are typically composed entirely of generalists that can exploit either host species equally well. As antigenic differentiation increases, more diverse stable communities emerge, typically around trait compositions of generalists, generalists and very similar specialists, and specialists roughly balanced between the two host species.

Correction: Evaluating strategies for control of tuberculosis in prisons and prevention of spillover into communities: An observational and modeling study from Brazil.

[This corrects the article DOI: 10.1371/journal.pmed.1002737.].

Evaluating strategies for control of tuberculosis in prisons and prevention of spillover into communities: An observational and modeling study from Brazil.

BACKGROUND: It has been hypothesized that prisons serve as amplifiers of general tuberculosis (TB) epidemics, but there is a paucity of data on this phenomenon and the potential population-level effects of prison-focused interventions. This study (1) quantifies the TB risk for prisoners as they traverse incarceration and release, (2) mathematically models the impact of prison-based interventions on TB burden in the general population, and (3) generalizes this model to a wide range of epidemiological contexts. METHODS AND FINDINGS: We obtained individual-level incarceration data for all inmates (n = 42,925) and all reported TB cases (n = 5,643) in the Brazilian state of Mato Grosso do Sul from 2007 through 2013. We matched individuals between prisoner and TB databases and estimated the incidence of TB from the time of incarceration and the time of prison release using Cox proportional hazards models. We identified 130 new TB cases diagnosed during incarceration and 170 among individuals released from prison. During imprisonment, TB rates increased from 111 cases per 100,000 person-years at entry to a maximum of 1,303 per 100,000 person-years at 5.2 years. At release, TB incidence was 229 per 100,000 person-years, which declined to 42 per 100,000 person-years (the average TB incidence in Brazil) after 7 years. We used these data to populate a compartmental model of TB transmission and incarceration to evaluate the effects of various prison-based interventions on the incidence of TB among prisoners and the general population. Annual mass TB screening within Brazilian prisons would reduce TB incidence in prisons by 47.4% (95% Bayesian credible interval [BCI], 44.4%-52.5%) and in the general population by 19.4% (95% BCI 17.9%-24.2%). A generalized model demonstrates that prison-based interventions would have maximum effectiveness in reducing community incidence in populations with a high concentration of TB in prisons and greater degrees of mixing between ex-prisoners and community members. Study limitations include our focus on a single Brazilian state and our retrospective use of administrative databases. CONCLUSIONS: Our findings suggest that the prison environment, more so than the prison population itself, drives TB incidence, and targeted interventions within prisons could have a substantial effect on the broader TB epidemic.

Detection, survival and infectious potential of Mycobacterium tuberculosis in the environment: a review of the evidence and epidemiological implications.

Much remains unknown about Mycobacterium tuberculosis transmission. Seminal experimental studies from the 1950s demonstrated that airborne expulsion of droplet nuclei from an infectious tuberculosis (TB) patient is the primary route of transmission. However, these findings did not rule out other routes of M. tuberculosis transmission. We reviewed historical scientific evidence from the late 19th/early 20th century and contemporary studies investigating the presence, persistence and infectiousness of environmental M. tuberculosis We found both experimental and epidemiological evidence supporting the presence and viability of M. tuberculosis in multiple natural and built environments for months to years, presumably following contamination by a human source. Furthermore, several studies confirm M. tuberculosis viability and virulence in the environment using guinea pig and mouse models. Most of this evidence was historical; however, several recent studies have reported consistent findings of M. tuberculosis detection and viability in the environment using modern methods. Whether M. tuberculosis in environments represents an infectious threat to humans requires further investigation; this may represent an untapped source of data with which to further understand M. tuberculosis transmission. We discuss potential opportunities for harnessing these data to generate new insights into TB transmission in congregate settings.

Vectors as Epidemiological Sentinels: Patterns of Within-Tick Borrelia burgdorferi Diversity.

Hosts including humans, other vertebrates, and arthropods, are frequently infected with heterogeneous populations of pathogens. Within-host pathogen diversity has major implications for human health, epidemiology, and pathogen evolution. However, pathogen diversity within-hosts is difficult to characterize and little is known about the levels and sources of within-host diversity maintained in natural populations of disease vectors. Here, we examine genomic variation of the Lyme disease bacteria, Borrelia burgdorferi (Bb), in 98 individual field-collected tick vectors as a model for study of within-host processes. Deep population sequencing reveals extensive and previously undocumented levels of Bb variation: the majority (~70%) of ticks harbor mixed strain infections, which we define as levels Bb diversity pre-existing in a diverse inoculum. Within-tick diversity is thus a sample of the variation present within vertebrate hosts. Within individual ticks, we detect signatures of positive selection. Genes most commonly under positive selection across ticks include those involved in dissemination in vertebrate hosts and evasion of the vertebrate immune complement. By focusing on tick-borne Bb, we show that vectors can serve as epidemiological and evolutionary sentinels: within-vector pathogen diversity can be a useful and unbiased way to survey circulating pathogen diversity and identify evolutionary processes occurring in natural transmission cycles.

Identifying climate drivers of infectious disease dynamics: recent advances and challenges ahead.

Climate change is likely to profoundly modulate the burden of infectious diseases. However, attributing health impacts to a changing climate requires being able to associate changes in infectious disease incidence with the potentially complex influences of climate. This aim is further complicated by nonlinear feedbacks inherent in the dynamics of many infections, driven by the processes of immunity and transmission. Here, we detail the mechanisms by which climate drivers can shape infectious disease incidence, from direct effects on vector life history to indirect effects on human susceptibility, and detail the scope of variation available with which to probe these mechanisms. We review approaches used to evaluate and quantify associations between climate and infectious disease incidence, discuss the array of data available to tackle this question, and detail remaining challenges in understanding the implications of climate change for infectious disease incidence. We point to areas where synthesis between approaches used in climate science and infectious disease biology provide potential for progress.

Babesia microti from humans and ticks hold a genomic signature of strong population structure in the United States.

BACKGROUND: Babesia microti is an emerging tick-borne apicomplexan parasite with increasing geographic range and incidence in the United States. The rapid expansion of B. microti into its current distribution in the northeastern USA has been due to the range expansion of the tick vector, Ixodes scapularis, upon which the causative agent is dependent for transmission to humans. RESULTS: To reconstruct the history of B. microti in the continental USA and clarify the evolutionary origin of human strains, we used multiplexed hybrid capture of 25 B. microti isolates obtained from I. scapularis and human blood. Despite low genomic variation compared with other Apicomplexa, B. microti was strongly structured into three highly differentiated genetic clusters in the northeastern USA. Bayesian analyses of the apicoplast genomes suggest that the origin of the current diversity of B. microti in northeastern USA dates back 46 thousand years with a signature of recent population expansion in the last 1000 years. Human-derived samples belonged to two rarely intermixing clusters, raising the possibility of highly divergent infectious phenotypes in humans. CONCLUSIONS: Our results validate the multiplexed hybrid capture strategy for characterizing genome-wide diversity and relatedness of B. microti from ticks and humans. We find strong population structure in B. microti samples from the Northeast indicating potential barriers to gene flow.

Invasion of two tick-borne diseases across New England: harnessing human surveillance data to capture underlying ecological invasion processes.

Modelling the spatial spread of vector-borne zoonotic pathogens maintained in enzootic transmission cycles remains a major challenge. The best available spatio-temporal data on pathogen spread often take the form of human disease surveillance data. By applying a classic ecological approach-occupancy modelling-to an epidemiological question of disease spread, we used surveillance data to examine the latent ecological invasion of tick-borne pathogens. Over the last half-century, previously undescribed tick-borne pathogens including the agents of Lyme disease and human babesiosis have rapidly spread across the northeast United States. Despite their epidemiological importance, the mechanisms of tick-borne pathogen invasion and drivers underlying the distinct invasion trajectories of the co-vectored pathogens remain unresolved. Our approach allowed us to estimate the unobserved ecological processes underlying pathogen spread while accounting for imperfect detection of human cases. Our model predicts that tick-borne diseases spread in a diffusion-like manner with occasional long-distance dispersal and that babesiosis spread exhibits strong dependence on Lyme disease.

Whole genome capture of vector-borne pathogens from mixed DNA samples: a case study of Borrelia burgdorferi.

BACKGROUND: Rapid and accurate retrieval of whole genome sequences of human pathogens from disease vectors or animal reservoirs will enable fine-resolution studies of pathogen epidemiological and evolutionary dynamics. However, next generation sequencing technologies have not yet been fully harnessed for the study of vector-borne and zoonotic pathogens, due to the difficulty of obtaining high-quality pathogen sequence data directly from field specimens with a high ratio of host to pathogen DNA. RESULTS: We addressed this challenge by using custom probes for multiplexed hybrid capture to enrich for and sequence 30 Borrelia burgdorferi genomes from field samples of its arthropod vector. Hybrid capture enabled sequencing of nearly the complete genome (~99.5 %) of the Borrelia burgdorferi pathogen with 132-fold coverage, and identification of up to 12,291 single nucleotide polymorphisms per genome. CONCLUSIONS: The proprosed culture-independent method enables efficient whole genome capture and sequencing of pathogens directly from arthropod vectors, thus making population genomic study of vector-borne and zoonotic infectious diseases economically feasible and scalable. Furthermore, given the similarities of invertebrate field specimens to other mixed DNA templates characterized by a high ratio of host to pathogen DNA, we discuss the potential applicabilty of hybrid capture for genomic study across diverse study systems.

Microhabitat partitioning of Aedes simpsoni (Diptera: Culicidae).

Yellow fever virus is a reemerging infection responsible for widespread, sporadic outbreaks across Africa. Although Aedes aegypti (L.) is the most important vector globally, in East Africa, epidemics may be vectored by Aedes bromeliae (Theobald), a member of the Aedes simpsoni (Theobald) species complex. The Ae. simpsoni complex contains 10 subspecies, of which Ae. bromeliae alone has been incriminated as a vector of yellow fever virus. However, morphological markers cannot distinguish Ae. bromeliae from conspecifics, including the sympatric and non-anthropophilic Aedes lilii (Theobald). Here, we used three sequenced nuclear markers to examine the population structure of Ae. simpsoni complex mosquitoes collected from diverse habitats in Rabai, Kenya. Gene trees consistently show strong support for the existence of two clades in Rabai, with segregation by habitat. Domestic mosquitoes segregate separately from forest-collected mosquitoes, providing evidence of habitat partitioning on a small spatial scale (< 5 km). Although speculative, these likely represent what have been described as Ae. bromeliae and Ae. lilii, respectively. The observation of high levels of diversity within Rabai indicates that this species complex may exhibit significant genetic differentiation across East Africa. The genetic structure, ecology, and range of this important disease vector are surprisingly understudied and need to be further characterized.

The concentration of tuberculosis within Paraguay's incarcerated and Indigenous populations, 2018-2022.

While incidence of tuberculosis (TB) has decreased globally, in Paraguay, considered a medium-incidence country by the WHO, TB incidence has increased slightly from 42 per 100,000 in 2010 to 46 per 100,000 in 2022. We conducted a retrospective study of TB cases notified to the Paraguay National Program for Tuberculosis Control (NPTC) from 2018 to 2022 and quantified trends in specific populations identified as vulnerable. Of the 13,725 TB cases notified in Paraguay from 2018 to 2022, 2,331 (17%) occurred among incarcerated individuals and 1,743 (12.7%) occurred among self-identified Indigenous individuals. In 2022, the relative risk of TB was 87 and 6.4 among the incarcerated and Indigenous populations, compared with the non-incarcerated and non-Indigenous populations respectively. We found significant heterogeneity in TB incidence across Paraguay's 17 departments. Our findings highlight the urgency of expanding access to TB diagnosis, treatment, and prevention in populations at heightened risk of TB in Paraguay.

Excess tuberculosis risk during and following incarceration in Paraguay: a retrospective cohort study.

Background: The increased risk of tuberculosis (TB) among people deprived of liberty (PDL) is due to individual and institution-level factors. We followed a cohort of PDL from 5 prisons in Paraguay to describe the risk of TB during incarceration and after they were released. Methods: We linked a 2013 national census of prisons with TB records from the TB Program from 2010 to 2021 to identify TB notifications among incarcerated and formerly incarcerated individuals. We used multivariable Cox regression models to quantify the risk of TB during and following incarceration and to identify risk factors associated with TB. Findings: Among 2996 individuals incarcerated, 451 (15.1%) were diagnosed with TB. Of these, 262 (58.1%) cases occurred during incarceration and 189 (41.9%) occurred in the community after release. In prison, the hazard ratio of developing TB was 1.97 (95% CI: 1.52-2.61) after six months of incarceration and increased to 2.78 (95% CI: 1.82-4.24) after 36 months compared with the first six months. The overall TB notification rate was 2940 per 100,000 person-years. This rate increased with the duration of incarceration from 1335 per 100,000 person-years in the first year to 8455 per 100,000 person-years after 8 years. Among former prisoners, the rate of TB decreased from 1717 in the first year after release to 593 per 100 000 person-years after 8 years of follow up. Interpretation: Our study shows the alarming risk of TB associated with prison environments in Paraguay, and how this risk persists for years following incarceration. Effective TB control measures to protect the health of people during and following incarceration are urgently needed. Funding: Paraguay National Commission of Science and Technology grant CONACYT PIN 15-705 (GS, GES, SA).

Rapid emergence and transmission of virulence-associated mutations in the oral poliovirus vaccine following vaccination campaigns.

There is an increasing burden of circulating vaccine-derived polioviruses (cVDPVs) due to the continued use of oral poliovirus vaccine (OPV). However, the informativeness of routine OPV VP1 sequencing for the early identification of viruses carrying virulence-associated reversion mutations has not been directly evaluated in a controlled setting. We prospectively collected 15,331 stool samples to track OPV shedding from vaccinated children and their contacts for ten weeks following an immunization campaign in Veracruz State, Mexico and sequenced VP1 genes from 358 samples. We found that OPV was genetically unstable and evolves at an approximately clocklike rate that varies across serotypes and by vaccination status. Alarmingly, 28% (13/47) of OPV-1, 12% (14/117) OPV-2, and 91% (157/173) OPV-3 of Sabin-like viruses had ≥1 known reversion mutation. Our results suggest that current definitions of cVDPVs may exclude circulating virulent viruses that pose a public health risk and underscore the need for intensive surveillance following OPV use.

Rapid emergence and transmission of virulence-associated mutations in the oral poliovirus vaccine following vaccination campaigns.

There is an increasing burden of circulating vaccine-derived polioviruses (cVDPVs) due to the continued use of oral poliovirus vaccine (OPV). However, the informativeness of routine OPV VP1 sequencing for the early identification of viruses carrying virulence-associated reversion mutations has not been directly evaluated in a controlled setting. We prospectively collected 15,331 stool samples to track OPV shedding from children receiving OPV and their contacts for ten weeks following an immunization campaign in Veracruz State, Mexico and sequenced VP1 genes from 358 samples. We found that OPV was genetically unstable and evolves at an approximately clocklike rate that varies across serotypes and by vaccination status. Overall, 61% (11/18) of OPV-1, 71% (34/48) OPV-2, and 96% (54/56) OPV-3 samples with available data had evidence of a reversion at the key 5' UTR attenuating position and 28% (13/47) of OPV-1, 12% (14/117) OPV-2, and 91% (157/173) OPV-3 of Sabin-like viruses had ≥1 known reversion mutations in the VP1 gene. Our results are consistent with previous work documenting rapid reversion to virulence of OPV and underscores the need for intensive surveillance following OPV use.