Strategies for containing an emerging infectious disease outbreak must be nonpharmaceutical when drugs or vaccines for the pathogen do not yet exist or are unavailable. The success of these ...nonpharmaceutical strategies will depend on not only the effectiveness of isolation measures but also the epidemiological characteristics of the infection. However, there is currently no systematic framework to assess the relationship between different containment strategies and the natural history and epidemiological dynamics of the pathogen. Here, we compare the effectiveness of quarantine and symptom monitoring, implemented via contact tracing, in controlling epidemics using an agent-based branching model. We examine the relationship between epidemic containment and the disease dynamics of symptoms and infectiousness for seven case-study diseases with diverse natural histories, including Ebola, influenza A, and severe acute respiratory syndrome (SARS). We show that the comparative effectiveness of symptom monitoring and quarantine depends critically on the natural history of the infectious disease, its inherent transmissibility, and the intervention feasibility in the particular healthcare setting. The benefit of quarantine over symptom monitoring is generally maximized for fast-course diseases, but we show the conditions under which symptom monitoring alone can control certain outbreaks. This quantitative framework can guide policymakers on how best to use nonpharmaceutical interventions and prioritize research during an outbreak of an emerging pathogen.
Many mosquito species, including the major malaria vector Anopheles gambiae, naturally undergo multiple reproductive cycles of blood feeding, egg development and egg laying in their lifespan. Such ...complex mosquito behavior is regularly overlooked when mosquitoes are experimentally infected with malaria parasites, limiting our ability to accurately describe potential effects on transmission. Here, we examine how Plasmodium falciparum development and transmission potential is impacted when infected mosquitoes feed an additional time. We measured P. falciparum oocyst size and performed sporozoite time course analyses to determine the parasite's extrinsic incubation period (EIP), i.e. the time required by parasites to reach infectious sporozoite stages, in An. gambiae females blood fed either once or twice. An additional blood feed at 3 days post infection drastically accelerates oocyst growth rates, causing earlier sporozoite accumulation in the salivary glands, thereby shortening the EIP (reduction of 2.3 ± 0.4 days). Moreover, parasite growth is further accelerated in transgenic mosquitoes with reduced reproductive capacity, which mimic genetic modifications currently proposed in population suppression gene drives. We incorporate our shortened EIP values into a measure of transmission potential, the basic reproduction number R0, and find the average R0 is higher (range: 10.1%-12.1% increase) across sub-Saharan Africa than when using traditional EIP measurements. These data suggest that malaria elimination may be substantially more challenging and that younger mosquitoes or those with reduced reproductive ability may provide a larger contribution to infection than currently believed. Our findings have profound implications for current and future mosquito control interventions.
Voluntary individual quarantine and voluntary active monitoring of contacts are core disease control strategies for emerging infectious diseases such as COVID-19. Given the impact of quarantine on ...resources and individual liberty, it is vital to assess under what conditions individual quarantine can more effectively control COVID-19 than active monitoring. As an epidemic grows, it is also important to consider when these interventions are no longer feasible and broader mitigation measures must be implemented.
To estimate the comparative efficacy of individual quarantine and active monitoring of contacts to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we fit a stochastic branching model to reported parameters for the dynamics of the disease. Specifically, we fit a model to the incubation period distribution (mean 5·2 days) and to two estimates of the serial interval distribution: a shorter one with a mean serial interval of 4·8 days and a longer one with a mean of 7·5 days. To assess variable resource settings, we considered two feasibility settings: a high-feasibility setting with 90% of contacts traced, a half-day average delay in tracing and symptom recognition, and 90% effective isolation; and a low-feasibility setting with 50% of contacts traced, a 2-day average delay, and 50% effective isolation.
Model fitting by sequential Monte Carlo resulted in a mean time of infectiousness onset before symptom onset of 0·77 days (95% CI −1·98 to 0·29) for the shorter serial interval, and for the longer serial interval it resulted in a mean time of infectiousness onset after symptom onset of 0·51 days (95% CI −0·77 to 1·50). Individual quarantine in high-feasibility settings, where at least 75% of infected contacts are individually quarantined, contains an outbreak of SARS-CoV-2 with a short serial interval (4·8 days) 84% of the time. However, in settings where the outbreak continues to grow (eg, low-feasibility settings), so too will the burden of the number of contacts traced for active monitoring or quarantine, particularly uninfected contacts (who never develop symptoms). When resources are prioritised for scalable interventions such as physical distancing, we show active monitoring or individual quarantine of high-risk contacts can contribute synergistically to mitigation efforts. Even under the shorter serial interval, if physical distancing reduces the reproductive number to 1·25, active monitoring of 50% of contacts can result in overall outbreak control (ie, effective reproductive number <1).
Our model highlights the urgent need for more data on the serial interval and the extent of presymptomatic transmission to make data-driven policy decisions regarding the cost–benefit comparisons of individual quarantine versus active monitoring of contacts. To the extent that these interventions can be implemented, they can help mitigate the spread of SARS-CoV-2.
National Institute of General Medical Sciences, National Institutes of Health.
Malaria remains one of the leading causes of death worldwide, despite decades of public health efforts. The recent commitment by many endemic countries to eliminate malaria marks a shift away from ...programs aimed at controlling disease burden towards one that emphasizes reducing transmission of the most virulent human malaria parasite, Plasmodium falciparum. Gametocytes, the only developmental stage of malaria parasites able to infect mosquitoes, have remained understudied, as they occur in low numbers, do not cause disease, and are difficult to detect in vivo by conventional methods. Here, we review the transmission biology of P. falciparum gametocytes, featuring important recent discoveries of genes affecting parasite commitment to gametocyte formation, microvesicles enabling parasites to communicate with each other, and the anatomical site where immature gametocytes develop. We propose potential parasite targets for future intervention and highlight remaining knowledge gaps.
The maternally inherited alpha-proteobacterium Wolbachia has been proposed as a tool to block transmission of devastating mosquito-borne infectious diseases like dengue and malaria. Here we study the ...reproductive manipulations induced by a recently identified Wolbachia strain that stably infects natural mosquito populations of a major malaria vector, Anopheles coluzzii, in Burkina Faso. We determine that these infections significantly accelerate egg laying but do not induce cytoplasmic incompatibility or sex-ratio distortion, two parasitic reproductive phenotypes that facilitate the spread of other Wolbachia strains within insect hosts. Analysis of 221 blood-fed A. coluzzii females collected from houses shows a negative correlation between the presence of Plasmodium parasites and Wolbachia infection. A mathematical model incorporating these results predicts that infection with these endosymbionts may reduce malaria prevalence in human populations. These data suggest that Wolbachia may be an important player in malaria transmission dynamics in Sub-Saharan Africa.
The asexual forms of the malaria parasite Plasmodium falciparum are adapted for chronic persistence in human red blood cells, continuously evading host immunity using epigenetically regulated ...antigenic variation of virulence-associated genes. Parasite survival on a population level also requires differentiation into sexual forms, an obligatory step for further human transmission. We reveal that the essential nuclear gene, P. falciparum histone deacetylase 2 (PfHda2), is a global silencer of virulence gene expression and controls the frequency of switching from the asexual cycle to sexual development. PfHda2 depletion leads to dysregulated expression of both virulence-associated var genes and PfAP2-g, a transcription factor controlling sexual conversion, and is accompanied by increases in gametocytogenesis. Mathematical modeling further indicates that PfHda2 has likely evolved to optimize the parasite’s infectious period by achieving low frequencies of virulence gene expression switching and sexual conversion. This common regulation of cellular transcriptional programs mechanistically links parasite transmissibility and virulence.
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•The class II histone deacetylase, PfHda2, is essential in malaria parasites•Depletion of PfHda2 activates heterochromatic, variantly expressed genes such as var•PfHda2 regulates expression of genes required for initiation of sexual conversion•A molecular link between persistence and sexual conversion in malaria is revealed
To ensure infection and transmission, Plasmodium falciparum requires regulation of genes involved in virulence and development. Coleman et al. identify P. falciparum histone deacetylase 2 (PfHda2) as an essential epigenetic regulator that globally silences virulence gene expression and regulates sexual conversion, highlighting a shared link between transmissibility and virulence.
The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread ...insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgently needed, including the identification of safe compounds that affect vectorial capacity via mechanisms that differ from fast-acting insecticides. Here, we show that compounds targeting steroid hormone signaling disrupt multiple biological processes that are key to the ability of mosquitoes to transmit malaria. When an agonist of the steroid hormone 20-hydroxyecdysone (20E) is applied to Anopheles gambiae females, which are the dominant malaria mosquito vector in Sub Saharan Africa, it substantially shortens lifespan, prevents insemination and egg production, and significantly blocks Plasmodium falciparum development, three components that are crucial to malaria transmission. Modeling the impact of these effects on Anopheles population dynamics and Plasmodium transmission predicts that disrupting steroid hormone signaling using 20E agonists would affect malaria transmission to a similar extent as insecticides. Manipulating 20E pathways therefore provides a powerful new approach to tackle malaria transmission by the mosquito vector, particularly in areas affected by the spread of insecticide resistance.
Plasmodium falciparum, the most virulent human malaria parasite, undergoes asexual reproduction within the human host, but reproduces sexually within its vector host, the Anopheles mosquito. ...Consequently, the mosquito stage of the parasite life cycle provides an opportunity to create genetically novel parasites in multiply-infected mosquitoes, potentially increasing parasite population diversity. Despite the important implications for disease transmission and malaria control, a quantitative mapping of how parasite diversity entering a mosquito relates to diversity of the parasite exiting, has not been undertaken. To examine the role that vector biology plays in modulating parasite diversity, we develop a two-part model framework that estimates the diversity as a consequence of different bottlenecks and expansion events occurring during the vector-stage of the parasite life cycle. For the underlying framework, we develop the first stochastic model of within-vector P. falciparum parasite dynamics and go on to simulate the dynamics of two parasite subpopulations, emulating multiply infected mosquitoes. We show that incorporating stochasticity is essential to capture the extensive variation in parasite dynamics, particularly in the presence of multiple parasites. In particular, unlike deterministic models, which always predict the most fit parasites to produce the most sporozoites, we find that occasionally only parasites with lower fitness survive to the sporozoite stage. This has important implications for onward transmission. The second part of our framework includes a model of sequence diversity generation resulting from recombination and reassortment between parasites within a mosquito. Our two-part model framework shows that bottlenecks entering the oocyst stage decrease parasite diversity from what is present in the initial gametocyte population in a mosquito's blood meal. However, diversity increases with the possibility for recombination and proliferation in the formation of sporozoites. Furthermore, when we begin with two parasite subpopulations in the initial gametocyte population, the probability of transmitting more than two unique parasites from mosquito to human is over 50% for a wide range of initial gametocyte densities.
Bites of Anopheles mosquitoes transmit Plasmodium falciparum parasites that cause malaria, which kills hundreds of thousands of people every year. Since the turn of this century, efforts to prevent ...the transmission of these parasites via the mass distribution of insecticide-treated bed nets have been extremely successful, and have led to an unprecedented reduction in deaths from malaria
. However, resistance to insecticides has become widespread in Anopheles populations
, which has led to the threat of a global resurgence of malaria and makes the generation of effective tools for controlling this disease an urgent public health priority. Here we show that the development of P. falciparum can be rapidly and completely blocked when female Anopheles gambiae mosquitoes take up low concentrations of specific antimalarials from treated surfaces-conditions that simulate contact with a bed net. Mosquito exposure to atovaquone before, or shortly after, P. falciparum infection causes full parasite arrest in the midgut, and prevents transmission of infection. Similar transmission-blocking effects are achieved using other cytochrome b inhibitors, which demonstrates that parasite mitochondrial function is a suitable target for killing parasites. Incorporating these effects into a model of malaria transmission dynamics predicts that impregnating mosquito nets with Plasmodium inhibitors would substantially mitigate the global health effects of insecticide resistance. This study identifies a powerful strategy for blocking Plasmodium transmission by female Anopheles mosquitoes, which has promising implications for efforts to eradicate malaria.
Theory assumes that multiplication rates of pathogenic organisms have substantial influence on disease severity and spread.Malaria infections represent one of the most straightforward systems in ...which to measure parasite multiplication rates (PMRs), but PMRs have proven difficult to link to health outcomes.Applied to human infection data, standard methods for estimating PMRs yield extraordinarily large values, far exceeding the maximum expansion rate (i.e., burst size) established in vitro.Spurious multiplication rates appear when some ages of parasites are more difficult to sample and when the age distribution of the parasite population changes through time, problems that are likely common among pathogenic organisms.Small changes in age distributions can lead to estimates of extraordinarily high multiplication rates that may explain why PMRs often fail to predict disease severity.
For pathogenic organisms, faster rates of multiplication promote transmission success, the potential to harm hosts, and the evolution of drug resistance. Parasite multiplication rates (PMRs) are often quantified in malaria infections, given the relative ease of sampling. Using modern and historical human infection data, we show that established methods return extraordinarily – and implausibly – large PMRs. We illustrate how inflated PMRs arise from two facets of malaria biology that are far from unique: (i) some developmental ages are easier to sample than others; (ii) the distribution of developmental ages changes over the course of infection. The difficulty of accurately quantifying PMRs demonstrates a need for robust methods and a subsequent re-evaluation of what is known even in the well-studied system of malaria.
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