Caroline O Buckee

Harvard Medical School, Boston, Massachusetts, United States

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Publications (45)266.32 Total impact

  • Lauren M Childs, Caroline O Buckee
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    ABSTRACT: The duration of infection is fundamental to the epidemiological behaviour of any infectious disease, but remains one of the most poorly understood aspects of malaria. In endemic areas, the malaria parasite Plasmodium falciparum can cause both acute, severe infections and asymptomatic, chronic infections through its interaction with the host immune system. Frequent superinfection and massive parasite genetic diversity make it extremely difficult to accurately measure the distribution of infection lengths, complicating the estimation of basic epidemiological parameters and the prediction of the impact of interventions. Mathematical models have qualitatively reproduced parasite dynamics early during infection, but reproducing long-lived chronic infections remains much more challenging. Here, we construct a model of infection dynamics to examine the consequences of common biological assumptions for the generation of chronicity and the impact of co-infection. We find that although a combination of host and parasite heterogeneities are capable of generating chronic infections, they do so only under restricted parameter choices. Furthermore, under biologically plausible assumptions, co-infection of parasite genotypes can alter the course of infection of both the resident and co-infecting strain in complex non-intuitive ways. We outline the most important puzzles for within-host models of malaria arising from our analysis, and their implications for malaria epidemiology and control.
    Journal of the Royal Society, Interface / the Royal Society. 03/2015; 12(104).
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    ABSTRACT: Poor physical access to health facilities has been identified as an important contributor to reduced uptake of preventive health services and is likely to be most critical in low-income settings. However, the relation among physical access, travel behavior, and the uptake of healthcare is difficult to quantify. Using anonymized mobile phone data from 2008 to 2009, we analyze individual and spatially aggregated travel patterns of 14,816,521 subscribers across Kenya and compare these measures to (1) estimated travel times to health facilities and (2) data on the uptake of 2 preventive healthcare interventions in an area of western Kenya: childhood immunizations and antenatal care. We document that long travel times to health facilities are strongly correlated with increased mobility in geographically isolated areas. Furthermore, we found that in areas with equal physical access to healthcare, mobile phone-derived measures of mobility predict which regions are lacking preventive care. Routinely collected mobile phone data provide a simple and low-cost approach to mapping the uptake of preventive healthcare in low-income settings.
    Epidemiology (Cambridge, Mass.) 03/2015; 26(2):223-8. · 6.18 Impact Factor
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    ABSTRACT: Malaria, HIV, and tuberculosis (TB) collectively account for several million deaths each year, with all three ranking among the top ten killers in low-income countries. Despite being caused by very different organisms, malaria, HIV, and TB present a suite of challenges for mathematical modellers that are particularly pronounced in these infections, but represent general problems in infectious disease modelling, and highlight many of the challenges described throughout this issue. Here, we describe some of the unifying challenges that arise in modelling malaria, HIV, and TB, including variation in dynamics within the host, diversity in the pathogen, and heterogeneity in human contact networks and behaviour. Through the lens of these three pathogens, we provide specific examples of the other challenges in this issue and discuss their implications for informing public health efforts.
    Epidemics 02/2015; 350. · 2.38 Impact Factor
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    ABSTRACT: As malaria transmission intensity has declined, Plasmodium falciparum parasite populations display decreased clonal diversity resulting from the emergence of many parasites with common genetic signatures (CGS). We have monitored such CGS parasite clusters from 2006-2013 in Thiès, Senegal using the molecular barcode. The first, and one of the largest observed clusters of CGS parasites was present in 24% of clinical isolates in 2008, declined to 3.4% of clinical isolates in 2009, and then disappeared. To begin to explore the relationship between the immune responses of the population and the emergence and decline of specific parasite genotypes, we have determined whether antibodies to CGS parasites correlate with their prevalence. We measured:1) antibodies capable of inhibiting parasite growth in culture and 2) antibodies recognizing the surface of infected RBCs. IgGs obtained from volunteers in 2009 showed increased reactivity to the surface of CGS-parasitized erythrocytes over IgGs from 2008. As PfEMP-1 is a major variant surface antigen, we characterized the var genes expressed by CGS parasites after short term in vitro culture, by var Ups qRT-PCR and sequencing using degenerate DBL1α domain primers. CGS parasites show an upregulation of UpsA vars and 2-cysteine containing PfEMP-1 molecules and express the same dominant var transcript. Our work indicates that the CGS parasites in this cluster express similar var genes, more than would be expected by chance in the population, and there is year-to-year variation in immune recognition of surface antigens on CGS infected erythrocytes. This study lays the groundwork for detailed investigations of the mechanisms driving the expansion or contraction of specific parasite clones in the population.
    Infection and Immunity 11/2014; · 4.16 Impact Factor
  • Caroline O Buckee
    Nature 10/2014; 514(7520):35. · 42.35 Impact Factor
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    ABSTRACT: 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.
    Cell host & microbe. 08/2014; 16(2):177-186.
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    ABSTRACT: Human travel impacts the spread of infectious diseases across spatial and temporal scales, with broad implications for the biological and social sciences. Individual data on travel patterns have been difficult to obtain, particularly in low-income countries. Travel survey data provide detailed demographic information, but sample sizes are often small and travel histories are hard to validate. Mobile phone records can provide vast quantities of spatio-temporal travel data but vary in spatial resolution and explicitly do not include individual information in order to protect the privacy of subscribers. Here we compare and contrast both sources of data over the same time period in a rural area of Kenya. Although both data sets are able to quantify broad travel patterns and distinguish regional differences in travel, each provides different insights that can be combined to form a more detailed picture of travel in low-income settings to understand the spread of infectious diseases.
    Scientific Reports 07/2014; 4:5678. · 5.08 Impact Factor
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    ABSTRACT: Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. That framework, especially Macdonald's formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases. A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross-Macdonald assumption of homogeneous transmission in a well-mixed population. Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory. Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement. Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.
    Transactions of the Royal Society of Tropical Medicine and Hygiene 03/2014; 108(4):185-197. · 1.93 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Pathogen evolution is influenced strongly by the host immune response. Previous studies of the effects of herd immunity on the population structure of directly transmitted, short-lived pathogens have primarily focused on the impact of competition for hosts. In contrast, for long-lived infections like HIV, theoretical work has focused on the mechanisms promoting antigenic variation within the host. In reality, successful transmission requires that pathogens balance both within- and between-host immune selection. The Opa adhesins in the bacterial Neisseria genus provide a unique system to study the evolution of the same antigens across two major pathogens: while N. meningitidis is an airborne, respiratory pathogen colonising the nasopharynx relatively transiently, N. gonorrhoeae can cause sexually transmitted, long-lived infections. We use a simple mathematical model and genomic data to show that trade-offs between immune selection pressures within- and between-hosts can explain the contrasting Opa repertoires observed in meningococci and gonococci.
    Scientific reports. 01/2014; 4:6554.
  • PLoS currents. 01/2014; 6.
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    ABSTRACT: Pathogen-mediated selection is commonly invoked as an explanation for the exceptional polymorphism of the HLA gene cluster, but its role in generating and maintaining linkage disequilibrium between HLA loci is unclear. Here we show that pathogen-mediated selection can promote nonrandom associations between HLA loci. These associations may be distinguished from linkage disequilibrium generated by other population genetic processes by virtue of being nonoverlapping as well as nonrandom. Within our framework, immune selection forces the pathogen population to exist as a set of antigenically discrete strains; this then drives nonoverlapping associations between the HLA loci through which recognition of these antigens is mediated. We demonstrate that this signature of pathogen-driven selection can be observed in existing data, and propose that analyses of HLA population structure can be combined with laboratory studies to help us uncover the functional relationships between HLA alleles. In a wider coevolutionary context, our framework also shows that the inclusion of memory immunity can lead to robust cyclical dynamics across a range of host-pathogen systems.
    Proceedings of the National Academy of Sciences 11/2013; · 9.81 Impact Factor
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    Daniel B Larremore, Aaron Clauset, Caroline O Buckee
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    ABSTRACT: The var genes of the human malaria parasite Plasmodium falciparum present a challenge to population geneticists due to their extreme diversity, which is generated by high rates of recombination. These genes encode a primary antigen protein called PfEMP1, which is expressed on the surface of infected red blood cells and elicits protective immune responses. Var gene sequences are characterized by pronounced mosaicism, precluding the use of traditional phylogenetic tools that require bifurcating tree-like evolutionary relationships. We present a new method that identifies highly variable regions (HVRs), and then maps each HVR to a complex network in which each sequence is a node and two nodes are linked if they share an exact match of significant length. Here, networks of var genes that recombine freely are expected to have a uniformly random structure, but constraints on recombination will produce network communities that we identify using a stochastic block model. We validate this method on synthetic data, showing that it correctly recovers populations of constrained recombination, before applying it to the Duffy Binding Like-α (DBLα) domain of var genes. We find nine HVRs whose network communities map in distinctive ways to known DBLα classifications and clinical phenotypes. We show that the recombinational constraints of some HVRs are correlated, while others are independent. These findings suggest that this micromodular structuring facilitates independent evolutionary trajectories of neighboring mosaic regions, allowing the parasite to retain protein function while generating enormous sequence diversity. Our approach therefore offers a rigorous method for analyzing evolutionary constraints in var genes, and is also flexible enough to be easily applied more generally to any highly recombinant sequences.
    PLoS Computational Biology 10/2013; 9(10):e1003268. · 4.83 Impact Factor
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    ABSTRACT: Acquired immunity to Plasmodium falciparum infection causes a change from frequent, sometimes life-threatening, malaria in young children to asymptomatic, chronic infections in older children and adults. Little is known about how this transition occurs but antibodies to the extremely diverse PfEMP1 parasite antigens are thought to play a role. PfEMP1 is encoded by a family of 60 var genes that undergo clonal antigenic variation, potentially creating an antigenically heterogeneous infecting population of parasites within the host. Previous theoretical work suggests that antibodies to PfEMP1 may play a role in "orchestrating" their expression within infections leading to sequential, homogeneous expression of var genes, and prolonged infection chronicity. Here, using a cloning and sequencing approach we compare the var expression homogeneity (VEH) between isolates from children with asymptomatic and clinical infections. We show that asymptomatic infections have higher VEH than clinical infections and a broader host antibody response. We discuss this in relation to the potential role of host antibodies in promoting chronicity of infection and parasite survival through the low transmission season.
    PLoS ONE 07/2013; 8(7):e70467. · 3.53 Impact Factor
  • Elsa Hansen, Caroline O Buckee
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    ABSTRACT: The complex biological relationships underlying malaria transmission make it difficult to predict the impact of interventions. Mathematical models simplify these relationships and capture essential components of malaria transmission and epidemiology. Models designed to predict the impact of control programs generally infer a relationship between transmission intensity and human infectiousness to the mosquito, requiring assumptions about how infectiousness varies between individuals. A lack of understanding of human infectiousness precludes a standard approach to this inference, however, and field data reveal no obvious correlation between transmission intensity and human population infectiousness. We argue that model assumptions will have important consequences for predicting the impact of control programs.
    Trends in Parasitology 04/2013; · 6.22 Impact Factor
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    ABSTRACT: Mathematical models of mosquito-borne pathogen transmission originated in the early twentieth century to provide insights into how to most effectively combat malaria. The foundations of the Ross-Macdonald theory were established by 1970. Since then, there has been a growing interest in reducing the public health burden of mosquito-borne pathogens and an expanding use of models to guide their control. To assess how theory has changed to confront evolving public health challenges, we compiled a bibliography of 325 publications from 1970 through 2010 that included at least one mathematical model of mosquito-borne pathogen transmission and then used a 79-part questionnaire to classify each of 388 associated models according to its biological assumptions. As a composite measure to interpret the multidimensional results of our survey, we assigned a numerical value to each model that measured its similarity to 15 core assumptions of the Ross-Macdonald model. Although the analysis illustrated a growing acknowledgement of geographical, ecological and epidemiological complexities in modelling transmission, most models during the past 40 years closely resemble the Ross-Macdonald model. Modern theory would benefit from an expansion around the concepts of heterogeneous mosquito biting, poorly mixed mosquito-host encounters, spatial heterogeneity and temporal variation in the transmission process.
    Journal of The Royal Society Interface 04/2013; 10(81):20120921. · 3.86 Impact Factor
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    ABSTRACT: The macaque malaria parasite Plasmodium knowlesi has recently emerged as an important zoonosis in Southeast Asia. Infections are typically mild but can cause severe disease, achieving parasite densities similar to fatal Plasmodium falciparum infections. Here we show that a primate-adapted P. knowlesi parasite proliferates poorly in human blood due to a strong preference for young red blood cells (RBCs). We establish a continuous in vitro culture system by using human blood enriched for young cells. Mathematical modelling predicts that parasite adaptation for invasion of older RBCs is a likely mechanism leading to high parasite densities in clinical infections. Consistent with this model, we find that P. knowlesi can adapt to invade a wider age range of RBCs, resulting in proliferation in normal human blood. Such cellular niche expansion may increase pathogenesis in humans and will be a key feature to monitor as P. knowlesi emerges in human populations.
    Nature Communications 03/2013; 4:1638. · 10.74 Impact Factor
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    ABSTRACT: Human mobility plays an important role in the dissemination of malaria parasites between regions of variable transmission intensity. Asymptomatic individuals can unknowingly carry parasites to regions where mosquito vectors are available, for example, undermining control programs and contributing to transmission when they travel. Understanding how parasites are imported between regions in this way is therefore an important goal for elimination planning and the control of transmission, and would enable control programs to target the principal sources of malaria. Measuring human mobility has traditionally been difficult to do on a population scale, but the widespread adoption of mobile phones in low-income settings presents a unique opportunity to directly measure human movements that are relevant to the spread of malaria. Here, we discuss the opportunities for measuring human mobility using data from mobile phones, as well as some of the issues associated with combining mobility estimates with malaria infection risk maps to meaningfully estimate routes of parasite importation.
    Travel Medicine and Infectious Disease 03/2013; · 1.54 Impact Factor
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    ABSTRACT: Mobile phone data are increasingly being used to quantify the movements of human populations for a wide range of social, scientific and public health research. However, making population-level inferences using these data is complicated by differential ownership of phones among different demographic groups that may exhibit variable mobility. Here, we quantify the effects of ownership bias on mobility estimates by coupling two data sources from the same country during the same time frame. We analyse mobility patterns from one of the largest mobile phone datasets studied, representing the daily movements of nearly 15 million individuals in Kenya over the course of a year. We couple this analysis with the results from a survey of socioeconomic status, mobile phone ownership and usage patterns across the country, providing regional estimates of population distributions of income, reported airtime expenditure and actual airtime expenditure across the country. We match the two data sources and show that mobility estimates are surprisingly robust to the substantial biases in phone ownership across different geographical and socioeconomic groups.
    Journal of The Royal Society Interface 01/2013; 10(81):20120986. · 3.86 Impact Factor
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    ABSTRACT: Human movement plays a key role in economies and development, the delivery of services, and the spread of infectious diseases. However, it remains poorly quantified partly because reliable data are often lacking, particularly for low-income countries. The most widely available are migration data from human population censuses, which provide valuable information on relatively long timescale relocations across countries, but do not capture the shorter-scale patterns, trips less than a year, that make up the bulk of human movement. Census-derived migration data may provide valuable proxies for shorter-term movements however, as substantial migration between regions can be indicative of well connected places exhibiting high levels of movement at finer time scales, but this has never been examined in detail. Here, an extensive mobile phone usage data set for Kenya was processed to extract movements between counties in 2009 on weekly, monthly, and annual time scales and compared to data on change in residence from the national census conducted during the same time period. We find that the relative ordering across Kenyan counties for incoming, outgoing and between-county movements shows strong correlations. Moreover, the distributions of trip durations from both sources of data are similar, and a spatial interaction model fit to the data reveals the relationships of different parameters over a range of movement time scales. Significant relationships between census migration data and fine temporal scale movement patterns exist, and results suggest that census data can be used to approximate certain features of movement patterns across multiple temporal scales, extending the utility of census-derived migration data.
    PLoS ONE 01/2013; 8(1):e52971. · 3.53 Impact Factor
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    ABSTRACT: Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Elimination's 'stickiness' must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health system's increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria elimination's stickiness at moderate-to-low transmission in areas with well-developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame.
    Philosophical Transactions of The Royal Society B Biological Sciences 01/2013; 368(1623):20120145. · 6.23 Impact Factor

Publication Stats

528 Citations
266.32 Total Impact Points


  • 2010–2014
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2013
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, MD, United States
  • 2012–2013
    • Carnegie Mellon University
      • Department of Engineering and Public Policy
      Pittsburgh, PA, United States
    • University of Florida
      • Emerging Pathogens Institute
      Gainesville, FL, United States
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
  • 2011–2013
    • Harvard University
      • Department of Epidemiology
      Cambridge, Massachusetts, United States
  • 2004–2012
    • University of Oxford
      • Department of Zoology
      Oxford, England, United Kingdom
  • 2008
    • Kenya Medical Research Institute
      • Centre for Clinical Research
      Nairoba, Nairobi Area, Kenya