Bryan T Grenfell

• Princeton University

While excess rainfall is associated with mosquito-borne disease because it supports mosquito breeding, drought may also counterintuitively increase disease transmission by altering mosquito and host behavior. This phenomenon is important to understand because climate change is projected to increase both extreme rainfall and drought. In this study,...

Climate and infectious diseases each present critical challenges on a warming planet, as does the influence of climate on disease. Both are governed by nonlinear feedbacks, which drive multi‐annual cycles in disease outbreaks and weather patterns. Although climate and weather can influence infectious disease transmission and have spawned rich liter...

Estimating the durability of immunity from vaccination is complicated by unreported re-vaccination, and unobserved natural infection or reexposure, which could result in overestimation of protection longevity. We tested serial cross-sectional serum samples from 2005 to 2015 (N=2,530) for IgG to examine measles seroprevalence, spatiotemporal pattern...

Nonpharmaceutical interventions (NPIs) implemented during the COVID-19 pandemic have disrupted the dynamics of respiratory syncytial virus (RSV) on a global scale; however, the cycling of RSV subtypes in the pre- and post-pandemic period remains poorly understood. Here, we used a two subtype RSV model supplemented with epidemiological data to study...

A key aim in the dynamics and control of infectious diseases is predicting competitive outcomes of pathogen interactions. Observed pathogen community structure indicates both considerable coexistence of related variants and spectacular instances of replacement, notably in seasonal influenza and SARS-CoV-2. However, an overall comparative quantitati...

Influenza A has two main clades, with stronger cross-immunity to reinfection within than between clades. Here, we explore the implications of this heterogeneity for proposed cross-protective influenza vaccines that may offer broad, but not universal, protection. While the development goal for the breadth of human influenza A vaccine is to provide c...

Highly pathogenic avian influenza virus (HPAIV) A H5, particularly clade 2.3.4.4, has caused worldwide outbreaks in domestic poultry, occasional spillover to humans, and increasing deaths of diverse species of wild birds since 2014. Wild bird migration is currently acknowledged as an important ecological process contributing to the global dispersal...

Understanding and accurately estimating epidemiological delay distributions is important for public health policy. These estimates directly influence epidemic situational awareness, control strategies, and resource allocation. In this study, we explore challenges in estimating these distributions, including truncation, interval censoring, and dynam...

Nonpharmaceutical interventions (NPIs) implemented during the COVID-19 pandemic have disrupted the dynamics of respiratory syncytial virus (RSV) on a global scale; however, the cycling of RSV subtypes in the pre- and post-pandemic period remains poorly understood. Here, we use a two subtype RSV model supplemented with epidemiological data to study...

Two different epidemiological models of vaccination are commonly used in dynamical modeling studies. The leaky vaccination model assumes that all vaccinated individuals experience a reduced force of infection by the same amount. The polarized vaccination model assumes that some fraction of vaccinated individuals are completely protected, while the...

Recent outbreaks of enterovirus D68 (EV-D68) infections, and their causal linkage with acute flaccid myelitis (AFM), continue to pose a serious public health concern. During 2020 and 2021, the dynamics of EV-D68 and other pathogens have been significantly perturbed by non-pharmaceutical interventions against COVID-19; this perturbation presents a p...

Significance Nonpharmaceutical interventions (NPIs), such as social distancing, reduce not only COVID-19 cases but also other circulating infections such as influenza and RSV. The susceptible population for these infections will increase while NPIs are in place. Using models fit to historic cases of RSV and influenza, we project large future outbre...

The COVID-19 pandemic is straining public health systems worldwide and major non-pharmaceutical interventions have been implemented to slow its spread. During the initial phase of the outbreak the spread was primarily determined by human mobility. Yet empirical evidence on the effect of key geographic factors on local epidemic spread is lacking. We...

Predictive models for the spatial spread of infectious diseases has received much attention in recent years as tools for the management of infectious diseas outbreaks. Prominently, various versions of the so-called gravity model, borrowed from transportation theory, have been used. However, the original literature suggests that the model has some p...

A bstract Existing methods to infer the relative roles of age groups in epidemic transmission can normally only accommodate a few age classes, and/or require data that are highly specific for the disease being studied. Here, symbolic transfer entropy (STE), a measure developed to identify asymmetric transfer of information between stochastic proces...

The yearly influx of susceptibles in a population (through births) is a key driver of seasonal disease outbreaks in many wildlife species. Environment can have additional effects on outbreak size and seasonality by acting on host immunity, transmission rates, or survival. A key challenge in disease ecology has been to assess the relative importance...

The path to elimination Measles is highly infectious and can be dangerous. The classic 1968 vaccine is highly effective, and it should be possible to eliminate measles. Graham et al. found that measles transmission changes as vaccination coverage and birth rates (that is, the rate of arrival of susceptible individuals into the population) change in...

Background Mathematical transmission models are increasingly used to guide public health interventions for infectious diseases, particularly in the context of emerging pathogens; however, the contribution of modeling to the growing issue of antimicrobial resistance (AMR) remains unclear. Here, we systematically evaluate publications on population-l...

Due to a combination of ecological, political, and demographic factors, the emergence of novel pathogens has been increasingly observed in animals and humans in recent decades. Enhancing global capacity to study and interpret infectious disease surveillance data, and to develop data-driven computational models to guide policy, represents one of the...

Across a range of pathogens, resistance to chemotherapy is a growing problem in both public health and animal health. Despite the ubiquity of coinfection, and its potential effects on within-host biology, the role played by coinfecting pathogens on the evolution of resistance and efficacy of antimicrobial chemotherapy is rarely considered. In this...

Zoonotic influenza viruses that are a few mutations away from pandemic viruses circulate in animals, and can evolve into airborne-transmissible viruses in human beings. Paradoxically, such viruses only occasionally emerge in people; the four influenza pandemics that occurred in the past 100 years were caused by zoonotic viruses that acquired effici...

Despite some notable successes in the control of infectious diseases, transmissible pathogens still pose an enormous threat to human and animal health. The ecological and evolutionary dynamics of infections play out on a wide range of interconnected temporal, organizational, and spatial scales, which span hours to months, cells to ecosystems, and l...

Introduction: Fine-grained influenza surveillance data are lacking in the US, hampering our ability to monitor disease spread at a local scale. Here we evaluate the performances of high-volume electronic medical claims data to assess local and regional influenza activity. Material and methods: We used electronic medical claims data compiled by I...

Rubella is a completely immunizing and mild infection in children. Understanding its behaviour is of considerable public health importance because of congenital rubella syndrome, which results from infection with rubella during early pregnancy and may entail a variety of birth defects. The recurrent dynamics of rubella are relatively poorly resolve...

Metapopulation rescue effects are thought to be key to the persistence of many acute immunizing infections. Yet the enhancement of persistence through spatial coupling has not been previously quantified. Here we estimate the metapopulation rescue effects for four childhood infections using global WHO reported incidence data by comparing persistence...

The global reduction of the burden of morbidity and mortality owing to measles has been a major triumph of public health. However, the continued persistence of measles infection probably not only reflects local variation in progress towards vaccination target goals, but may also reflect local variation in dynamic processes of transmission, suscepti...

Norovirus (NoV) transmission may be impacted by changes in symptom intensity. Sudden onset of vomiting, which may cause an initial period of hyper-infectiousness, often marks the beginning of symptoms. This is often followed by: a 1-3 day period of milder symptoms, environmental contamination following vomiting, and post-symptomatic shedding that m...

Influenza A viruses are characterized by their ability to evade host immunity, even in vaccinated individuals. To determine how prior immunity shapes viral diversity in vivo, we studied the intra- and interhost evolution of equine influenza virus in vaccinated horses. Although the level and structure of genetic diversity were similar to those in na...

Influenza A viruses (IAVs) cause acute, highly transmissible infections in a wide range of animal species. Understanding how these viruses are transmitted within and between susceptible host populations is critical to the development of effective control strategies. While viral gene sequences have been used to make inferences about IAV transmission...

Models of infectious disease spread that incorporate contact heterogeneity through contact networks are an important tool for epidemiologists studying disease dynamics and assessing intervention strategies. One of the challenges of contact network epidemiology has been the difficulty of collecting individual and population-level data needed to deve...

Rubella is generally a mild childhood disease, but infection during early pregnancy may cause spontaneous abortion or congenital rubella syndrome (CRS), which may entail a variety of birth defects. Since vaccination at levels short of those necessary to achieve eradication may increase the average age of infection, and thus potentially the CRS burd...

Advances in vaccine technology over the past two centuries have facilitated far-reaching impact in the control of many infections, and today's emerging vaccines could likewise open new opportunities in the control of several diseases. Here we consider the potential, population-level effects of a particular class of emerging vaccines that use specif...

Background Use of cholera vaccines in response to epidemics (reactive vaccination) may provide an effective supplement to traditional control measures. In Haiti, reactive vaccination was considered but, until recently, rejected in part due to limited global supply of vaccine. Using Bissau City, Guinea-Bissau as a case study, we explore neighborhood...

Outbreaks of avian influenza in poultry can be devastating, yet many of the basic epidemiological parameters have not been accurately characterised. In 1999-2000 in Northern Italy, outbreaks of H7N1 low pathogenicity avian influenza virus (LPAI) were followed by the emergence of H7N1 highly pathogenic avian influenza virus (HPAI). This study invest...

Influenza virus tissue tropism defines the host cells and tissues that support viral replication and contributes to determining which regions of the respiratory tract are infected in humans. The location of influenza virus infection along the respiratory tract is a key determinant of virus pathogenicity and transmissibility, which are at the basis...

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccinati...

For vaccine-preventable infections, immunization generally needs to be supplemented by palliative care of individuals missed by the vaccination. Costs and availability of vaccine doses and palliative care vary by disease and by region. In many situations, resources for delivery of palliative care are independent of resources required for vaccinatio...

Measles virus (MeV) is the poster child for acute infection followed by lifelong immunity. However, recent work shows the presence of MeV RNA in multiple sites for up to 3 mo after infection in a proportion of infected children. Here, we use experimental infection of rhesus macaques to show that prolonged RNA presence is characteristic of primary i...

Rotavirus vaccine efficacy ranges from >90% in high socio-economic settings (SES) to 50% in low SES. With the imminent introduction of rotavirus vaccine in low SES countries, understanding reasons for reduced efficacy in these settings could identify strategies to improve vaccine performance. We developed a mathematical model to predict rotavirus v...

Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals before emerging in humans. Al...

Antivirals are an important defence against novel strains of influenza. However, the impact of widespread drug usage on strain circulation across multiple epidemic waves – via their impact on host immunity – is unknown despite antivirals having the likelihood of extensive use during a pandemic. To explore how drug usage by individuals affects popul...

Large-scale immunization has profoundly impacted control of many infectious diseases such as measles and smallpox because of the ability of vaccination campaigns to maintain long-term herd immunity and, hence, indirect protection of the unvaccinated. In the case of human influenza, such potential benefits of mass vaccination have so far proved elus...

SUMMARYChildhood rubella infection in early pregnancy can lead to fetal death or congenital rubella syndrome (CRS) with multiple disabilities. Reduction of transmission via universal vaccination can prevent CRS, but inadequate coverage may increase CRS numbers by increasing the average age at infection. Consequently, many countries do not vaccinate...

Measles epidemics in West Africa cause a significant proportion of vaccine-preventable childhood mortality. Epidemics are strongly seasonal, but the drivers of these fluctuations are poorly understood, which limits the predictability of outbreaks and the dynamic response to immunization. We show that measles seasonality can be explained by spatiote...

The usage of structured population models can make substantial contributions to public health, particularly for infections where clinical outcomes vary over age. There are three theoretical challenges in implementing such analyses: (i) developing an appropriate framework that models both demographic and epidemiological transitions; (ii) parameteriz...

Understanding how immunity shapes the dynamics of multistrain pathogens is essential in determining the selective pressures imposed by vaccines. There is currently much interest in elucidating the strain dynamics of rotavirus to determine whether vaccination may lead to the replacement of vaccine-type strains. In developed countries, G1P[8] strains...

Probabilistic models for infectious disease dynamics are useful for understanding the mechanism underlying the spread of infection. When the likelihood function for these models is expensive to evaluate, traditional likelihood-based inference may be computationally intractable. Furthermore, traditional inference may lead to poor parameter estimates...

Throughout the African meningitis belt, meningococcal meningitis outbreaks occur only during the dry season. Measles in Niger exhibits similar seasonality, where increased population density during the dry season probably escalates measles transmission. Because meningococcal meningitis and measles are both directly transmitted, we propose that host...

Background: The performance of routine and supplemental immunization activities is usually measured by the administrative method: dividing the number of doses distributed by the size of the target population. This method leads to coverage estimates that are sometimes impossible (e.g., vaccination of 102% of the target population), and are generall...

Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number...

Epidemic theory predicts that the vaccination threshold required to interrupt local transmission of an immunizing infection like measles depends only on the basic reproductive number and hence transmission rates. When the search for optimal strategies is expanded to incorporate economic constraints, the optimum for disease control in a single popul...

Since the seminal article of May (1976), the search for chaos continues to exert a fascination for ecologists. An ideal system in which to carry out such a quest would provide long replicated time series, of observations uncomplicated by measurement error or process noise. This dynamicist’s paradise would also lend itself to accurate mechanistic mo...

Rotavirus is a major cause of mortality in developing countries, and yet the dynamics of rotavirus in such settings are poorly understood. Rotavirus is typically less seasonal in the tropics, although recent observational studies have challenged the universality of this pattern. While numerous studies have examined the association between environme...

Measles vaccine efficacy is higher at 12 months than 9 months because of maternal immunity, but delaying vaccination exposes the children most vulnerable to measles mortality to infection. We explored how this trade-off changes as a function of regionally varying epidemiological drivers, e.g. demography, transmission seasonality, and vaccination co...

The probability distribution of charge states occupied by each amino acid position in the HA1 sequence, in the year 2000. The majority of points lie along the edges, indicating a strong dominance of the corresponding charge state at those sites. (TIF)

HA and NA charge distribution for two illustrative subtype/host species pairs. Other subtypes, and hosts, show a comparable behaviour, with no discernible pattern over time. (TIF)

Number of HA1 amino acid sequences available from GenBank, as a function of time. (TIF)

HA charge distribution in avian hosts, for H3 viruses. The figure above was obtained using all 364 full-length avian H3 virus sequences in the NIAID influenza database [14]. Of these, the majority (349) lie in the charge range +4 to +9. Chickens, as poultry, are considered one of the possible routes of introduction of novel human influenza viruses....

Influenza viruses show a significant capacity to evade host immunity; this is manifest both as large occasional jumps in the antigenic phenotype of viral surface molecules and in gradual antigenic changes leading to annual influenza epidemics in humans. Recent mouse studies show that avidity for host cells can play an important role in polyclonal a...

Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent re-analysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here we show that the onset of increased wintertime influenza-related mortal...

The factors underlying the temporal dynamics of rubella outside of Europe and North America are not well known. Here we used 20 years of incidence reports from Mexico to identify variation in seasonal forcing and magnitude of transmission across the country and to explore determinants of inter-annual variability in epidemic magnitude in rubella. We...

Though largely controlled in developed countries, measles remains a major global public health issue. Regional and local transmission patterns are rooted in human mixing behaviour across spatial scales. Identifying spatial interactions that contribute to recurring epidemics helps define and predict outbreak patterns. Using spatially explicit report...

Rubella is generally a mild childhood disease, but infection during early pregnancy may cause spontaneous abortion or congenital rubella syndrome (CRS), which may entail a variety of birth defects. Consequently, understanding the age-structured dynamics of this infection has considerable public health value. Vaccination short of the threshold for l...

We develop a framework for simulating a realistic, evolving social network (a city) into which a disease is introduced. We compare our results to prevaccine era measles data for England and Wales, and find that they capture the quantitative and qualitative features of epidemics in populations spanning two orders of magnitude. Our results provide un...

Bordetella pertussis infection remains an important public health problem worldwide despite decades of routine vaccination. A key indicator of the impact of vaccination programmes is the inter-epidemic period, which is expected to increase with vaccine uptake if there is significant herd immunity. Based on empirical data from 64 countries across th...

Seasonally driven cycles of incidence have been consistently observed for a range of directly transmitted pathogens. Though frequently observed, the mechanism of seasonality for directly transmitted human pathogens is rarely well understood. Despite significant annual variation in magnitude, measles outbreaks in Niger consistently begin in the dry...

The evolution of viruses to escape prevailing host immunity involves selection at multiple integrative scales, from within-host viral and immune kinetics to the host population level. In order to understand how viral immune escape occurs, we develop an analytical framework that links the dynamical nature of immunity and viral variation across these...

[This corrects the article on p. e1000316 in vol. 8.].

Supporting methods and analysis. (0.42 MB PDF)

As Pandemic (H1N1) 2009 influenza spreads around the globe, it strikes school-age children more often than adults. Although there is some evidence of pre-existing immunity among older adults, this alone may not explain the significant gap in age-specific infection rates. Based on a retrospective analysis of pandemic strains of influenza from the la...

With more emphasis being put on global infectious disease monitoring, viral genetic data are being collected at an astounding rate, both within and without the context of a long-term disease surveillance plan. Concurrent with this increase have come improvements to the sophisticated and generalized statistical techniques used for extracting populat...

Author Summary The origin of seasonality in influenza transmission is both of palpable public health importance and basic scientific interest. Here, we present statistical analyses and a mathematical model of epidemic influenza transmission that provide strong epidemiological evidence for the hypothesis that absolute humidity (AH) drives seasonal v...

A key question in pandemic influenza is the relative roles of innate immunity and target cell depletion in limiting primary infection and modulating pathology. Here, we model these interactions using detailed data from equine influenza virus infection, combining viral and immune (type I interferon) kinetics with estimates of cell depletion. The res...

Determining the evolutionary basis of cross-species transmission and immune evasion is key to understanding the mechanisms that control the emergence of either new viruses or novel antigenic variants with pandemic potential. The hemagglutinin glycoprotein of influenza A viruses is a critical host range determinant and a major target of neutralizing...

Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent re-analysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here we extend these findings to the human population level, showing that th...

Few infectious diseases are entirely human-specific: Most human pathogens also circulate in animals or else originated in nonhuman hosts. Influenza, plague, and trypanosomiasis are classic examples of zoonotic infections that transmit from animals to humans. The multihost ecology of zoonoses leads to complex dynamics, and analytical tools, such as...