Virginia E. Pitzer

Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States

Here, the authors demonstrate that variations of absolute humidity explain both the onset of wintertime influenza transmission and the overarching seasonality of this pathogen in temperate regions.

Epidemic dynamics at the human-animal interface.

Zeroing in on Zoonoses Influenza, plague, and Lyme disease are classic examples of zoonoses—diseases that circulate in livestock and wildlife, as well as in humans. When a pathogen transfers among multiple hosts, the dynamics of circulation, transmission, and outbreak are complex. Lloyd-Smith et al. (p. 1362) review the use of analytical mathematical tools, particularly modeling, in the development of control policies and research agendas. Significant gaps are highlighted in analytical efforts during spillover transmission from animals into humans. Moreover, the tendency has been to focus on pathogens with simpler life cycles and of immediate global urgency, such as influenza, whereas insect-transmitted pathogens with complex, multihost life cycles are less well understood. 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 mathematical modeling, are vital to the development of effective control policies and research agendas. Much attention has focused on modeling pathogens with simpler life cycles and immediate global urgency, such as influenza and severe acute respiratory syndrome. Meanwhile, vector-transmitted, chronic, and protozoan infections have been neglected, as have crucial processes such as cross-species transmission. Progress in understanding and combating zoonoses requires a new generation of models that addresses a broader set of pathogen life histories and integrates across host species and scientific disciplines.

Demographic Variability, Vaccination, and the Spatiotemporal Dynamics of Rotavirus Epidemics

Ecology of Diarrhea Rotavirus is an important cause of morbidity and mortality globally, and, although the infection takes a terrible toll on infant lives, its epidemiology is rather poorly known. New vaccines have become available and are being introduced in the United States prior to global rollout, but they may have some unexpected effects on disease dynamics. Pitzer et al. (p. 290; see the Perspective by Medley and Nokes) analyzed data and developed models describing the epidemiology of rotavirus before and during adoption of the vaccine. Ecological analysis showed that the birth rate predicted the timing of epidemics much better than climatic variables and that shifts in birth rates explained changes over the years. But as increasing numbers of infants are vaccinated, the pool of susceptible individuals in the population will be reduced, which will affect the annual waves of geographic spread of rotavirus. Diarrhea-causing rotavirus epidemics can be predicted by shifts in birth rate rather than by seasonal variables. Historically, annual rotavirus activity in the United States has started in the southwest in late fall and ended in the northeast 3 months later; this trend has diminished in recent years. Traveling waves of infection or local environmental drivers cannot account for these patterns. A transmission model calibrated against epidemiological data shows that spatiotemporal variation in birth rate can explain the timing of rotavirus epidemics. The recent large-scale introduction of rotavirus vaccination provides a natural experiment to further test the impact of susceptible recruitment on disease dynamics. The model predicts a pattern of reduced and lagged epidemics postvaccination, closely matching the observed dynamics. Armed with this validated model, we explore the relative importance of direct and indirect protection, a key issue in determining the worldwide benefits of vaccination.

Anaplasma phagocytophilum in white-tailed deer.

We examined the reservoir potential of white-tailed deer for Anaplasma phagocytophilum. Results suggest that white-tailed deer harbor a variant strain not associated with human infection, but contrary to published reports, white-tailed deer are not a reservoir for strains that cause human disease. These results will affect surveillance studies of vector and reservoir populations.

Global seasonality of rotavirus disease.

Background: A substantial number of surveillance studies have documented rotavirus prevalence among children admitted for dehydrating diarrhea. We sought to establish global seasonal patterns of rotavirus disease before the introduction of widespread vaccination. Methods: We reviewed studies of rotavirus detection in children with diarrhea published since 1995. We assessed potential relationships between seasonal prevalence and locality by plotting the average monthly proportion of diarrhea cases positive for rotavirus according to geography, country development and latitude. We used linear regression to identify variables that were potentially associated with the seasonal intensity of rotavirus. Results: Among a total of 99 studies representing all 6 geographic regions of the world, patterns of year-round disease were more evident in low- and low-middle income countries compared with upper-middle and high-income countries where disease was more likely to be seasonal. The level of country development was a stronger predictor of strength of seasonality (P = 0.001) than geographic location or climate. However, the observation of distinctly different seasonal patterns of rotavirus disease in some countries with similar geographic location, climate and level of development indicate that a single unifying explanation for variation in seasonality of rotavirus disease is unlikely. Conclusion: While no unifying explanation emerged for varying rotavirus seasonality globally, the country income level was somewhat more predictive of the likelihood of having seasonal disease than other factors. Future evaluation of the effect of rotavirus vaccination on seasonal patterns of disease in different settings may help understand factors that drive the global seasonality of rotavirus disease.

Understanding Reduced Rotavirus Vaccine Efficacy in Low Socio-Economic Settings

Introduction 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. Methods We developed a mathematical model to predict rotavirus vaccine efficacy in high, middle and low SES based on data specific for each setting on incidence, protection conferred by natural infection and immune response to vaccination. We then examined factors affecting efficacy. Results Vaccination was predicted to prevent 93%, 86% and 51% of severe rotavirus gastroenteritis in high, middle and low SES, respectively. Also predicted was that vaccines are most effective against severe disease and efficacy declines with age in low but not high SES. Reduced immunogenicity of vaccination and reduced protection conferred by natural infection are the main factors that compromise efficacy in low SES. Discussion The continued risk of severe disease in non-primary natural infections in low SES is a key factor underpinning reduced efficacy of rotavirus vaccines. Predicted efficacy was remarkably consistent with observed clinical trial results from different SES, validating the model. The phenomenon of reduced vaccine efficacy can be predicted by intrinsic immunological and epidemiological factors of low SES populations. Modifying aspects of the vaccine (e.g. improving immunogenicity in low SES) and vaccination program (e.g. additional doses) may bring improvements.

Modeling rotavirus strain dynamics in developed countries to understand the potential impact of vaccination on genotype distributions

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 constitute the majority of rotavirus infections most years, but occasionally other genotypes dominate for reasons that are not well understood. We developed a mathematical model to examine the interaction of five common rotavirus genotypes. We explored a range of estimates for the relative strength of homotypic vs. heterotypic immunity and compared model predictions against observed genotype patterns from six countries. We then incorporated vaccination in the model to examine its impact on rotavirus incidence and the distribution of strains. Our model can explain the coexistence and cyclical pattern in the distribution of genotypes observed in most developed countries. The predicted frequency of cycling depends on the relative strength of homotypic vs. heterotypic immunity. Vaccination that provides strong protection against G1 and weaker protection against other strains will likely lead to an increase in the relative prevalence of non-G1 strains, whereas a vaccine that provides equally strong immunity against all strains may promote the continued predominance of G1. Overall, however, disease incidence is expected to be substantially reduced under both scenarios and remain below prevaccination levels despite the possible emergence of new strains. Better understanding of homotypic vs. heterotypic immunity, both natural and vaccine-induced, will be critical in predicting the impact of vaccination.

Influence of birth rates and transmission rates on the global seasonality of rotavirus incidence

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 environmental factors and rotavirus incidence, here we explore the role of intrinsic factors. By fitting a mathematical model of rotavirus transmission dynamics to published age distributions of cases from 15 countries, we obtain estimates of local transmission rates. Model-predicted patterns of seasonal incidence based solely on differences in birth rates and transmission rates are significantly correlated with those observed (Spearmans ρ = 0.65, p < 0.05). We then examine seasonal patterns of rotavirus predicted across a range of different birth rates and transmission rates and explore how vaccination may impact these patterns. Our results suggest that the relative lack of rotavirus seasonality observed in many tropical countries may be due to the high birth rates and transmission rates typical of developing countries rather than being driven primarily by environmental conditions. While vaccination is expected to decrease the overall burden of disease, it may increase the degree of seasonal variation in the incidence of rotavirus in some settings.

Impact of rotavirus vaccination on epidemiological dynamics in England and Wales.

Rotavirus infection causes severe gastroenteritis (RVGE) in children worldwide. Its disease burden has been reduced in countries where mass vaccination programs have been introduced. However, England and Wales have not yet implemented such a mass vaccination program. This paper uses a dynamic model to predict the effect of a mass vaccination program in England and Wales beginning in the fall of 2011. The dynamic model is parameterized with country-specific data for the introduction of a rotavirus vaccine. We report the impact of vaccination, in both the short- and long-term, on disease incidence reduction, timing of seasonal epidemics and the level of herd protection. Our results predict that vaccination can reduce the burden of severe RVGE by 70% and delay the rotavirus epidemic peak by two and a half months with a coverage of 95%. Our calculations further show that herd protection accounts for about a quarter of the reduction in RVGE incidence. If vaccine-induced protection does not wane over three years, severe RVGE in children under five years of age could be eliminated within two years after the introduction of vaccination. This work lays the foundation for policy-makers to determine the impact of a mass vaccination program against rotavirus in England and Wales.

Direct and Indirect Effects of Rotavirus Vaccination: Comparing Predictions from Transmission Dynamic Models

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 vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8–2.9 times more than expected from the direct effects of the vaccine alone (28–50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1–1.7 times more than expected from the direct effects (54–90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research.