Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza

Veronika I. Zarnitsyna, Ali H. Ellebedy, Carl Davis,  Joshy Jacob, Rafi Ahmed, Rustom Antia

Philosophical Transactions B

July 20, 2015

ABSTRACT

The immune responses to influenza, a virus that exhibits strain variation, show complex dynamics where prior immunity shapes the response to the subsequent infecting strains. Original antigenic sin (OAS) describes the observation that antibodies to the first encountered influenza strain, specifically antibodies to the epitopes on the head of influenza's main surface glycoprotein, haemagglutinin (HA), dominate following infection with new drifted strains. OAS suggests that responses to the original strain are preferentially boosted. Recent studies also show limited boosting of the antibodies to conserved epitopes on the stem of HA, which are attractive targets for a ‘universal vaccine’. We develop multi-epitope models to explore how pre-existing immunity modulates the immune response to new strains following immunization. Our models suggest that the masking of antigenic epitopes by antibodies may play an important role in describing the complex dynamics of OAS and limited boosting of antibodies to the stem of HA. Analysis of recently published data confirms model predictions for how pre-existing antibodies to an epitope on HA decrease the magnitude of boosting of the antibody response to this epitope following immunization. We explore strategies for boosting of antibodies to conserved epitopes and generating broadly protective immunity to multiple strains.

Efficient Transition Probability Computation for Continuous-Time Branching Processes via Compressed Sensing

Jason Xu, Vladimir N. Minin

UNCERTAINTY IN ARTIFICIAL INTELLIGENCE

July, 2015

ABSTRACT

Branching processes are a class of continuous-time Markov chains (CTMCs) with ubiquitous applications. A general difficulty in statistical inference under partially observed CTMC models arises in computing transition probabilities when the discrete state space is large or uncountable. Classical methods such as matrix exponentiation are infeasible for large or countably infinite state spaces, and sampling-based alternatives are computationally intensive, requiring integration over all possible hidden events. Recent work has successfully applied generating function techniques to computingtransition probabilities for linear multi-type branching processes. While these techniques often require significantly fewer computations than matrix exponentiation, they also become prohibitive in applications with large populations. We propose a compressed sensing framework that significantly accelerates the generating function method, decreasing computational cost up to a logarithmic factor by only assuming the probability mass of transitions is sparse. We demonstrate accurate and efficient transition probability computations in branching process models for blood cell formation and evolution of self-replicating transposable elements in bacterial genomes.

Crossing the scale from within-host infection dynamics to between-host transmission fitness: a discussion of current assumptions and knowledge

Andreas Handel, Pejman Rohani

Philosophical Transactions B

July 6, 2016

ABSTRACT

The progression of an infection within a host determines the ability of a pathogen to transmit to new hosts and to maintain itself in the population. While the general connection between the infection dynamics within a host and the population-level transmission dynamics of pathogens is widely acknowledged, a comprehensive and quantitative understanding that would allow full integration of the two scales is still lacking. Here, we provide a brief discussion of both models and data that have attempted to provide quantitative mappings from within-host infection dynamics to transmission fitness. We present a conceptual framework and provide examples of studies that have taken first steps towards development of a quantitative framework that scales from within-host infections to population-level fitness of different pathogens. We hope to illustrate some general themes, summarize some of the recent advances and—maybe most importantly—discuss gaps in our ability to bridge these scales, and to stimulate future research on this important topic.

nextflu: Real-time tracking of seasonal influenza virus evolution in humans

Richard A. Neher and Trevor Bedford

Bioinformatics

June 26, 2015

Summary

Seasonal influenza viruses evolve rapidly, allowing them to evade immunity in their human hosts and reinfect previously infected individuals. Similarly, vaccines against seasonal influenza need to be updated frequently to protect against an evolving virus population. We have thus developed a processing pipeline and browser-based visualization that allows convenient exploration and analysis of the most recent influenza virus sequence data. This web-application displays a phylogenetic tree that can be decorated with additional information such as the viral genotype at specific sites, sampling location and derived statistics that have been shown to be predictive of future virus dynamics. In addition, mutation, genotype and clade frequency trajectories are calculated and displayed.

Availability and implementation

Python and Javascript source code is freely available from https://github.com/blab/nextflu, while the web-application is live at http://nextflu.org.

One versus two doses: What is the best use of vaccine in an influenza pandemic?

Laura Matrajt, Tom Britton, M. Elizabeth Halloran, Ira M. Longini Jr

Epidemics

June 22, 2015

Abstract

Avian influenza A (H7N9), emerged in China in April 2013, sparking fears of a new, highly pathogenic, influenza pandemic. In addition, avian influenza A (H5N1) continues to circulate and remains a threat. Currently, influenza H7N9 vaccines are being tested to be stockpiled along with H5N1 vaccines. These vaccines require two doses, 21 days apart, for maximal protection. We developed a mathematical model to evaluate two possible strategies for allocating limited vaccine supplies: a one-dose strategy, where a larger number of people are vaccinated with a single dose, or a two-dose strategy, where half as many people are vaccinated with two doses. We prove that there is a threshold in the level of protection obtained after the first dose, below which vaccinating with two doses results in a lower illness attack rate than with the one-dose strategy; but above the threshold, the one-dose strategy would be better. For reactive vaccination, we show that the optimal use of vaccine depends on several parameters, with the most important one being the level of protection obtained after the first dose. We describe how these vaccine dosing strategies can be integrated into effective pandemic control plans.

Unraveling the Transmission Ecology of Polio

Micaela Martinez-Bakker, Aaron A. King, Pejman Rohani

PLOS Biology

June 19, 2015

ABSTRACT

Sustained and coordinated vaccination efforts have brought polio eradication within reach. Anticipating the eradication of wild poliovirus (WPV) and the subsequent challenges in preventing its re-emergence, we look to the past to identify why polio rose to epidemic levels in the mid-20th century, and how WPV persisted over large geographic scales. We analyzed an extensive epidemiological dataset, spanning the 1930s to the 1950s and spatially replicated across each state in the United States, to glean insight into the drivers of polio’s historical expansion and the ecological mode of its persistence prior to vaccine introduction. We document a latitudinal gradient in polio’s seasonality. Additionally, we fitted and validated mechanistic transmission models to data from each US state independently. The fitted models revealed that: (1) polio persistence was the product of a dynamic mosaic of source and sink populations; (2) geographic heterogeneity of seasonal transmission conditions account for the latitudinal structure of polio epidemics; (3) contrary to the prevailing “disease of development” hypothesis, our analyses demonstrate that polio’s historical expansion was straightforwardly explained by demographic trends rather than improvements in sanitation and hygiene; and (4) the absence of clinical disease is not a reliable indicator of polio transmission, because widespread polio transmission was likely in the multiyear absence of clinical disease. As the world edges closer to global polio eradication and continues the strategic withdrawal of the Oral Polio Vaccine (OPV), the regular identification of, and rapid response to, these silent chains of transmission is of the utmost importance.

Ebola Virus Epidemiology, Transmission, and Evolution during Seven Months in Sierra Leone

Daniel J. Park, Gytis Dudas, Shirlee Wohl, Augustine Goba, Shannon L.M. Whitmer, Kristian G. Andersen,  Rachel S. Sealfon, Jason T. Ladner, Jeffrey R. Kugelman, Christian B. Matranga, Sarah M. Winnicki, James Qu, Stephen K. Gire, Adrianne Gladden-Young, Simbirie Jalloh, Dolo Nosamiefan, Nathan L. Yozwiak, Lina M. Moses, Pan-Pan Jiang, Aaron E. Lin, Stephen F. Schaffner, Brian Bird, Jonathan Towner, Mambu Mamoh, Michael Gbakie, Lansana Kanneh, David Kargbo, James L.B. Massally, Fatima K. Kamara, Edwin Konuwa, Josephine Sellu, Abdul A. Jalloh, Ibrahim Mustapha, Momoh Foday, Mohamed Yillah, Bobbie R. Erickson, Tara Sealy, Dianna Blau, Christopher Paddock, Aaron Brault, Brian Amman, Jane Basile, Scott Bearden, Jessica Belser, Eric Bergeron, Shelley Campbell, Ayan Chakrabarti, Kimberly Dodd, Mike Flint, Aridth Gibbons, Christin Goodman, John Klena, Laura McMullan, Laura Morgan, Brandy Russell, Johanna Salzer, Angela Sanchez, David Wang, Irwin Jungreis, Christopher Tomkins-Tinch, Andrey Kislyuk, Michael F. Lin, Sinead Chapman, Bronwyn MacInnis, Ashley Matthews, James Bochicchio, Lisa E. Hensley, Jens H. Kuhn, Chad Nusbaum, John S. Schieffelin, Bruce W. Birren, Marc Forget, Stuart T. Nichol, Gustavo F. Palacios, Daouda Ndiaye, Christian Happi, Sahr M. Gevao, Mohamed A. Vandi, Brima Kargbo, Edward C. Holmes, Trevor Bedford, Andreas Gnirke, Ute Ströher, Andrew Rambaut, Robert F. Garry, Pardis C. Sabeti

Cell

June 18, 2015

ABSTRACT

The 2013–2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission.

Synonymous and nonsynonymous distances help untangle convergent evolution and recombination

Peter B. Chi, Sujay Chattopadhyay, Philippe Lemey, Evgeni V. Sokurenko, Vladimir N. Minin

Statistical Applications in Genetics and Molecular Biology

June 10, 2015

Abstract

When estimating a phylogeny from a multiple sequence alignment, researchers often assume the absence of recombination. However, if recombination is present, then tree estimation and all downstream analyses will be impacted, because different segments of the sequence alignment support different phylogenies. Similarly, convergent selective pressures at the molecular level can also lead to phylogenetic tree incongruence across the sequence alignment. Current methods for detection of phylogenetic incongruence are not equipped to distinguish between these two different mechanisms and assume that the incongruence is a result of recombination or other horizontal transfer of genetic information. We propose a new recombination detection method that can make this distinction, based on synonymous codon substitution distances. Although some power is lost by discarding the information contained in the nonsynonymous substitutions, our new method has lower false positive probabilities than the comparable recombination detection method when the phylogenetic incongruence signal is due to convergent evolution. We apply our method to three empirical examples, where we analyze: (1) sequences from a transmission network of the human immunodeficiency virus, (2) tlpB gene sequences from a geographically diverse set of 38 Helicobacter pylori strains, and (3) hepatitis C virus sequences sampled longitudinally from one patient.

Global circulation patterns of seasonal influenza viruses vary with antigenic drift

Trevor Bedford, Steven Riley, Ian G. Barr, Shobha Broor, Mandeep Chadha, Nancy J. Cox, Rodney S. Daniels, C. Palani Gunasekaran, Aeron C. Hurt, Anne Kelso, Alexander Klimov, Nicola S. Lewis, Xiyan Li, John W. McCauley, Takato Odagiri, Varsha Potdar, Andrew Rambaut, Yuelong Shu, Eugene Skepner, Derek J. Smith, Marc A. Suchard, Masato Tashiro, Dayan Wang, Xiyan Xu, Philippe Lemey, Colin A. Russell

Nature

June 8, 2015

Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour.

Dynamics of Pertussis Transmission in the United States

F. M. G. Magpantay and P. Rohani

American Journal of Epidemiology

May 27, 2015

Past patterns of infectious disease transmission set the stage on which modern epidemiologic dynamics are played out. Here, we present a comprehensive account of pertussis (whooping cough) transmission in the United States during the early vaccine era. We analyzed recently digitized weekly incidence records from Morbidity and Mortality Weekly Reports from 1938 to 1955, when the whole-cell pertussis vaccine was rolled out, and related them to contemporary patterns of transmission and resurgence documented in monthly incidence data from the National Notifiable Diseases Surveillance System. We found that, during the early vaccine era, pertussis epidemics in US states could be categorized as 1) annual, 2) initially annual and later multiennial, or 3) multiennial. States with predominantly annual cycles tended to have higher per capita birth rates, more household crowding, more children per family, and lower rates of school attendance than the states with multiennial cycles. Additionally, states that exhibited annual epidemics during 1938–1955 have had the highest recent (2001–2010) incidence, while those states that transitioned from annual cycles to multiennial cycles have had relatively low recent incidence. Our study provides an extensive picture of pertussis epidemiology in the United States dating back to the onset of vaccination, a back-story that could aid epidemiologists in understanding contemporary transmission patterns.

Software for the analysis and visualization of deep mutational scanning data

Jesse D. Bloom

BMC Bioinformatics

May 20, 2015

Abstract

Background: Deep mutational scanning is a technique to estimate the impacts of mutations on a gene by using deep sequencing to count mutations in a library of variants before and after imposing a functional selection. The impacts of mutations must be inferred from changes in their counts after selection.

Results: I describe a software package, dms_tools, to infer the impacts of mutations from deep mutational scanning data using a likelihood-based treatment of the mutation counts. I show that dms_tools yields more accurate inferences on simulated data than simply calculating ratios of counts pre- and post-selection. Using dms_tools, one can infer the preference of each site for each amino acid given a single selection pressure, or assess the extent to which these preferences change under different selection pressures. The preferences and their changes can be intuitively visualized with sequence-logo-style plots created using an extension to weblogo.

Conclusions: dms_tools implements a statistically principled approach for the analysis and subsequent visualization of deep mutational scanning data.

Keywords: Deep mutational scanning, Sequence logo, Amino-acid preferences

The dengue vaccine pipeline: Implications for the future of dengue control

Lauren M. Schwartz, M. Elizabeth Halloran, Anna P. Durbin, Ira M. Longini Jr

Vaccine

May 16, 2015

Abtract

Dengue has become the most rapidly expanding mosquito-borne infectious disease on the planet, surpassing malaria and infecting at least 390 million people per year. There is no effective treatment for dengue illness other than supportive care, especially for severe cases. Symptoms can be mild or life-threatening as in dengue hemorrhagic fever and dengue shock syndrome. Vector control has been only partially successful in decreasing dengue transmission. The potential use of safe and effective tetravalent dengue vaccines is an attractive addition to prevent disease or minimize the possibility of epidemics. There are currently no licensed dengue vaccines. This review summarizes the current status of all dengue vaccine candidates in clinical evaluation. Currently five candidate vaccines are in human clinical trials. One has completed two Phase III trials, two are in Phase II trials, and three are in Phase I testing.

The contribution of neighbours to an individual's risk of typhoid outcome

D. L. CHAO, J. K. PARK, F. MARKS , R. L. OCHIAI , I. M. LONGINI JR., AND M. E. HALLORAN

Epidemiology & Infection

May 4, 2015

Summary

An individual’s risk of infection from an infectious agent can depend on both the individual’s own risk and protective factors and those of individuals in the same community. We hypothesize that an individual’s exposure to an infectious agent is associated with the risks of infection of those living nearby, whether their risks are modified by pharmaceutical interventions or by other factors, because of the potential for transmission from them. For example, unvaccinated individuals living in a highly vaccinated community can benefit from indirect protection, or living near more children in a typhoid-endemic region (where children are at highest risk) might result in more exposure to typhoid. We tested this hypothesis using data from a cluster-randomized typhoid vaccine trial. We first estimated each individual’s relative risk of confirmed typhoid outcome using their vaccination status and age. We defined a new covariate, potential exposure, to be the sum of the relative risks of all who live within 100 m of each person. We found that potential exposure was significantly associated with an individual’s typhoid outcome, and adjusting for potential exposure affected estimates of vaccine efficacy. We suggest that it is useful and feasible to adjust for spatially heterogeneous distributions of individual-level risk factors, but further work is required to develop and test such approaches.

Vaccine Testing: Ebola and beyond

Marc Lipsitch, Nir Eyal, M. Elizabeth Halloran, Miguel A. Hernán, Ira M. Longini , Eli N. Perencevich, Rebecca F. Grais  

 

Science

April 3, 2015

Recent experiences in confronting the Ebola epidemic suggest principles for vaccine efficacy trials in challenging environments.

Many epidemic-prone infectious diseases present challenges that the current West African Ebola outbreak brings into sharp relief. Specifically, the urgency to evaluate vaccines, initially limited vaccine supplies, and large and unpredictable spatial and temporal fluctuations in incidence have presented huge logistical, ethical, and statistical challenges to trial design.

Household Transmissibility of Avian Influenza A (H7N9) Virus, China, February to May 2013 and October 2013 to March 2014

Y. Yang, Y. Zhang, L. Fang, M.E. Halloran, M. Ma, S. Liang, E. Kenah, T. Britton, E. Chen, J. Hu, F. Tang, W. Cao, Z. Feng, I.M. Longini Jr.

Eurosurveillance

March 12, 2015

Abstract

To study human-to-human transmissibility of the avian influenza A (H7N9) virus in China, household contact information was collected for 125 index cases during the spring wave (February to May 2013), and for 187 index cases during the winter wave (October 2013 to March 2014). Using a statistical model, we found evidence for human-to-human transmission, but such transmission is not sustainable. Under plausible assumptions about the natural history of disease and the relative transmission frequencies in settings other than household, we estimate the household secondary attack rate (SAR) among humans to be 1.4% (95% CI: 0.8 to 2.3), and the basic reproductive number R0 to be 0.08 (95% CI: 0.05 to 0.13). The estimates range from 1.3% to 2.2% for SAR and from 0.07 to 0.12 for R0 with reasonable changes in the assumptions. There was no significant change in the human-to-human transmissibility of the virus between the two waves, although a minor increase was observed in the winter wave. No sex or age difference in the risk of infection from a human source was found. Human-to-human transmissibility of H7N9 continues to be limited, but it needs to be closely monitored for potential increase via genetic reassortment or mutation.

Transmissibility of tuberculosis among school contacts: An outbreak investigation in a boarding middle school, China

Mai-Juan Ma, Yang Yang, Hai-Bin Wang, Yi-Fan Zhu, Li-Qun Fang, Xiao-Ping An, Kang-Lin Wan, Christopher C. Whalen, Xiao-Xian Yang, Michael Lauzardo, Zhi-Yi Zhang, Jin-Feng Cao, Yi-Gang Tong, Er-Hei Dai, Wu-Chun Cao

Science Direct

March 7, 2015

Abstract

Tuberculosis (TB) outbreak occurred in a boarding middle school of China. We explored its probable sources and quantified the transmissibility and pathogenicity of TB. Clinical evaluation, tuberculin skin testing and chest radiography were conducted to identify TB cases. Mycobacterium tuberculosis isolates underwent genotyping analysis to identify the outbreak source. A chain-binomial transmission model was used to evaluate transmissibility and pathogenicity of TB. A total of 46 active cases were ascertained among 258 students and 15 teachers/staff, an attack rate of 16.8%. Genetic analyses revealed two groups of M. tuberculosis cocirculating during the outbreak and possible importation from local communities. Secondary attack rates among students were 4.1% (2.9%, 5.3%) within grade and 7.9% (4.9%, 11%) within class. An active TB case was estimated to infect 8.4 (7.2, 9.6) susceptible people on average. The smear-positive cases were 28 (8, 101) times as infective as smear-negative cases. Previous BCG vaccination could reduce the probability of developing symptoms after infection by 70% (1.4%, 91%). The integration of clinical evaluation, genetic sequencing, and statistical modeling greatly enhanced our understanding of TB transmission dynamics. Timely diagnosis of smear-positive cases, especially in the early phase of the outbreak, is the key to preventing further spread among close contacts.

Avoidable errors in the modeling of outbreaks of emerging pathogens, with special reference to Ebola

Aaron A. King, Matthieu Domenech de Cellès, Felicia M. G. Magpantay, Pejman Rohani

arXiv

March 3, 2015

Abstract

As an emergent infectious disease outbreak unfolds, public health response is reliant on information on key epidemiological quantities, such as transmission potential and serial interval. Increasingly, transmission models fit to incidence data are used to estimate these parameters and guide policy. Some widely-used modeling practices lead to potentially large errors in parameter estimates and, consequently, errors in model-based forecasts. Even more worryingly, in such situations, confidence in parameter estimates and forecasts can itself be far over-estimated, leading to the potential for large errors that mask their own presence. Fortunately, straightforward and computationally inexpensive alternatives exist that avoid these problems. Here, we first use a simulation study to demonstrate potential pitfalls of the standard practice of fitting deterministic models to cumulative incidence data. Next, we demonstrate an alternative based on stochastic models fit to raw data from an early phase of 2014 West Africa Ebola Virus Disease outbreak. We show not only that bias is thereby reduced, but that uncertainty in estimates and forecasts is better quantified and that, critically, lack of model fit is more readily diagnosed. We conclude with a short list of principles to guide the modeling response to future infectious disease outbreaks.

The Spatiotemporal Expansion of Human Rabies and Its Probable Explanation in Mainland China, 2004-2013

Hong-Wu Yao, Yang Yang, Kun Liu, Xin-Lou Li, Shu-Qing Zuo, Ruo-Xi Sun, Li-Qun Fang , Wu-Chun Cao 

PLOS Neglected Tropical Diseases

February 18, 2015

Background

Human rabies is a significant public health concern in mainland China. However, the neglect of rabies expansion and scarce analyses of the dynamics have made the spatiotemporal spread pattern of human rabies and its determinants being poorly understood.

Methods

We collected geographic locations and timeline of reported human rabies cases, rabies sequences and socioeconomic variables for the years 2004-2013, and integrated multidisciplinary approaches, including epidemiological characterization, hotspots identification, risk factors analysis and phylogeographic inference, to explore the spread pattern of human rabies in mainland China during the last decade.

Results

The results show that human rabies distribution and hotspots were expanding from southeastern regions to north or west regions, which could be associated with the evolution of the virus, especially the clade I-G. A Panel Poisson Regression analysis reveals that human rabies incidences had significant correlation with the education level, GDP per capita, temperature at one-month lag and canine rabies outbreak at two-month lag.

Conclusions

The reduction in the overall human rabies incidence was accompanied by a westward and northward expansion of the circulating region in mainland China. Higher risk of human rabies was associated with lower level of education and economic status. New clades of rabies, especial Clade I-G, played an important role in recent spread. Our findings provide valuable information for rabies control and prevention in the future.

Author Summary

Although the number of human rabies cases has slightly decreased since 2008 in mainland China, the rabies seemed to be gradually expanding to the low-incidence or non-epidemic areas. The neglect of rabies expansion and scarce analyses of the dynamics have made the spatiotemporal spread pattern of human rabies and its determinants poorly understood. Here, we integrate multidisciplinary approaches to explore and describe the spread pattern and evolution dynamic of human rabies in mainland China during the last decade. The results indicated that the reduction in the overall human rabies incidence was accompanied by a westward and northward expansion of the circulating region, which could be associated with the evolution of the virus, especially the clade I-G. And the education level, GDP per capita, temperature at one-month lag and canine rabies outbreak at two-month lag were firstly found to be significant correlation human rabies incidences according to the Panel Poisson Regression analysis. Our findings give a relatively complete picture about the human rabies spatiotemporal dynamics and spread pattern, thus provide new insights on risk factors and control strategies for the disease spread.

Combating Pertussis Resurgence: One Booster Vaccination Schedule Doesn't Fit All.

Maria A. Riolo and Pejman Rohani

PNAS

January 20, 2015

Abstract

Pertussis has reemerged as a major public health concern in many countries where it was once considered well controlled. Although the mechanisms responsible for continued pertussis circulation and resurgence remain elusive and contentious, many countries have nevertheless recommended booster vaccinations, the timing and number of which vary widely. Here, using a stochastic, age-stratified transmission model, we searched for cost-effective booster vaccination strategies using a genetic algorithm. We did so assuming four hypothesized mechanisms underpinning contemporary pertussis epidemiology: (I) insufficient coverage, (II) frequent primary vaccine failure, (III) waning of vaccine-derived protection, and (IV) vaccine “leakiness.” For scenarios I–IV, successful booster strategies were identified and varied considerably by mechanism. Especially notable is the inability of booster schedules to alleviate resurgence when vaccines are leaky. Critically, our findings argue that the ultimate effectiveness of vaccine booster schedules will likely depend on correctly pinpointing the causes of resurgence, with misdiagnosis of the problem epidemiologically ineffective and economically costly.

Inference for dynamic and latent variable models via iterated, perturbed Bayes maps

Edward L. Ionides, Dao Nguyen, Yves Atchadé, Stilian Stoev, and Aaron A. King

PNAS

January 7, 2015

Abstract

Iterated filtering algorithms are stochastic optimization procedures for latent variable models that recursively combine parameter perturbations with latent variable reconstruction. Previously, theoretical support for these algorithms has been based on the use of conditional moments of perturbed parameters to approximate derivatives of the log likelihood function. Here, a theoretical approach is introduced based on the convergence of an iterated Bayes map. An algorithm supported by this theory displays substantial numerical improvement on the computational challenge of inferring parameters of a partially observed Markov process.