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.

Spatiotemporal spread of the 2014 outbreak of Ebola virus disease in Liberia and the effectiveness of non-pharmaceutical interventions: a computational modelling analysis

Stefano Merler, Marco Ajelli, Laura Fumanelli, Marcelo F C Gomes, Ana Pastore y Piontti, Luca Rossi, Dennis L Chao, Ira M Longini Jr, M Elizabeth Halloran, Alessandro Vespignani

The Lancet Infectious Diseases

January 6, 2015

Background

The 2014 epidemic of Ebola virus disease in parts of west Africa defines an unprecedented health threat. We developed a model of Ebola virus transmission that integrates detailed geographical and demographic data from Liberia to overcome the limitations of non-spatial approaches in projecting the disease dynamics and assessing non-pharmaceutical control interventions.

Methods

We modelled the movements of individuals, including patients not infected with Ebola virus, seeking assistance in health-care facilities, the movements of individuals taking care of patients infected with Ebola virus not admitted to hospital, and the attendance of funerals. Individuals were grouped into randomly assigned households (size based on Demographic Health Survey data) that were geographically placed to match population density estimates on a grid of 3157 cells covering the country. The spatial agent-based model was calibrated with a Markov chain Monte Carlo approach. The model was used to estimate Ebola virus transmission parameters and investigate the effectiveness of interventions such as availability of Ebola treatment units, safe burials procedures, and household protection kits.

Findings

Up to Aug 16, 2014, we estimated that 38·3% of infections (95% CI 17·4–76·4) were acquired in hospitals, 30·7% (14·1–46·4) in households, and 8·6% (3·2–11·8) while participating in funerals. We noted that the movement and mixing, in hospitals at the early stage of the epidemic, of patients infected with Ebola virus and those not infected was a sufficient driver of the reported pattern of spatial spread. The subsequent decrease of incidence at country and county level is attributable to the increasing availability of Ebola treatment units (which in turn contributed to drastically decreased hospital transmission), safe burials, and distribution of household protection kits.

Interpretation

The model allows assessment of intervention options and the understanding of their role in the decrease in incidence reported since Sept 7, 2014. High-quality data (eg, to estimate household secondary attack rate, contact patterns within hospitals, and effects of ongoing interventions) are needed to reduce uncertainty in model estimates.

Funding

US Defense Threat Reduction Agency, US National Institutes of Health.