Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-30 (of 32 Records) |
Query Trace: Gambhir M[original query] |
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Review of mathematical models of vaccination for preventing congenital cytomegalovirus infection
Lanzieri TM , Gastanaduy PA , Gambhir M , Plotkin SA . J Infect Dis 2020 221 S86-s93 BACKGROUND: Several cytomegalovirus (CMV) vaccine candidates are under development. To reduce the burden of congenital CMV infection, potential strategies under consideration include vaccination of adult women, adolescent girls, and/or young children (both sexes). METHODS: We reviewed 5 studies that used infectious disease modeling to assess the potential impact of vaccination for preventing congenital CMV infection. All models assumed CMV vaccination would prevent primary infection and 2 models also assumed prevention of reinfections and reactivations. RESULTS: Despite differences in structure, assumptions, and population data, infant vaccination (both sexes) was the optimal strategy in all models, but in 1 model vaccinating seronegative women at 19-21 years of age was also optimal (for duration of vaccine protection >/=8 years). In 3 models, infant vaccination increased average age at primary infection as a result of decreased secondary transmission (herd immunity) combined with waning vaccine-induced immunity. This effect could increase the risk of congenital CMV infections in populations where primary CMV infection occurs early in childhood but could be minimized by administering a second dose of vaccine during adolescence. CONCLUSIONS: Understanding vaccine efficacy and duration of immunity, and how these might vary depending on CMV serostatus and age at vaccination, will be key to defining CMV vaccination strategies. |
Forecasting the 2014 West African Ebola outbreak
Carias C , O'Hagan JJ , Gambhir M , Kahn EB , Swerdlow DL , Meltzer MI . Epidemiol Rev 2019 41 (1) 34-50 In 2014/15 an Ebola outbreak of unprecedented dimensions afflicted the West African countries of Liberia, Guinea, and Sierra Leone. We performed a systematic review of manuscripts that forecasted the outbreak while it was occurring, and derive implications on the ways results could be interpreted by policy-makers. We reviewed 26 manuscripts, published between 2014 and April 2015, that presented forecasts of the West African Ebola outbreak. Forecasted case counts varied widely. An important determinant of forecast accuracy for case counts was how far into the future predictions were made. Generally, those that made forecasts less than 2 months into the future tended to be more accurate than those that made forecasts more than 10 weeks into the future. The exceptions were parsimonious statistical models in which the decay of the rate of spread of the pathogen among susceptible individuals was dealt with explicitly. Regarding future outbreaks, the most important lessons for policy makers when using similar modeling results are: i) uncertainty of forecasts will be higher in the beginning of the outbreak, ii) when data are limited, forecasts produced by models designed to inform specific decisions should be used in complimentary fashion for robust decision making - for this outbreak, two statistical models produced the most reliable case counts forecasts, but did not allow to understand the impact of interventions, while several compartmental models could estimate the impact of interventions but required data that was not available; iii) timely collection of essential data is necessary for optimal model use. |
Factors associated with measles transmission in the United States during the postelimination era
Gastanaduy PA , Funk S , Lopman BA , Rota PA , Gambhir M , Grenfell B , Paul P . JAMA Pediatr 2019 174 (1) 56-62 Importance: Measles cases and outbreaks continue to occur in the United States after the introduction of measles from endemic settings. Objective: To discern the factors associated with measles transmission in the United States after measles had been eliminated. Design, Setting, and Participants: This cross-sectional study was conducted from January 1, 2001, to December 31, 2017, in the United States among US residents and international visitors with confirmed measles. A maximum likelihood algorithm that uses the observed dates of rash onset and the known distribution of the serial interval (time between symptom onset in related consecutive cases) was applied to outbreak notification data to estimate the effective reproduction number (R), or the mean number of new infections generated per case. Transmissibility was assessed by comparing R based on the characteristics of primary and secondary cases of measles. Exposures: Measles virus. Main Outcomes and Measures: Effective reproduction number (R), or the mean number of successful transmission events per case of measles (ie, the mean number of persons to whom each patient with measles spreads measles). Results: A total of 2218 individuals with confirmed measles cases (1025 female, 1176 male, and 17 sex not reported; median age, 15 years [range, 0-89 years]) reported from 2001 to 2017 were evaluated. Among patients who received no doses of measles vaccine, R was 0.76 (95% CI, 0.71-0.81); among patients who received 1 dose of measles vaccine, R was 0.17 (95% CI, 0.11-0.26); among patients who received 2 doses or more of measles vaccine, R was 0.27 (95% CI, 0.17-0.39); and among patients with unknown vaccination status, R was 0.52 (95% CI, 0.44-0.60). Among patients born before 1957, R was 0.35 (95% CI, 0.20-0.58), and among those born on or after 1957, R was 0.64 (95% CI, 0.61-0.68). R was higher when primary and secondary cases of measles were patients aged 5 to 17 years (0.36 [95% CI, 0.31-0.42]) compared with assortative transmission in other age groups (<1 year, 0.14 [95% CI, 0.10-0.20]; 1-4 years, 0.25 [95% CI, 0.20-0.30]; 18-29 years, 0.19 [95% CI, 0.15-0.24]; 30-49 years, 0.15 [95% CI, 0.11-0.20]; >/=50 years, 0.04 [95% CI, 0.01-0.10]). Conclusions and Relevance: The findings of this study support having high targets for 2-dose measles vaccine coverage, particularly among school-aged children in the United States. |
School dismissal as a pandemic influenza response: When, where and for how long
Germann TC , Gao H , Gambhir M , Plummer A , Biggerstaff M , Reed C , Uzicanin A . Epidemics 2019 28 100348 We used individual-based computer simulation models at community, regional and national levels to evaluate the likely impact of coordinated pre-emptive school dismissal policies during an influenza pandemic. Such policies involve three key decisions: when, over what geographical scale, and how long to keep schools closed. Our evaluation includes uncertainty and sensitivity analyses, as well as model output uncertainties arising from variability in serial intervals and presumed modifications of social contacts during school dismissal periods. During the period before vaccines become widely available, school dismissals are particularly effective in delaying the epidemic peak, typically by 4-6 days for each additional week of dismissal. Assuming the surveillance is able to correctly and promptly diagnose at least 5-10% of symptomatic individuals within the jurisdiction, dismissals at the city or county level yield the greatest reduction in disease incidence for a given dismissal duration for all but the most severe pandemic scenarios considered here. Broader (multi-county) dismissals should be considered for the most severe and fast-spreading (1918-like) pandemics, in which multi-month closures may be necessary to delay the epidemic peak sufficiently to allow for vaccines to be implemented. |
Cost-effectiveness of dog rabies vaccination programs in East Africa
Borse RH , Atkins CY , Gambhir M , Undurraga EA , Blanton JD , Kahn EB , Dyer JL , Rupprecht CE , Meltzer MI . PLoS Negl Trop Dis 2018 12 (5) e0006490 BACKGROUND: Dog rabies annually causes 24,000-70,000 deaths globally. We built a spreadsheet tool, RabiesEcon, to aid public health officials to estimate the cost-effectiveness of dog rabies vaccination programs in East Africa. METHODS: RabiesEcon uses a mathematical model of dog-dog and dog-human rabies transmission to estimate dog rabies cases averted, the cost per human rabies death averted and cost per year of life gained (YLG) due to dog vaccination programs (US 2015 dollars). We used an East African human population of 1 million (approximately 2/3 living in urban setting, 1/3 rural). We considered, using data from the literature, three vaccination options; no vaccination, annual vaccination of 50% of dogs and 20% of dogs vaccinated semi-annually. We assessed 2 transmission scenarios: low (1.2 dogs infected per infectious dog) and high (1.7 dogs infected). We also examined the impact of annually vaccinating 70% of all dogs (World Health Organization recommendation for dog rabies elimination). RESULTS: Without dog vaccination, over 10 years there would a total of be approximately 44,000-65,000 rabid dogs and 2,100-2,900 human deaths. Annually vaccinating 50% of dogs results in 10-year reductions of 97% and 75% in rabid dogs (low and high transmissions scenarios, respectively), approximately 2,000-1,600 human deaths averted, and an undiscounted cost-effectiveness of $451-$385 per life saved. Semi-annual vaccination of 20% of dogs results in in 10-year reductions of 94% and 78% in rabid dogs, and approximately 2,000-1,900 human deaths averted, and cost $404-$305 per life saved. In the low transmission scenario, vaccinating either 50% or 70% of dogs eliminated dog rabies. Results were most sensitive to dog birth rate and the initial rate of dog-to-dog transmission (Ro). CONCLUSIONS: Dog rabies vaccination programs can control, and potentially eliminate, dog rabies. The frequency and coverage of vaccination programs, along with the level of dog rabies transmission, can affect the cost-effectiveness of such programs. RabiesEcon can aid both the planning and assessment of dog rabies vaccination programs. |
Prevalence of Chlamydia trachomatis-specific antibodies before and after mass drug administration for trachoma in community-wide surveys of four communities in Nepal
Gwyn SE , Xiang L , Kandel RP , Dean D , Gambhir M , Martin DL . Am J Trop Med Hyg 2017 98 (1) 216-220 The target end date for the global elimination of trachoma as a public health problem is 2020. As countries begin the process for submitting their dossier for the validation of elimination of trachoma as a public health problem, strategies for post-validation surveillance must be considered. Seroprevalence of antibodies against antigens from the causative bacteria Chlamydia trachomatis (Ct) in young children has been shown to reflect trachomatous inflammation-follicular (TF) rates in both endemic and previously endemic settings. However, none of these studies has directly compared age seroprevalence in the same communities before and after mass drug administration (MDA) for trachoma. Here we report a marked shift in age seroprevalence curves in four villages in Kapilvastu District, Nepal, before and after MDA. Clinical examinations were performed and blood was taken before (N = 659) and 5 years after (N = 646) MDA. Rates of TF decreased from 17.6% in ≤ 9-year-olds before MDA (N = 52) to 0% in ≤ 9-year-olds (N = 73) after MDA. Positive antibody responses to Ct in the entire population decreased from 82.1% pre-MDA to 35.8% post-MDA, whereas those among ≤ 9-year-olds decreased from 59.6% to 4.1%. These data show that the postintervention decrease in TF was reflected in a drop in anti-Ct antibody responses, suggesting that antibody responses could be useful indicators for post-validation surveillance. |
Estimating direct and indirect protective effect of influenza vaccination in the United States
Arinaminpathy N , Kim IK , Gargiullo P , Haber M , Foppa IM , Gambhir M , Bresee J . Am J Epidemiol 2017 186 (1) 1-9 ![]() With influenza vaccination rates in the United States recently exceeding 45% of the population, it is important to understand the impact that vaccination is having on influenza transmission. In this study, we used a Bayesian modeling approach, combined with a simple dynamical model of influenza transmission, to estimate this impact. The combined framework synthesized evidence from a range of data sources relating to influenza transmission and vaccination in the United States. We found that, for seasonal epidemics, the number of infections averted ranged from 9.6 million in the 2006-2007 season (95% credible interval (CI): 8.7, 10.9) to 37.2 million (95% CI: 34.1, 39.6) in the 2012-2013 season. Expressed in relative terms, the proportion averted ranged from 20.8% (95% CI: 16.8, 24.3) of potential infections in the 2011-2012 season to 47.5% (95% CI: 43.7, 50.8) in the 2008-2009 season. The percentage averted was only 1.04% (95% CI: 0.15, 3.2) for the 2009 H1N1 pandemic, owing to the late timing of the vaccination program in relation to the pandemic in the Northern hemisphere. In the future, further vaccination coverage, as well as improved influenza vaccines (especially those offering better protection in the elderly), could have an even stronger effect on annual influenza epidemics. |
Assessment of the status of measles elimination in the United States, 2001-2014
Gastanaduy PA , Paul P , Fiebelkorn AP , Redd SB , Lopman BA , Gambhir M , Wallace GS . Am J Epidemiol 2017 185 (7) 562-569 We assessed the status of measles elimination in the United States using outbreak notification data. Measles transmissibility was assessed by estimation of the reproduction number, R, the average number of secondary cases per infection, using 4 methods; elimination requires maintaining R at <1. Method 1 estimates R as 1 minus the proportion of cases that are imported. Methods 2 and 3 estimate R by fitting a model of the spread of infection to data on the sizes and generations of chains of transmission, respectively. Method 4 assesses transmissibility before public health interventions, by estimating R for the case with the earliest symptom onset in each cluster (Rindex). During 2001-2014, R and Rindex estimates obtained using methods 1-4 were 0.72 (95% confidence interval (CI): 0.68, 0.76), 0.66 (95% CI: 0.62, 0.70), 0.45 (95% CI: 0.40, 0.49), and 0.63 (95% CI: 0.57, 0.69), respectively. Year-to-year variability in the values of R and Rindex and an increase in transmissibility in recent years were noted with all methods. Elimination of endemic measles transmission is maintained in the United States. A suggested increase in measles transmissibility since elimination warrants continued monitoring and emphasizes the importance of high measles vaccination coverage throughout the population. |
Targeting pediatric versus elderly populations for norovirus vaccines: A model-based analysis of mass vaccination options
Steele MK , Remais JV , Gambhir M , Glasser JW , Handel A , Parashar UD , Lopman BA . Epidemics 2016 17 42-49 BACKGROUND: Noroviruses are the leading cause of acute gastroenteritis and foodborne diarrheal disease in the United States. Norovirus vaccine development has progressed in recent years, but critical questions remain regarding which age groups should be vaccinated to maximize population impact. METHODS: We developed a deterministic, age-structured compartmental model of norovirus transmission and immunity in the U.S. POPULATION: The model was fit to age-specific monthly U.S. hospitalizations between 1996 and 2007. We simulated mass immunization of both pediatric and elderly populations assuming realistic coverages of 90% and 65%, respectively. We considered two mechanism of vaccine action, resulting in lower vaccine efficacy (lVE) between 22% and 43% and higher VE (hVE) of 50%. RESULTS: Pediatric vaccination was predicted to avert 33% (95% CI: 27%, 40%) and 60% (95% CI: 49%, 71%) of norovirus episodes among children under five years for lVE and hVE, respectively. Vaccinating the elderly averted 17% (95% CI: 12%, 20%) and 38% (95% CI: 34%, 42%) of cases in 65+ year olds for lVE and hVE, respectively. At a population level, pediatric vaccination was predicted to avert 18-21 times more cases and twice as many deaths per vaccinee compared to elderly vaccination. CONCLUSIONS: The potential benefits are likely greater for a pediatric program, both via direct protection of vaccinated children and indirect protection of unvaccinated individuals, including adults and the elderly. These findings argue for a clinical development plan that will deliver a vaccine with a safety and efficacy profile suitable for use in children. |
Estimation of severe Middle East Respiratory Syndrome cases in the Middle East, 2012-2016
O'Hagan JJ , Carias C , Rudd JM , Pham HT , Haber Y , Pesik N , Cetron MS , Gambhir M , Gerber SI , Swerdlow DL . Emerg Infect Dis 2016 22 (10) 1797-9 Using data from travelers to 4 countries in the Middle East, we estimated 3,250 (95% CI 1,300-6,600) severe cases of Middle East respiratory syndrome occurred in this region during September 2012-January 2016. This number is 2.3-fold higher than the number of laboratory-confirmed cases recorded in these countries. |
Influence of parity and sexual history on cytomegalovirus seroprevalence among women aged 20-49 years in the USA
Lanzieri TM , Kruszon-Moran D , Gambhir M , Bialek SR . Int J Gynaecol Obstet 2016 135 (1) 82-5 OBJECTIVE: To assess the influence of parity, as a proxy for exposure to children, and sexual history on cytomegalovirus (CMV) seroprevalence. METHODS: Data were retrospectively analyzed from women aged 20-49 years who were tested for CMV immunoglobulin G antibodies in the 1999-2004 National Health and Nutrition Examination Survey, a nationally representative survey of the US population. Logistic regression was used to determine independent variables associated with CMV seroprevalence. RESULTS: Among 3710 women, the age-adjusted CMV seroprevalence was 61.3% (95% CI 58.9%-63.6%). In age-adjusted univariate analysis, women who had given birth at least once had higher overall CMV seroprevalence (66.0%, 95% CI 63.1%-68.9%) than did those who had not given birth (49.0%, 95% CI 44.4%-53.7%; P<0.001). In multivariate logistic analysis, higher CMV seroprevalence was independently associated with number of live births (each additional birth: adjusted odds ratio [aOR] 1.2, 95% CI 1.1-1.3), age at first sexual intercourse (<18 vs ≥18years: aOR 1.3, 95% CI 1.1-1.6), lifetime sexual partners (≥10 vs <10: aOR 1.4, 95% CI 1.1-1.9), and herpes type 2 seropositivity (aOR 1.9, 95% CI 1.5-2.6) after controlling for age, race/Hispanic origin, place of birth, poverty index, and education. CONCLUSION: Among US women of reproductive age, parity and sexual exposures were independently associated with increased CMV seroprevalence. |
Modeling in real time during the Ebola response
Meltzer MI , Santibanez S , Fischer LS , Merlin TL , Adhikari BB , Atkins CY , Campbell C , Fung IC , Gambhir M , Gift T , Greening B , Gu W , Jacobson EU , Kahn EB , Carias C , Nerlander L , Rainisch G , Shankar M , Wong K , Washington ML . MMWR Suppl 2016 65 (3) 85-9 To aid decision-making during CDC's response to the 2014-2016 Ebola virus disease (Ebola) epidemic in West Africa, CDC activated a Modeling Task Force to generate estimates on various topics related to the response in West Africa and the risk for importation of cases into the United States. Analysis of eight Ebola response modeling projects conducted during August 2014-July 2015 provided insight into the types of questions addressed by modeling, the impact of the estimates generated, and the difficulties encountered during the modeling. This time frame was selected to cover the three phases of the West African epidemic curve. Questions posed to the Modeling Task Force changed as the epidemic progressed. Initially, the task force was asked to estimate the number of cases that might occur if no interventions were implemented compared with cases that might occur if interventions were implemented; however, at the peak of the epidemic, the focus shifted to estimating resource needs for Ebola treatment units. Then, as the epidemic decelerated, requests for modeling changed to generating estimates of the potential number of sexually transmitted Ebola cases. Modeling to provide information for decision-making during the CDC Ebola response involved limited data, a short turnaround time, and difficulty communicating the modeling process, including assumptions and interpretation of results. Despite these challenges, modeling yielded estimates and projections that public health officials used to make key decisions regarding response strategy and resources required. The impact of modeling during the Ebola response demonstrates the usefulness of modeling in future responses, particularly in the early stages and when data are scarce. Future modeling can be enhanced by planning ahead for data needs and data sharing, and by open communication among modelers, scientists, and others to ensure that modeling and its limitations are more clearly understood. The activities summarized in this report would not have been possible without collaboration with many U.S. and international partners (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/partners.html). |
Exportations of symptomatic cases of MERS-CoV infection to countries outside the Middle East
Carias C , O'Hagan JJ , Jewett A , Gambhir M , Cohen NJ , Haber Y , Pesik N , Swerdlow DL . Emerg Infect Dis 2016 22 (3) 723-5 In 2012, an outbreak of infection with Middle East respiratory syndrome coronavirus (MERS-CoV), was detected in the Arabian Peninsula. Modeling can produce estimates of the expected annual number of symptomatic cases of MERS-CoV infection exported and the likelihood of exportation from source countries in the Middle East to countries outside the region. |
Serological measures of trachoma transmission intensity
Martin DL , Wiegand R , Goodhew B , Lammie P , Black CM , West S , Gaydos CA , Dize L , Mkocha H , Kasubi M , Gambhir M . Sci Rep 2015 5 18532 Ocular infection with Chlamydia trachomatis can lead to trachoma, a leading infectious cause of blindness. Trachoma is targeted for elimination by 2020. Clinical grading for ocular disease is currently used for evaluating trachoma elimination programs, but serological surveillance can be a sensitive measure of disease transmission and provide a more objective testing strategy than clinical grading. We calculated the basic reproduction number from serological data in settings with high, medium, and low disease transmission based on clinical disease. The data showed a striking relationship between age seroprevalence and clinical data, demonstrating the proof-of-principle that age seroprevalence predicts transmission rates and therefore could be used as an indicator of decreased transmission of ocular trachoma. |
Evaluating Ebola vaccine trials: insights from simulation.
Pulliam JRC , Bellan SE , Gambhir M , Meyers LA , Dushoff J . Lancet Infect Dis 2015 15 (10) 1134 ![]() Piszczek and Parlow1 outlined expected benefits of a stepped-wedge cluster trial (SWCT) design, with specific reference to the Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE). STRIVE, however, is not an SWCT, but a phased-rollout trial in which randomization to immediate or delayed vaccination arms occurs at the individual level (RCT) within trial clusters.2 While the SWCT design is advantageous in certain circumstances, many of the benefits described by Piszczek and Parlow would not apply to evaluation of Ebola vaccine candidates in Sierra Leone. | In a recently published study, we used simulations to compare statistical validity and power for an SWCT and a STRIVE-like RCT in the same trial population.3 Piszczek and Parlow contend that an SWCT can achieve greater statistical power than an RCT via multiple before-and-after and between-group comparisons; however, we found that the declining and heterogeneous epidemic incidence across Sierra Leone undermine such cluster-level comparisons and, consequently, the power of an SWCT. Specifically, we estimated that the SWCT design would be 3–10 times less likely than an individually randomized, phased roll-out RCT to definitively identify an efficacious vaccine. For example, an SWCT starting in April 2015 was expected to have a less than 10% chance of detecting the effect of a 90% efficacious vaccine. |
Case-ascertained study of household transmission of seasonal influenza - South Africa, 2013
Iyengar P , von Mollendorf C , Tempia S , Moerdyk A , Valley-Omar Z , Hellferscee O , Martinson N , Chhagan M , McMorrow M , Gambhir M , Cauchemez S , Variava E , Masonoke K , Cohen AL , Cohen C . J Infect 2015 71 (5) 578-86 OBJECTIVES: The household is important in influenza transmission due to intensity of contact. Previous studies reported secondary attack rates (SAR) of 4-10% for laboratory-confirmed influenza in the household. Few have been conducted in middle-income countries. METHODS: We performed a case-ascertained household transmission study during May-October 2013. Index cases were patients with influenza like illness(cough and self-reported or measured fever (≥38 degrees C)) with onset in the last 3 days and no sick household contacts, at clinics in South Africa. Household contacts of index cases with laboratory-confirmed influenza were followed for 12 days. RESULTS: Thirty index cases in 30 households and 107/110 (97%) eligible household contacts were enrolled. Assuming those not enrolled were influenza negative, 21/110 household contacts had laboratory-confirmed influenza (SAR 19%); the mean serial interval was 2.1 days (SD = 0.35, range 2-3 days). Most (62/82; 76%) household contacts who completed the risk factor questionnaire never avoided contact and 43/82 (52%) continued to share a bed with the index case after illness onset. CONCLUSION: SAR for laboratory-confirmed influenza in South Africa was higher than previously reported SARs. Household contacts did not report changing behaviors to prevent transmission. These results can be used to understand and predict influenza transmission in similar middle-income settings. |
Estimating Ebola treatment needs, United States
Rainisch G , Asher J , George D , Clay M , Smith TL , Kosmos C , Shankar M , Washington ML , Gambhir M , Atkins C , Hatchett R , Lant T , Meltzer MI . Emerg Infect Dis 2015 21 (7) 1273-5 By December 31, 2014, the Ebola epidemic in West Africa had resulted in treatment of 10 Ebola case-patients in the United States; a maximum of 4 patients received treatment at any one time (1). Four of these 10 persons became clinically ill in the United States (2 infected outside the United States and 2 infected in the United States), and 6 were clinically ill persons medically evacuated from West Africa (Technical Appendix 1 Table 6). | To plan for possible future cases in the United States, policy makers requested we produce a tool to estimate future numbers of Ebola case-patients needing treatment at any one time in the United States. Gomes et al. previously estimated the potential size of outbreaks in the United States and other countries for 2 different dates in September 2014 (2). Another study considered the overall risk for exportation of Ebola from West Africa but did not estimate the number of potential cases in the United States at any one time (3). |
Statistical power and validity of Ebola vaccine trials in Sierra Leone: a simulation study of trial design and analysis
Bellan SE , Pulliam JR , Pearson CA , Champredon D , Fox SJ , Skrip L , Galvani AP , Gambhir M , Lopman BA , Porco TC , Meyers LA , Dushoff J . Lancet Infect Dis 2015 15 (6) 703-10 BACKGROUND: Safe and effective vaccines could help to end the ongoing Ebola virus disease epidemic in parts of west Africa, and mitigate future outbreaks of the virus. We assess the statistical validity and power of randomised controlled trial (RCT) and stepped-wedge cluster trial (SWCT) designs in Sierra Leone, where the incidence of Ebola virus disease is spatiotemporally heterogeneous, and is decreasing rapidly. METHODS: We projected district-level Ebola virus disease incidence for the next 6 months, using a stochastic model fitted to data from Sierra Leone. We then simulated RCT and SWCT designs in trial populations comprising geographically distinct clusters at high risk, taking into account realistic logistical constraints, and both individual-level and cluster-level variations in risk. We assessed false-positive rates and power for parametric and non-parametric analyses of simulated trial data, across a range of vaccine efficacies and trial start dates. FINDINGS: For an SWCT, regional variation in Ebola virus disease incidence trends produced increased false-positive rates (up to 0.15 at alpha=0.05) under standard statistical models, but not when analysed by a permutation test, whereas analyses of RCTs remained statistically valid under all models. With the assumption of a 6-month trial starting on Feb 18, 2015, we estimate the power to detect a 90% effective vaccine to be between 49% and 89% for an RCT, and between 6% and 26% for an SWCT, depending on the Ebola virus disease incidence within the trial population. We estimate that a 1-month delay in trial initiation will reduce the power of the RCT by 20% and that of the SWCT by 49%. INTERPRETATION: Spatiotemporal variation in infection risk undermines the statistical power of the SWCT. This variation also undercuts the SWCT's expected ethical advantages over the RCT, because an RCT, but not an SWCT, can prioritise vaccination of high-risk clusters. FUNDING: US National Institutes of Health, US National Science Foundation, and Canadian Institutes of Health Research. |
A change in vaccine efficacy and duration of protection explains recent rises in pertussis incidence in the United States
Gambhir M , Clark TA , Cauchemez S , Tartof SY , Swerdlow DL , Ferguson NM . PLoS Comput Biol 2015 11 (4) e1004138 Over the past ten years the incidence of pertussis in the United States (U.S.) has risen steadily, with 2012 seeing the highest case number since 1955. There has also been a shift over the same time period in the age group reporting the largest number of cases (aside from infants), from adolescents to 7-11 year olds. We use epidemiological modelling and a large case incidence dataset to explain the upsurge. We investigate several hypotheses for the upsurge in pertussis cases by fitting a suite of dynamic epidemiological models to incidence data from the National Notifiable Disease Surveillance System (NNDSS) between 1990-2009, as well as incidence data from a variety of sources from 1950-1989. We find that: the best-fitting model is one in which vaccine efficacy and duration of protection of the acellular pertussis (aP) vaccine is lower than that of the whole-cell (wP) vaccine, (efficacy of the first three doses 80% [95% CI: 78%, 82%] versus 90% [95% CI: 87%, 94%]), increasing the rate at which disease is reported to NNDSS is not sufficient to explain the upsurge and 3) 2010-2012 disease incidence is predicted well. In this study, we use all available U.S. surveillance data to: 1) fit a set of mathematical models and determine which best explains these data and 2) determine the epidemiological and vaccine-related parameter values of this model. We find evidence of a difference in efficacy and duration of protection between the two vaccine types, wP and aP (aP efficacy and duration lower than wP). Future refinement of the model presented here will allow for an exploration of alternative vaccination strategies such as different age-spacings, further booster doses, and cocooning. |
Estimating the potential effects of a vaccine program against an emerging influenza pandemic - United States
Biggerstaff M , Reed C , Swerdlow DL , Gambhir M , Graitcer S , Finelli L , Borse RH , Rasmussen SA , Meltzer MI , Bridges CB . Clin Infect Dis 2015 60 Suppl 1 S20-9 BACKGROUND: Human illness from influenza A(H7N9) was identified in March 2013, and candidate vaccine viruses were soon developed. To understand factors that may impact influenza vaccination programs, we developed a model to evaluate hospitalizations and deaths averted considering various scenarios. METHODS: We utilized a model incorporating epidemic curves with clinical attack rates of 20% or 30% in a single wave of illness, case hospitalization ratios of 0.5% or 4.2%, and case fatality ratios of 0.08% or 0.53%. We considered scenarios that achieved 80% vaccination coverage, various starts of vaccination programs (16 or 8 weeks before, the same week of, or 8 or 16 weeks after start of pandemic), an administration rate of 10 or 30 million doses per week (the latter rate is an untested assumption), and 2 levels of vaccine effectiveness (2 doses of vaccine required; either 62% or 80% effective for persons aged <60 years, and either 43% or 60% effective for persons aged ≥60 years). RESULTS: The start date of vaccination campaigns most influenced impact; 141 000-2 200 000 hospitalizations and 11 000-281 000 deaths were averted when campaigns started before a pandemic, and <100-1 300 000 hospitalizations and 0-165 000 deaths were averted for programs beginning the same time as or after the introduction of the pandemic virus. The rate of vaccine administration and vaccine effectiveness did not influence campaign impact as much as timing of the start of campaign. CONCLUSIONS: Our findings suggest that efforts to improve the timeliness of vaccine production will provide the greatest impacts for future pandemic vaccination programs. |
Infectious disease modeling methods as tools for informing response to novel influenza viruses of unknown pandemic potential
Gambhir M , Bozio C , O'Hagan JJ , Uzicanin A , Johnson LE , Biggerstaff M , Swerdlow DL . Clin Infect Dis 2015 60 Suppl 1 S11-9 The rising importance of infectious disease modeling makes this an appropriate time for a guide for public health practitioners tasked with preparing for, and responding to, an influenza pandemic. We list several questions that public health practitioners commonly ask about pandemic influenza and match these with analytical methods, giving details on when during a pandemic the methods can be used, how long it might take to implement them, and what data are required. Although software to perform these tasks is available, care needs to be taken to understand: (1) the type of data needed, (2) the implementation of the methods, and (3) the interpretation of results in terms of model uncertainty and sensitivity. Public health leaders can use this article to evaluate the modeling literature, determine which methods can provide appropriate evidence for decision-making, and to help them request modeling work from in-house teams or academic groups. |
Modeling the effect of school closures in a pandemic scenario: exploring two different contact matrices
Fung IC , Gambhir M , Glasser JW , Gao H , Washington ML , Uzicanin A , Meltzer MI . Clin Infect Dis 2015 60 Suppl 1 S58-63 BACKGROUND: School closures may delay the epidemic peak of the next influenza pandemic, but whether school closure can delay the peak until pandemic vaccine is ready to be deployed is uncertain. METHODS: To study the effect of school closures on the timing of epidemic peaks, we built a deterministic susceptible-infected-recovered model of influenza transmission. We stratified the U.S. population into 4 age groups (0-4, 5-19, 20-64, and ≥65 years), and used contact matrices to model the average number of potentially disease transmitting, nonphysical contacts. RESULTS: For every week of school closure at day 5 of introduction and a 30% clinical attack rate scenario, epidemic peak would be delayed by approximately 5 days. For a 15% clinical attack rate scenario, 1 week closure would delay the peak by 9 days. Closing schools for less than 84 days (12 weeks) would not, however, reduce the estimated total number of cases. CONCLUSIONS: Unless vaccine is available early, school closure alone may not be able to delay the peak until vaccine is ready to be deployed. Conversely, if vaccination begins quickly, school closure may be helpful in providing the time to vaccinate school-aged children before the pandemic peaks. |
Standardizing scenarios to assess the need to respond to an influenza pandemic
Meltzer MI , Gambhir M , Atkins CY , Swerdlow DL . Clin Infect Dis 2015 60 Suppl 1 S1-8 An outbreak of human infections with an avian influenza A(H7N9) virus was first reported in eastern China by the World Health Organization on 1 April 2013 [1]. This novel influenza virus was fatal in approximately one-third of the 135 confirmed cases detected in the 4 months following its initial identification [2], and limited human-to-human H7N9 virus transmission could not be excluded in some Chinese clusters of cases [3, 4]. There was, and still is, the possibility that the virus would mutate to the point where there would be sustained human-to-human transmission. Given that most of the human population has no prior immunity (either due to natural challenge or vaccine induced), such a strain presents the danger of starting an influenza pandemic. | In response to such a threat, the Joint Modeling Unit at the Centers for Disease Control and Prevention (CDC) was asked to conduct a rapid assessment of both the potential burden of unmitigated disease and the possible impacts of different mitigation measures. We were tasked to evaluate the 6 following interventions: invasive mechanical ventilators, influenza antiviral drugs for treatment (but not large-scale prophylaxis), influenza vaccines, respiratory protective devices for healthcare workers and surgical face masks for patients, school closings to reduce transmission, and airport-based screening to identify those ill with novel influenza virus entering the United States. This supplement presents reports on the methods and estimates for the first 5 listed interventions, and in this introduction we outline the general approach and standardized epidemiological assumptions used in all the articles. |
Deaths averted by influenza vaccination in the U.S. during the seasons 2005/06 through 2013/14.
Foppa IM , Cheng PY , Reynolds SB , Shay DK , Carias C , Bresee JS , Kim IK , Gambhir M , Fry AM . Vaccine 2015 33 (26) 3003-9 ![]() ![]() BACKGROUND: Excess mortality due to seasonal influenza is substantial, yet quantitative estimates of the benefit of annual vaccination programs on influenza-associated mortality are lacking. METHODS: We estimated the numbers of deaths averted by vaccination in four age groups (0.5 to 4, 5 to 19, 20 to 64 and ≥65 yrs.) for the nine influenza seasons from 2005/6 through 2013/14. These estimates were obtained using a Monte Carlo approach applied to weekly U.S. age group-specific estimates of influenza-associated excess mortality, monthly vaccination coverage estimates and summary seasonal influenza vaccine effectiveness estimates to obtain estimates of the number of deaths averted by vaccination. The estimates are conservative as they do not include indirect vaccination effects. RESULTS: From August, 2005 through June, 2014, we estimated that 40,127 (95% confidence interval [CI] 25,694 to 59,210) deaths were averted by influenza vaccination. We found that of all studied seasons the most deaths were averted by influenza vaccination during the 2012/13 season (9398; 95% CI 2,386 to 19,897) and the fewest during the 2009/10 pandemic (222; 95% CI 79 to 347). Of all influenza-associated deaths averted, 88.9% (95% CI 83 to 92.5%) were in people ≥65 yrs. old. CONCLUSIONS: The estimated number of deaths averted by the US annual influenza vaccination program is considerable, especially among elderly adults and even when vaccine effectiveness is modest, such as in the 2012/13 season. As indirect effects ("herd immunity") of vaccination are ignored, these estimates represent lower bound estimates and are thus conservative given valid excess mortality estimates. |
Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature
Biggerstaff M , Cauchemez S , Reed C , Gambhir M , Finelli L . BMC Infect Dis 2014 14 480 BACKGROUND: The potential impact of an influenza pandemic can be assessed by calculating a set of transmissibility parameters, the most important being the reproduction number (R), which is defined as the average number of secondary cases generated per typical infectious case. METHODS: We conducted a systematic review to summarize published estimates of R for pandemic or seasonal influenza and for novel influenza viruses (e.g. H5N1). We retained and summarized papers that estimated R for pandemic or seasonal influenza or for human infections with novel influenza viruses. RESULTS: The search yielded 567 papers. Ninety-one papers were retained, and an additional twenty papers were identified from the references of the retained papers. Twenty-four studies reported 51 R values for the 1918 pandemic. The median R value for 1918 was 1.80 (interquartile range [IQR]: 1.47-2.27). Six studies reported seven 1957 pandemic R values. The median R value for 1957 was 1.65 (IQR: 1.53-1.70). Four studies reported seven 1968 pandemic R values. The median R value for 1968 was 1.80 (IQR: 1.56-1.85). Fifty-seven studies reported 78 2009 pandemic R values. The median R value for 2009 was 1.46 (IQR: 1.30-1.70) and was similar across the two waves of illness: 1.46 for the first wave and 1.48 for the second wave. Twenty-four studies reported 47 seasonal epidemic R values. The median R value for seasonal influenza was 1.28 (IQR: 1.19-1.37). Four studies reported six novel influenza R values. Four out of six R values were <1. CONCLUSIONS: These R values represent the difference between epidemics that are controllable and cause moderate illness and those causing a significant number of illnesses and requiring intensive mitigation strategies to control. Continued monitoring of R during seasonal and novel influenza outbreaks is needed to document its variation before the next pandemic. |
Improvements in pandemic preparedness in 8 Central American countries, 2008 - 2012
Johnson LE , Clara W , Gambhir M , Fuentes RC , Marin-Correa C , Jara J , Minaya P , Rodriguez D , Blanco N , Iihoshi N , Orozco M , Lange C , Perez SV , Amador N , Widdowson MA , Moen AC , Azziz-Baumgartner E . BMC Health Serv Res 2014 14 (1) 209 BACKGROUND: In view of ongoing pandemic threats such as the recent human cases of novel avian influenza A(H7N9) in China, it is important that all countries continue their preparedness efforts. Since 2006, Central American countries have received donor funding and technical assistance from the U.S. Centers for Disease Control and Prevention (CDC) to build and improve their capacity for influenza surveillance and pandemic preparedness. Our objective was to measure changes in pandemic preparedness in this region, and explore factors associated with these changes, using evaluations conducted between 2008 and 2012. METHODS: Eight Central American countries scored their pandemic preparedness across 12 capabilities in 2008, 2010 and 2012, using a standardized tool developed by CDC. Scores were calculated by country and capability and compared between evaluation years using the Student's t-test and Wilcoxon Rank Sum test, respectively. Virological data reported to WHO were used to assess changes in testing capacity between evaluation years. Linear regression was used to examine associations between scores, donor funding, technical assistance and WHO reporting. RESULTS: All countries improved their pandemic preparedness between 2008 and 2012 and seven made statistically significant gains (p < 0.05). Increases in median scores were observed for all 12 capabilities over the same period and were statistically significant for eight of these (p < 0.05): country planning, communications, routine influenza surveillance, national respiratory disease surveillance, outbreak response, resources for containment, community interventions and health sector response. We found a positive association between preparedness scores and cumulative funding between 2006 and 2011 (R2 = 0.5, p < 0.01). The number of specimens reported to WHO from participating countries increased significantly from 5,551 (2008) to 18,172 (2012) (p < 0.01). CONCLUSIONS: Central America has made significant improvements in influenza pandemic preparedness between 2008 and 2012. U.S. donor funding and technical assistance provided to the region is likely to have contributed to the improvements we observed, although information on other sources of funding and support was unavailable to study. Gains are also likely the result of countries' response to the 2009 influenza pandemic. Further research is required to determine the degree to which pandemic improvements are sustainable. |
Modeling the potential impact of vaccination on the epidemiology of congenital cytomegalovirus infection
Lanzieri TM , Bialek SR , Ortega-Sanchez IR , Gambhir M . Vaccine 2014 32 (30) 3780-6 BACKGROUND: Understanding the potential for vaccination to change cytomegalovirus (CMV) epidemiology is important for developing CMV vaccines and designing clinical trials. METHODS: We constructed a deterministic, age-specific and time-dependent mathematical model of pathogen transmission, parameterized using CMV seroprevalence from the United States and Brazil, to predict the impact of vaccination on congenital CMV infection. FINDINGS: Concurrent vaccination of young children and adolescents would result in the greatest reductions in congenital CMV infections in populations with moderate and high baseline maternal seroprevalence. Such a vaccination strategy, assuming 70% vaccine efficacy, 90% coverage and 5-year duration of protection, could ultimately prevent 30-50% of congenital CMV infections. At equilibrium, this strategy could result in a 30% reduction in congenital CMV infections due to primary maternal infection in the United States but a 3% increase in Brazil. The potential for an increase in congenital CMV infections due to primary maternal infections in Brazil was not predicted with use of a vaccine that confers protection for greater than 5 years. INTERPRETATION: Modeling suggests that vaccination strategies that include young children will result in greater declines in congenital CMV infection than those restricted to adolescents or women of reproductive age. Our study highlights the critical need for better understanding of the relative contribution of type of maternal infection to congenital CMV infection and disease, the main focus of vaccine prevention. |
Epidemiologic implications of asymptomatic reinfection: a mathematical modeling study of norovirus
Lopman B , Simmons K , Gambhir M , Vinje J , Parashar U . Am J Epidemiol 2014 179 (4) 507-12 The pathogenicity of norovirus is definitively established. However, norovirus is frequently detected in the stool of healthy individuals. To gain understanding of the apparent high prevalence of asymptomatic infection, we analyzed a dynamic transmission model of norovirus infection, disease, and immunity. We simulated norovirus epidemiology in low- and high-transmission settings by varying the basic reproduction number (R0). We predicted annual disease incidence values in children aged 0-4 years of 25% with a low R0 and 29% with a high R0. However, the point prevalence of asymptomatic infection rose sharply from 3% to 48% from the low to high R0 settings. Among older children and adults, the models projected that incidence of disease would rise from 6% to 16% from the low to high R0 settings, whereas asymptomatic infection prevalence was lower in this age group. Asymptomatic prevalence of norovirus can change dramatically with small changes in R0. The ratio of prevalence in cases to controls could be high in a developed country and close to or even less than 1 in a high-exposure setting, despite similar disease incidence. These findings highlight an important limitation of case-control studies for pathogens for which there is suboptimal diagnostic specificity. |
Duration of immunity to norovirus gastroenteritis
Simmons K , Gambhir M , Leon J , Lopman B . Emerg Infect Dis 2013 19 (8) 1260-7 ![]() The duration of immunity to norovirus (NoV) gastroenteritis has been believed to be from 6 months to 2 years. However, several observations are inconsistent with this short period. To gain better estimates of the duration of immunity to NoV, we developed a mathematical model of community NoV transmission. The model was parameterized from the literature and also fit to age-specific incidence data from England and Wales by using maximum likelihood. We developed several scenarios to determine the effect of unknowns regarding transmission and immunity on estimates of the duration of immunity. In the various models, duration of immunity to NoV gastroenteritis was estimated at 4.1 (95% CI 3.2-5.1) to 8.7 (95% CI 6.8-11.3) years. Moreover, we calculated that children (<5 years) are much more infectious than older children and adults. If a vaccine can achieve protection for duration of natural immunity indicated by our results, its potential health and economic benefits could be substantial. |
Transmissibility of variant influenza from swine to humans: a modeling approach
Wong KK , Gambhir M , Finelli L , Swerdlow DL , Ostroff S , Reed C . Clin Infect Dis 2013 57 Suppl 1 S16-22 BACKGROUND: Respiratory illness was reported among humans and swine at an agricultural fair in 2011; 3 human infections with an influenza A(H3N2) variant (H3N2v) virus were confirmed. Using epidemiologic investigation data, we sought to estimate H3N2v transmissibility from swine to humans. METHODS: We developed a model of H3N2v transmission among swine and humans and fit it to data from a cohort of 100 agricultural club members reporting swine contact to estimate transmissibility. A sensitivity analysis was performed varying H3N2v prevalence in the club cohort. Using the best-fit transmission probability, we simulated the number of swine-acquired infections among all fair attendees. RESULTS: We estimated the best-fit probability of swine-to-human H3N2v transmission per minute of swine contact. Applying this probability to 14 910 people with swine contact at the fair, we estimate that there were 80 (95% confidence interval [CI], 40-133) H3N2v infections among persons aged <20 years and 58 (95% CI, 29-96) H3N2v infections among person aged ≥20 years. CONCLUSIONS: Using early data from investigation of a new virus with unclear transmission properties, we estimated the transmissibility of H3N2v from swine to humans and the burden of H3N2v among fair attendees. Although the risk of H3N2v virus infection is small for fair attendees with minimal swine contact, large populations attend agricultural events each year, and human cases will likely occur when infected swine are present. |
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