Showing papers by "M. Elizabeth Halloran published in 2021"

Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study.

Abstract: Summary Background Wuhan was the first epicentre of COVID-19 in the world, accounting for 80% of cases in China during the first wave. We aimed to assess household transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and risk factors associated with infectivity and susceptibility to infection in Wuhan. Methods This retrospective cohort study included the households of all laboratory-confirmed or clinically confirmed COVID-19 cases and laboratory-confirmed asymptomatic SARS-CoV-2 infections identified by the Wuhan Center for Disease Control and Prevention between Dec 2, 2019, and April 18, 2020. We defined households as groups of family members and close relatives who did not necessarily live at the same address and considered households that shared common contacts as epidemiologically linked. We used a statistical transmission model to estimate household secondary attack rates and to quantify risk factors associated with infectivity and susceptibility to infection, accounting for individual-level exposure history. We assessed how intervention policies affected the household reproductive number, defined as the mean number of household contacts a case can infect. Findings 27 101 households with 29 578 primary cases and 57 581 household contacts were identified. The secondary attack rate estimated with the transmission model was 15·6% (95% CI 15·2–16·0), assuming a mean incubation period of 5 days and a maximum infectious period of 22 days. Individuals aged 60 years or older were at a higher risk of infection with SARS-CoV-2 than all other age groups. Infants aged 0–1 years were significantly more likely to be infected than children aged 2–5 years (odds ratio [OR] 2·20, 95% CI 1·40–3·44) and children aged 6–12 years (1·53, 1·01–2·34). Given the same exposure time, children and adolescents younger than 20 years of age were more likely to infect others than were adults aged 60 years or older (1·58, 1·28–1·95). Asymptomatic individuals were much less likely to infect others than were symptomatic cases (0·21, 0·14–0·31). Symptomatic cases were more likely to infect others before symptom onset than after (1·42, 1·30–1·55). After mass isolation of cases, quarantine of household contacts, and restriction of movement policies were implemented, household reproductive numbers declined by 52% among primary cases (from 0·25 [95% CI 0·24–0·26] to 0·12 [0·10–0·13]) and by 63% among secondary cases (from 0·17 [0·16–0·18] to 0·063 [0·057–0·070]). Interpretation Within households, children and adolescents were less susceptible to SARS-CoV-2 infection but were more infectious than older individuals. Presymptomatic cases were more infectious and individuals with asymptomatic infection less infectious than symptomatic cases. These findings have implications for devising interventions for blocking household transmission of SARS-CoV-2, such as timely vaccination of eligible children once resources become available. Funding National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities, US National Institutes of Health, and US National Science Foundation.

Inferring high-resolution human mixing patterns for disease modeling.

Abstract: Mathematical and computational modeling approaches are increasingly used as quantitative tools in the analysis and forecasting of infectious disease epidemics. The growing need for realism in addressing complex public health questions is, however, calling for accurate models of the human contact patterns that govern the disease transmission processes. Here we present a data-driven approach to generate effective population-level contact matrices by using highly detailed macro (census) and micro (survey) data on key socio-demographic features. We produce age-stratified contact matrices for 35 countries, including 277 sub-national administratvie regions of 8 of those countries, covering approximately 3.5 billion people and reflecting the high degree of cultural and societal diversity of the focus countries. We use the derived contact matrices to model the spread of airborne infectious diseases and show that sub-national heterogeneities in human mixing patterns have a marked impact on epidemic indicators such as the reproduction number and overall attack rate of epidemics of the same etiology. The contact patterns derived here are made publicly available as a modeling tool to study the impact of socio-economic differences and demographic heterogeneities across populations on the epidemiology of infectious diseases. The growing need for realism in addressing complex public health questions calls for accurate models of the human contact patterns that govern disease transmission. Here, the authors generate effective population-level contact matrices by using highly detailed macro (census) and micro (survey) data on key socio-demographic features.

Factors Associated With Household Transmission of SARS-CoV-2: An Updated Systematic Review and Meta-analysis.

Abstract: Importance A previous systematic review and meta-analysis of household transmission of SARS-CoV-2 that summarized 54 published studies through October 19, 2020, found an overall secondary attack rate (SAR) of 16.6% (95% CI, 14.0%-19.3%). However, the understanding of household secondary attack rates for SARS-CoV-2 is still evolving, and updated analysis is needed. Objective To use newly published data to further the understanding of SARS-CoV-2 transmission in the household. Data sources PubMed and reference lists of eligible articles were used to search for records published between October 20, 2020, and June 17, 2021. No restrictions on language, study design, time, or place of publication were applied. Studies published as preprints were included. Study selection Articles with original data that reported at least 2 of the following factors were included: number of household contacts with infection, total number of household contacts, and secondary attack rates among household contacts. Studies that reported household infection prevalence (which includes index cases), that tested contacts using antibody tests only, and that included populations overlapping with another included study were excluded. Search terms were SARS-CoV-2 or COVID-19 with secondary attack rate, household, close contacts, contact transmission, contact attack rate, or family transmission. Data extraction and synthesis Meta-analyses were performed using generalized linear mixed models to obtain SAR estimates and 95% CIs. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Main outcomes and measures Overall household SAR for SARS-CoV-2, SAR by covariates (contact age, sex, ethnicity, comorbidities, and relationship; index case age, sex, symptom status, presence of fever, and presence of cough; number of contacts; study location; and variant), and SAR by index case identification period. Results A total of 2722 records (2710 records from database searches and 12 records from the reference lists of eligible articles) published between October 20, 2020, and June 17, 2021, were identified. Of those, 93 full-text articles reporting household transmission of SARS-CoV-2 were assessed for eligibility, and 37 studies were included. These 37 new studies were combined with 50 of the 54 studies (published through October 19, 2020) from our previous review (4 studies from Wuhan, China, were excluded because their study populations overlapped with another recent study), resulting in a total of 87 studies representing 1 249 163 household contacts from 30 countries. The estimated household SAR for all 87 studies was 18.9% (95% CI, 16.2%-22.0%). Compared with studies from January to February 2020, the SAR for studies from July 2020 to March 2021 was higher (13.4% [95% CI, 10.7%-16.7%] vs 31.1% [95% CI, 22.6%-41.1%], respectively). Results from subgroup analyses were similar to those reported in a previous systematic review and meta-analysis; however, the SAR was higher to contacts with comorbidities (3 studies; 50.0% [95% CI, 41.4%-58.6%]) compared with previous findings, and the estimated household SAR for the B.1.1.7 (α) variant was 24.5% (3 studies; 95% CI, 10.9%-46.2%). Conclusions and relevance The findings of this study suggest that the household remains an important site of SARS-CoV-2 transmission, and recent studies have higher household SAR estimates compared with the earliest reports. More transmissible variants and vaccines may be associated with further changes.

Efficacy Estimates for Various COVID-19 Vaccines: What we Know from the Literature and Reports

Abstract: In this report, we provide summary estimates, from publications and reports, of vaccine efficacy (VE) for the COVID-19 vaccines that are being rolled out on a global scale. We find that, on average, the efficacy against any disease with infection is 85% (95% CI: 71 - 93%) after a fully course of vaccination. The VE against severe disease, hospitalization or death averages close to 100%. The average VE against infection, regardless of symptoms, is 84% (95% CI: 70 - 91%). We also find that the average VE against transmission to others for infected vaccinated people is 54% (95% CI: 38 - 66%). Finally, we prove summary estimates of the VE against any disease with infection for some of the variants of concern (VOC). The average VE for the VOC B.1.1.7, B.1.1.28 (P1) and B.1.351 are 86% (95% CI: 65 - 84%), 61% (95% CI: 43 - 73%) and 56% (95% CI: 29 - 73%), respectively.

Cryptic transmission of SARS-CoV-2 and the first COVID-19 wave.

Abstract: Considerable uncertainty surrounds the timeline of introductions and onsets of local transmission of SARS-CoV-2 globally1–7. Although a limited number of SARS-CoV-2 introductions were reported in January and February 20208,9, the narrowness of the initial testing criteria, combined with a slow growth in testing capacity and porous travel screening10, left many countries vulnerable to unmitigated, cryptic transmission. Here we use a global metapopulation epidemic model to provide a mechanistic understanding of the early dispersal of infections, and the temporal windows of the introduction and onset of SARS-CoV-2 local transmission in Europe and the United States. We find that community transmission of SARS-CoV-2 was likely in several areas of Europe and the United States by January 2020, and estimate that by early March, only 1 to 3 in 100 SARS-CoV-2 infections were detected by surveillance systems. The modelling results highlight international travel as the key driver of the introduction of SARS-CoV-2 with possible introductions and transmission events as early as December 2019–January 2020. We find a heterogeneous, geographic distribution of cumulative infection attack rates by 4 July 2020, ranging from 0.78%–15.2% across US states and 0.19%–13.2% in European countries. Our approach complements phylogenetic analyses and other surveillance approaches and provides insights that can be used to design innovative, model-driven surveillance systems that guide enhanced testing and response strategies.

Dengue and Zika virus infections in children elicit cross-reactive protective and enhancing antibodies that persist long term.

Abstract: Dengue virus serotypes 1 to 4 (DENV1–4) and Zika virus (ZIKV) are mosquito-borne flaviviruses that induce both virus-specific and broadly reactive antibodies. A first DENV infection is thought to i...

Cryptic transmission of SARS-CoV-2 and the first COVID-19 wave in Europe and the United States

Abstract: Given the narrowness of the initial testing criteria, the SARS-CoV-2 virus spread through cryptic transmission in January and February, setting the stage for the epidemic wave experienced in March and April, 2020 We use a global metapopulation epidemic model to provide a mechanistic understanding of the global dynamic underlying the establishment of the COVID-19 pandemic in Europe and the United States (US) The model is calibrated on international case introductions at the early stage of the pandemic We find that widespread community transmission of SARS-CoV-2 was likely in several areas of Europe and the US by January 2020, and estimate that by early March, only 1 - 3 in 100 SARS-CoV-2 infections were detected by surveillance systems Modeling results indicate international travel as the key driver of the introduction of SARS-CoV-2 with possible importation and transmission events as early as December, 2019 We characterize the resulting heterogeneous spatio-temporal spread of SARS-CoV-2 and the burden of the first COVID-19 wave (February-July 2020) We estimate infection attack rates ranging from 078%-152% in the US and 019%-132% in Europe The spatial modeling of SARS-CoV-2 introductions and spreading provides insights into the design of innovative, model-driven surveillance systems and preparedness plans that have a broader initial capacity and indication for testing

Estimates of Inactivated Influenza Vaccine Effectiveness Among Children in Senegal: Results From 2 Consecutive Cluster-Randomized Controlled Trials in 2010 and 2011

Abstract: Background We report results of years 2 and 3 of consecutive cluster-randomized controlled trials of trivalent inactivated influenza vaccine (IIV3) in Senegal. Methods We cluster-randomized (1:1) 20 villages to annual vaccination with IIV3 or inactivated poliovirus vaccine (IPV) of age-eligible residents (6 months–10 years). The primary outcome was total vaccine effectiveness against laboratory-confirmed influenza illness (LCI) among age-eligible children (modified intention-to-treat population [mITT]). Secondary outcomes were indirect (herd protection) and population (overall community) vaccine effectiveness. Results We vaccinated 74% of 12 408 age-eligible children in year 2 (June 2010–April 11) and 74% of 11 988 age-eligible children in year 3 (April 2011–December 2011) with study vaccines. Annual cumulative incidence of LCI was 4.7 (year 2) and 4.2 (year 3) per 100 mITT child vaccinees of IPV villages. In year 2, IIV3 matched circulating influenza strains. The total effectiveness was 52.8% (95% confidence interval [CI], 32.3–67.0), and the population effectiveness was 36.0% (95% CI, 10.2–54.4) against LCI caused by any influenza strain. The indirect effectiveness against LCI by A/H3N2 was 56.4% (95% CI, 39.0–68.9). In year 3, 74% of influenza detections were vaccine-mismatched to circulating B/Yamagata and 24% were vaccine-matched to circulating A/H3N2. The year 3 total effectiveness against LCI was −14.5% (95% CI, −81.2–27.6). Vaccine effectiveness varied by type/subtype of influenza in both years. Conclusions IIV3 was variably effective against influenza illness in Senegalese children, with total and indirect vaccine effectiveness present during the year when all circulating strains matched the IIV3 formulation. Clinical Trials Registration NCT00893906.

Incorporating Real-time Influenza Detection Into the Test-negative Design for Estimating Influenza Vaccine Effectiveness: The Real-time Test-negative Design (rtTND).

Abstract: With rapid and accurate molecular influenza testing now widely available in clinical settings, influenza vaccine effectiveness (VE) studies can prospectively select participants for enrollment based on real-time results rather than enrolling all eligible patients regardless of influenza status, as in the traditional test-negative design (TND). Thus, we explore advantages and disadvantages of modifying the TND for estimating VE by using real-time, clinically available viral testing results paired with acute respiratory infection eligibility criteria for identifying influenza cases and test-negative controls prior to enrollment. This modification, which we have called the real-time test-negative design (rtTND), has the potential to improve influenza VE studies by optimizing the case-to-test-negative control ratio, more accurately classifying influenza status, improving study efficiency, reducing study cost, and increasing study power to adequately estimate VE. Important considerations for limiting biases in the rtTND include the need for comprehensive clinical influenza testing at study sites and accurate influenza tests.

Association of Diphtheria-Tetanus-Acellular Pertussis Vaccine Timeliness and Number of Doses With Age-Specific Pertussis Risk in Infants and Young Children.

Abstract: Importance In most countries, the diphtheria-tetanus–acellular pertussis (DTaP) vaccine is administered as a 3-dose infant series followed by additional booster doses in the first 5 years of life. Short-term immunity from the DTaP vaccine can depend on the number, timing, and interval between doses. Not receiving doses in a timely manner might be associated with a higher pertussis risk. Objective To examine the association between number and timeliness of vaccine doses and age-specific pertussis risk. Design, Setting, and Participants This population-based, retrospective cohort study used Washington State Immunization Information System data and pertussis surveillance data from Public Health Seattle and King County, Washington. Included participants were children aged 3 months to 9 years born or living in King County, Washington, between January 1, 2008, and December 31, 2017. Data were analyzed from June 30 to December 1, 2019. Exposures Being undervaccinated (receiving fewer than recommended doses at a given age) or delayed vaccination (not receiving doses within time frames recommended by Centers for Disease Control and Prevention). Main Outcomes and Measures Suspected, probable, and confirmed pertussis diagnosis. Results A total of 316 404 children (median age, 65.2 months [interquartile range, 35.3-94.1 months]; 162 025 boys [51.2%]) as of December 31, 2017, with 17.4 million person-months of follow-up were included in the analysis. A total of 19 943 children (6.3%) had no vaccines recorded in the Immunization Information System, 116 193 (36.7%) received a vaccine with a delay, and 180 268 (56.9%) were fully vaccinated with no delay. Delayed vaccination and undervaccination rates were higher for older children (17.6% delayed or undervaccinated at age 2 months for dose 1 at 3 months vs 41.6% at age 5 years for dose 5) but improved for successive birth cohorts (52.2% for 2008 birth cohort vs 32.3% for 2017 birth cohort). Undervaccination was significantly associated with higher risk of pertussis for the 3-dose primary series (adjusted relative risk [aRR], 4.8; 95% CI, 3.1-7.6), the first booster (aRR, 3.2; 95% CI, 2.3-4.5), and the second booster (aRR, 4.6; 95% CI, 2.6-8.2). However, delay in vaccination among children who received the recommended number of vaccine doses was not associated with pertussis risk. Conclusions and Relevance The results of this cohort study suggest that undervaccination is associated with higher pertussis risk. Short delays in vaccine receipt may be less important if the age-appropriate number of doses is administered, but delaying doses is not recommended. Ensuring that children receive all doses of pertussis vaccine, even if there is some delay, is important.

Modeling the impacts of clinical influenza testing on influenza vaccine effectiveness estimates.

Abstract: BACKGROUND Test-negative design studies for evaluating influenza vaccine effectiveness (VE) enroll patients with acute respiratory infection. Enrollment typically occurs before influenza status is determined, resulting in over-enrollment of influenza-negative patients. With availability of rapid and accurate molecular clinical testing, influenza status could be ascertained prior to enrollment, thus improving study efficiency. We estimate potential biases in VE when using clinical testing. METHODS We simulate data assuming 60% vaccinated, 25% of those vaccinated are influenza positive, and VE of 50%. We show the effect on VE in five scenarios. RESULTS VE is affected only when clinical testing preferentially targets patients based on both vaccination and influenza status. VE is overestimated by 10% if non-testing occurs in 39% of vaccinated influenza-positive patients and 24% of others; and if non-testing occurs in 8% of unvaccinated influenza-positive patients and 27% of others. VE is underestimated by 10% if non-testing occurs in 32% of unvaccinated influenza-negative patients and 18% of others. CONCLUSIONS Although differential clinical testing by vaccine receipt and influenza positivity may produce errors in estimated VE, bias in testing would have to be substantial and overall proportion of patients tested would have to be small to result in a meaningful difference in VE.

Inverse probability weighted estimators of vaccine effects accommodating partial interference and censoring

Abstract: Estimating population-level effects of a vaccine is challenging because there may be interference, that is, the outcome of one individual may depend on the vaccination status of another individual. Partial interference occurs when individuals can be partitioned into groups such that interference occurs only within groups. In the absence of interference, inverse probability weighted (IPW) estimators are commonly used to draw inference about causal effects of an exposure or treatment. Tchetgen Tchetgen and VanderWeele proposed a modified IPW estimator for causal effects in the presence of partial interference. Motivated by a cholera vaccine study in Bangladesh, this paper considers an extension of the Tchetgen Tchetgen and VanderWeele IPW estimator to the setting where the outcome is subject to right censoring using inverse probability of censoring weights (IPCW). Censoring weights are estimated using proportional hazards frailty models. The large sample properties of the IPCW estimators are derived, and simulation studies are presented demonstrating the estimators' performance in finite samples. The methods are then used to analyze data from the cholera vaccine study.

Using simulated infectious disease outbreaks to inform site selection and sample size for individually randomized vaccine trials during an ongoing epidemic

Abstract: Background:Novel strategies are needed to make vaccine efficacy trials more robust given uncertain epidemiology of infectious disease outbreaks, such as arboviruses like Zika. Spatially resolved ma...

Using social contact data to improve the overall effect estimate of a cluster‐randomized influenza vaccination program in Senegal

Abstract: This study estimates the overall effect of two influenza vaccination programs consecutively administered in a cluster-randomized trial in western Senegal over the course of two influenza seasons from 2009-2011. We apply cutting-edge methodology combining social contact data with infection data to reduce bias in estimation arising from contamination between clusters. Our time-varying estimates reveal a reduction in seasonal influenza from the intervention and a nonsignificant increase in H1N1 pandemic influenza. We estimate an additive change in overall cumulative incidence (which was 6.13% in the control arm) of -0.68 percentage points during Year 1 of the study (95% CI: -2.53, 1.18). When H1N1 pandemic infections were excluded from analysis, the estimated change was -1.45 percentage points and was significant (95% CI, -2.81, -0.08). Because cross-cluster contamination was low (0-3% of contacts for most villages), an estimator assuming no contamination was only slightly attenuated (-0.65 percentage points). These findings are encouraging for studies carefully designed to minimize spillover. Further work is needed to estimate contamination, and its effect on estimation, in a variety of settings.

Estimating population-level effects of the acellular pertussis vaccine using routinely collected immunization data.

Abstract: Background Measuring and reporting the different population-level effects of the acellular pertussis vaccine on pertussis disease in addition to direct effects can increase the cost-effectiveness of a vaccine. Methods We conducted a retrospective cohort study of children born between January 1, 2008, and December 31, 2017, in King County, Washington, who were enrolled in the Washington State Immunization Information System. Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccination data from WA-IIS was linked with pertussis case data from Public Health Seattle and King County. Census-level vaccination coverage was estimated as proportion of age-appropriately vaccinated children residing in it. Direct vaccine effectiveness was estimated by comparing pertussis risk in fully-vaccinated and under-vaccinated children. Population-level vaccine effects were estimated by comparing pertussis risk in census tracts in the highest vaccination coverage quartile to that in the lowest vaccination coverage quartile. Results For direct protection, estimated vaccine effectiveness was 76% (95% CI: 63% - 84%) in low vaccination coverage clusters and it decreased to 47% (95% CI: 13% - 68%) in high vaccination coverage clusters, after adjusting for potential confounders. The estimated indirect effect was 45.0% (95% CI: 1%, 70%), total effect was 93.9% (95% CI: 91%, 96%), and overall effect was 42.2% (95% CI: 19%, 60%). Conclusion Our findings suggest that DTaP vaccination provided direct as well as indirect protection in the highly immunized King County, WA. Routine DTaP vaccination programs may have the potential to provide not only protection for vaccinated individuals but also for the under-vaccinated individuals living in the same area.

Estimating Causal Effects of Non-Randomized HIV Prevention Interventions with Interference in Network-based Studies among People who Inject Drugs

Abstract: Evaluating causal effects in the presence of interference is challenging in network-based studies of hard to reach populations. Like many such populations, people who inject drugs (PWID) are embedded in social networks and often exert influence on others in their network. In our setting, the study design is observational with a non-randomized network-based HIV prevention intervention. The information is available on each participant and their connections that confer possible shared HIV risk behaviors through injection and sexual risk behaviors. We consider two inverse probability weighted (IPW) estimators to quantify the population-level effects of non-randomized interventions on subsequent health outcomes. We demonstrated that these two IPW estimators are consistent, asymptotically normal, and derived a closed form estimator for the asymptotic variance, while allowing for overlapping interference sets (groups of individuals in which the interference is assumed possible). A simulation study was conducted to evaluate the finite-sample performance of the estimators. We analyzed data from the Transmission Reduction Intervention Project, which ascertained a network of PWID and their contacts in Athens, Greece, from 2013 to 2015. We evaluated the effects of community alerts on HIV risk behavior in this observed network, where the links between participants were defined by using substances or having unprotected sex together. In the study, community alerts were distributed to inform people of recent HIV infections among individuals in close proximity in the observed network. The estimates of the risk differences for both IPW estimators demonstrated a protective effect. The results suggest that HIV risk behavior can be mitigated by exposure to a community alert when an increased risk of HIV is detected in the network.

Validation of a Pictorial Survey Tool to Measure Time Use in an African Urban Setting

Abstract: Background:Disease often depends on how a host interacts with his or her environment. This interaction is important for respiratory infectious diseases, where built environments may promote transmi...