Publications by authors named "Derek A T Cummings"

151 Publications

Factors associated with clinical severity in emergency department patients presenting with symptomatic SARS-CoV-2 infection.

J Am Coll Emerg Physicians Open 2021 Aug 29;2(4):e12453. Epub 2021 Jun 29.

School of Medicine and Health Sciences Department of Emergency Medicine, The George Washington University Washington District of Columbia USA.

Objective: To measure the association of race, ethnicity, comorbidities, and insurance status with need for hospitalization of symptomatic emergency department patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods: This study is a cohort study of symptomatic patients presenting to a single emergency department (ED) with laboratory-confirmed SARS-CoV-2 infection from March 7-August 9, 2020. We collected patient-level information regarding demographics, insurance status, comorbidities, level of care, and mortality using a structured chart review. We compared characteristics of patients categorized by (1) home discharge, (2) general hospital ward admission, and (3) intensive care unit (ICU) admission or death within 30 days of the index visit. Univariate and multivariable logistic regression analyses were performed to report odds ratios (OR) and 95% confidence intervals (95% CI) between hospital admission versus ED discharge home and between ICU care versus general hospital ward admission.

Results: In total, 994 patients who presented to the ED with symptoms were included in the analysis with 551 (55.4%) patients discharged home, 314 (31.6%) patients admitted to the general hospital ward, and 129 (13.0%) admitted to the ICU or dying. Patients requiring admission were more likely to be Black or to have public insurance (Medicaid and/or Medicare). Patients who were admitted to the ICU or dying were more likely aged ≥ 65 years or male. In multivariable logistic regression, old age, public insurance, diabetes, hypertension, obesity, heart failure, and hyperlipidemia were independent predictors of hospital admission. When comparing those who needed ICU care versus general hospital ward admission in univariate logistic regression, patients with Medicaid (OR 2.4, 95% CI 1.2-4.6), Medicare (OR 4.2, 95% CI 2.1-8.4), Medicaid and Medicare (OR 4.3, 95% CI 2.4-7.7), history of chronic obstructive pulmonary disease (OR 2.2, 95% CI 1.2-4.2), hypertension (OR 1.7, 95% CI 1.1-2.7), and heart failure (OR 2.6, 95% CI 1.4-4.7) were more likely to be admitted into the ICU or die; Black (OR 1.1, 95% CI 0.4-2.9) and Hispanic/Latino (OR 1.0, 95% CI 0.6-1.8) patients were less likely to be admitted into the ICU; however, the associations were not statistically significant. In multivariable logistic regression, old age, male sex, public insurance, and heart failure were independent predictors of ICU care/death.

Conclusion: Comorbidities and public insurance are predictors of more severe illness for patients with SARS-CoV-2. This study suggests that the disparities in severity seen in COVID-19 among Black patients may be attributable, in part, to low socioeconomic status and chronic health conditions.
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http://dx.doi.org/10.1002/emp2.12453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240469PMC
August 2021

Outpatient Healthcare Personnel Knowledge and Attitudes Towards Infection Prevention Measures for Protection from Respiratory Infections.

Am J Infect Control 2021 Jun 25. Epub 2021 Jun 25.

Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA; Baylor College of Medicine, Houston, TX, USA.

Background: Healthcare personnel (HCP) knowledge and attitudes toward infection control measures are important determinants of practices that can protect them from transmission of infectious diseases.

Methods: Healthcare personnel were recruited from Emergency Departments and outpatient clinics at seven sites. They completed knowledge surveys at the beginning and attitude surveys at the beginning and end of each season of participation. Attitudes toward infection prevention and control measures, especially medical masks and N95 respirators, were compared. The proportion of participants who correctly identified all components of an infection control bundle for seven clinical scenarios was calculated.

Results: The proportion of participants in the medical mask group who reported at least one reason to avoid using medical masks fell from 88.5% on the pre-season survey to 39.6% on the post-season survey (odds ratio [OR] for preseason vs. postseason 0.11, 95% CI 0.10-0.14). Among those wearing N95 respirators, the proportion fell from 87.9% to 53.6% (OR 0.24, 95% CI 0.21-0.28). Participants correctly identified all components of the infection control bundle for 4.9% to 38.5% of scenarios.

Conclusions: Attitudes toward medical masks and N95 respirators improved significantly between the beginning and end of each season. The proportion of HCP who correctly identified the infection control precautions needed for clinical scenarios was low, but it improved over successive years of participation in the study.
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http://dx.doi.org/10.1016/j.ajic.2021.06.011DOI Listing
June 2021

Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection.

Nat Med 2021 Jun 24. Epub 2021 Jun 24.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, RI, USA.

More than half of the world's population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.
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http://dx.doi.org/10.1038/s41591-021-01392-9DOI Listing
June 2021

Insights into household transmission of SARS-CoV-2 from a population-based serological survey.

Nat Commun 2021 06 15;12(1):3643. Epub 2021 Jun 15.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Understanding the risk of infection from household- and community-exposures and the transmissibility of asymptomatic infections is critical to SARS-CoV-2 control. Limited previous evidence is based primarily on virologic testing, which disproportionately misses mild and asymptomatic infections. Serologic measures are more likely to capture all previously infected individuals. We apply household transmission models to data from a cross-sectional, household-based population serosurvey of 4,534 people ≥5 years from 2,267 households enrolled April-June 2020 in Geneva, Switzerland. We found that the risk of infection from exposure to a single infected household member aged ≥5 years (17.3%,13.7-21.7) was more than three-times that of extra-household exposures over the first pandemic wave (5.1%,4.5-5.8). Young children had a lower risk of infection from household members. Working-age adults had the highest extra-household infection risk. Seropositive asymptomatic household members had 69.4% lower odds (95%CrI,31.8-88.8%) of infecting another household member compared to those reporting symptoms, accounting for 14.5% (95%CrI, 7.2-22.7%) of all household infections.
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http://dx.doi.org/10.1038/s41467-021-23733-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206123PMC
June 2021

Effect of specific non-pharmaceutical intervention policies on SARS-CoV-2 transmission in the counties of the United States.

Nat Commun 2021 06 11;12(1):3560. Epub 2021 Jun 11.

Department of Biology, University of Florida, Gainesville, FL, USA.

Non-pharmaceutical interventions (NPIs) remain the only widely available tool for controlling the ongoing SARS-CoV-2 pandemic. We estimated weekly values of the effective basic reproductive number (R) using a mechanistic metapopulation model and associated these with county-level characteristics and NPIs in the United States (US). Interventions that included school and leisure activities closure and nursing home visiting bans were all associated with a median R below 1 when combined with either stay at home orders (median R 0.97, 95% confidence interval (CI) 0.58-1.39) or face masks (median R 0.97, 95% CI 0.58-1.39). While direct causal effects of interventions remain unclear, our results suggest that relaxation of some NPIs will need to be counterbalanced by continuation and/or implementation of others.
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http://dx.doi.org/10.1038/s41467-021-23865-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195990PMC
June 2021

Novel coronavirus 2019-nCoV (COVID-19): early estimation of epidemiological parameters and epidemic size estimates.

Philos Trans R Soc Lond B Biol Sci 2021 07 31;376(1829):20200265. Epub 2021 May 31.

Centre for Health Informatics, Computing and Statistics, Lancaster Medical School, Lancaster University, Lancaster LA1 4AT, UK.

Since it was first identified, the epidemic scale of the recently emerged novel coronavirus (2019-nCoV) in Wuhan, China, has increased rapidly, with cases arising across China and other countries and regions. Using a transmission model, we estimate a basic reproductive number of 3.11 (95% CI, 2.39-4.13), indicating that 58-76% of transmissions must be prevented to stop increasing. We also estimate a case ascertainment rate in Wuhan of 5.0% (95% CI, 3.6-7.4). The true size of the epidemic may be significantly greater than the published case counts suggest, with our model estimating 21 022 (prediction interval, 11 090-33 490) total infections in Wuhan between 1 and 22 January. We discuss our findings in the light of more recent information. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.
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http://dx.doi.org/10.1098/rstb.2020.0265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165596PMC
July 2021

Lying in wait: the resurgence of dengue virus after the Zika epidemic in Brazil.

Nat Commun 2021 05 11;12(1):2619. Epub 2021 May 11.

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University, New Haven, CT, USA.

After the Zika virus (ZIKV) epidemic in the Americas in 2016, both Zika and dengue incidence declined to record lows in many countries in 2017-2018, but in 2019 dengue resurged in Brazil, causing ~2.1 million cases. In this study we use epidemiological, climatological and genomic data to investigate dengue dynamics in recent years in Brazil. First, we estimate dengue virus force of infection (FOI) and model mosquito-borne transmission suitability since the early 2000s. Our estimates reveal that DENV transmission was low in 2017-2018, despite conditions being suitable for viral spread. Our study also shows a marked decline in dengue susceptibility between 2002 and 2019, which could explain the synchronous decline of dengue in the country, partially as a result of protective immunity from prior ZIKV and/or DENV infections. Furthermore, we performed phylogeographic analyses using 69 newly sequenced genomes of dengue virus serotype 1 and 2 from Brazil, and found that the outbreaks in 2018-2019 were caused by local DENV lineages that persisted for 5-10 years, circulating cryptically before and after the Zika epidemic. We hypothesize that DENV lineages may circulate at low transmission levels for many years, until local conditions are suitable for higher transmission, when they cause major outbreaks.
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http://dx.doi.org/10.1038/s41467-021-22921-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113494PMC
May 2021

Modelling distributions of Aedes aegypti and Aedes albopictus using climate, host density and interspecies competition.

PLoS Negl Trop Dis 2021 03 25;15(3):e0009063. Epub 2021 Mar 25.

Miami-Dade County Mosquito Control, Florida, United States of America.

Florida faces the challenge of repeated introduction and autochthonous transmission of arboviruses transmitted by Aedes aegypti and Aedes albopictus. Empirically-based predictive models of the spatial distribution of these species would aid surveillance and vector control efforts. To predict the occurrence and abundance of these species, we fit a mixed-effects zero-inflated negative binomial regression to a mosquito surveillance dataset with records from more than 200,000 trap days, representative of 53% of the land area and ranging from 2004 to 2018 in Florida. We found an asymmetrical competitive interaction between adult populations of Aedes aegypti and Aedes albopictus for the sampled sites. Wind speed was negatively associated with the occurrence and abundance of both vectors. Our model predictions show high accuracy (72.9% to 94.5%) in validation tests leaving out a random 10% subset of sites and data since 2017, suggesting a potential for predicting the distribution of the two Aedes vectors.
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http://dx.doi.org/10.1371/journal.pntd.0009063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051819PMC
March 2021

Reconstructing unseen transmission events to infer dengue dynamics from viral sequences.

Nat Commun 2021 03 22;12(1):1810. Epub 2021 Mar 22.

Department of Biology, University of Florida, Gainesville, FL, USA.

For most pathogens, transmission is driven by interactions between the behaviours of infectious individuals, the behaviours of the wider population, the local environment, and immunity. Phylogeographic approaches are currently unable to disentangle the relative effects of these competing factors. We develop a spatiotemporally structured phylogenetic framework that addresses these limitations by considering individual transmission events, reconstructed across spatial scales. We apply it to geocoded dengue virus sequences from Thailand (N = 726 over 18 years). We find infected individuals spend 96% of their time in their home community compared to 76% for the susceptible population (mainly children) and 42% for adults. Dynamic pockets of local immunity make transmission more likely in places with high heterotypic immunity and less likely where high homotypic immunity exists. Age-dependent mixing of individuals and vector distributions are not important in determining spread. This approach provides previously unknown insights into one of the most complex disease systems known and will be applicable to other pathogens.
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http://dx.doi.org/10.1038/s41467-021-21888-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985522PMC
March 2021

Influenza and other respiratory viral infections associated with absence from school among schoolchildren in Pittsburgh, Pennsylvania, USA: a cohort study.

BMC Infect Dis 2021 Mar 22;21(1):291. Epub 2021 Mar 22.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Information on the etiology and age-specific burden of respiratory viral infections among school-aged children remains limited. Though school aged children are often recognized as driving the transmission of influenza as well as other respiratory viruses, little detailed information is available on the distribution of respiratory infections among children of different ages within this group. Factors other than age including gender and time spent in school may also be important in determining risk of infection but have been little studied in this age group.

Methods: We conducted a cohort study to determine the etiology of influenza like illness (ILI) among 2519 K-12 students during the 2012-13 influenza season. We obtained nasal swabs from students with ILI-related absences. Generalized linear mixed-effect regressions determined associations of outcomes, including ILI and laboratory-confirmed respiratory virus infection, with school grade and other covariates.

Results: Overall, 459 swabs were obtained from 552 ILI-related absences. Respiratory viruses were found in 292 (63.6%) samples. Influenza was found in 189 (41.2%) samples. With influenza B found in 134 (70.9%). Rates of influenza B were significantly higher in grades 1 (10.1, 95% CI 6.8-14.4%), 2 (9.7, 6.6-13.6%), 3 (9.3, 6.3-13.2%), and 4 (9.9, 6.8-13.8%) than in kindergarteners (3.2, 1.5-6.0%). After accounting for grade, sex and self-reported vaccination status, influenza B infection risk was lower among kindergarteners in half-day programs compared to kindergarteners in full-day programs (OR = 0.19; 95% CI 0.08-0.45).

Conclusions: ILI and influenza infection is concentrated in younger schoolchildren. Reduced infection by respiratory viruses is associated with a truncated school day for kindergarteners but this finding requires further investigation in other grades and populations.
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http://dx.doi.org/10.1186/s12879-021-05922-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983083PMC
March 2021

Development and dissemination of infectious disease dynamic transmission models during the COVID-19 pandemic: what can we learn from other pathogens and how can we move forward?

Lancet Digit Health 2021 01 7;3(1):e41-e50. Epub 2020 Dec 7.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

The current COVID-19 pandemic has resulted in the unprecedented development and integration of infectious disease dynamic transmission models into policy making and public health practice. Models offer a systematic way to investigate transmission dynamics and produce short-term and long-term predictions that explicitly integrate assumptions about biological, behavioural, and epidemiological processes that affect disease transmission, burden, and surveillance. Models have been valuable tools during the COVID-19 pandemic and other infectious disease outbreaks, able to generate possible trajectories of disease burden, evaluate the effectiveness of intervention strategies, and estimate key transmission variables. Particularly given the rapid pace of model development, evaluation, and integration with decision making in emergency situations, it is necessary to understand the benefits and pitfalls of transmission models. We review and highlight key aspects of the history of infectious disease dynamic models, the role of rigorous testing and evaluation, the integration with data, and the successful application of models to guide public health. Rather than being an expansive history of infectious disease models, this Review focuses on how the integration of modelling can continue to be advanced through policy and practice in appropriate and conscientious ways to support the current pandemic response.
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http://dx.doi.org/10.1016/S2589-7500(20)30268-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836381PMC
January 2021

Take-home kits to detect respiratory viruses among healthcare personnel: Lessons learned from a cluster randomized clinical trial.

Am J Infect Control 2021 Jul 10;49(7):893-899. Epub 2021 Feb 10.

Johns Hopkins University School of Medicine, Baltimore, MD; University of Texas Southwestern Medical Center, Dallas, TX.

Background: Health care personnel (HCP) working in outpatient settings routinely interact with patients with acute respiratory illnesses. Absenteeism following symptom development and lack of staff trained to obtain samples limit efforts to identify pathogens among infected HCP.

Methods: The Respiratory Protection Effectiveness Clinical Trial assessed respiratory infection incidence among HCP between 2011 and 2015. Research assistants obtained anterior nasal and oropharyngeal swabs from HCP in the workplace following development of respiratory illness symptoms and randomly while asymptomatic. Participants received take-home kits to self-collect swabs when absent from work. Samples mailed to a central laboratory were tested for respiratory viruses by reverse transcription polymerase chain reaction.

Results: Among 2,862 participants, 3,467 swabs were obtained from symptomatic participants. Among symptomatic HCP, respiratory virus was detected in 904 of 3,467 (26.1%) samples. Self-collected samples by symptomatic HCP at home had higher rates of viral detection (40.3%) compared to 24% obtained by trained research assistants in the workplace (P < .001).

Conclusions: In this randomized clinical trial, take-home kits were an easily implemented, effective method to self-collect samples by HCP. Other studies have previously shown relative equivalence of self-collected samples to those obtained by trained healthcare workers. Take-home kit self-collection could diminish workforce exposures and decrease the demand for personnel protective equipment worn to protect workers who collect respiratory samples.
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http://dx.doi.org/10.1016/j.ajic.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874979PMC
July 2021

The Usefulness of the Test-Positive Proportion of Severe Acute Respiratory Syndrome Coronavirus 2 as a Surveillance Tool.

Am J Epidemiol 2021 07;190(7):1396-1405

Comparison of coronavirus disease 2019 (COVID-19) case numbers over time and between locations is complicated by limits to virological testing to confirm severe acute respiratory syndrome coronavirus 2 infection. The proportion of tested individuals who have tested positive (test-positive proportion, TPP) can potentially be used to inform trends in incidence. We propose a model for testing in a population experiencing an epidemic of COVID-19 and derive an expression for TPP in terms of well-defined parameters related to testing and presence of other pathogens causing COVID-19-like symptoms. In the absence of dramatic shifts of testing practices in time or between locations, the TPP is positively correlated with the incidence of infection. We show that the proportion of tested individuals who present COVID-19-like symptoms encodes information similar to the TPP but has different relationships with the testing parameters, and can thus provide additional information regarding dynamic changes in TPP and incidence. Finally, we compare data on confirmed cases and TPP from US states up to October 2020. We conjecture why states might have higher or lower TPP than average. Collection of symptom status and age/risk category of tested individuals can increase the utility of TPP in assessing the state of the pandemic in different locations and times.
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http://dx.doi.org/10.1093/aje/kwab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929422PMC
July 2021

Age-specific social mixing of school-aged children in a US setting using proximity detecting sensors and contact surveys.

Sci Rep 2021 Jan 27;11(1):2319. Epub 2021 Jan 27.

Centre for Health Informatics Computing and Statistics, Lancaster Medical School, Lancaster University, Lancaster, LA1 4YW, UK.

Comparisons of the utility and accuracy of methods for measuring social interactions relevant to disease transmission are rare. To increase the evidence base supporting specific methods to measure social interaction, we compared data from self-reported contact surveys and wearable proximity sensors from a cohort of schoolchildren in the Pittsburgh metropolitan area. Although the number and type of contacts recorded by each participant differed between the two methods, we found good correspondence between the two methods in aggregate measures of age-specific interactions. Fewer, but longer, contacts were reported in surveys, relative to the generally short proximal interactions captured by wearable sensors. When adjusted for expectations of proportionate mixing, though, the two methods produced highly similar, assortative age-mixing matrices. These aggregate mixing matrices, when used in simulation, resulted in similar estimates of risk of infection by age. While proximity sensors and survey methods may not be interchangeable for capturing individual contacts, they can generate highly correlated data on age-specific mixing patterns relevant to the dynamics of respiratory virus transmission.
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http://dx.doi.org/10.1038/s41598-021-81673-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840989PMC
January 2021

Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial.

Lancet 2021 01;397(10269):119-127

Epicentre, Paris, France. Electronic address:

Background: Stocks of yellow fever vaccine are insufficient to cover exceptional demands for outbreak response. Fractional dosing has shown efficacy, but evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared with standard dose of four WHO-prequalified yellow fever vaccines produced from three substrains.

Methods: We did this randomised, double-blind, non-inferiority trial at research centres in Mbarara, Uganda, and Kilifi, Kenya. Eligible participants were aged 18-59 years, had no contraindications for vaccination, were not pregnant or lactating, had no history of yellow fever vaccination or infection, and did not require yellow fever vaccination for travel. Eligible participants were recruited from communities and randomly assigned to one of eight groups, corresponding to the four vaccines at standard or fractional dose. The vaccine was administered subcutaneously by nurses who were not masked to treatment, but participants and other study personnel were masked to vaccine allocation. The primary outcome was proportion of participants with seroconversion 28 days after vaccination. Seroconversion was defined as post-vaccination neutralising antibody titres at least 4 times pre-vaccination measurement measured by 50% plaque reduction neutralisation test (PRNT). We defined non-inferiority as less than 10% decrease in seroconversion in fractional compared with standard dose groups 28 days after vaccination. The primary outcome was measured in the per-protocol population, and safety analyses included all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT02991495.

Findings: Between Nov 6, 2017, and Feb 21, 2018, 1029 participants were assessed for inclusion. 69 people were ineligible, and 960 participants were enrolled and randomly assigned to vaccine manufacturer and dose (120 to Bio-Manguinhos-Fiocruz standard dose, 120 to Bio-Manguinhos-Fiocruz fractional dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides standard dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides fractional dose, 120 to Institut Pasteur Dakar standard dose, 120 to Institut Pasteur Dakar fractional dose, 120 to Sanofi Pasteur standard dose, and 120 to Sanofi Pasteur fractional dose). 49 participants had detectable PRNT at baseline and 11 had missing PRNT results at baseline or 28 days. 900 were included in the per-protocol analysis. 959 participants were included in the safety analysis. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1·71% (95% CI -2·60 to 5·28) for Bio-Manguinhos-Fiocruz, -0·90% (-4·24 to 3·13) for Chumakov Institute of Poliomyelitis and Viral Encephalitides, 1·82% (-2·75 to 5·39) for Institut Pasteur Dakar, and 0·0% (-3·32 to 3·29) for Sanofi Pasteur. Fractional doses from all four vaccines met the non-inferiority criterion. The most common treatment-related adverse events were headache (22·2%), fatigue (13·7%), myalgia (13·3%) and self-reported fever (9·0%). There were no study-vaccine related serious adverse events.

Interpretation: Fractional doses of all WHO-prequalified yellow fever vaccines were non-inferior to the standard dose in inducing seroconversion 28 days after vaccination, with no major safety concerns. These results support the use of fractional dosage in the general adult population for outbreak response in situations of vaccine shortage.

Funding: The study was funded by Médecins Sans Frontières Foundation, Wellcome Trust (grant no. 092654), and the UK Department for International Development. Vaccines were donated in kind.
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http://dx.doi.org/10.1016/S0140-6736(20)32520-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794660PMC
January 2021

SARS-CoV-2 Testing in Florida, Illinois, and Maryland: Access and Barriers.

medRxiv 2020 Dec 24. Epub 2020 Dec 24.

Objective: To characterize the SARS-CoV-2 testing cascade and associated barriers in three US states.

Methods: We recruited participants from Florida, Illinois, and Maryland (∼1000/state) for an online survey September 16 - October 15, 2020. The survey covered demographics, COVID-19 symptoms, and experiences around SARS-CoV-2 PCR testing in the prior 2 weeks. Logistic regression was used to analyze associations with outcomes of interest.

Results: Overall, 316 (10%) of 3,058 respondents wanted/needed a test in the two weeks prior to the survey. Of these, 166 (53%) were able to get tested and 156 (94%) received results; 53% waited ≥ 8 days to get results from when they wanted/needed a test. There were no significant differences by state. Among those wanting/needing a test, getting tested was significantly less common among men (aOR: 0.46) and those reporting black race (aOR: 0.53) and more common in those reporting recent travel (aOR: 3.35).

Conclusions: There is an urgent need for a national communication strategy on who should get tested and where one can get tested. Additionally, measures need to be taken to improve access and reduce turn-around-time.
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http://dx.doi.org/10.1101/2020.12.23.20248789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781341PMC
December 2020

A mixture model to assess the the immunogenicity of an oral rotavirus vaccine among healthy infants in Niger.

Vaccine 2020 12 6;38(51):8161-8166. Epub 2020 Nov 6.

Department of Research, Epicentre, Paris, France; Departments of Nutrition and Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, United States.

Analysis of immunogenicity data is a critical component of vaccine development, providing a biological basis to support any observed protection from vaccination. Conventional methods for analyzing immunogenicity data use either post-vaccination titer or change in titer, often defined as a binary variable using a threshold. These methods are simple to implement but can be limited especially in populations experiencing natural exposure to the pathogen. A mixture model can overcome the limitations of the conventional approaches by jointly modeling the probability of an immune response and the level of the immune marker among those who respond. We apply a mixture model to analyze the immunogenicity of an oral, pentavalent rotavirus vaccine in a cohort of children enrolled into a placebo-controlled vaccine efficacy trial in Niger. Among children with undetectable immunoglobulin A (IgA) at baseline, vaccinated children had 5.2-fold (95% credible interval (CrI) 3.7, 8.3) higher odds of having an IgA response than placebo children, but the mean log IgA among vaccinated responders was 0.9-log lower (95% CrI 0.6, 1.3) than among placebo responders. This result implies that the IgA response generated by vaccination is weaker than that generated by natural infection. Multivariate logistic regression of seroconversion defined by ≥ 3-fold rise in IgA similarly found increased seroconversion among vaccinated children, but could not demonstrate lower IgA among those who seroresponded. In addition, we found that the vaccine was less immunogenic among children with detectable IgA pre-vaccination, and that pre-vaccination infant serum IgG and mother's breast milk IgA modified the vaccine immunogenicity. Increased maternal antibodies were associated with weaker IgA response in placebo and vaccinated children, with the association being stronger among vaccinated children. The mixture model is a powerful and flexible method for analyzing immunogenicity data and identifying modifiers of vaccine response and independent predictors of immune response.
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http://dx.doi.org/10.1016/j.vaccine.2020.10.079DOI Listing
December 2020

Age-specific mortality and immunity patterns of SARS-CoV-2.

Nature 2021 02 2;590(7844):140-145. Epub 2020 Nov 2.

Department of Genetics, University of Cambridge, Cambridge, UK.

Estimating the size of the coronavirus disease 2019 (COVID-19) pandemic and the infection severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is made challenging by inconsistencies in the available data. The number of deaths associated with COVID-19 is often used as a key indicator for the size of the epidemic, but the observed number of deaths represents only a minority of all infections. In addition, the heterogeneous burdens in nursing homes and the variable reporting of deaths of older individuals can hinder direct comparisons of mortality rates and the underlying levels of transmission across countries. Here we use age-specific COVID-19-associated death data from 45 countries and the results of 22 seroprevalence studies to investigate the consistency of infection and fatality patterns across multiple countries. We find that the age distribution of deaths in younger age groups (less than 65 years of age) is very consistent across different settings and demonstrate how these data can provide robust estimates of the share of the population that has been infected. We estimate that the infection fatality ratio is lowest among 5-9-year-old children, with a log-linear increase by age among individuals older than 30 years. Population age structures and heterogeneous burdens in nursing homes explain some but not all of the heterogeneity between countries in infection fatality ratios. Among the 45 countries included in our analysis, we estimate that approximately 5% of these populations had been infected by 1 September 2020, and that much higher transmission rates have probably occurred in a number of Latin American countries. This simple modelling framework can help countries to assess the progression of the pandemic and can be applied in any scenario for which reliable age-specific death data are available.
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http://dx.doi.org/10.1038/s41586-020-2918-0DOI Listing
February 2021

Differentiation of Multiple Fluorescent Powders, Powder Transfer, and Effect on Mating in (Diptera: Culicidae).

Insects 2020 Oct 24;11(11). Epub 2020 Oct 24.

Florida Medical Entomology Laboratory, Department of Entomology and Nematology, IFAS, University of Florida, Vero Beach, FL 32962, USA.

Five different fluorescent powders (orange, yellow, green, blue, and violet) were tested on adults to evaluate the differentiation of multiple fluorescent powder colors applied externally in the same female mosquito, their effect on coupling time, copulation time, insemination success, mate choice, and the extent of transference of powders between marked and unmarked individuals, either during copulation or same-sex interactions. Marking with multiple powders was evaluated after applying different powders in the same female at different times and combinations. The comparative effect of powders on mating was explored using different cross-combinations of marked/unmarked couples. Transference of powders between marked/unmarked individuals after copulation was checked in mated individuals, and between same-sex interactions by allowing them to interact under crowded and uncrowded conditions. Identification of the colors included in multiple markings in the same individual was possible when exploring almost all combinations (exception: green-yellow). No important effect of powder marking between cross-combinations was found on coupling time (overall 95% CI (Confidence Interval) 37.6-49.6 min), copulation time (overall 95% CI 17-20 s), insemination success, nor their mate choice. Transferred powder after copulation activity, concentrated in genitalia, legs, and the tip of wings, occurred in >80% of females and 100% of males. Powder transference in legs and genitalia, between same-sex individuals, occurred only in males (ranged between 23-35%) under both density conditions. The lack of important effects of these powders on the studied aspects of provides information about their usefulness and limitations, which should be recognized for future applications and to avoid bias.
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http://dx.doi.org/10.3390/insects11110727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690904PMC
October 2020

Using serological measures to estimate influenza incidence in the presence of secular trends in exposure and immuno-modulation of antibody response.

Influenza Other Respir Viruses 2021 Mar 27;15(2):235-244. Epub 2020 Oct 27.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Influenza infection is often measured by a fourfold antibody titer increase over an influenza season (ie seroconversion). However, this approach may fail when influenza seasons are less distinct as it does not account for transient effects from recent infections. Here, we present a method to determine seroconversion for non-paired sera, adjusting for changes in individuals' antibody titers to influenza due to the transient impact of recent exposures, varied sampling times, and laboratory processes.

Methods: We applied our method using data for five H3N2 strains collected from 942 individuals, aged 2-90 years, during the first two study visits of the Fluscape cohort study (2009-2012) in Guangzhou, China.

Results: After adjustment, apparent seroconversion rates for non-circulating strains decreased while we observed a 20% increase in seroconversion rates to recently circulating strains. When examining seroconversion to the most recently circulating strain (A/Brisbane/20/2007) in our study, participants aged under 18, and over 64 had the highest seroconversion rates compared to other age groups.

Conclusions: Our results highlight the need for improved methods when using antibody titers as an endpoint in settings where there is no clear influenza "off" season. Methods, like those presented here, that use titers from circulating and non-circulating strains may be key.
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http://dx.doi.org/10.1111/irv.12807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902255PMC
March 2021

Ensemble forecast modeling for the design of COVID-19 vaccine efficacy trials.

Vaccine 2020 10 15;38(46):7213-7216. Epub 2020 Sep 15.

Department of Biostatistics, University of Florida, Gainesville, FL, United States.

To rapidly evaluate the safety and efficacy of COVID-19 vaccine candidates, prioritizing vaccine trial sites in areas with high expected disease incidence can speed endpoint accrual and shorten trial duration. Mathematical and statistical forecast models can inform the process of site selection, integrating available data sources and facilitating comparisons across locations. We recommend the use of ensemble forecast modeling - combining projections from independent modeling groups - to guide investigators identifying suitable sites for COVID-19 vaccine efficacy trials. We describe an appropriate structure for this process, including minimum requirements, suggested output, and a user-friendly tool for displaying results. Importantly, we advise that this process be repeated regularly throughout the trial, to inform decisions about enrolling new participants at existing sites with waning incidence versus adding entirely new sites. These types of data-driven models can support the implementation of flexible efficacy trials tailored to the outbreak setting.
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http://dx.doi.org/10.1016/j.vaccine.2020.09.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492005PMC
October 2020

The use of mobile phone data to inform analysis of COVID-19 pandemic epidemiology.

Nat Commun 2020 09 30;11(1):4961. Epub 2020 Sep 30.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has heightened discussion of the use of mobile phone data in outbreak response. Mobile phone data have been proposed to monitor effectiveness of non-pharmaceutical interventions, to assess potential drivers of spatiotemporal spread, and to support contact tracing efforts. While these data may be an important part of COVID-19 response, their use must be considered alongside a careful understanding of the behaviors and populations they capture. Here, we review the different applications for mobile phone data in guiding and evaluating COVID-19 response, the relevance of these applications for infectious disease transmission and control, and potential sources and implications of selection bias in mobile phone data. We also discuss best practices and potential pitfalls for directly integrating the collection, analysis, and interpretation of these data into public health decision making.
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http://dx.doi.org/10.1038/s41467-020-18190-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528106PMC
September 2020

A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity.

Nat Commun 2020 09 17;11(1):4704. Epub 2020 Sep 17.

Department of Biology, University of Florida, Gainesville, FL, USA.

Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV, MERS-CoV and endemic human coronaviruses (HCoVs). We reviewed 2,452 abstracts and identified 491 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While further studies of SARS-CoV-2 are necessary to determine immune responses, evidence from other coronaviruses can provide clues and guide future research.
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http://dx.doi.org/10.1038/s41467-020-18450-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499300PMC
September 2020

The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature.

Am J Hum Genet 2020 09 12;107(3):381-402. Epub 2020 Aug 12.

Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, systematically focusing on human studies. We identified 1,832 articles of potential relevance. Seventy-five involved human host genetic factors, 36 of which involved analysis of specific genes or loci; aside from one meta-analysis, all were candidate-driven studies, typically investigating small numbers of research subjects and loci. Three additional case reports were described. Multiple significant loci were identified, including 16 related to susceptibility (seven of which identified protective alleles) and 16 related to outcomes (three of which identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Among other studies, 30 involved both human and non-human host genetic factors related to coronavirus, 178 involved study of non-human (animal) host genetic factors related to coronavirus, and 984 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis. Previous human studies have been limited by issues that may be less impactful now, including low numbers of eligible participants and limited availability of advanced genomic methods; however, these may raise additional considerations. We outline key genes and loci from animal and human host genetic studies that may bear investigation in the study of COVID-19. We also discuss how previous studies may direct current lines of inquiry.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7420067PMC
September 2020

Life course exposures continually shape antibody profiles and risk of seroconversion to influenza.

PLoS Pathog 2020 07 23;16(7):e1008635. Epub 2020 Jul 23.

Department of Biology, University of Florida, Gainesville, Florida, United States of America.

Complex exposure histories and immune mediated interactions between influenza strains contribute to the life course of human immunity to influenza. Antibody profiles can be generated by characterizing immune responses to multiple antigenically variant strains, but how these profiles vary across individuals and determine future responses is unclear. We used hemagglutination inhibition titers from 21 H3N2 strains to construct 777 paired antibody profiles from people aged 2 to 86, and developed novel metrics to capture features of these profiles. Total antibody titer per potential influenza exposure increases in early life, then decreases in middle age. Increased titers to one or more strains were seen in 97.8% of participants during a roughly four-year interval, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest titer rise. Higher pre-existing, homologous titers at baseline reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion against recent strains among those with higher immunity to older previously exposed strains. Including immunity to previously exposures also improved the deviance explained by the models. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza infection.
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http://dx.doi.org/10.1371/journal.ppat.1008635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377380PMC
July 2020

Age-specific social mixing of school-aged children in a US setting using proximity detecting sensors and contact surveys.

medRxiv 2020 Jul 14. Epub 2020 Jul 14.

Comparisons of the utility and accuracy of methods for measuring social interactions relevant to disease transmission are rare. To increase the evidence base supporting specific methods to measure social interaction, we compared data from self-reported contact surveys and wearable proximity sensors from a cohort of schoolchildren in the Pittsburgh metropolitan area. Although the number and type of contacts recorded by each participant differed between the two methods, we found good correspondence between the two methods in aggregate measures of age-specific interactions. Fewer, but longer, contacts were reported in surveys, relative to the generally short proximal interactions captured by wearable sensors. When adjusted for expectations of proportionate mixing, though, the two methods produced highly similar, assortative age-mixing matrices. These aggregate mixing matrices, when used in simulation, resulted in similar estimates of risk of infection by age. While proximity sensors and survey methods may not be interchangeable for capturing individual contacts, they can generate highly correlated data on age-specific mixing patterns relevant to the dynamics of respiratory virus transmission.
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http://dx.doi.org/10.1101/2020.07.12.20151696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373148PMC
July 2020

Risk Factors for Healthcare Personnel Infection with Endemic Coronaviruses (HKU1, OC43, NL63, 229E): Results from the Respiratory Protection Effectiveness Clinical Trial (ResPECT).

Clin Infect Dis 2020 Jul 9. Epub 2020 Jul 9.

Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: SARS-CoV-2 presents a large risk to healthcare personnel. Quantifying the risk of coronavirus infection associated with workplace activities is an urgent need.

Methods: We assessed the association of worker characteristics, occupational roles and behaviors, and participation in procedures with the risk of endemic coronavirus infection among healthcare personnel who participated in the Respiratory Protection Effectiveness Trial (ResPECT), a cluster randomized trial to assess personal protective equipment to prevent respiratory infections and illness conducted from 2011 to 2016.

Results: Among 4,689 HCP-seasons, we detected coronavirus infection in 387 (8%). HCP who participated in an aerosol generation procedure (AGP) at least once during the viral respiratory season were 105% (95% CI 21%, 240%) more likely to be diagnosed with a laboratory-confirmed coronavirus infection. Younger individuals, those who saw pediatric patients and those with household members under the age of five were at increased risk of coronavirus infection.

Conclusions: Our analysis suggests the risk of HCP becoming infected with an endemic coronavirus increases approximately two-fold with exposures to AGP. Our findings may be relevant to the Coronavirus Disease 2019 (COVID-19) pandemic; however, SARS-COV-2, the virus that causes COVID-19, may differ from endemic coronaviruses in important ways.
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http://dx.doi.org/10.1093/cid/ciaa900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454439PMC
July 2020

The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature.

medRxiv 2020 Jun 3. Epub 2020 Jun 3.

Background: The recent SARS-CoV-2 pandemic raises many scientific and clinical questions. One set of questions involves host genetic factors that may affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species.

Objectives: We aimed to review the literature on host genetic factors related to coronaviruses, with a systematic focus on human studies.

Methods: We conducted a PubMed-based search and analysis for articles relevant to host genetic factors in coronavirus. We categorized articles, summarized themes related to animal studies, and extracted data from human studies for analyses.

Results: We identified 1,187 articles of potential relevance. Forty-five studies were related to human host genetic factors related to coronavirus, of which 35 involved analysis of specific genes or loci; aside from one meta-analysis on respiratory infections, all were candidate-driven studies, typically investigating small number of research subjects and loci. Multiple significant loci were identified, including 16 related to susceptibility to coronavirus (of which 7 identified protective alleles), and 16 related to outcomes or clinical variables (of which 3 identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Of the other studies, 28 involved both human and non-human host genetic factors related to coronavirus, 174 involved study of non-human (animal) host genetic factors related to coronavirus, 584 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis, 16 involved study of other pathogens (not coronavirus), 321 involved other studies of coronavirus, and 18 studies were assigned to the other categories and removed.

Key Findings: We have outlined key genes and loci from animal and human host genetic studies that may bear investigation in the nascent host genetic factor studies of COVID-19. Previous human studies to date have been limited by issues that may be less impactful on current endeavors, including relatively low numbers of eligible participants and limited availability of advanced genomic methods.
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http://dx.doi.org/10.1101/2020.05.30.20117788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276057PMC
June 2020

A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease.

medRxiv 2020 Apr 17. Epub 2020 Apr 17.

Department of Biology, University of Florida, USA.

The duration and nature of immunity generated in response to SARS-CoV-2 infection is unknown. Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARSCoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The timescale of protection is a critical determinant of the future impact of the pathogen. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. The dynamics of immunity and nature of protection are relevant to discussions surrounding therapeutic use of convalescent sera as well as efforts to identify individuals with protective immunity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV-1, MERS-CoV and human endemic coronaviruses (HCoVs). We reviewed 1281 abstracts and identified 322 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While studies of SARS-CoV-2 are necessary to determine immune responses to it, evidence from other coronaviruses can provide clues and guide future research.
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http://dx.doi.org/10.1101/2020.04.14.20065771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217088PMC
April 2020

An open source tool to infer epidemiological and immunological dynamics from serological data: serosolver.

PLoS Comput Biol 2020 05 4;16(5):e1007840. Epub 2020 May 4.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, United Kingdom.

We present a flexible, open source R package designed to obtain biological and epidemiological insights from serological datasets. Characterising past exposures for multi-strain pathogens poses a specific statistical challenge: observed antibody responses measured in serological assays depend on multiple unobserved prior infections that produce cross-reactive antibody responses. We provide a general modelling framework to jointly infer infection histories and describe immune responses generated by these infections using antibody titres against current and historical strains. We do this by linking latent infection dynamics with a mechanistic model of antibody kinetics that generates expected antibody titres over time. Our aim is to provide a flexible package to identify infection histories that can be applied to a range of pathogens. We present two case studies to illustrate how our model can infer key immunological parameters, such as antibody titre boosting, waning and cross-reaction, as well as latent epidemiological processes such as attack rates and age-stratified infection risk.
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http://dx.doi.org/10.1371/journal.pcbi.1007840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241836PMC
May 2020
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