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Article ; Online: Characterising antibody kinetics from multiple influenza infection and vaccination events in ferrets.

James A Hay / Karen Laurie / Michael White / Steven Riley

PLoS Computational Biology, Vol 15, Iss 8, p e

2019 Volume 1007294

Abstract: The strength and breadth of an individual's antibody repertoire is an important predictor of their response to influenza infection or vaccination. Although progress has been made in understanding qualitatively how repeated exposures shape the antibody ... ...

Abstract	The strength and breadth of an individual's antibody repertoire is an important predictor of their response to influenza infection or vaccination. Although progress has been made in understanding qualitatively how repeated exposures shape the antibody mediated immune response, quantitative understanding remains limited. We developed a set of mathematical models describing short-term antibody kinetics following influenza infection or vaccination and fit them to haemagglutination inhibition (HI) titres from 5 groups of ferrets which were exposed to different combinations of trivalent inactivated influenza vaccine (TIV with or without adjuvant), A/H3N2 priming inoculation and post-vaccination A/H1N1 inoculation. We fit models with various immunological mechanisms that have been empirically observed but have not previously been included in mathematical models of antibody landscapes, including: titre ceiling effects, antigenic seniority and exposure-type specific cross reactivity. Based on the parameter estimates of the best supported models, we describe a number of key immunological features. We found quantifiable differences in the degree of homologous and cross-reactive antibody boosting elicited by different exposure types. Infection and adjuvanted vaccination generally resulted in strong, broadly reactive responses whereas unadjuvanted vaccination resulted in a weak, narrow response. We found that the order of exposure mattered: priming with A/H3N2 improved subsequent vaccine response, and the second dose of adjuvanted vaccination resulted in substantially greater antibody boosting than the first. Either antigenic seniority or a titre ceiling effect were included in the two best fitting models, suggesting a role for a mechanism describing diminishing antibody boosting with repeated exposures. Although there was considerable uncertainty in our estimates of antibody waning parameters, our results suggest that both short and long term waning were present and would be identifiable with a larger set of experiments. ...
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-08-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Efficient prevalence estimation and infected sample identification with group testing for SARS-CoV-2

Brian Cleary / James A Hay / Brendan Blumenstiel / Stacey Gabriel / Aviv Regev / Michael J Mina

Abstract: The ongoing pandemic of SARS-CoV-2, a novel coronavirus, caused over 3 million reported cases of coronavirus disease 2019 (COVID-19) and 200,000 reported deaths between December 2019 and April 2020. Cases and deaths will increase as the virus continues ... ...

Abstract	The ongoing pandemic of SARS-CoV-2, a novel coronavirus, caused over 3 million reported cases of coronavirus disease 2019 (COVID-19) and 200,000 reported deaths between December 2019 and April 2020. Cases and deaths will increase as the virus continues its global march outward. In the absence of effective pharmaceutical interventions or a vaccine, wide-spread virological screening is required to inform where restrictive isolation measures should be targeted and when they can be lifted. However, limitations on testing capacity have restricted the ability of governments and institutions to identify individual clinical cases, appropriately measure community prevalence, and mitigate transmission. Group testing offers a way to increase efficiency, by combining samples and testing a small number of pools. Here, we evaluate the effectiveness of group testing designs for individual identification or prevalence estimation of SARS-CoV-2 infection when testing capacity is limited. To do this, we developed mathematical models for epidemic spread, incorporating empirically measured individual-level viral kinetics to simulate changing viral loads in a large population over the course of an epidemic. We used these to construct representative populations and assess pooling strategies for community screening, accounting for variability in viral load samples, dilution effects, changing prevalence and resource constraints. We confirmed our group testing framework through pooled tests on de-identified human nasopharyngeal specimens with viral loads representative of the larger population. We show that group testing designs can both accurately estimate overall prevalence using a small number of measurements and substantially increase the identification rate of infected individuals in resource-limited settings.
Keywords	covid19
Publisher	medrxiv
Document type	Article ; Online
DOI	10.1101/2020.05.01.20086801
Database	COVID19

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Article ; Online: Viral kinetics of sequential SARS-CoV-2 infections

Stephen M. Kissler / James A. Hay / Joseph R. Fauver / Christina Mack / Caroline G. Tai / Deverick J. Anderson / David D. Ho / Nathan D. Grubaugh / Yonatan H. Grad

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 7

Abstract: Abstract The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 ... ...

Abstract	Abstract The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11th, 2020, and July 28th, 2022. We compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person’s relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person’s relative ability to clear SARS-CoV-2 infection that persists across sequential infections.
Keywords	Science ; Q
Subject code	570
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Potential inconsistencies in Zika surveillance data and our understanding of risk during pregnancy.

James A Hay / Pierre Nouvellet / Christl A Donnelly / Steven Riley

PLoS Neglected Tropical Diseases, Vol 12, Iss 12, p e

2018 Volume 0006991

Abstract: Background A significant increase in microcephaly incidence was reported in Northeast Brazil at the end of 2015, which has since been attributed to an epidemic of Zika virus (ZIKV) infections earlier that year. Further incidence of congenital Zika ... ...

Abstract	Background A significant increase in microcephaly incidence was reported in Northeast Brazil at the end of 2015, which has since been attributed to an epidemic of Zika virus (ZIKV) infections earlier that year. Further incidence of congenital Zika syndrome (CZS) was expected following waves of ZIKV infection throughout Latin America; however, only modest increases in microcephaly and CZS incidence have since been observed. The quantitative relationship between ZIKV infection, gestational age and congenital outcome remains poorly understood. Methodology/principle findings We characterised the gestational-age-varying risk of microcephaly given ZIKV infection using publicly available incidence data from multiple locations in Brazil and Colombia. We found that the relative timings and shapes of ZIKV infection and microcephaly incidence curves suggested different gestational risk profiles for different locations, varying in both the duration and magnitude of gestational risk. Data from Northeast Brazil suggested a narrow window of risk during the first trimester, whereas data from Colombia suggested persistent risk throughout pregnancy. We then used the model to estimate which combination of behavioural and reporting changes would have been sufficient to explain the absence of a second microcephaly incidence wave in Bahia, Brazil; a population for which we had two years of data. We found that a 18.9-fold increase in ZIKV infection reporting rate was consistent with observed patterns. Conclusions Our study illustrates how surveillance data may be used in principle to answer key questions in the absence of directed epidemiological studies. However, in this case, we suggest that currently available surveillance data are insufficient to accurately estimate the gestational-age-varying risk of microcephaly from ZIKV infection. The methods used here may be of use in future outbreaks and may help to inform improved surveillance and interpretation in countries yet to experience an outbreak of ZIKV infection.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Estimating the number of undetected COVID-19 cases exported internationally from all of China

Tigist Ferede Menkir / Taylor Chin / James A Hay / Erik Surface / Pablo Martinez de Salazar / Caroline Buckee / Michael J Mina / Kamran Khan / Alexander Watts / Marc Lipsitch / Rene Niehus

Abstract: During the early phase of the COVID-19 pandemic, when SARS-CoV-2 was chiefly reported in the city of Wuhan, cases exported to other locations were largely predicted using flight travel data from Wuhan. However, given Wuhan's connectivity to other cities ... ...

Abstract	During the early phase of the COVID-19 pandemic, when SARS-CoV-2 was chiefly reported in the city of Wuhan, cases exported to other locations were largely predicted using flight travel data from Wuhan. However, given Wuhan's connectivity to other cities in mainland China prior to the lockdown, there has likely been a substantial risk of exportation of cases from other Chinese cities. It is likely that many of these exportations remained undetected because early international case definitions for COVID-19 required a recent travel history from Wuhan. Here, we combine estimates of prevalence in 18 Chinese cities with estimates of flight volume, accounting for the effects of travel bans and the timing of Lunar New Year, to approximate the number of cases exported from cities outside of Wuhan from early December 2019 to late February 2020. We predict that for every one case from Wuhan exported internationally, there were approximately 2.9 cases from large Chinese cities exported internationally that likely remained undetected. Additionally, we predict the number of exported cases in six destinations for which predictions on exported cases have yet to be made, surveillance has likely been low, and where health care systems will likely face issues in managing current or potential outbreaks. We observe heterogeneities in exported case counts across these destinations. The predicted number of cases exported to Egypt and South Africa exceeds the predicted number of cases exported to Mauritania. These trends may anticipate differences in the timing and emergence of local transmission in these countries. Our findings highlight the importance of setting accurate travel history requirements for case definition guidelines in the initial phase of an epidemic, and actively updating these guidelines as the epidemic advances.
Keywords	covid19
Publisher	medrxiv
Document type	Article ; Online
DOI	10.1101/2020.03.23.20038331
Database	COVID19

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Article ; Online: Life course exposures continually shape antibody profile and risk of seroconversion to influenza

Bingyi Yang / Justin Lessler / Huachen Zhu / Chaoqiang Jiang / Jonathan M. Read / James A Hay / Kin On Kwok / Ruiyin Shen / Yi Guan / Steven Riley / Derek A.T. Cummings

Abstract: 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 ... ...

Abstract	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, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest variation. Higher pre-existing, homologous titers reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion among those with higher immunity to older previously exposed strains. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza.
Keywords	covid19
Publisher	medrxiv
Document type	Article ; Online
DOI	10.1101/2020.01.15.19015693
Database	COVID19

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Article ; Online: An open source tool to infer epidemiological and immunological dynamics from serological data

James A Hay / Amanda Minter / Kylie E C Ainslie / Justin Lessler / Bingyi Yang / Derek A T Cummings / Adam J Kucharski / Steven Riley

PLoS Computational Biology, Vol 16, Iss 5, p e

serosolver.

2020 Volume 1007840

Abstract: 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 ... ...

Abstract	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.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Life course exposures continually shape antibody profiles and risk of seroconversion to influenza.

Bingyi Yang / Justin Lessler / Huachen Zhu / Chao Qiang Jiang / Jonathan M Read / James A Hay / Kin On Kwok / Ruiyin Shen / Yi Guan / Steven Riley / Derek A T Cummings

PLoS Pathogens, Vol 16, Iss 7, p e

2020 Volume 1008635

Abstract	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.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Estimating internationally imported cases during the early COVID-19 pandemic

Tigist F. Menkir / Taylor Chin / James A. Hay / Erik D. Surface / Pablo M. De Salazar / Caroline O. Buckee / Alexander Watts / Kamran Khan / Ryan Sherbo / Ada W. C. Yan / Michael J. Mina / Marc Lipsitch / Rene Niehus

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 10

Abstract: Sparse testing early in the SARS-CoV-2 pandemic hinders estimation of the dates and origins of initial case importations. Here, the authors show that the main source of cases imported from China shifted from Wuhan to other Chinese cities by mid-February, ...

Abstract	Sparse testing early in the SARS-CoV-2 pandemic hinders estimation of the dates and origins of initial case importations. Here, the authors show that the main source of cases imported from China shifted from Wuhan to other Chinese cities by mid-February, especially for African locations.
Keywords	Science ; Q
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Near real-time surveillance of the SARS-CoV-2 epidemic with incomplete data.

Pablo M De Salazar / Fred Lu / James A Hay / Diana Gómez-Barroso / Pablo Fernández-Navarro / Elena V Martínez / Jenaro Astray-Mochales / Rocío Amillategui / Ana García-Fulgueiras / Maria D Chirlaque / Alonso Sánchez-Migallón / Amparo Larrauri / María J Sierra / Marc Lipsitch / Fernando Simón / Mauricio Santillana / Miguel A Hernán

PLoS Computational Biology, Vol 18, Iss 3, p e

2022 Volume 1009964

Abstract: When responding to infectious disease outbreaks, rapid and accurate estimation of the epidemic trajectory is critical. However, two common data collection problems affect the reliability of the epidemiological data in real time: missing information on ... ...

Abstract	When responding to infectious disease outbreaks, rapid and accurate estimation of the epidemic trajectory is critical. However, two common data collection problems affect the reliability of the epidemiological data in real time: missing information on the time of first symptoms, and retrospective revision of historical information, including right censoring. Here, we propose an approach to construct epidemic curves in near real time that addresses these two challenges by 1) imputation of dates of symptom onset for reported cases using a dynamically-estimated "backward" reporting delay conditional distribution, and 2) adjustment for right censoring using the NobBS software package to nowcast cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number (Rt) in real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We evaluate how these real-time estimates compare with more complete epidemiological data that became available later. We explore the impact of the different assumptions on the estimates, and compare our estimates with those obtained from commonly used surveillance approaches. Our framework can help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health systems in other locations.
Keywords	Biology (General) ; QH301-705.5
Subject code	310
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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