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1. Immunogenicity of Abdala COVID-19 vaccine in Vietnamese people after primary and booster vaccinations: A prospective observational study in Vietnam

Author

Tran Tan Thanh, Nguyen Thi Kha Tu, Lam Anh Nguyet, Cao Thu Thuy, Nguyen Lam Thai Thuan, Nguyen Thi Han Ny, Le Nguyen Truc Nhu, Le Kim Thanh, Nguyen Thi Thu Hong, Nguyen To Anh, Nguyen Thanh Truong, Nguyen Van Vinh Chau, Lam Minh Yen, Phan Van E, Nguyen Phong Thuong, Nguyen Van Truc, Pham Huu Trung, Wee Chee Yap, Rahul Pandey, Sidney Yee, Ruifen Weng, Juthathip Mongkolsapaya, Wanwisa Dejnirattisai, Raph L Hamers, Narisara Chantratita, Gavin Screaton, Susanna J Dunachie, E Yvonne Jones, David I Stuart, Nguyen Thanh Dung, Guy Thwaites, Lin-Fa Wang, Chee Wah Tan, and Le Van Tan

Subjects
Abdala COVID-19 vaccine, Immunogenicity, Anti-spike antibody, Neutralizing antibody, Cross-neutralization, Infectious and parasitic diseases, RC109-216
Abstract

Objectives: We studied the immunogenicity after primary and booster vaccinations of the Abdala COVID-19 vaccine, a receptor-binding domain protein subunit vaccine, in Vietnamese people by determining the level of neutralization and cross-neutralization activities against the ancestral SARS-CoV-2 and its variants and SARS-CoV-1. Methods: We performed a prospective observational study, enrolling adults aged 19-59 years in Dong Thap province, southern Vietnam, and collected blood samples from baseline until 4 weeks after the booster dose. We measured anti-nucleocapsid, anti-spike, and neutralizing antibodies against SARS-CoV-2 and assessed the cross-neutralization against 14 SARS-CoV-2 variants and SARS-CoV-1. Complementary antibody data came from Vietnamese health care workers fully vaccinated with ChAdOx1-S. Results: After primary vaccination, anti-spike antibody and neutralizing antibodies were detectable in 98.4% and 87% of 251 study participants, respectively, with neutralizing antibody titers similar to that induced by ChAdOx1-S vaccine. Antibody responses after a homologous (Abdala COVID-19) or heterologous (messenger RNA BNT162b2) booster could neutralize 14 SARS-CoV-2 variants (including Omicron) and SARS-CoV-1. Conclusions: Abdala COVID-19 vaccine is immunogenic in Vietnamese people. Enhanced antibody response after a booster dose could cross-neutralize 14 SARS-CoV-2 variants and SARS-CoV-1. Our results have added to the growing body of knowledge about the contribution of protein subunit vaccine platforms to pandemic control.

Published
2024
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2. Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium [version 1; peer review: 2 approved, 1 approved with reservations]

Author

Susanna J. Dunachie, Raph L. Hamers, Alba Grifoni, Narisara Chantratita, Juthathip Mongkolsapaya, E. Yvonne Jones, Vu Duy Thanh, David I. Stuart, Alessandro Sette, Lin-Fa Wang, Chee Wah Tan, Paul Klenerman, Le Van Tan, Guy Thwaites, Phaik Yeong Cheah, Jennifer Hill, Gavin Screaton, Mary Chambers, Le Nguyen Truc Nhu, Wanwisa Dejnirattisai, and Nicholas P.J. Day

Subjects
SARS-CoV-2 variants, pandemic responses, eng, Medicine, Science
Abstract

A strong and effective COVID-19 and future pandemic responses rely on global efforts to carry out surveillance of infections and emerging SARS-CoV-2 variants and to act accordingly in real time. Many countries in Southeast Asia lack capacity to determine the potential threat of new variants, or other emerging infections. Funded by Wellcome, the Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium aims to develop and apply a multidisciplinary research platform in Southeast Asia (SEA) for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby informing coordinated local, regional and global responses to the COVID-19 pandemic. Our proposal is delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in Indonesia, Thailand and Vietnam with partners in Singapore, the UK and the USA. Herein we outline five work packages to deliver strengthened regional scientific capacity that can be rapidly deployed for future outbreak responses.

Published
2024
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3. Omicron infection following vaccination enhances a broad spectrum of immune responses dependent on infection history

Author

Hailey Hornsby, Alexander R. Nicols, Stephanie Longet, Chang Liu, Adriana Tomic, Adrienn Angyal, Barbara Kronsteiner, Jessica K. Tyerman, Tom Tipton, Peijun Zhang, Marta Gallis, Piyada Supasa, Muneeswaran Selvaraj, Priyanka Abraham, Isabel Neale, Mohammad Ali, Natalie A. Barratt, Jeremy M. Nell, Lotta Gustafsson, Scarlett Strickland, Irina Grouneva, Timothy Rostron, Shona C. Moore, Luisa M. Hering, Susan L. Dobson, Sagida Bibi, Juthathip Mongkolsapaya, Teresa Lambe, Dan Wootton, Victoria Hall, Susan Hopkins, Tao Dong, Eleanor Barnes, Gavin Screaton, The PITCH Consortium, Alex Richter, Lance Turtle, Sarah L. Rowland-Jones, Miles Carroll, Christopher J. A. Duncan, Paul Klenerman, Susanna J. Dunachie, Rebecca P. Payne, and Thushan I. de Silva

Subjects
Science
Abstract

Abstract Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in many individuals possessing hybrid immunity, generated through a combination of vaccination and infection. Concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that prior SARS-CoV-2 infection is associated with immune dampening. Taking a broad and comprehensive approach, we characterize mucosal and blood immunity to spike and non-spike antigens following BA.1/BA.2 infections in triple mRNA-vaccinated individuals, with and without prior SARS-CoV-2 infection. We find that most individuals increase BA.1/BA.2/BA.5-specific neutralizing antibodies following infection, but confirm that the magnitude of increase and post-omicron titres are higher in the infection-naive. In contrast, significant increases in nasal responses, including neutralizing activity against BA.5 spike, are seen regardless of infection history. Spike-specific T cells increase only in infection-naive vaccinees; however, post-omicron T cell responses are significantly higher in the previously-infected, who display a maximally induced response with a highly cytotoxic CD8+ phenotype following their 3rd mRNA vaccine dose. Responses to non-spike antigens increase significantly regardless of prior infection status. These findings suggest that hybrid immunity induced by omicron breakthrough infections is characterized by significant immune enhancement that can help protect against future omicron variants.

Published
2023
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4. Blockade-of-Binding Activities toward Envelope-Associated, Type-Specific Epitopes as a Correlative Marker for Dengue Virus-Neutralizing Antibody

Author

Poonsook Keelapang, Romchat Kraivong, Rojjanaporn Pulmanausahakul, Rungtawan Sriburi, Eakachai Prompetchara, Jutamart Kaewmaneephong, Nicha Charoensri, Pattarakul Pakchotanon, Thaneeya Duangchinda, Piyanan Suparattanagool, Prasit Luangaram, Promsin Masrinoul, Juthathip Mongkolsapaya, Gavin Screaton, Kiat Ruxrungtham, Prasert Auewarakul, Sutee Yoksan, Prida Malasit, Chunya Puttikhunt, Chutitorn Ketloy, and Nopporn Sittisombut

Subjects
dengue virus, blockade of binding, ELISA, neutralizing antibody, Microbiology, QR1-502
Abstract

ABSTRACT Humans infected with dengue virus (DENV) acquire long-term protection against the infecting serotype, whereas cross-protection against other serotypes is short-lived. Long-term protection induced by low levels of type-specific neutralizing antibodies can be assessed using the virus-neutralizing antibody test. However, this test is laborious and time-consuming. In this study, a blockade-of-binding enzyme-linked immunoassay was developed to assess antibody activity by using a set of neutralizing anti-E monoclonal antibodies and blood samples from dengue virus-infected or -immunized macaques. Diluted blood samples were incubated with plate-bound dengue virus particles before the addition of an enzyme-conjugated antibody specific to the epitope of interest. Based on blocking reference curves constructed using autologous purified antibodies, sample blocking activity was determined as the relative concentration of unconjugated antibody that resulted in the same percent signal reduction. In separate DENV-1-, -2-, -3-, and -4-related sets of samples, moderate to strong correlations of the blocking activity with neutralizing antibody titers were found with the four type-specific antibodies 1F4, 3H5, 8A1, and 5H2, respectively. Significant correlations were observed for single samples taken 1 month after infection as well as samples drawn before and at various time points after infection/immunization. Similar testing using a cross-reactive EDE-1 antibody revealed a moderate correlation between the blocking activity and the neutralizing antibody titer only for the DENV-2-related set. The potential usefulness of the blockade-of-binding activity as a correlative marker of neutralizing antibodies against dengue viruses needs to be validated in humans. IMPORTANCE This study describes a blockade-of-binding assay for the determination of antibodies that recognize a selected set of serotype-specific or group-reactive epitopes in the envelope of dengue virus. By employing blood samples collected from dengue virus-infected or -immunized macaques, moderate to strong correlations of the epitope-blocking activities with the virus-neutralizing antibody titers were observed with serotype-specific blocking activities for each of the four dengue serotypes. This simple, rapid, and less laborious method should be useful for the evaluation of antibody responses to dengue virus infection and may serve as, or be a component of, an in vitro correlate of protection against dengue in the future.

Published
2023
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5. Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

Author

Anna L. McNaughton, Robert S. Paton, Matthew Edmans, Jonathan Youngs, Judith Wellens, Prabhjeet Phalora, Alex Fyfe, Sandra Belij-Rammerstorfer, Jai S. Bolton, Jonathan Ball, George W. Carnell, Wanwisa Dejnirattisai, Christina Dold, David W. Eyre, Philip Hopkins, Alison Howarth, Kreepa Kooblall, Hannah Klim, Susannah Leaver, Lian Ni Lee, César López-Camacho, Sheila F. Lumley, Derek C. Macallan, Alexander J. Mentzer, Nicholas M. Provine, Jeremy Ratcliff, Jose Slon-Compos, Donal Skelly, Lucas Stolle, Piyada Supasa, Nigel Temperton, Chris Walker, Beibei Wang, Duncan Wyncoll, Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium, Scottish National Blood Transfusion Service (SNBTS) consortium, Peter Simmonds, Teresa Lambe, John Kenneth Baillie, Malcolm G. Semple, Peter J.M. Openshaw, International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators, Uri Obolski, Marc Turner, Miles Carroll, Juthathip Mongkolsapaya, Gavin Screaton, Stephen H. Kennedy, Lisa Jarvis, Eleanor Barnes, Susanna Dunachie, José Lourenço, Philippa C. Matthews, Tihana Bicanic, Paul Klenerman, Sunetra Gupta, and Craig P. Thompson

Subjects
Immunology, Infectious disease, Medicine
Abstract

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an “original antigenic sin” type response.

Published
2022
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6. T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses

Author

Ane Ogbe, Barbara Kronsteiner, Donal T. Skelly, Matthew Pace, Anthony Brown, Emily Adland, Kareena Adair, Hossain Delowar Akhter, Mohammad Ali, Serat-E Ali, Adrienn Angyal, M. Azim Ansari, Carolina V. Arancibia-Cárcamo, Helen Brown, Senthil Chinnakannan, Christopher Conlon, Catherine de Lara, Thushan de Silva, Christina Dold, Tao Dong, Timothy Donnison, David Eyre, Amy Flaxman, Helen Fletcher, Joshua Gardner, James T. Grist, Carl-Philipp Hackstein, Kanoot Jaruthamsophon, Katie Jeffery, Teresa Lambe, Lian Lee, Wenqin Li, Nicholas Lim, Philippa C. Matthews, Alexander J. Mentzer, Shona C. Moore, Dean J. Naisbitt, Monday Ogese, Graham Ogg, Peter Openshaw, Munir Pirmohamed, Andrew J. Pollard, Narayan Ramamurthy, Patpong Rongkard, Sarah Rowland-Jones, Oliver Sampson, Gavin Screaton, Alessandro Sette, Lizzie Stafford, Craig Thompson, Paul J. Thomson, Ryan Thwaites, Vinicius Vieira, Daniela Weiskopf, Panagiota Zacharopoulou, Oxford Immunology Network Covid-19 Response T Cell Consortium, Oxford Protective T Cell Immunology for COVID-19 (OPTIC) Clinical Team, Lance Turtle, Paul Klenerman, Philip Goulder, John Frater, Eleanor Barnes, and Susanna Dunachie

Subjects
Science
Abstract

Understanding the immune response to SARS-CoV-2 is dependent on being able to distinguish COVID-19 immune responses from cross-reactive immune responses to other coronaviruses. Here the authors show that choice of antigens and whether an ICS, ELISPOT or T cell proliferation assay is used has a major effect on this discriminatory ability.

Published
2021
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7. Analysis of SARS-CoV-2 in Nasopharyngeal Samples from Patients with COVID-19 Illustrates Population Variation and Diverse Phenotypes, Placing the Growth Properties of Variants of Concern in Context with Other Lineages

Author

Tessa Prince, Xiaofeng Dong, Rebekah Penrice-Randal, Nadine Randle, Catherine Hartley, Hannah Goldswain, Benjamin Jones, Malcolm G. Semple, J. Kenneth Baillie, Peter J. M. Openshaw, Lance Turtle, Grant L. Hughes, Enyia R. Anderson, Edward I. Patterson, Julian Druce, Gavin Screaton, Miles W. Carroll, James P. Stewart, and Julian A. Hiscox

Subjects
SARS-CoV-2, COVID-19, clinical samples, minor genomic variants, growth kinetics, cell culture, Microbiology, QR1-502
Abstract

ABSTRACT New variants of SARS-CoV-2 are continuing to emerge and dominate the global sequence landscapes. Several variants have been labeled variants of concern (VOCs) because they may have a transmission advantage, increased risk of morbidity and/or mortality, or immune evasion upon a background of prior infection or vaccination. Placing the VOCs in context with the underlying variability of SARS-CoV-2 is essential in understanding virus evolution and selection pressures. Dominant genome sequences and the population genetics of SARS-CoV-2 in nasopharyngeal swabs from hospitalized patients were characterized. Nonsynonymous changes at a minor variant level were identified. These populations were generally preserved when isolates were amplified in cell culture. To place the Alpha, Beta, Delta, and Omicron VOCs in context, their growth was compared to clinical isolates of different lineages from earlier in the pandemic. The data indicated that the growth in cell culture of the Beta variant was more than that of the other variants in Vero E6 cells but not in hACE2-A549 cells. Looking at each time point, Beta grew more than the other VOCs in hACE2-A549 cells at 24 to 48 h postinfection. At 72 h postinfection there was no difference in the growth of any of the variants in either cell line. Overall, this work suggested that exploring the biology of SARS-CoV-2 is complicated by population dynamics and that these need to be considered with new variants. In the context of variation seen in other coronaviruses, the variants currently observed for SARS-CoV-2 are very similar in terms of their clinical spectrum of disease. IMPORTANCE SARS-CoV-2 is the causative agent of COVID-19. The virus has spread across the planet, causing a global pandemic. In common with other coronaviruses, SARS-CoV-2 genomes can become quite diverse as a consequence of replicating inside cells. This has given rise to multiple variants from the original virus that infected humans. These variants may have different properties and in the context of a widespread vaccination program may render vaccines less effective. Our research confirms the degree of genetic diversity of SARS-CoV-2 in patients. By comparing the growth of previous variants to the pattern seen with four variants of concern (VOCs) (Alpha, Beta, Delta, and Omicron), we show that, at least in cells, Beta variant growth exceeds that of Alpha, Delta, and Omicron VOCs at 24 to 48 h in both Vero E6 and hACE2-A549 cells, but by 72 h postinfection, the amount of virus is not different from that of the other VOCs.

Published
2022
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8. Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections

Author

David W. Eyre, Sheila F. Lumley, Denise O’Donnell, Nicole E. Stoesser, Philippa C. Matthews, Alison Howarth, Stephanie B. Hatch, Brian D. Marsden, Stuart Cox, Tim James, Richard J. Cornall, David I. Stuart, Gavin Screaton, Daniel Ebner, Derrick W. Crook, Christopher P. Conlon, Katie Jeffery, Timothy M. Walker, and Timothy E. A. Peto

Subjects
SARS-CoV-2, COVID-19, Serology, Antibodies, Anosmia, Ageusia, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Thresholds for SARS-CoV-2 antibody assays have typically been determined using samples from symptomatic, often hospitalised, patients. In this setting the sensitivity and specificity of the best performing assays can both exceed 98%. However, antibody assay performance following mild infection is less clear. Methods We assessed quantitative IgG responses in a cohort of healthcare workers in Oxford, UK, with a high pre-test probability of Covid-19, in particular the 991/11,475(8.6%) who reported loss of smell/taste. We use anosmia/ageusia and other risk factors as probes for Covid-19 infection potentially undiagnosed by immunoassays by investigating their relationship with antibody readings either side of assay thresholds. Results The proportion of healthcare workers reporting anosmia/ageusia increased at antibody readings below diagnostic thresholds using an in-house ELISA (n = 9324) and the Abbott Architect chemiluminescent microparticle immunoassay (CMIA; n = 11,324): 426/906 (47%) reported anosmia/ageusia with a positive ELISA, 59/449 (13.1%) with high-negative and 326/7969 (4.1%) with low-negative readings. Similarly, by CMIA, 518/1093 (47.4%) with a positive result reported anosmia/ageusia, 106/686 (15.5%) with a high-negative and 358/9563 (3.7%) with a low-negative result. Adjusting for the proportion of staff reporting anosmia/ageusia suggests the sensitivity of both assays in mild infection is lower than previously reported: Oxford ELISA 89.8% (95%CI 86.6–92.8%) and Abbott CMIA 79.3% (75.9–82.7%). Conclusion Following mild SARS-CoV-2 infection 10–30% of individuals may have negative immunoassay results. While lowered diagnostic thresholds may result in unacceptable specificity, our findings have implications for epidemiological analyses and result interpretation in individuals with a high pre-test probability. Samples from mild PCR-confirmed infections should be included in SARS-CoV-2 immunoassay evaluations.

Published
2021
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9. The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 beta (B.1.351) and other variants of concern in preclinical studies

Author

Alexandra J Spencer, Susan Morris, Marta Ulaszewska, Claire Powers, Reshma Kailath, Cameron Bissett, Adam Truby, Nazia Thakur, Joseph Newman, Elizabeth R Allen, Indra Rudiansyah, Chang Liu, Wanwisa Dejnirattisai, Juthathip Mongkolsapaya, Hannah Davies, Francesca R Donnellan, David Pulido, Thomas P. Peacock, Wendy S. Barclay, Helen Bright, Kuishu Ren, Gavin Screaton, Patrick McTamney, Dalan Bailey, Sarah C Gilbert, and Teresa Lambe

Subjects
Vaccines, SARS CoV2, variants of concern, Antibodies, T cells, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: There is an ongoing global effort to design, manufacture, and clinically assess vaccines against SARS-CoV-2. Over the course of the ongoing pandemic a number of new SARS-CoV-2 virus isolates or variants of concern (VoC) have been identified containing mutations in key proteins. Methods: In this study we describe the generation and preclinical assessment of a ChAdOx1-vectored vaccine (AZD2816) which expresses the spike protein of the Beta VoC (B.1.351). Findings: We demonstrate that AZD2816 is immunogenic after a single dose. When AZD2816 is used as a booster dose in animals primed with a vaccine encoding the original spike protein (ChAdOx1 nCoV-19/ [AZD1222]), an increase in binding and neutralising antibodies against Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) is observed following each additional dose. In addition, a strong and polyfunctional T cell response was measured all booster regimens. Interpretation: Real world data is demonstrating that one or more doses of licensed SARS-CoV-2 vaccines confer reduced protection against hospitalisation and deaths caused by divergent VoC, including Omicron. Our data support the ongoing clinical development and testing of booster vaccines to increase immunity against highly mutated VoC. Funding: This research was funded by AstraZeneca with supporting funds from MRC and BBSRC.

Published
2022
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10. High flavivirus structural plasticity demonstrated by a non-spherical morphological variant

Author

Seamus R. Morrone, Valerie S. Y. Chew, Xin-Ni Lim, Thiam-Seng Ng, Victor A. Kostyuchenko, Shuijun Zhang, Melissa Wirawan, Pau-Ling Chew, Jaime Lee, Joanne L. Tan, Jiaqi Wang, Ter Yong Tan, Jian Shi, Gavin Screaton, Marc C. Morais, and Shee-Mei Lok

Subjects
Science
Abstract

Dengue (DENV) and Zika (ZIKV) viruses normally display as smooth spherical particles, while DENV can also become bumpy-surfaced, resulting in immune evasion. Here, Morrone et al. report DENV and ZIKV infectious club-shaped particles (clubSP) that display distinct antibody binding properties.

Published
2020
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11. SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus [version 2; peer review: 2 approved]

Author

Monique I. Andersson, Carolina V. Arancibia-Carcamo, Kathryn Auckland, J. Kenneth Baillie, Eleanor Barnes, Tom Beneke, Sagida Bibi, Tim Brooks, Miles Carroll, Derrick Crook, Kate Dingle, Christina Dold, Louise O. Downs, Laura Dunn, David W. Eyre, Javier Gilbert Jaramillo, Heli Harvala, Sarah Hoosdally, Samreen Ijaz, Tim James, William James, Katie Jeffery, Anita Justice, Paul Klenerman, Julian C. Knight, Michael Knight, Xu Liu, Sheila F. Lumley, Philippa C. Matthews, Anna L. McNaughton, Alexander J. Mentzer, Juthathip Mongkolsapaya, Sarah Oakley, Marta S. Oliveira, Timothy Peto, Rutger J. Ploeg, Jeremy Ratcliff, Melanie J. Robbins, David J. Roberts, Justine Rudkin, Rebecca A. Russell, Gavin Screaton, Malcolm G. Semple, Donal Skelly, Peter Simmonds, Nicole Stoesser, Lance Turtle, Susan Wareing, and Maria Zambon

Subjects
Medicine, Science
Abstract

Background: Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. Methods: We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. Results: We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. There was a relationship between RT-PCR negativity and the presence of total SARS-CoV-2 antibody (p=0.02). Conclusions: vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.

Published
2020
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12. Differential occupational risks to healthcare workers from SARS-CoV-2 observed during a prospective observational study

Author

David W Eyre, Sheila F Lumley, Denise O'Donnell, Mark Campbell, Elizabeth Sims, Elaine Lawson, Fiona Warren, Tim James, Stuart Cox, Alison Howarth, George Doherty, Stephanie B Hatch, James Kavanagh, Kevin K Chau, Philip W Fowler, Jeremy Swann, Denis Volk, Fan Yang-Turner, Nicole Stoesser, Philippa C Matthews, Maria Dudareva, Timothy Davies, Robert H Shaw, Leon Peto, Louise O Downs, Alexander Vogt, Ali Amini, Bernadette C Young, Philip George Drennan, Alexander J Mentzer, Donal T Skelly, Fredrik Karpe, Matt J Neville, Monique Andersson, Andrew J Brent, Nicola Jones, Lucas Martins Ferreira, Thomas Christott, Brian D Marsden, Sarah Hoosdally, Richard Cornall, Derrick W Crook, David I Stuart, Gavin Screaton, Oxford University Hospitals Staff Testing Group, Timothy EA Peto, Bruno Holthof, Anne-Marie O'Donnell, Daniel Ebner, Christopher P Conlon, Katie Jeffery, and Timothy M Walker

Subjects
Covid-19, SARS-CoV-2, healthcare workers, serology, risk factors, symptoms, Medicine, Science, Biology (General), QH301-705.5
Abstract

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45–6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99–3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07–2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28–0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25–2.21]) and Asian (1.51 [1.28–1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34–3.15]).

Published
2020
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13. The immunology of Zika Virus [version 1; referees: 2 approved]

Author

Abigail Culshaw, Juthathip Mongkolsapaya, and Gavin Screaton

Subjects
Immune Response, Viral Infections (without HIV), Medicine, Science
Abstract

Zika virus (ZIKV) was initially thought to cause only mild, self-limiting symptoms. However, recent outbreaks have been associated with the autoimmune disease Guillain-Barré syndrome and causally linked to a congenital malformation known as microcephaly. This has led to an urgent need for a safe and effective vaccine. A comprehensive understanding of the immunology of ZIKV infection is required to aid in the design of such a vaccine. Whilst details of both innate and adaptive immune responses to ZIKV are emerging, further research is needed. As immunopathogenesis has been implicated in poor outcomes following infection with the related dengue virus, identification of cross-reactive immune responses between flaviviruses and the impact they may have on disease progression is also of high importance.

Published
2018
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14. Recent advances in understanding dengue [version 1; referees: 3 approved]

Author

Sophie Yacoub, Juthathip Mongkolsapaya, and Gavin Screaton

Subjects
Antimicrobials & Drug Resistance, Drug Discovery & Design, Immunity to Infections, Immunomodulation, Medical Genetics, Medical Microbiology, Pediatric Infectious Diseases, Tropical & Travel-Associated Diseases, Viral Infections (without HIV), Virology, Medicine, Science
Abstract

Dengue is an emerging threat to billions of people worldwide. In the last 20 years, the incidence has increased four-fold and this trend appears to be continuing. Caused by one of four viral serotypes, dengue can present as a wide range of clinical phenotypes with the severe end of the spectrum being defined by a syndrome of capillary leak, coagulopathy, and organ impairment. The pathogenesis of severe disease is thought to be in part immune mediated, but the exact mechanisms remain to be defined. The current treatment of dengue relies on supportive measures with no licensed therapeutics available to date. There have been recent advances in our understanding of a number of areas of dengue research, of which the following will be discussed in this review: the drivers behind the global dengue pandemic, viral structure and epitope binding, risk factors for severe disease and its pathogenesis, as well as the findings of recent clinical trials including therapeutics and vaccines. We conclude with current and future dengue control measures and key areas for future research.

Published
2016
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15. Invariant NKT cell response to dengue virus infection in human.

Author

Ponpan Matangkasombut, Wilawan Chan-In, Anunya Opasawaschai, Pisut Pongchaikul, Nattaya Tangthawornchaikul, Sirijitt Vasanawathana, Wannee Limpitikul, Prida Malasit, Thaneeya Duangchinda, Gavin Screaton, and Juthathip Mongkolsapaya

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

BACKGROUND:Dengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection. METHODS:Blood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured. RESULTS:iNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated. CONCLUSION:iNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future.

Published
2014
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16. Isolation of a pair of potent broadly neutralizing mAb binding to RBD and SD1 domains of SARS-CoV-2

Author

David Stuart, Chang Liu, Raksha Das, Aiste Dijokaite-Guraliuc, Daming Zhou, Helen Duyvesteyn, Alexander Mentzer, Piyasa Supasa, Muneeswaran Selvaraj, Thomas Ritter, Nigel Temperton, Paul Klenerman, Susanna Dunachie, Neil Paterson, Mark Williams, David Hall, Elizabeth Fry, Juthathip Mongkolsapaya, Jingshan Ren, and Gavin Screaton

Abstract

Commercially developed monoclonal antibodies (mAb) have been effective in the prevention or treatment of SARS-CoV-2 infection1-3 but the rapid antigenic evolution of the Omicron sub-lineages has reduced their activity4-8 and they are no longer licensed for use in many countries. Here, we isolate spike binding monoclonal antibodies from vaccinees who suffered vaccine break-through infections with Omicron sublineages BA.4/5. We find that it is possible for antibodies targeting highly mutated regions to recover broad activity through allosteric effects (mAb BA.4/5-35) and characterise a pair of potent mAbs with extremely broad neutralization against current and historical SARS-CoV-2 variants. One, mAb BA.4/5-2, binds at the back of the left shoulder of the receptor binding domain (RBD) in an area which has resisted mutational change to date. The second, mAb BA.4/5-5, binds a conserved epitope in sub-domain 1 (SD1). The isolation of this pair of antibodies with non-overlapping epitopes shows that potent and extremely broadly neutralizing antibodies are still generated following infection and SD1 directed mAbs may increase the resilience of mAb therapeutics/prophylactics against SARS-CoV-2.

Published
2023

17. Omicron BA.1/BA.2 infections in triple-vaccinated individuals enhance a diverse repertoire of mucosal and blood immune responses

Author

Hailey Hornsby, Alexander R. Nicols, Stephanie Longet, Chang Liu, Adriana Tomic, Adrienn Angyal, Barbara Kronsteiner, Jessica K. Tyerman, Tom Tipton, Peijun Zhang, Marta Gallis Ramalho, Piyada Supasa, Muneeswaran Selvaraj, Priyanka Abraham, Isabel Neale, Mohammad Ali, Natalie A. Barratt, Jeremy M. Nell, Lotta Gustafsson, Scarlett Strickland, Irina Grouneva, Timothy Rostron, Shona C. Moore, Luisa M. Hering, Susan L. Dobson, Sagida Bibi, Juthathip Mongkolsapaya, Teresa Lambe, Dan Wootton, Victoria Hall, Susan Hopkins, Tao Dong, Eleanor Barnes, Gavin Screaton, Alex Richter, Lance Turtle, Sarah L. Rowland-Jones, Miles Carroll, Christopher J.A. Duncan, Paul Klenerman, Susanna J. Dunachie, Rebecca P. Payne, and Thushan I. de Silva

Abstract

Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in large numbers of individuals with hybrid immunity, generated through a combination of vaccination and infection. Based primarily on circulating neutralizing antibody (NAb) data, concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that a history of prior SARS-CoV-2 in particular is associated with profound immune dampening. Taking a broader and comprehensive approach, we characterized mucosal and blood immunity to both spike and non-spike antigens following BA.1/BA.2 infections in triple mRNA-vaccinated individuals, with and without a history of previous SARS-CoV-2 infection. We find that the majority of individuals increase BA.1/BA.2/BA.5-specific NAb following infection, but confirm that the magnitude of increase and post-omicron titres are indeed higher in those who were infection-naive. In contrast, significant increases in nasal antibody responses are seen regardless of prior infection history, including neutralizing activity against BA.5 spike. Spike-specific T cells increase only in infection-naive vaccinees; however, post-omicron T cell responses are still significantly higher in previously-infected individuals, who appear to have maximally induced responses with a CD8+ phenotype of high cytotoxic potential after their 3rdmRNA vaccine dose. Antibody and T cell responses to non-spike antigens also increase significantly regardless of prior infection status, with a boost seen in previously-infected individuals to immunity primed by their first infection. These findings suggest that hybrid immunity induced by omicron breakthrough infections is highly dynamic, complex, and compartmentalised, with significant immune enhancement that can help protect against COVID-19 caused by future omicron variants.

Published
2023

18. Inhibition of Phosphodiesterase 12 results in Antiviral Activity against several RNA Viruses including SARS-CoV-2

Author

Mark Thursz, Fouzia Sadiq, Julia A. Tree, Peter Karayiannis, David W. C. Beasley, Wanwissa Dejnirattisai, Juthathip Mongkolsapaya, Gavin Screaton, Matthew Wand, Michael J. Elmore, Miles W. Carroll, Ian Matthews, and Howard Thomas

Abstract

Phosphodiesterase 12 (PDE12) is a negative regulator of the type 1 interferon (IFN) response and here we show that PDE12 inhibitors (lead compounds 63 and 17) are associated with increased RNAseL activity, are well tolerated at the therapeutic range and inhibit, both in vitro and in vivo, the replication of several RNA viruses including hepatitis C virus (HCV), dengue virus (DENV), West Nile Virus (WNV) and SARS-CoV-2.

Published
2022

19. Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19

Author

Christos P Kotanidis, Cheng Xie, Donna Alexander, Jonathan C L Rodrigues, Katie Burnham, Alexander Mentzer, Daniel O’Connor, Julian Knight, Muhammad Siddique, Helen Lockstone, Sheena Thomas, Rafail Kotronias, Evangelos K Oikonomou, Ileana Badi, Maria Lyasheva, Cheerag Shirodaria, Sheila F Lumley, Bede Constantinides, Nicholas Sanderson, Gillian Rodger, Kevin K Chau, Archie Lodge, Maria Tsakok, Fergus Gleeson, David Adlam, Praveen Rao, Das Indrajeet, Aparna Deshpande, Amrita Bajaj, Benjamin J Hudson, Vivek Srivastava, Shakil Farid, George Krasopoulos, Rana Sayeed, Ling-Pei Ho, Stefan Neubauer, David E Newby, Keith M Channon, John Deanfield, Charalambos Antoniades, David J Ahern, Zhichao Ai, Mark Ainsworth, Chris Allan, Alice Allcock, Brian Angus, M Azim Ansari, Carolina Arancibia-Cárcamo, Dominik Aschenbrenner, Moustafa Attar, J Kenneth Baillie, Eleanor Barnes, Rachael Bashford-Rogers, Archana Bashyal, Sally Beer, Georgina Berridge, Amy Beveridge, Sagida Bibi, Tihana Bicanic, Luke Blackwell, Paul Bowness, Andrew Brent, Andrew Brown, John Broxholme, David Buck, Helen Byrne, Susana Camara, Ivan Candido Ferreira, Philip Charles, Wentao Chen, Yi-Ling Chen, Amanda Chong, Elizabeth Clutterbuck, Mark Coles, Christopher Conlon, Richard Cornall, Adam Cribbs, Fabiola Curion, Emma Davenport, Neil Davidson, Simon Davis, Calliope Dendrou, Julie Dequaire, Lea Dib, James Docker, Christina Dold, Tao Dong, Damien Downes, Hal Drakesmith, Susanna Dunachie, David Duncan, Chris Eijsbouts, Robert Esnouf, Alexis Espinosa, Rachel Etherington, Benjamin Fairfax, Rory Fairhead, Hai Fang, Shayan Fassih, Sally Felle, Maria Fernandez Mendoza, Ricardo Ferreira, Roman Fischer, Thomas Foord, Aden Forrow, John Frater, Anastasia Fries, Veronica Gallardo Sanchez, Lucy Garner, Clementine Geeves, Dominique Georgiou, Leila Godfrey, Tanya Golubchik, Maria Gomez Vazquez, Angie Green, Hong Harper, Heather Harrington, Raphael Heilig, Svenja Hester, Jennifer Hill, Charles Hinds, Clare Hird, Renee Hoekzema, Benjamin Hollis, Jim Hughes, Paula Hutton, Matthew Jackson-Wood, Ashwin Jainarayanan, Anna James-Bott, Kathrin Jansen, Katie Jeffery, Elizabeth Jones, Luke Jostins, Georgina Kerr, David Kim, Paul Klenerman, Vinod Kumar, Piyush Kumar Sharma, Prathiba Kurupati, Andrew Kwok, Angela Lee, Aline Linder, Teresa Lockett, Lorne Lonie, Maria Lopopolo, Martyna Lukoseviciute, Jian Luo, Spyridoula Marinou, Brian Marsden, Jose Martinez, Philippa Matthews, Michalina Mazurczyk, Simon McGowan, Stuart McKechnie, Adam Mead, Yuxin Mi, Claudia Monaco, Ruddy Montadon, Giorgio Napolitani, Isar Nassiri, Alex Novak, Darragh O'Brien, Daniel O'Connor, Denise O'Donnell, Graham Ogg, Lauren Overend, Inhye Park, Ian Pavord, Yanchun Peng, Frank Penkava, Mariana Pereira Pinho, Elena Perez, Andrew Pollard, Fiona Powrie, Bethan Psaila, T Phuong Quan, Emmanouela Repapi, Santiago Revale, Laura Silva-Reyes, Jean-Baptiste Richard, Charlotte Rich-Griffin, Thomas Ritter, Christine Rollier, Matthew Rowland, Fabian Ruehle, Mariolina Salio, Stephen Nicholas Sansom, Raphael Sanches Peres, Alberto Santos Delgado, Tatjana Sauka-Spengler, Ron Schwessinger, Giuseppe Scozzafava, Gavin Screaton, Anna Seigal, Malcolm Semple, Martin Sergeant, Christina Simoglou Karali, David Sims, Donal Skelly, Hubert Slawinski, Alberto Sobrinodiaz, Nikolaos Sousos, Lizzie Stafford, Lisa Stockdale, Marie Strickland, Otto Sumray, Bo Sun, Chelsea Taylor, Stephen Taylor, Adan Taylor, Supat Thongjuea, Hannah Thraves, John Todd, Adriana Tomic, Orion Tong, Amy Trebes, Dominik Trzupek, Felicia Anna Tucci, Lance Turtle, Irina Udalova, Holm Uhlig, Erinke van Grinsven, Iolanda Vendrell, Marije Verheul, Alexandru Voda, Guanlin Wang, Lihui Wang, Dapeng Wang, Peter Watkinson, Robert Watson, Michael Weinberger, Justin Whalley, Lorna Witty, Katherine Wray, Luzheng Xue, Hing Yuen Yeung, Zixi Yin, Rebecca Young, Jonathan Youngs, Ping Zhang, Yasemin-Xiomara Zurke, Adrian Banning, Alexios Antonopoulos, Andrew Kelion, Attila Kardos, Benjamin Hudson, Bon-Kwon Koo, Christos Kotanidis, Ciara Mahon, Colin Berry, David Newby, Derek Connolly, Diane Scaletta, Ed Nicol, Elisa McAlindon, Evangelos Oikonomou, Francesca Pugliese, Gianluca Pontone, Giulia Benedetti, Guo-Wei He, Henry West, Hidekazu Kondo, Imre Benedek, Intrajeet Das, John Graby, John Greenwood, Jonathan Rodrigues, Junbo Ge, Keith Channon, Larissa Fabritz, Li-Juan Fan, Lucy Kingham, Marco Guglielmo, Matthias Schmitt, Meinrad Beer, Michelle Anderson, Milind Desai, Mohamed Marwan, Naohiko Takahashi, Nehal Mehta, Neng Dai, Nicholas Screaton, Nikant Sabharwal, Pál Maurovich-Horvat, Rajesh Kharbanda, Rebecca Preston, Richard Wood, Ron Blankstein, Ronak Rajani, Saeed Mirsadraee, Shahzad Munir, Steffen Klömpken, Steffen Petersen, Stephan Achenbach, Susan Anthony, Sze Mak, Tarun Mittal, Theodora Benedek, Vinoda Sharma, and Wen-Hua Lin

Subjects
Inflammation, SARS-CoV-2, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Angiography, Medicine (miscellaneous), COVID-19, Health Informatics, State Medicine, Health Information Management, Artificial Intelligence, Cytokines, Humans, Decision Sciences (miscellaneous), Prospective Studies, Tomography, X-Ray Computed
Abstract

Contains fulltext : 286832.pdf (Publisher’s version ) (Open Access) BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [

Published
2022

20. Evolution of long-term vaccine induced and hybrid immunity in healthcare workers after different COVID-19 vaccination regimens: a longitudinal observational cohort study

Author

Shona C. Moore, Barbara Kronsteiner, Stephanie Longet, Sandra Adele, Alexandra S. Deeks, Chang Liu, Wanwisa Dejnirattisai, Laura Silva Reyes, Naomi Meardon, Sian Faustini, Saly Al-Taei, Tom Tipton, Luisa M Hering, Adrienn Angyal, Rebecca Brown, Alexander R Nicols, Susan L Dobson, Piyada Supasa, Aekkachai Tuekprakhon, Andrew Cross, Jessica K Tyerman, Hailey Hornsby, Irina Grouneva, Megan Plowright, Peijun Zhang, Thomas A.H. Newman, Jeremy M. Nell, Priyanka Abraham, Mohammad Ali, Tom Malone, Isabel Neale, Eloise Phillips, Joseph D. Wilson, Sam M. Murray, Martha Zewdie, Adrian Shields, Emily C. Horner, Lucy H. Booth, Lizzie Stafford, Sagida Bibi, Daniel G. Wootton, Alexander J. Mentzer, Christopher P. Conlon, Katie Jeffery, Philippa C. Matthews, Andrew J. Pollard, Anthony Brown, Sarah L. Rowland-Jones, Juthathip Mongkolsapaya, Rebecca P. Payne, Christina Dold, Teresa Lambe, James E.D. Thaventhiran, Gavin Screaton, Eleanor Barnes, Susan Hopkins, Victoria Hall, Christopher JA Duncan, Alex Richter, Miles Carroll, Thushan I. de Silva, Paul Klenerman, Susanna Dunachie, and Lance Turtle

Abstract

Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARS-CoV-2. However, the maintenance of such responses – and hence protection from disease – requires careful characterisation. In a large prospective study of UK healthcare workers (Protective immunity from T cells in Healthcare workers (PITCH), within the larger SARS-CoV-2 immunity & reinfection evaluation (SIREN) study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Here, we report longer follow up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. We make three observations: Firstly, the dynamics of humoral and cellular responses differ; binding and neutralising antibodies declined whereas T and memory B cell responses were maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels, broadened neutralising activity against variants of concern including omicron BA.1, BA.2 and BA.5, and boosted T cell responses above the 6 month level post dose 2. Thirdly, prior infection maintained its impact driving larger as well as broader T cell responses compared with never-infected people – a feature maintained until 6 months after the third dose. In conclusion, broadly cross-reactive T cell responses are well maintained over time – especially in those with combined vaccine and infection-induced immunity (“hybrid” immunity) – and may contribute to continued protection against severe disease.

Published
2022

21. Accelerating Inhibitor Discovery for Multiple SARS-CoV-2 Targets with a Single, Sequence-Guided Deep Generative Framework

Author

Vijil Chenthamarakshan, Samuel Hoffman, C. David Owen, Petra Lukacik, Claire Strain-damerell, Daren Fearon, Tika Malla, Anthony Tumber, Christopher Schofield, Helen Duyvesteyn, Wanwisa Ddejnirattisai, Loic Carrique, Thomas Walter, Gavin Screaton, Tetiana Matviyuk, Aleksandra Mojsilovic, Jason Crain, Martin Walsh, David Stuart, and Payel Das

Abstract

The COVID-19 pandemic has highlighted the urgency for developing more efficient molecular discovery pathways. As exhaustive exploration of the vast chemical space is infeasible, discovering novel inhibitor molecules for emerging drug-target proteins is challenging, particularly for targets with unknown structure or ligands. We demonstrate the broad utility of a single deep generative framework toward discovering novel drug-like inhibitor molecules against two distinct SARS-CoV-2 targets — the main protease (Mpro) and the receptor binding domain (RBD) of the spike protein. To perform target-aware design, the framework employs a target sequence-conditioned sampling of novel molecules from a generative model. Micromolar-level in vitro inhibition was observed for two candidates (out of four synthesized) for each target. The most potent spike RBD inhibitor also emerged as a rare non-covalent antiviral with broad-spectrum activity against several SARS-CoV-2 variants in live virus neutralization assays. These results show that a broadly deployable machine intelligence framework can accelerate hit discovery across different emerging drug-targets.

Published
2022

22. Further antibody escape by Omicron BA.4 and BA.5 from vaccine and BA.1 serum

Author

Susanna Dunachie, Gavin Screaton, David Stuart, Donal Skelly, Nigel Temperton, Eleanor Barnes, and Aekkachai Tuekprakhon

Abstract

SummaryThe Omicron lineage of SARS-CoV-2, first described in November 2021, spread rapidly to become globally dominant and has split into a number of sub-lineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa’s Gauteng region uncovered two new sub-lineages, BA.4 and BA.5 which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences and, although closely related to BA.2, contain further mutations in the receptor binding domain of spike. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by serum from triple AstraZeneca or Pfizer vaccinated individuals compared to BA.1 and BA.2. Furthermore, using serum from BA.1 vaccine breakthrough infections there are likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.

Published
2022

23. Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers

Author

Stephanie Hatch, Alexander Mentzer, Aisling M. Curtis, Philippa Matthews, David Eyre, Robert Shaw, Thomas Ritter, Timothy Walker, Gavin Screaton, Ahmed Alhussni, Rebecca Jurdon, Sarah Hoosdally, Nicole Stoesser, Seren Waite, Rebecca Conway-Jones, Greg Howgego, Angus Livingstone, Benjamin Holloway, Koen Pouwels, Matthew Wedlich, Mark Campbell, Laura Wilkins, Afrah Shibu, Liam Peck, Hayleah Pickford, Charlotte Lee, Susan Hopkins, Derrick Crook, Zoe De Toledo, Tariq Ahmed-Firani, Donal Skelly, Joseph Cutteridge, Philip Fowler, Andrey Nezhentsev, Imogen Vorley, Maria Pikoula, Gillian Rodger, and Sheila Lumley

Subjects
Adult, Male, 2019-20 coronavirus outbreak, medicine.medical_specialty, Adolescent, Health Personnel, viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 030204 cardiovascular system & hematology, Antibodies, Viral, Polymerase Chain Reaction, COVID-19 Serological Testing, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Health care, Epidemiology, Coronavirus Nucleocapsid Proteins, Humans, Medicine, Longitudinal Studies, 030212 general & internal medicine, Seroconversion, Young adult, Aged, Aged, 80 and over, biology, SARS-CoV-2, business.industry, Incidence, Incidence (epidemiology), COVID-19, virus diseases, General Medicine, Middle Aged, United Kingdom, COVID-19 Nucleic Acid Testing, Immunoglobulin G, Spike Glycoprotein, Coronavirus, Immunology, biology.protein, Female, Original Article, Antibody, business
Abstract

Background The relationship between the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the risk of subsequent reinfection remains unclear. Methods We investigated the incidence of SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) in seropositive and seronegative health care workers attending testing of asymptomatic and symptomatic staff at Oxford University Hospitals in the United Kingdom. Baseline antibody status was determined by anti-spike (primary analysis) and anti-nucleocapsid IgG assays, and staff members were followed for up to 31 weeks. We estimated the relative incidence of PCR-positive test results and new symptomatic infection according to antibody status, adjusting for age, participant-reported gender, and changes in incidence over time. Results A total of 12,541 health care workers participated and had anti-spike IgG measured; 11,364 were followed up after negative antibody results and 1265 after positive results, including 88 in whom seroconversion occurred during follow-up. A total of 223 anti-spike–seronegative health care workers had a positive PCR test (1.09 per 10,000 days at risk), 100 during screening while they were asymptomatic and 123 while symptomatic, whereas 2 anti-spike–seropositive health care workers had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested (adjusted incidence rate ratio, 0.11; 95% confidence interval, 0.03 to 0.44; P=0.002). There were no symptomatic infections in workers with anti-spike antibodies. Rate ratios were similar when the anti-nucleocapsid IgG assay was used alone or in combination with the anti-spike IgG assay to determine baseline status. Conclusions The presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months. (Funded by the U.K. Government Department of Health and Social Care and others.)

Published
2021

24. Memory cytotoxic SARS-CoV-2 spike protein-specific CD4+ T cells associate with viral control

Author

Tao Dong, Guihai Liu, Suet Felce, Xuan Yao, Zixi Yin, Anastasia Fries, Alexander Mentzer, Danning Dong, Wenbo Wang, Wanwisa Dejnirattisai, Piyada Supasa, Chang Liu, Peter Wing, Timothy Rostron, Craig Waugh, Sally-Ann Clark, Kevin Clark, Paul Sopp, Philip Hublitz, Ryan Beveridge, Jeremy Fry, Jane McKeating, Juthathip Mongkolsapaya, Gavin Screaton, Graham Ogg, Julian Knight, and Yanchun Peng

Abstract

Little is known of the role of cytotoxic CD4+ T-cells in the control of viral replication. Here, we investigate CD4+ T-cell responses to three dominant SARS-CoV-2 epitopes and evaluate antiviral activity, including cytotoxicity and antiviral cytokine production. Diverse T cell receptor (TCR) usage including public TCRs were identified; surprisingly, cytotoxic CD4+ T-cells were found to have signalling and cytotoxic pathways distinct from classical CD8+ T-cells, with increased expression of chemokines and tissue homing receptors promoting migration. We show the presence of cytolytic CD4+ T-cells during primary infection associates with COVID-19 disease severity. Robust immune memory 6-9 months post-infection or vaccination provides CD4+ T-cells with potent antiviral activity. Our data support a model where CD4+ killer cells drive immunopathogenesis during primary infection and CD4+ memory responses are protective during secondary infection. Our study highlights the unique features of cytotoxic CD4+ T-cells that use distinct functional pathways, providing preventative and therapeutic opportunities.

Published
2022

25. Reduced neutralisation of SARS-COV-2 Omicron-B.1.1.529 variant by post-immunisation serum

Author

Gavin Screaton

Abstract

In this report, we present live neutralisation titres against SARS-CoV-2 Omicron variant, compared with neutralisation against Victoria, Beta and Delta variants. Sera from day-28 post second-dose were obtained from participants in the Com-COV2 study who had received a two-dose COVID-19 vaccination schedule with either AstraZeneca (AZD1222) or Pfizer (BNT162b2) vaccines. There was a substantial fall in neutralisation titres in recipients of both AZD1222 and BNT16b2 primary courses, with evidence of some recipients failing to neutralise at all. This will likely lead to increased breakthrough infections in previously infected or double vaccinated individuals, which could drive a further wave of infection, although there is currently no evidence of increased potential to cause severe disease, hospitalization or death.

Published
2021

26. Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

Author

Anna L. McNaughton, Robert S. Paton, Matthew Edmans, Jonathan Youngs, Judith Wellens, Prabhjeet Phalora, Alex Fyfe, Sandra Belij-Rammerstorfer, Jai S. Bolton, Jonathan Ball, George W. Carnell, Wanwisa Dejnirattisai, Christina Dold, David W. Eyre, Philip Hopkins, Alison Howarth, Kreepa Kooblall, Hannah Klim, Susannah Leaver, Lian Ni Lee, César López-Camacho, Sheila F. Lumley, Derek C. Macallan, Alexander J. Mentzer, Nicholas M. Provine, Jeremy Ratcliff, Jose Slon-Compos, Donal Skelly, Lucas Stolle, Piyada Supasa, Nigel Temperton, Chris Walker, Beibei Wang, Duncan Wyncoll, Peter Simmonds, Teresa Lambe, John Kenneth Baillie, Malcolm G. Semple, Peter J.M. Openshaw, Uri Obolski, Marc Turner, Miles Carroll, Juthathip Mongkolsapaya, Gavin Screaton, Stephen H. Kennedy, Lisa Jarvis, Eleanor Barnes, Susanna Dunachie, José Lourenço, Philippa C. Matthews, Tihana Bicanic, Paul Klenerman, Sunetra Gupta, and Craig P. Thompson

Subjects
QR355, Infectious disease, SARS-CoV-2, viruses, Adaptive immunity, Immunology, virus diseases, COVID-19, Imprinting, General Medicine, Antibodies, Viral, Epitopes, Antibody Formation, Spike Glycoprotein, Coronavirus, Humans
Abstract

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an "original antigenic sin" type response. ispartof: JCI INSIGHT vol:7 issue:13 ispartof: location:United States status: published

Published
2021

27. Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine

Author

Rebecca P. Payne, Stephanie Longet, James A. Austin, Donal T. Skelly, Wanwisa Dejnirattisai, Sandra Adele, Naomi Meardon, Sian Faustini, Saly Al-Taei, Shona C. Moore, Tom Tipton, Luisa M. Hering, Adrienn Angyal, Rebecca Brown, Alexander R. Nicols, Natalie Gillson, Susan L. Dobson, Ali Amini, Piyada Supasa, Andrew Cross, Alice Bridges-Webb, Laura Silva Reyes, Aline Linder, Gurjinder Sandhar, Jonathan A. Kilby, Jessica K. Tyerman, Thomas Altmann, Hailey Hornsby, Rachel Whitham, Eloise Phillips, Tom Malone, Alexander Hargreaves, Adrian Shields, Ayoub Saei, Sarah Foulkes, Lizzie Stafford, Sile Johnson, Daniel G. Wootton, Christopher P. Conlon, Katie Jeffery, Philippa C. Matthews, John Frater, Alexandra S. Deeks, Andrew J. Pollard, Anthony Brown, Sarah L. Rowland-Jones, Juthathip Mongkolsapaya, Eleanor Barnes, Susan Hopkins, Victoria Hall, Christina Dold, Christopher J.A. Duncan, Alex Richter, Miles Carroll, Gavin Screaton, Thushan I. de Silva, Lance Turtle, Paul Klenerman, Susanna Dunachie, Hibatullah Abuelgasim, Emily Adland, Syed Adlou, Hossain Delowar Akther, Ahmed Alhussni, Mohammad Ali, M. Azim Ansari, Carolina V. Arancibia-Cárcamo, Martin Bayley, Helen Brown, Jeremy Chalk, Meera Chand, Anu Chawla, Senthil Chinnakannan, Joseph Cutteridge, Catherine de Lara, Lucy Denly, Ben Diffey, Stavros Dimitriadis, Thomas M. Drake, Timothy Donnison, Maeva Dupont, David Eyre, Alex Fairman, Siobhan Gardiner, Javier Gilbert-Jarmillo, Philip Goulder, Carl-Philipp Hackstein, Sophie Hambleton, Muzlifah Haniffa, Jenny Haworth, Jennifer Holmes, Emily Horner, Anni Jämsén, Chris Jones, Mwila Kasanyinga, Sinead Kelly, Rosemary Kirk, Michael L. Knight, Allan Lawrie, Lian Lee, Lauren Lett, Katy Lillie, Nicholas Lim, Hema Mehta, Alexander J. Mentzer, Denise O’Donnell, Ane Ogbe, Matthew Pace, Brendan A.I. Payne, Gareth Platt, Sonia Poolan, Nicholas Provine, Narayan Ramamurthy, Nichola Robinson, Leigh Romaniuk, Patpong Rongkard, Oliver L. Sampson, Beatrice Simmons, Jarmila S. Spegarova, Emily Stephenson, Kris Subramaniam, James Thaventhiran, Sarah Thomas, Simon Travis, Stephanie Tucker, Helena Turton, Adam Watson, Lisa Watson, Esme Weeks, Robert Wilson, Steven Wood, Rachel Wright, Huiyuan Xiao, Amira A.T. Zawia, and Consortium, PITCH

Subjects
Adult, Male, COVID-19 Vaccines, T-Lymphocytes, Population, Dose-Response Relationship, Immunologic, Antibodies, Viral, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, Cross-Priming, Immunity, Ethnicity, medicine, Humans, Dosing, education, Neutralizing antibody, BNT162 Vaccine, B cell, Aged, Vaccines, Synthetic, education.field_of_study, biology, SARS-CoV-2, Immunogenicity, COVID-19, Middle Aged, Reference Standards, Antibodies, Neutralizing, Regimen, Treatment Outcome, medicine.anatomical_structure, Immunoglobulin G, Immunology, Linear Models, biology.protein, Female, Antibody
Abstract

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the UK to accelerate population coverage with a single dose. At this time, trial data was lacking, and we addressed this in a study of UK healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a sub-study of 589 individuals, we show that this single dose induces SARS-CoV-2 neutralizing antibody (NAb) responses and a sustained B and T cell response to spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared to the conventional 3-4 week regimen, accompanied by enrichment of CD4+ T cells expressing IL2. Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective, immunogenic protocol., After giving a primary dose, delaying administration of a second dose of BNT162b2 COVID-19 vaccine up to 6-14 weeks continues to provide strong protection and contributes to favorable antibody, B cell, and T cell responses.

Published
2021

28. The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 beta (B.1.351) and other variants of concern in preclinical studies

Author

Alexandra J Spencer, Susan Morris, Marta Ulaszewska, Claire Powers, Reshma Kailath, Cameron Bissett, Adam Truby, Nazia Thakur, Joseph Newman, Elizabeth R Allen, Indra Rudiansyah, Chang Liu, Wanwisa Dejnirattisai, Juthathip Mongkolsapaya, Hannah Davies, Francesca R Donnellan, David Pulido, Thomas P. Peacock, Wendy S. Barclay, Helen Bright, Kuishu Ren, Gavin Screaton, Patrick McTamney, Dalan Bailey, Sarah C Gilbert, and Teresa Lambe

Subjects
COVID-19 Vaccines, SARS-CoV-2, ChAdOx1 nCoV-19, COVID-19, Humans, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

Background There is an ongoing global effort to design, manufacture, and clinically assess vaccines against SARS-CoV-2. Over the course of the ongoing pandemic a number of new SARS-CoV-2 virus isolates or variants of concern (VoC) have been identified containing mutations in key proteins. Methods In this study we describe the generation and preclinical assessment of a ChAdOx1-vectored vaccine (AZD2816) which expresses the spike protein of the Beta VoC (B.1.351). Findings We demonstrate that AZD2816 is immunogenic after a single dose. When AZD2816 is used as a booster dose in animals primed with a vaccine encoding the original spike protein (ChAdOx1 nCoV-19/ [AZD1222]), an increase in binding and neutralising antibodies against Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) is observed following each additional dose. In addition, a strong and polyfunctional T cell response was measured all booster regimens. Interpretation Real world data is demonstrating that one or more doses of licensed SARS-CoV-2 vaccines confer reduced protection against hospitalisation and deaths caused by divergent VoC, including Omicron. Our data support the ongoing clinical development and testing of booster vaccines to increase immunity against highly mutated VoC. Funding This research was funded by AstraZeneca with supporting funds from MRC and BBSRC.

Published
2021

29. Immunodominant NP105-113-B*0702 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease

Author

Tao Dong, Graham Ogg, Yan-Chun Peng, Suet Felce, Danning Dong, Frank Penkava, Alexander Mentzer, Xuan Lao, Guihai Liu, Zixi Yin, Ji-Li Chen, YongXu Lu, Dannielle Wellington, Peter Wing, Delaney Dominey-Foy, Julian Knight, Chen Jin, Wenbo Wang, Megat Abd Hamid, Ricardo Fernandes, Beibei Wang, Anastasia Fries, Xiaodong Zhuang, Neil Ashley, Timothy Rostron, Craig Waugh, Paul Sopp, Philip Hublitz, Ryan Beveridge, Tiong Kit Tan, Christina Dold, Andrew Kwok, Charlotte Rich-Griffin, Wanwisa Dejnirattisai, Isar Nassiri, Robert Watson, Orion Tong, Chelsea Taylor, Piyush Kumar Sharma, Fabiola Curion, Santiago Revale, Lucy Garner, Kathrin Jansen, Ricardo Ferreira, Moustafa Attar, Jeremy Fry, Rebecca Russell, Hans Stauss, William James, Alain Townsend, Ling-Pei Ho, Juthathip Mongkolsapaya, Paul Klenerman, Gavin Screaton, Calliope Dendrou, Stephen Sansom, Rachael Bashford-Rogers, Benny Chain, Geoffrey Smith, Jane McKeating, Benjamin Fairfax, Paul Bowness, and Andrew McMichael

Abstract

NP105-113-B*07:02 specific CD8+ T-cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02 specific T-cell clones and single cell sequencing were performed concurrently, with functional avidity and anti-viral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with TCR usage, transcriptome signature, and disease severity (acute N=77, convalescent N=52). We demonstrated a beneficial association of NP105-113-B*07:02 specific T-cells in COVID-19 disease progression, linked with expansion of T-cell precursors, high functional avidity and anti-viral effector function. Broad immune memory pools were narrowed post-infection but NP105-113-B*07:02 specific T-cells were maintained 6 months after infection with preserved anti-viral efficacy to the SARS-CoV-2 Victoria strain, as well as new Alpha, Beta and Gamma variants. Our data shows that NP105-113-B*07:02 specific T-cell responses associate with mild disease and high anti-viral efficacy, pointing to inclusion for future vaccine design.

Published
2021

30. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

Author

David J. Ahern, Zhichao Ai, Mark Ainsworth, Chris Allan, Alice Allcock, Brian Angus, M. Azim Ansari, Carolina V. Arancibia-Cárcamo, Dominik Aschenbrenner, Moustafa Attar, J. Kenneth Baillie, Eleanor Barnes, Rachael Bashford-Rogers, Archana Bashyal, Sally Beer, Georgina Berridge, Amy Beveridge, Sagida Bibi, Tihana Bicanic, Luke Blackwell, Paul Bowness, Andrew Brent, Andrew Brown, John Broxholme, David Buck, Katie L. Burnham, Helen Byrne, Susana Camara, Ivan Candido Ferreira, Philip Charles, Wentao Chen, Yi-Ling Chen, Amanda Chong, Elizabeth A. Clutterbuck, Mark Coles, Christopher P. Conlon, Richard Cornall, Adam P. Cribbs, Fabiola Curion, Emma E. Davenport, Neil Davidson, Simon Davis, Calliope A. Dendrou, Julie Dequaire, Lea Dib, James Docker, Christina Dold, Tao Dong, Damien Downes, Hal Drakesmith, Susanna J. Dunachie, David A. Duncan, Chris Eijsbouts, Robert Esnouf, Alexis Espinosa, Rachel Etherington, Benjamin Fairfax, Rory Fairhead, Hai Fang, Shayan Fassih, Sally Felle, Maria Fernandez Mendoza, Ricardo Ferreira, Roman Fischer, Thomas Foord, Aden Forrow, John Frater, Anastasia Fries, Veronica Gallardo Sanchez, Lucy C. Garner, Clementine Geeves, Dominique Georgiou, Leila Godfrey, Tanya Golubchik, Maria Gomez Vazquez, Angie Green, Hong Harper, Heather A. Harrington, Raphael Heilig, Svenja Hester, Jennifer Hill, Charles Hinds, Clare Hird, Ling-Pei Ho, Renee Hoekzema, Benjamin Hollis, Jim Hughes, Paula Hutton, Matthew A. Jackson-Wood, Ashwin Jainarayanan, Anna James-Bott, Kathrin Jansen, Katie Jeffery, Elizabeth Jones, Luke Jostins, Georgina Kerr, David Kim, Paul Klenerman, Julian C. Knight, Vinod Kumar, Piyush Kumar Sharma, Prathiba Kurupati, Andrew Kwok, Angela Lee, Aline Linder, Teresa Lockett, Lorne Lonie, Maria Lopopolo, Martyna Lukoseviciute, Jian Luo, Spyridoula Marinou, Brian Marsden, Jose Martinez, Philippa C. Matthews, Michalina Mazurczyk, Simon McGowan, Stuart McKechnie, Adam Mead, Alexander J. Mentzer, Yuxin Mi, Claudia Monaco, Ruddy Montadon, Giorgio Napolitani, Isar Nassiri, Alex Novak, Darragh P. O'Brien, Daniel O'Connor, Denise O'Donnell, Graham Ogg, Lauren Overend, Inhye Park, Ian Pavord, Yanchun Peng, Frank Penkava, Mariana Pereira Pinho, Elena Perez, Andrew J. Pollard, Fiona Powrie, Bethan Psaila, T. Phuong Quan, Emmanouela Repapi, Santiago Revale, Laura Silva-Reyes, Jean-Baptiste Richard, Charlotte Rich-Griffin, Thomas Ritter, Christine S. Rollier, Matthew Rowland, Fabian Ruehle, Mariolina Salio, Stephen Nicholas Sansom, Raphael Sanches Peres, Alberto Santos Delgado, Tatjana Sauka-Spengler, Ron Schwessinger, Giuseppe Scozzafava, Gavin Screaton, Anna Seigal, Malcolm G. Semple, Martin Sergeant, Christina Simoglou Karali, David Sims, Donal Skelly, Hubert Slawinski, Alberto Sobrinodiaz, Nikolaos Sousos, Lizzie Stafford, Lisa Stockdale, Marie Strickland, Otto Sumray, Bo Sun, Chelsea Taylor, Stephen Taylor, Adan Taylor, Supat Thongjuea, Hannah Thraves, John A. Todd, Adriana Tomic, Orion Tong, Amy Trebes, Dominik Trzupek, Felicia Anna Tucci, Lance Turtle, Irina Udalova, Holm Uhlig, Erinke van Grinsven, Iolanda Vendrell, Marije Verheul, Alexandru Voda, Guanlin Wang, Lihui Wang, Dapeng Wang, Peter Watkinson, Robert Watson, Michael Weinberger, Justin Whalley, Lorna Witty, Katherine Wray, Luzheng Xue, Hing Yuen Yeung, Zixi Yin, Rebecca K. Young, Jonathan Youngs, Ping Zhang, Yasemin-Xiomara Zurke, Cribbs, AP, and Consortium, COvid-19 Multi-omics Blood ATlas (COMBAT)

Subjects
Resource, Adult, Male, Myeloid, Proteome, coronavirus, Cell Cycle Proteins, Disease, Severity of Illness Index, General Biochemistry, Genetics and Molecular Biology, Monocytes, Sepsis, Machine Learning, Mitogen-Activated Protein Kinase 14, transcriptomics, Immune system, proteomics, blood, Influenza, Human, medicine, Humans, Lymphocytes, Progenitor cell, Principal Component Analysis, epigenetics, business.industry, SARS-CoV-2, Clinical study design, Acute-phase protein, COVID-19, personalized medicine, Blood Proteins, multi-omics, Middle Aged, medicine.disease, Coronavirus, Transcription Factor AP-1, medicine.anatomical_structure, Drug development, Immunology, Female, immune, business, Biomarkers
Abstract

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design and personalized medicine approaches for COVID-19., Graphical Abstract, A multi-omic analysis of patient blood samples reveals both similarities and specific features of COVID-19 when compared with samples obtained from sepsis or influenza patients which could yield better targetted therapies for severe COVID-19.

Published
2021

31. Community prevalence of SARS-CoV-2 in England from April to November, 2020: results from the ONS Coronavirus Infection Survey

Author

Koen B Pouwels, Thomas House, Emma Pritchard, Julie V Robotham, Paul J Birrell, Andrew Gelman, Karina-Doris Vihta, Nikola Bowers, Ian Boreham, Heledd Thomas, James Lewis, Iain Bell, John I Bell, John N Newton, Jeremy Farrar, Ian Diamond, Pete Benton, Ann Sarah Walker, Koen B. Pouwels, A. Sarah Walker, Derrick Crook, Philippa C. Matthews, Tim Peto, Nicole Stoesser, Alison Howarth, George Doherty, James Kavanagh, Kevin K. Chau, Stephanie B. Hatch, Daniel Ebner, Lucas Martins Ferreira, Thomas Christott, Brian D. Marsden, Wanwisa Dejnirattisai, Juthathip Mongkolsapaya, Sarah Hoosdally, Richard Cornall, David I. Stuart, Gavin Screaton, David Eyre, John Bell, Stuart Cox, Kevin Paddon, Tim James, John N. Newton, Julie V. Robotham, Paul Birrell, Helena Jordan, Tim Sheppard, Graham Athey, Dan Moody, Leigh Curry, Pamela Brereton, Jodie Hay, Harper Vansteenhouse, Alex Lambert, Emma Rourke, Stacey Hawkes, Sarah Henry, James Scruton, Peter Stokes, Tina Thomas, John Allen, Russell Black, Heather Bovill, David Braunholtz, Dominic Brown, Sarah Collyer, Megan Crees, Colin Daglish, Byron Davies, Hannah Donnarumma, Julia Douglas-Mann, Antonio Felton, Hannah Finselbach, Eleanor Fordham, Alberta Ipser, Joe Jenkins, Joel Jones, Katherine Kent, Geeta Kerai, Lina Lloyd, Victoria Masding, Ellie Osborn, Alpi Patel, Elizabeth Pereira, Tristan Pett, Melissa Randall, Donna Reeve, Palvi Shah, Ruth Snook, Ruth Studley, Esther Sutherland, Eliza Swinn, Anna Tudor, Joshua Weston, Shayla Leib, James Tierney, Gabor Farkas, Raf Cobb, Folkert Van Galen, Lewis Compton, James Irving, John Clarke, Rachel Mullis, Lorraine Ireland, Diana Airimitoaie, Charlotte Nash, Danielle Cox, Sarah Fisher, Zoe Moore, James McLean, and Matt Kerby

Subjects
Adult, Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Adolescent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Population, 01 natural sciences, 03 medical and health sciences, Young Adult, 0302 clinical medicine, COVID-19 Testing, Residence Characteristics, Epidemiology, Pandemic, Credible interval, Prevalence, Medicine, Humans, Public Health Surveillance, 030212 general & internal medicine, Positive test, 0101 mathematics, Young adult, education, Child, Aged, education.field_of_study, business.industry, 010102 general mathematics, Public Health, Environmental and Occupational Health, COVID-19, Articles, Middle Aged, Health Surveys, England, Child, Preschool, Female, business, Demography
Abstract

Summary Background Decisions about the continued need for control measures to contain the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rely on accurate and up-to-date information about the number of people testing positive for SARS-CoV-2 and risk factors for testing positive. Existing surveillance systems are generally not based on population samples and are not longitudinal in design. Methods Samples were collected from individuals aged 2 years and older living in private households in England that were randomly selected from address lists and previous Office for National Statistics surveys in repeated cross-sectional household surveys with additional serial sampling and longitudinal follow-up. Participants completed a questionnaire and did nose and throat self-swabs. The percentage of individuals testing positive for SARS-CoV-2 RNA was estimated over time by use of dynamic multilevel regression and poststratification, to account for potential residual non-representativeness. Potential changes in risk factors for testing positive over time were also assessed. The study is registered with the ISRCTN Registry, ISRCTN21086382. Findings Between April 26 and Nov 1, 2020, results were available from 1 191 170 samples from 280 327 individuals; 5231 samples were positive overall, from 3923 individuals. The percentage of people testing positive for SARS-CoV-2 changed substantially over time, with an initial decrease between April 26 and June 28, 2020, from 0·40% (95% credible interval 0·29–0·54) to 0·06% (0·04–0·07), followed by low levels during July and August, 2020, before substantial increases at the end of August, 2020, with percentages testing positive above 1% from the end of October, 2020. Having a patient-facing role and working outside your home were important risk factors for testing positive for SARS-CoV-2 at the end of the first wave (April 26 to June 28, 2020), but not in the second wave (from the end of August to Nov 1, 2020). Age (young adults, particularly those aged 17–24 years) was an important initial driver of increased positivity rates in the second wave. For example, the estimated percentage of individuals testing positive was more than six times higher in those aged 17–24 years than in those aged 70 years or older at the end of September, 2020. A substantial proportion of infections were in individuals not reporting symptoms around their positive test (45–68%, dependent on calendar time. Interpretation Important risk factors for testing positive for SARS-CoV-2 varied substantially between the part of the first wave that was captured by the study (April to June, 2020) and the first part of the second wave of increased positivity rates (end of August to Nov 1, 2020), and a substantial proportion of infections were in individuals not reporting symptoms, indicating that continued monitoring for SARS-CoV-2 in the community will be important for managing the COVID-19 pandemic moving forwards. Funding Department of Health and Social Care.

Published
2021
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32. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Author

Merryn Voysey, Sue Ann Costa Clemens, Shabir A Madhi, Lily Y Weckx, Pedro M Folegatti, Parvinder K Aley, Brian Angus, Vicky L Baillie, Shaun L Barnabas, Qasim E Bhorat, Sagida Bibi, Carmen Briner, Paola Cicconi, Andrea M Collins, Rachel Colin-Jones, Clare L Cutland, Thomas C Darton, Keertan Dheda, Christopher J A Duncan, Katherine R W Emary, Katie J Ewer, Lee Fairlie, Saul N Faust, Shuo Feng, Daniela M Ferreira, Adam Finn, Anna L Goodman, Catherine M Green, Christopher A Green, Paul T Heath, Catherine Hill, Helen Hill, Ian Hirsch, Susanne H C Hodgson, Alane Izu, Susan Jackson, Daniel Jenkin, Carina C D Joe, Simon Kerridge, Anthonet Koen, Gaurav Kwatra, Rajeka Lazarus, Alison M Lawrie, Alice Lelliott, Vincenzo Libri, Patrick J Lillie, Raburn Mallory, Ana V A Mendes, Eveline P Milan, Angela M Minassian, Alastair McGregor, Hazel Morrison, Yama F Mujadidi, Anusha Nana, Peter J O’Reilly, Sherman D Padayachee, Ana Pittella, Emma Plested, Katrina M Pollock, Maheshi N Ramasamy, Sarah Rhead, Alexandre V Schwarzbold, Nisha Singh, Andrew Smith, Rinn Song, Matthew D Snape, Eduardo Sprinz, Rebecca K Sutherland, Richard Tarrant, Emma C Thomson, M Estée Török, Mark Toshner, David P J Turner, Johan Vekemans, Tonya L Villafana, Marion E E Watson, Christopher J Williams, Alexander D Douglas, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Andrew J Pollard, Marites Aban, Fatola Abayomi, Kushala Abeyskera, Jeremy Aboagye, Matthew Adam, Kirsty Adams, James Adamson, Yemi A. Adelaja, Gbadebo Adewetan, Syed Adlou, Khatija Ahmed, Yasmeen Akhalwaya, Saajida Akhalwaya, Andrew Alcock, Aabidah Ali, Elizabeth R. Allen, Lauren Allen, Thamires C. D. S. C Almeida, Mariana P.S. Alves, Fabio Amorim, Foteini Andritsou, Rachel Anslow, Matthew Appleby, Edward H. Arbe-Barnes, Mark P. Ariaans, Beatriz Arns, Laiana Arruda, Paula Azi, Lorena Azi, Gavin Babbage, Catherine Bailey, Kenneth F. Baker, Megan Baker, Natalie Baker, Philip Baker, Lisa Baldwin, Ioana Baleanu, Danieli Bandeira, Anna Bara, Marcella A.S. Barbosa, Debbie Barker, Gavin D. Barlow, Eleanor Barnes, Andrew S. Barr, Jordan R. Barrett, Jessica Barrett, Louise Bates, Alexander Batten, Kirsten Beadon, Emily Beales, Rebecca Beckley, Sandra Belij-Rammerstorfer, Jonathan Bell, Duncan Bellamy, Nancy Bellei, Sue Belton, Adam Berg, Laura Bermejo, Eleanor Berrie, Lisa Berry, Daniella Berzenyi, Amy Beveridge, Kevin R. Bewley, Helen Bexhell, Sutika Bhikha, Asad E. Bhorat, Zaheda E. Bhorat, Else Bijker, Geeta Birch, Sarah Birch, Adam Bird, Olivia Bird, Karen Bisnauthsing, Mustapha Bittaye, Katherine Blackstone, Luke Blackwell, Heather Bletchly, Caitlin L. Blundell, Susannah R. Blundell, Pritesh Bodalia, Bruno C. Boettger, Emma Bolam, Elena Boland, Daan Bormans, Nicola Borthwick, Francesca Bowring, Amy Boyd, Penny Bradley, Tanja Brenner, Phillip Brown, Claire Brown, Charlie Brown-O'Sullivan, Scott Bruce, Emily Brunt, Ruaridh Buchan, William Budd, Yusuf A. Bulbulia, Melanie Bull, Jamie Burbage, Hassan Burhan, Aileen Burn, Karen R. Buttigieg, Nicholas Byard, Ingrid Cabera Puig, Gloria Calderon, Anna Calvert, Susana Camara, Michelangelo Cao, Federica Cappuccini, João R. Cardoso, Melanie Carr, Miles W. Carroll, Andrew Carson-Stevens, Yasmin de M. Carvalho, José A.M. Carvalho, Helen R. Casey, Paul Cashen, Thais Castro, Lucia Carratala Castro, Katrina Cathie, Ana Cavey, José Cerbino-Neto, Jim Chadwick, David Chapman, Sue Charlton, Irina Chelysheva, Oliver Chester, Sunder Chita, Jee-Sun Cho, Liliana Cifuentes, Elizabeth Clark, Matthew Clark, Andrea Clarke, Elizabeth A. Clutterbuck, Sarah L.K. Collins, Christopher P. Conlon, Sean Connarty, Naomi Coombes, Cushla Cooper, Rachel Cooper, Lynne Cornelissen, Tumena Corrah, Catherine Cosgrove, Tony Cox, Wendy E.M. Crocker, Sarah Crosbie, Lorraine Cullen, Dan Cullen, Debora R.M.F. Cunha, Christina Cunningham, Fiona C. Cuthbertson, Suzete N. Farias Da Guarda, Larissa P. da Silva, Brad E. Damratoski, Zsofia Danos, Maria T.D.C. Dantas, Paula Darroch, Mehreen S. Datoo, Chandrabali Datta, Malika Davids, Sarah L. Davies, Hannah Davies, Elizabeth Davis, Judith Davis, John Davis, Maristela M.D. De Nobrega, Lis Moreno De Oliveira Kalid, David Dearlove, Tesfaye Demissie, Amisha Desai, Stefania Di Marco, Claudio Di Maso, Maria I.S. Dinelli, Tanya Dinesh, Claire Docksey, Christina Dold, Tao Dong, Francesca R. Donnellan, Tannyth Dos Santos, Thainá G. dos Santos, Erika Pachecho Dos Santos, Naomi Douglas, Charlotte Downing, Jonathan Drake, Rachael Drake-Brockman, Kimberley Driver, Ruth Drury, Susanna J. Dunachie, Benjamin S. Durham, Lidiana Dutra, Nicholas J.W. Easom, Samual van Eck, Mandy Edwards, Nick J. Edwards, Omar M. El Muhanna, Sean C. Elias, Mike Elmore, Marcus English, Alisgair Esmail, Yakub Moosa Essack, Eoghan Farmer, Mutjaba Farooq, Madi Farrar, Leonard Farrugia, Beverley Faulkner, Sofiya Fedosyuk, Sally Felle, Carla Ferreira Da Silva, Samantha Field, Richard Fisher, Amy Flaxman, James Fletcher, Hazel Fofie, Henry Fok, Karen J. Ford, Jamie Fowler, Pedro H.A. Fraiman, Emma Francis, Marilia M. Franco, John Frater, Marilúcia S.M. Freire, Samantha H. Fry, Sabrina Fudge, Julie Furze, Michelle Fuskova, Pablo Galian-Rubio, Eva Galiza, Harriet Garlant, Madita Gavrila, Ailsa Geddes, Karyna A. Gibbons, Ciaran Gilbride, Hardeep Gill, Sharon Glynn, Kerry Godwin, Karishma Gokani, Ursula Carvalho Goldoni, Maria Goncalves, Isabela G.S. Gonzalez, Jayne Goodwin, Amina Goondiwala, Katherine Gordon-Quayle, Giacomo Gorini, Janet Grab, Lara Gracie, Melanie Greenland, Nicola Greenwood, Johann Greffrath, Marisa M. Groenewald, Leonardo Grossi, Gaurav Gupta, Mark Hackett, Bassam Hallis, Mainga Hamaluba, Elizabeth Hamilton, Joseph Hamlyn, Daniel Hammersley, Aidan T. Hanrath, Brama Hanumunthadu, Stephanie A. Harris, Clair Harris, Tara Harris, Thomas D. Harrison, Daisy Harrison, Thomas C. Hart, Birgit Hartnell, Shadin Hassan, John Haughney, Sophia Hawkins, Jodie Hay, Ian Head, John Henry, Macarena Hermosin Herrera, David B. Hettle, Jennifer Hill, Gina Hodges, Elizea Horne, Mimi M. Hou, Catherine Houlihan, Elizabeth Howe, Nicola Howell, Jonathan Humphreys, Holly E. Humphries, Katrina Hurley, Claire Huson, Angela Hyder-Wright, Catherine Hyams, Sabina Ikram, Alka Ishwarbhai, Monica Ivan, Poppy Iveson, Vidyashankara Iyer, Frederic Jackson, Jeanne De Jager, Shameem Jaumdally, Helen Jeffers, Natasha Jesudason, Bryony Jones, Kathryn Jones, Elizabeth Jones, Christopher Jones, Marianna Rocha Jorge, Aylin Jose, Amar Joshi, Eduardo A.M.S. Júnior, Joanne Kadziola, Reshma Kailath, Faeeza Kana, Konstantinos Karampatsas, Mwila Kasanyinga, Jade Keen, Elizabeth J. Kelly, Dearbhla M. Kelly, Debbie Kelly, Sarah Kelly, David Kerr, Renato de Ávila Kfouri, Liaquat Khan, Baktash Khozoee, Sarah Kidd, Annabel Killen, Jasmin Kinch, Patrick Kinch, Lloyd D.W. King, Thomas B. King, Lucy Kingham, Paul Klenerman, Francesca Knapper, Julian C. Knight, Daniel Knott, Stanislava Koleva, Matilda Lang, Gail Lang, Colin W. Larkworthy, Jessica P.J. Larwood, Rebecca Law, Erica M. Lazarus, Amanda Leach, Emily A. Lees, Nana-Marie Lemm, Alvaro Lessa, Stephanie Leung, Yuanyuan Li, Amelia M. Lias, Kostas Liatsikos, Aline Linder, Samuel Lipworth, Shuchang Liu, Xinxue Liu, Adam Lloyd, Stephanie Lloyd, Lisa Loew, Raquel Lopez Ramon, Leandro Lora, Vicki Lowthorpe, Kleber Luz, Jonathan C. MacDonald, Gordon MacGregor, Meera Madhavan, David O. Mainwaring, Edson Makambwa, Rebecca Makinson, Mookho Malahleha, Ross Malamatsho, Garry Mallett, Kushal Mansatta, Takalani Maoko, Katlego Mapetla, Natalie G. Marchevsky, Spyridoula Marinou, Emma Marlow, Gabriela N. Marques, Paula Marriott, Richard P. Marshall, Julia L. Marshall, Flávia J. Martins, Masebole Masenya, Mduduzi Masilela, Shauna K. Masters, Moncy Mathew, Hosea Matlebjane, Kedidimetse Matshidiso, Olga Mazur, Andrea Mazzella, Hugh McCaughan, Joanne McEwan, Joanna McGlashan, Lorna McInroy, Zoe McIntyre, Daniela McLenaghan, Nicky McRobert, Steve McSwiggan, Clare Megson, Savviz Mehdipour, Wilma Meijs, Renata N.Á. Mendonça, Alexander J. Mentzer, Neginsadat Mirtorabi, Celia Mitton, Sibusiso Mnyakeni, Fiona Moghaddas, Kgaogelo Molapo, Mapule Moloi, Maria Moore, M. Isabel Moraes-Pinto, Marni Moran, Ella Morey, Róisín Morgans, Susan Morris, Sheila Morris, Helen C. Morris, Franca Morselli, Gertraud Morshead, Richard Morter, Lynelle Mottal, Andrew Moultrie, Nathifa Moya, Mushiya Mpelembue, Sibekezelo Msomi, Yvonne Mugodi, Ekta Mukhopadhyay, Jilly Muller, Alasdair Munro, Claire Munro, Sarah Murphy, Philomena Mweu, Celia Hatsuko Myasaki, Gurudutt Naik, Kush Naker, Eleni Nastouli, Abida Nazir, Bongani Ndlovu, Fabio Neffa, Cecilia Njenga, Helena Noal, Andrés Noé, Gabrielle Novaes, Fay L. Nugent, Géssika Nunes, Katie O'Brien, Daniel O'Connor, Miranda Odam, Suzette Oelofse, Blanche Oguti, Victoria Olchawski, Neil J. Oldfield, Marianne G. Oliveira, Catarina Oliveira, Angela Oosthuizen, Paula O'Reilly, Piper Osborne, David R.J. Owen, Lydia Owen, Daniel Owens, Nelly Owino, Mihaela Pacurar, Brenda V.B. Paiva, Edna M.F. Palhares, Susan Palmer, Sivapriyai Parkinson, Helena M.R.T. Parracho, Karen Parsons, Dipak Patel, Bhumika Patel, Faeezah Patel, Kelly Patel, Maia Patrick-Smith, Ruth O. Payne, Yanchun Peng, Elizabeth J. Penn, Anna Pennington, Marco Polo Peralta Alvarez, James Perring, Nicola Perry, Rubeshan Perumal, Sahir Petkar, Tricia Philip, Daniel J. Phillips, Jennifer Phillips, Mary Kgomotso Phohu, Lorinda Pickup, Sonja Pieterse, Jo Piper, Dimitra Pipini, Mary Plank, Joan Du Plessis, Samuel Pollard, Jennifer Pooley, Anil Pooran, Ian Poulton, Claire Powers, Fernando B. Presa, David A. Price, Vivien Price, Marcelo Primeira, Pamela C. Proud, Samuel Provstgaard-Morys, Sophie Pueschel, David Pulido, Sheena Quaid, Ria Rabara, Alexandra Radford, Kajal Radia, Durga Rajapaska, Thurkka Rajeswaran, Alberto San Francisco Ramos, Fernando Ramos Lopez, Tommy Rampling, Jade Rand, Helen Ratcliffe, Tom Rawlinson, David Rea, Byron Rees, Jesús Reiné, Mila Resuello-Dauti, Emilia Reyes Pabon, Carla M. Ribiero, Marivic Ricamara, Alex Richter, Neil Ritchie, Adam J. Ritchie, Alexander J. Robbins, Hannah Roberts, Ryan E. Robinson, Hannah Robinson, Talita T. Rocchetti, Beatriz Pinho Rocha, Sophie Roche, Christine Rollier, Louisa Rose, Amy L. Ross Russell, Lindie Rossouw, Simon Royal, Indra Rudiansyah, Sarah Ruiz, Stephen Saich, Claudia Sala, Jessica Sale, Ahmed M. Salman, Natalia Salvador, Stephannie Salvador, Milla Sampaio, Annette D. Samson, Amada Sanchez-Gonzalez, Helen Sanders, Katherine Sanders, Erika Santos, Mayara F.S. Santos Guerra, Iman Satti, Jack E. Saunders, Caroline Saunders, Aakifah Sayed, Ina Schim van der Loeff, Annina B. Schmid, Ella Schofield, Gavin Screaton, Samiullah Seddiqi, Rameswara R. Segireddy, Roberta Senger, Sonia Serrano, Rajiv Shah, Imam Shaik, Hannah E. Sharpe, Katherine Sharrocks, Robert Shaw, Adam Shea, Amy Shepherd, James G. Shepherd, Farah Shiham, Emad Sidhom, Sarah E. Silk, Antonio Carlos da Silva Moraes, Gilberto Silva-Junior, Laura Silva-Reyes, Anderson D. Silveira, Mariana B.V. Silveira, Jaisi Sinha, Donal T. Skelly, Daniel C. Smith, Nick Smith, Holly E. Smith, David J. Smith, Catherine C. Smith, Airanuédida Soares, Tiago Soares, Carla Solórzano, Guilherme L. Sorio, Kim Sorley, Tiffany Sosa-Rodriguez, Cinthia M.C.D.L. Souza, Bruno S.D.F. Souza, Alessandra R. Souza, Alexandra J. Spencer, Fernanda Spina, Louise Spoors, Lizzie Stafford, Imogen Stamford, Igor Starinskij, Ricardo Stein, Jill Steven, Lisa Stockdale, Lisa V. Stockwell, Louise H. Strickland, Arabella C. Stuart, Ann Sturdy, Natalina Sutton, Anna Szigeti, Abdessamad Tahiri-Alaoui, Rachel Tanner, Carol Taoushanis, Alexander W. Tarr, Keja Taylor, Ursula Taylor, Iona Jennifer Taylor, Justin Taylor, Rebecca te Water Naude, Yrene Themistocleous, Andreas Themistocleous, Merin Thomas, Kelly Thomas, Tonia M. Thomas, Asha Thombrayil, Fawziyah Thompson, Amber Thompson, Kevin Thompson, Ameeka Thompson, Julia Thomson, Viv Thornton-Jones, Patrick J. Tighe, Lygia Accioly Tinoco, Gerlynn Tiongson, Bonolo Tladinyane, Michele Tomasicchio, Adriana Tomic, Susan Tonks, James Towner, Nguyen Tran, Julia Tree, Gerry Trillana, Charlotte Trinham, Rose Trivett, Adam Truby, Betty Lebogang Tsheko, Aadil Turabi, Richard Turner, Cheryl Turner, Marta Ulaszewska, Benjamin R. Underwood, Rachel Varughese, Dennis Verbart, Marije Verheul, Iason Vichos, Taiane Vieira, Claire S. Waddington, Laura Walker, Erica Wallis, Matthew Wand, Deborah Warbick, Theresa Wardell, George Warimwe, Sarah C. Warren, Bridget Watkins, Ekaterina Watson, Stewart Webb, Alice Webb-Bridges, Angela Webster, Jessica Welch, Jeanette Wells, Alison West, Caroline White, Rachel White, Paul Williams, Rachel L. Williams, Rebecca Winslow, Mark Woodyer, Andrew T. Worth, Danny Wright, Marzena Wroblewska, Andy Yao, Rafael Zimmer, Dalila Zizi, Peter Zuidewind, Group, Oxford COVID Vaccine Trial, Toshner, Mark [0000-0002-3969-6143], and Apollo - University of Cambridge Repository

Subjects
Male, COVID-19/prevention & control, 030204 cardiovascular system & hematology, law.invention, South Africa, 0302 clinical medicine, Randomized controlled trial, law, Oxford COVID Vaccine Trial Group, wc_505, Single-Blind Method, 030212 general & internal medicine, Young adult, 11 Medical and Health Sciences, wa_105, Covid19, General Medicine, Articles, Middle Aged, Treatment Outcome, Cohort, Perspective, Female, Brazil, Adult, medicine.medical_specialty, COVID-19 Vaccines, Adolescent, qw_806, qw_805, 03 medical and health sciences, Young Adult, Double-Blind Method, Conjugate vaccine, Internal medicine, General & Internal Medicine, ChAdOx1 nCoV-19, medicine, Humans, Adverse effect, Aged, business.industry, SARS-CoV-2, COVID-19, Viral Vaccines, Vaccine efficacy, Interim analysis, United Kingdom, Clinical trial, bf023de6, business, COVID-19 Vaccines/adverse effects
Abstract

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Published
2020

33. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

Author

Maheshi N Ramasamy, Angela M Minassian, Katie J Ewer, Amy L Flaxman, Pedro M Folegatti, Daniel R Owens, Merryn Voysey, Parvinder K Aley, Brian Angus, Gavin Babbage, Sandra Belij-Rammerstorfer, Lisa Berry, Sagida Bibi, Mustapha Bittaye, Katrina Cathie, Harry Chappell, Sue Charlton, Paola Cicconi, Elizabeth A Clutterbuck, Rachel Colin-Jones, Christina Dold, Katherine R W Emary, Sofiya Fedosyuk, Michelle Fuskova, Diane Gbesemete, Catherine Green, Bassam Hallis, Mimi M Hou, Daniel Jenkin, Carina C D Joe, Elizabeth J Kelly, Simon Kerridge, Alison M Lawrie, Alice Lelliott, May N Lwin, Rebecca Makinson, Natalie G Marchevsky, Yama Mujadidi, Alasdair P S Munro, Mihaela Pacurar, Emma Plested, Jade Rand, Thomas Rawlinson, Sarah Rhead, Hannah Robinson, Adam J Ritchie, Amy L Ross-Russell, Stephen Saich, Nisha Singh, Catherine C Smith, Matthew D Snape, Rinn Song, Richard Tarrant, Yrene Themistocleous, Kelly M Thomas, Tonya L Villafana, Sarah C Warren, Marion E E Watson, Alexander D Douglas, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Saul N Faust, Andrew J Pollard, Jeremy Aboagye, Kelly Adams, Aabidah Ali, Elizabeth R. Allen, Lauren Allen, Jennifer L. Allison, Foteini Andritsou, Rachel Anslow, Edward H. Arbe-Barnes, Megan Baker, Natalie Baker, Philip Baker, Ioana Baleanu, Debbie Barker, Eleanor Barnes, Jordan R. Barrett, Kelly Barrett, Louise Bates, Alexander Batten, Kirsten Beadon, Rebecca Beckley, Duncan Bellamy, Adam Berg, Laura Bermejo, Eleanor Berrie, Amy Beveridge, Kevin Bewley, Else M. Bijker, Geeta Birch, Luke Blackwell, Heather Bletchly, Caitlin L. Blundell, Susannah R. Blundell, Emma Bolam, Elena Boland, Daan Bormans, Nicola Borthwick, Konstantinos Boukas, Thomas Bower, Francesca Bowring, Amy Boyd, Tanja Brenner, Phillip Brown, Charlie Brown-O'Sullivan, Scott Bruce, Emily Brunt, Jamie Burbage, Joshua Burgoyne, Karen R. Buttigieg, Nicholas Byard, Ingrid Cabera Puig, Susana Camara, Michelangelo Cao, Federica Cappuccini, Melanie Carr, Miles W. Carroll, Paul Cashen, Ana Cavey, Jim Chadwick, Ruth Challis, David Chapman, David Charles, Irina Chelysheva, Jee-Sun Cho, Liliana Cifuentes, Elizabeth Clark, Sarah Collins, Christopher P. Conlon, Naomi S. Coombes, Rachel Cooper, Cushla Cooper, Wendy E.M. Crocker, Sarah Crosbie, Dan Cullen, Christina Cunningham, Fiona Cuthbertson, Brad E. Datoo, Lynne Dando, Mehreen S. Datoo, Chandrabali Datta, Hannah Davies, Sarah Davies, Elizabeth J. Davis, Judith Davis, David Dearlove, Tesfaye Demissie, Stefania Di Marco, Claudio Di Maso, Danielle DiTirro, Claire Docksey, Tao Dong, Francesca R. Donnellan, Naomi Douglas, Charlotte Downing, Jonathan Drake, Rachael Drake-Brockman, Ruth E. Drury, Susanna J. Dunachie, Christopher J. Edwards, Nick J. Edwards, Omar El Muhanna, Sean C. Elias, Ryan S. Elliott, Michael J. Elmore, Marcus Rex English, Sally Felle, Shuo Feng, Carla Ferreira Da Silva, Samantha Field, Richard Fisher, Carine Fixmer, Karen J. Ford, Jamie Fowler, Emma Francis, John Frater, Julie Furze, Pablo Galian-Rubio, Celine Galloway, Harriet Garlant, Madita Gavrila, Felicity Gibbons, Karyna Gibbons, Ciaran Gilbride, Hardeep Gill, Kerry Godwin, Katherine Gordon-Quayle, Giacomo Gorini, Lyndsey Goulston, Caroline Grabau, Lara Gracie, Nichola Graham, Nicola Greenwood, Oliver Griffiths, Gaurav Gupta, Elizabeth Hamilton, Brama Hanumunthadu, Stephanie A. Harris, Tara Harris, Daisy Harrison, Thomas C. Hart, Birgit Hartnell, Louise Haskell, Sophia Hawkins, John Aaron Henry, Macarena Hermosin Herrera, David Hill, Jennifer Hill, Gina Hodges, Susanne H.C. Hodgson, Katie L. Horton, Elizabeth Howe, Nicola Howell, Jessica Howes, Ben Huang, Jonathan Humphreys, Holly E. Humphries, Poppy Iveson, Frederic Jackson, Susan Jackson, Sam Jauregui, Helen Jeffers, Bryony Jones, Christine E. Jones, Elizabeth Jones, Kathryn Jones, Amar Joshi, Reshma Kailath, Jade Keen, Dearbhla M. Kelly, Sarah Kelly, Debbie Kelly, David Kerr, Liaquat Khan, Baktash Khozoee, Annabel Killen, Jasmin Kinch, Lloyd D.W. King, Thomas B. King, Lucy Kingham, Paul Klenerman, Julian C. Knight, Daniel Knott, Stanislava Koleva, Gail Lang, Colin W. Larkworthy, Jessica P.J. Larwood, Rebecca Law, Arlene Lee, Kim Y.N. Lee, Emily A. Lees, Stephanie Leung, Yuanyuan Li, Amelia M. Lias, Aline Linder, Samuel Lipworth, Shuchang Liu, Xinxue Liu, Stephanie Lloyd, Lisa Loew, Raquel Lopez Ramon, Meera Madhavan, David O. Mainwaring, Garry Mallett, Kushal Mansatta, Spyridoula Marinou, Phedra Marius, Emma Marlow, Paula Marriott, Julia L. Marshall, Jane Martin, Shauna Masters, Joanne McEwan, Joanna L. McGlashan, Lorna McInroy, Nicky McRobert, Clare Megson, Alexander J. Mentzer, Neginsadat Mirtorabi, Celia Mitton, Maria Moore, Marni Moran, Ella Morey, Róisín Morgans, Susan J. Morris, Hazel Morrison Morrison, Gertraud Morshead, Richard Morter, Nathifa A. Moya, Ekta Mukhopadhyay, Jilly Muller, Claire Munro, Sarah Murphy, Philomena Mweu, Andrés Noé, Fay L. Nugent, Katie O'Brien, Daniel O'Connor, Blanché Oguti, Victoria Olchawski, Catarina Oliveira, Peter John O'Reilly, Piper Osborne, Lydia Owen, Nelly Owino, Panagiotis Papageorgiou, Helena Parracho, Karen Parsons, Bhumika Patel, Maia Patrick-Smith, Yanchun Peng, Elizabeth J. Penn, Marco Polo Peralta-Alvarez, James Perring, Christos Petropoulos, Daniel J. Phillips, Dimitra Pipini, Samuel Pollard, Ian Poulton, Danny Pratt, Laura Presland, Pamela C. Proud, Samuel Provstgaard-Morys, Sophie Pueschel, David Pulido, Ria Rabara, Kajal Radia, Durga Rajapaska, Fernando Ramos Lopez, Helen Ratcliffe, Sara Rayhan, Byron Rees, Emilia Reyes Pabon, Hannah Roberts, Isla Robertson, Sophie Roche, Christine S. Rollier, Rossana Romani, Zoe Rose, Indra Rudiansyah, Sabeha Sabheha, Stephannie Salvador, Helen Sanders, Katherine Sanders, Iman Satti, Chloe Sayce, Annina B. Schmid, Ella Schofield, Gavin Screaton, Cynthia Sedik, Samiullah Seddiqi, Rameswara R. Segireddy, Beatrice Selby, Imam Shaik, Hannah R. Sharpe, Robert Shaw, Adam Shea, Sarah Silk, Laura Silva-Reyes, Donal T. Skelly, David J. Smith, Daniel C. Smith, Nicholas Smith, Alexandra J. Spencer, Louise Spoors, Elizabeth Stafford, Imogen Stamford, Lisa Stockdale, David Stockley, Lisa V. Stockwell, Matthew Stokes, Louise H. Strickland, Arabella Stuart, Sulaiman Sulaiman, Eloise Summerton, Zoe Swash, Anna Szigeti, Abdessamad Tahiri-Alaoui, Rachel Tanner, Iona Taylor, Keja Taylor, Ursula Taylor, Rebecca te Water Naude, Andreas Themistocleous, Merin Thomas, Tonia M. Thomas, Amber Thompson, Kevin Thompson, Viv Thornton-Jones, Lan Tinh, Adriana Tomic, Susan Tonks, James Towner, Nguyen Tran, Julian A. Tree, Adam Truby, Cheryl Turner, Richard Turner, Marta Ulaszewska, Rachel Varughese, Dennis Verbart, Marije K. Verheul, Iason Vichos, Laura Walker, Matthew E. Wand, Bridget Watkins, Jessica Welch, Alison J. West, Caroline White, Rachel White, Paul Williams, Mark Woodyer, Andrew T. Worth, Daniel Wright, Terri Wrin, Xin Li Yao, Diana-Andreea Zbarcea, and Dalila Zizi

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, COVID-19 Vaccines, Adolescent, Immunization, Secondary, Department of Error, 030204 cardiovascular system & hematology, law.invention, Young Adult, 03 medical and health sciences, Immunogenicity, Vaccine, 0302 clinical medicine, Randomized controlled trial, law, ChAdOx1 nCoV-19, medicine, Humans, Single-Blind Method, 030212 general & internal medicine, Young adult, Adverse effect, Aged, Aged, 80 and over, Reactogenicity, SARS-CoV-2, business.industry, Age Factors, COVID-19, Articles, General Medicine, Middle Aged, Clinical trial, Vaccination, Regimen, Immunoglobulin G, Cohort, Female, business
Abstract

BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Published
2020

34. Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020

Author

Alexander Mentzer, Mahdad Noursadeghi, Charlotte Summers, Graciela Isabel García Dorival, CESAR LOPEZ-CAMACHO, Gavin Screaton, Andrew Ustianowski, Ryan Thwaites, Lorna Finch, Innocent Gerald Asiimwe, Anna McNaughton, Stuart Hartshorn, Robert Paton, Gary Leeming, Lance Turtle, Thushan De Silva, Lauren Lett, Maria Vittoria Mancini, Chris Davis, Wei Shen Lim, Malcolm Gracie Semple, Tom Fletcher, Katie Ahmed, Jeremy Ratcliff, Chrysa Koukorava, Patrick Lillie, Kreepa Kooblall, Oliver Sampson, Benjamin Small, Craig Thompson, Beibei Wang, Ingeborg Welters, Suzannah Lant, Paul Klenerman, Anil Sharma, Paul Matthew Ridley, Rebecca Jensen, Nigel Temperton, José Lourenço, Effrossyni Gkrania-Klotsas, James Moon, Robyn Kiy, Ahilanandan Dushianthan, Christopher Green, Mark Peters, Sarah McDonald, Paul Dark, Emma Thomson, William Paxton, Ascanio Tridente, Georgios Pollakis, Shona Moore, Dan Hawcutt, John Kenneth Baillie, Kooblall, Kreepa [0000-0001-9547-2067], López-Camacho, César [0000-0001-7932-2341], Sampson, Oliver [0000-0001-8727-0588], Screaton, Gavin R [0000-0002-3549-4309], Temperton, Nigel [0000-0002-7978-3815], Apollo - University of Cambridge Repository, National Institute for Health Research, UK Research and Innovation, GlaxoSmithKline Biologicals, and UKRI MRC COVID-19 Rapid Response Call

Subjects
0301 basic medicine, Male, Urban Population, Epidemiology, COVID19, serology, Blood Donors, ResearchInstitutes_Networks_Beacons/humanitarian_conflict_response_institute, Antibodies, Viral, Serology, 0302 clinical medicine, Seroepidemiologic Studies, Pandemic, Prevalence, Medicine, Cluster Analysis, 030212 general & internal medicine, Geography, Medical, education.field_of_study, biology, surveillance, Scotland, Population Surveillance, Humanitarian and Conflict Response Institute, Female, Antibody, Coronavirus Infections, 0605 Microbiology, Adult, RM, Population, Pneumonia, Viral, Enzyme-Linked Immunosorbent Assay, Sensitivity and Specificity, Virus, 1117 Public Health and Health Services, 03 medical and health sciences, Betacoronavirus, Inhibitory Concentration 50, Neutralization Tests, Virology, Humans, education, ISARIC4C Investigators, Pandemics, QR355, business.industry, SARS-CoV-2, Research, pandemic, fungi, Public Health, Environmental and Occupational Health, Models, Immunological, Outbreak, COVID-19, biology.organism_classification, Antibodies, Neutralizing, QR, 030104 developmental biology, Scotland, biology.protein, business, RA, 1199 Other Medical and Health Sciences
Abstract

Background The progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression. Aim Our objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic. Methods A pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019. Results All samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5–6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic. Conclusion Although blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.

Published
2020

35. A haemagglutination test for rapid detection of antibodies to SARS-CoV-2

Author

Alain Townsend, Pramila Rijal, Julie Xiao, Tiong Kit Tan, Kuan-Ying Huang, Lisa Schimanski, Jiandong Huo, Nimesh Gupta, Rolle Rahikainen, Philippa Matthews, Derrick Crook, Sarah Hoosdally, Teresa Street, Justine Rudkin, Nicole Stoesser, Fredrik Karpe, Matthew Neville, Rutger Ploeg, Marta Oliveira, David Roberts, Abigail Lamikanra, Hoi Tsang, Abbie Bown, Richard Vipond, Alexander Mentzer, Julian Knight, Andrew Kwok, Gavin Screaton, Juthathip Mongkolsapaya, Wanwisa Dejnirattisai, Piyasa Supasa, Paul Klenerman, Christina Dold, J Baillie, Shona Moore, Peter Openshaw, Malcolm Semple, Lance Turtle, Mark Ainsworth, Alice Allcock, Sally Beer, Sagida Bibi, Elizabeth Clutterbuck, Alexis Espinosa, Maria Mendoza, Dominique Georgiou, Teresa Lockett, Jose Martinez, Elena Perez, Veronica Sanchez, Giuseppe Scozzafava, Alberto Sobrinodiaz, Hannah Thraves, and Etienne Joly

Abstract

Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, detection of seroconversion after vaccination, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests have a long history in blood typing, and general serology through linkage of reporter molecules to the red cell surface. They do not require special equipment, are read by eye, have short development times, low cost and can be applied as a Point of Care Test (POCT). We describe a red cell agglutination test for the detection of antibodies to the SARS-CoV-2 receptor binding domain (RBD). We show that the Haemagglutination Test (HAT) has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. The HAT can be titrated, detects rising titres in the first five days of hospital admission, correlates well with a commercial test that detects antibodies to the RBD, and can be applied as a point of care test. The developing reagent is composed of a previously described nanobody to a conserved glycophorin A epitope on red cells, linked to the RBD from SARS-CoV-2. It can be lyophilised for ease of shipping. We have scaled up production of this reagent to one gram, which is sufficient for ten million tests, at a cost of ~0.27 UK pence per test well. Aliquots of this reagent are ready to be supplied to qualified groups anywhere in the world that need to detect antibodies to SARS-CoV-2, but do not have the facilities for high throughput commercial tests.

Published
2020

36. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

Author

Pedro M Folegatti, Katie J Ewer, Parvinder K Aley, Brian Angus, Stephan Becker, Sandra Belij-Rammerstorfer, Duncan Bellamy, Sagida Bibi, Mustapha Bittaye, Elizabeth A Clutterbuck, Christina Dold, Saul N Faust, Adam Finn, Amy L Flaxman, Bassam Hallis, Paul Heath, Daniel Jenkin, Rajeka Lazarus, Rebecca Makinson, Angela M Minassian, Katrina M Pollock, Maheshi Ramasamy, Hannah Robinson, Matthew Snape, Richard Tarrant, Merryn Voysey, Catherine Green, Alexander D Douglas, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Andrew J Pollard, Jeremy Aboagye, Kelly Adams, Aabidah Ali, Elizabeth Allen, Jennifer L. Allison, Rachel Anslow, Edward H. Arbe-Barnes, Gavin Babbage, Kenneth Baillie, Megan Baker, Natalie Baker, Philip Baker, Ioana Baleanu, Juliana Ballaminut, Eleanor Barnes, Jordan Barrett, Louise Bates, Alexander Batten, Kirsten Beadon, Rebecca Beckley, Eleanor Berrie, Lisa Berry, Amy Beveridge, Kevin R. Bewley, Else Margreet Bijker, Tracey Bingham, Luke Blackwell, Caitlin L. Blundell, Emma Bolam, Elena Boland, Nicola Borthwick, Thomas Bower, Amy Boyd, Tanja Brenner, Philip D. Bright, Charlie Brown-O'Sullivan, Emily Brunt, Jamie Burbage, Sharon Burge, Karen R. Buttigieg, Nicholas Byard, Ingrid Cabera Puig, Anna Calvert, Susana Camara, Michelangelo Cao, Federica Cappuccini, Melanie Carr, Miles W. Carroll, Victoria Carter, Katrina Cathie, Ruth J. Challis, Sue Charlton, Irina Chelysheva, Jee-Sun Cho, Paola Cicconi, Liliana Cifuentes, Helen Clark, Elizabeth Clark, Tom Cole, Rachel Colin-Jones, Christopher P. Conlon, Aislinn Cook, Naomi S. Coombes, Rachel Cooper, Catherine A. Cosgrove, Karen Coy, Wendy E.M. Crocker, Christina J. Cunningham, Brad E. Damratoski, Lynne Dando, Mehreen S. Datoo, Hannah Davies, Hans De Graaf, Tesfaye Demissie, Claudio Di Maso, Isabelle Dietrich, Tao Dong, Francesca R. Donnellan, Naomi Douglas, Charlotte Downing, Jonathan Drake, Rachael Drake-Brockman, Ruth Elizabeth Drury, Susanna Jane Dunachie, Nick J. Edwards, Frances D.L. Edwards, Chris J. Edwards, Sean C. Elias, Michael J. Elmore, Katherine R.W. Emary, Marcus Rex English, Susanne Fagerbrink, Sally Felle, Shuo Feng, Samantha Field, Carine Fixmer, Clare Fletcher, Karen J. Ford, Jamie Fowler, Polly Fox, Emma Francis, John Frater, Julie Furze, Michelle Fuskova, Eva Galiza, Diane Gbesemete, Ciaran Gilbride, Kerry Godwin, Giacomo Gorini, Lyndsey Goulston, Caroline Grabau, Lara Gracie, Zoe Gray, Lucy Belle Guthrie, Mark Hackett, Sandro Halwe, Elizabeth Hamilton, Joseph Hamlyn, Brama Hanumunthadu, Irasha Harding, Stephanie A. Harris, Andrew Harris, Daisy Harrison, Clare Harrison, Thomas C. Hart, Louise Haskell, Sophia Hawkins, Ian Head, John Aaron Henry, Jennifer Hill, Susanne H.C. Hodgson, Mimi M. Hou, Elizabeth Howe, Nicola Howell, Cecilia Hutlin, Sabina Ikram, Catherine Isitt, Poppy Iveson, Susan Jackson, Frederic Jackson, Sir William James, Megan Jenkins, Elizabeth Jones, Kathryn Jones, Christine E. Jones, Bryony Jones, Reshma Kailath, Konstantinos Karampatsas, Jade Keen, Sarah Kelly, Dearbhla Kelly, David Kerr, Simon Kerridge, Liaquat Khan, Uzma Khan, Annabel Killen, Jasmin Kinch, Thomas B. King, Lloyd King, Jade King, Lucy Kingham-Page, Paul Klenerman, Francesca Knapper, Julian C. Knight, Daniel Knott, Stanislava Koleva, Alexandra Kupke, Colin W. Larkworthy, Jessica P.J. Larwood, Anna Laskey, Alison M. Lawrie, Arlene Lee, Kim Yee Ngan Lee, Emily A Lees, Helen Legge, Alice Lelliott, Nana-Marie Lemm, Amelia M. Lias, Aline Linder, Samuel Lipworth, Xinxue Liu, Shuchang Liu, Raquel Lopez Ramon, May Lwin, Francesca Mabesa, Meera Madhavan, Garry Mallett, Kushal Mansatta, Ines Marcal, Spyridoula Marinou, Emma Marlow, Julia L. Marshall, Jane Martin, Joanne McEwan, Lorna McInroy, Gretchen Meddaugh, Alexander J. Mentzer, Neginsadat Mirtorabi, Maria Moore, Edward Moran, Ella Morey, Victoria Morgan, Susan Jane Morris, Hazel Morrison, Gertraud Morshead, Richard Morter, Yama F. Mujadidi, Jilly Muller, Tatiana Munera-Huertas, Claire Munro, Alasdair Munro, Sarah Murphy, Vincent J. Munster, Philomena Mweu, Andrés Noé, Fay L. Nugent, Elizabeth Nuthall, Katie O'Brien, Daniel O'Connor, Blanché Oguti, Jennifer L. Oliver, Catarina Oliveira, Peter John O'Reilly, Mairead Osborn, Piper Osborne, Cathy Owen, Daniel Owens, Nelly Owino, Mihaela Pacurar, Kaye Parker, Helena Parracho, Maia Patrick-Smith, Victoria Payne, Jennifer Pearce, Yanchun Peng, Marco Polo Peralta Alvarez, James Perring, Katja Pfafferott, Dimitra Pipini, Emma Plested, Helen Pluess-Hall, Katrina Pollock, Ian Poulton, Laura Presland, Samuel Provstgaard-Morys, David Pulido, Kajal Radia, Fernando Ramos Lopez, Jade Rand, Helen Ratcliffe, Thomas Rawlinson, Sarah Rhead, Amy Riddell, Adam John Ritchie, Hannah Roberts, Joanna Robson, Sophie Roche, Cornelius Rohde, Christine S. Rollier, Rossana Romani, Indra Rudiansyah, Stephen Saich, Sara Sajjad, Stephannie Salvador, Lidia Sanchez Riera, Helen Sanders, Katherine Sanders, Shari Sapaun, Chloe Sayce, Ella Schofield, Gavin Screaton, Beatrice Selby, Calum Semple, Hannah R. Sharpe, Imam Shaik, Adam Shea, Holly Shelton, Sarah Silk, Laura Silva-Reyes, Donal T. Skelly, Heather Smee, Catherine C. Smith, David J. Smith, Rinn Song, Alexandra J. Spencer, Elizabeth Stafford, Amy Steele, Elena Stefanova, Lisa Stockdale, Anna Szigeti, Abdessamad Tahiri-Alaoui, Moira Tait, Helen Talbot, Rachel Tanner, Iona Jennifer Taylor, Victoria Taylor, Rebecca Te Water Naude, Nazia Thakur, Yrene Themistocleous, Andreas Themistocleous, Merin Thomas, Tonia M. Thomas, Amber Thompson, Samantha Thomson-Hill, Jennifer Tomlins, Susan Tonks, James Towner, Nguyen Tran, Julia A. Tree, Adam Truby, Kate Turkentine, Cheryl Turner, Nicola Turner, Sally Turner, Toby Tuthill, Marta Ulaszewska, Rachel Varughese, Neeltje Van Doremalen, Kristin Veighey, Marije K. Verheul, Iason Vichos, Elia Vitale, Laura Walker, Marion E.E. Watson, Benjamin Welham, Julie Wheat, Caroline White, Rachel White, Andrew T. Worth, Danny Wright, Suzie Wright, Xin Li Yao, Yasmine Yau, and Hodgson, S

Subjects
Male, T-Lymphocytes, Booster dose, 030204 cardiovascular system & hematology, Antibodies, Viral, law.invention, 0302 clinical medicine, Immunogenicity, Vaccine, Randomized controlled trial, law, Oxford COVID Vaccine Trial Group, Medicine, Single-Blind Method, 030212 general & internal medicine, 11 Medical and Health Sciences, Viral Vaccine, Immunogenicity, Covid19, General Medicine, Analgesics, Non-Narcotic, Vaccination, Spike Glycoprotein, Coronavirus, Female, Coronavirus Infections, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, COVID-19 Vaccines, UNCOVER, Genetic Vectors, Pneumonia, Viral, Immunization, Secondary, Department of Error, Article, 03 medical and health sciences, Betacoronavirus, Medicine, General & Internal, Internal medicine, General & Internal Medicine, Humans, Adverse effect, Pandemics, Acetaminophen, Reactogenicity, Science & Technology, business.industry, SARS-CoV-2, COVID-19, Viral Vaccines, Antibodies, Neutralizing, United Kingdom, Clinical trial, Immunoglobulin G, Adenoviruses, Simian, business, ACUTE RESPIRATORY SYNDROME
Abstract

Background: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 10 10 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT 50]; a microneutralisation assay [MNA 50, MNA 80, and MNA 90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings: Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p80 and in 35 (100%) participants when measured in PRNT 50. After a booster dose, all participants had neutralising activity (nine of nine in MNA 80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R 2=0·67 by Marburg VN; p

Published
2020

37. Stringent thresholds for SARS-CoV-2 IgG assays result in under-detection of cases reporting loss of taste/smell

Author

David W Eyre, Sheila F Lumley, Denise O’Donnell, Nicole E Stoesser, Philippa C Matthews, Alison Howarth, Stephanie B Hatch, Brian D Marsden, Stuart Cox, Tim James, Richard J Cornall, David I Stuart, Gavin Screaton, Daniel Ebner, Derrick W Crook, Christopher P Conlon, Katie Jeffery, Timothy M Walker, and Timothy EA Peto

Subjects
Taste, medicine.medical_specialty, biology, medicine.diagnostic_test, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Anosmia, Ageusia, Asymptomatic, Gastroenterology, Immunoassay, Internal medicine, medicine, biology.protein, medicine.symptom, Antibody, business
Abstract

Thresholds for SARS-CoV-2 antibody assays have typically been determined using samples from symptomatic, often hospitalised, patients. Assay performance following mild/asymptomatic infection is unclear. We assessed IgG responses in asymptomatic healthcare workers with a high pre-test probability of Covid-19, e.g. 807/9292(8.9%) reported loss of smell/taste. The proportion reporting anosmia/ageusia increased at antibody titres below diagnostic thresholds for both an in-house ELISA and the Abbott Architect chemiluminescent microparticle immunoassay (CMIA): 424/903(47%) reported anosmia/ageusia with a positive ELISA, 59/387(13.2%) with high-negative titres, and 324/7943(4.1%) with low-negative results. Adjusting for the proportion of staff reporting anosmia/ageusia suggests the sensitivity of both assays is lower than previously reported: Oxford ELISA 90.8% (95%CI 86.1-92.1%) and Abbott CMIA 80.9% (77.5-84.3%). However, the sensitivity may be lower if some anosmia/ageusia in those with low-negative titres is Covid-19-associated. Samples from individuals with mild/asymptomatic infection should be included in SARS-CoV-2 immunoassay evaluations. Reporting equivocal SARS-CoV-2 antibody results should be considered.

Published
2020
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38. Immune correlates of protection for dengue: State of the art and research agenda

Author

Leah C. Katzelnick, Eva Harris, Ralph Baric, Beth-Ann Coller, Josefina Coloma, James E. Crowe, Derek A.T. Cummings, Hansi Dean, Aravinda de Silva, Michael S. Diamond, Anna Durbin, Neil Ferguson, Peter B. Gilbert, Aubree Gordon, Duane J. Gubler, Bruno Guy, M. Elizabeth Halloran, Scott Halstead, Nicholas Jackson, Richard Jarman, Shee-mei Lok, Nelson L. Michael, Eng Eong Ooi, Athanasios Papadopoulos, Stanley Plotkin, Alexander R. Precioso, Robert Reiner, Felix A. Rey, Isabel Rodríguez-Barraquer, Alan Rothman, Alexander C. Schmidt, Gavin Screaton, Alessandro Sette, Cameron Simmons, Ashley L. St. John, Wellington Sun, Stephen Thomas, Joseph Torresi, John S. Tsang, Kirsten Vannice, Stephen Whitehead, Annelies Wilder-Smith, In Kyu Yoon, and Simmons, C

Subjects
0301 basic medicine, and promotion of well-being, Disease, Dengue virus, medicine.disease_cause, Antibodies, Viral, Medical and Health Sciences, Dengue fever, Dengue, Immune correlates of protection, Viral, Neutralizing, Biological Sciences, Phase III as Topic, Infectious Diseases, 3.4 Vaccines, Immune correlates, Molecular Medicine, Immune correlates of risk, Infection, Context (language use), Dengue Vaccines, Antibodies, Severe dengue, Article, Vaccine Related, 03 medical and health sciences, Rare Diseases, Clinical Trials, Phase II as Topic, Biodefense, Virology, Environmental health, medicine, Humans, Clinical Trials, Severe Dengue, Dengue vaccine, Agricultural and Veterinary Sciences, General Veterinary, General Immunology and Microbiology, business.industry, Prevention, Phase II as Topic, Public Health, Environmental and Occupational Health, Congresses as Topic, Dengue Virus, Prevention of disease and conditions, Vaccine efficacy, medicine.disease, Antibodies, Neutralizing, Vector-Borne Diseases, Natural infection, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, Clinical Trials, Phase III as Topic, Immunology, Participants in the Summit on Dengue Immune Correlates of Protection, Immunization, business, Vaccine
Abstract

Dengue viruses (DENV1-4) are mosquito-borne flaviviruses estimated to cause up to ∼400 million infections and ∼100 million dengue cases each year. Factors that contribute to protection from and risk of dengue and severe dengue disease have been studied extensively but are still not fully understood. Results from Phase 3 vaccine efficacy trials have recently become available for one vaccine candidate, now licensed for use in several countries, and more Phase 2 and 3 studies of additional vaccine candidates are ongoing, making these issues all the more urgent and timely. At the "Summit on Dengue Immune Correlates of Protection", held in Annecy, France, on March 8-9, 2016, dengue experts from diverse fields came together to discuss the current understanding of the immune response to and protection from DENV infection and disease, identify key unanswered questions, discuss data on immune correlates and plans for comparison of results across assays/consortia, and propose a research agenda for investigation of dengue immune correlates, all in the context of both natural infection studies and vaccine trials.

Published
2017

39. Dengue Research Funded by the European Commission-Scientific Strategies of Three European Dengue Research Consortia

Author

Axel Kroeger, Fernando Augusto Bozza, Gavin Screaton, Peter Byass, Joacim Rocklöv, Bernard Cazelles, Marco Vignuzzi, Simon Hay, Annelies Wilder-Smith, Bridget Wills, Kerstin Rosenberger, Jeremy Farrar, Gabriela Maron, Adriana Tami, Michael Schreiber, Ernesto T A Marques, Andrea Caprara, Eric Daudé, Section Clinical Tropical Medicine [Heidelberg], Department of Infectious Diseases [Heidelberg, Germany], Heidelberg University Hospital [Heidelberg]-Heidelberg University Hospital [Heidelberg], Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Public Health and Clinical Medicine, Umeå University, This work was supported by the IDAMS project (European Union 7th FP, grant 281803), the DENFREE project (European Union 7th FP, grant 282378), and the DengueTools project (European Union 7th FP, grant 282589)., IDAMS - International Research Consortium on Dengue Risk Assessment, Management, and Surveillance : Thomas Jaenisch, Thomas Junghanss, Kerstin Rosenberger, Jaswinder Kaur (Section Clinical Tropical Medicine, Heidelberg Universty Hospital), Simon Hay, Janey Messina, Adrian Hill (Oxford University), Bridget Wills, Cameron Simmons, Marcel Wolbers, Jeremy Farrar (Oxford University Clinical Research Unit, Vietnam), Phil McCall (Liverpool School of Tropical Medicine), Antonio Lanzavecchia, Federica Sallusto (Institute for Research in Biomedicine, Bellinzona, Switzerland), Axel Kroeger, Silvia Runge-Ranzinger (TDR-WHO), Lucy Lum (University of Malaya Medical Center), Ida Safitri (Gadja Madah University, Indonesia), Varun Kumar (Angkor Hospital for Children, Cambodia), Maria Guzman (Instituto Pedro Kouri, Cuba), Gabriela Maron, Ernesto Pleitess (Hospital National de Ninos Benjamin Bloom, San Salvador), Andrea Caprara, Bruno Benevides (State University of Ceara, Brazil), Willy Wint (Environmental Research Group Oxford Ltd.), Osman Sankoh (INDEPTH-Network, Ghana), Fleur Monasso (Red Cross/Red Crescent Climate Centre, The Netherlands), Adriana Tami (University of Carabobo, Venezuela), Ernesto T. A. Marques, Fernando A. Bozza (FIOCRUZ, Brazil), DENFREE - Dengue Research Framework for Resisting Epidemics in Europe : Anavaj Sakuntabhai, Richard Paul, Félix Rey, Anna-Bella Failloux, Marco Vignuzzi, Louis Lambrechts (Institut Pasteur, France), Gavin Screaton, Juthathip Mongkolsapaya (Imperial College, United Kingdom), Michael Schreiber, Rolf Horstmann (Bernard Nocht Institute, Germany), Pattamaporn Kittayapong, Pratap Singhasivanon, Sutee Yoksan (Mahidol University, Thailand), Philippe Buchy, Vincent Deubel (Institut Pasteur Cambodia, Cambodia), Xavier Rodó (Fundacio Institut Catala De Ciencies Del Clima, Spain), Eric Daude, Alain Vaguet (University of Rouen, France), Bernard Cazelles (CNRS, France), Nico Stollenwerk (Cmaf, Fundacao Da Faculdade De Ciencias Da Universidade De Lisboa, Portugal), Luísa Pereira (Instituto De Patologia E Imunologia Molecular Da Universidade Do Porto, Portugal), Timo Kanninen (Biocomputing Platforms Ltd Oy, Finland), Guido Krupp (Amptec Gmbh, Germany), Mark Thursz (Riotech Pharmaceticals Ltd, United Kingdom), María G. Guzmán (Instituto Pedro Kouri, Cuba), DengueTools - Innovative Tools and Strategies for the Surveillance and Control of Dengue : Annelies Wilder-Smith, Joacim Rocklöv, Peter Byass (Umeå University, Sweden), Paba Palihawadana, Hasitha Tissera (Epidemiological Unit, Ministry of Health, Sri Lanka), David Brooks (TwistDx Ltd, UK), Sazaly Abu Bakar (University of Malaya), Luke Alphey (Oxitec Ltd, UK), Pattamaporn Kittayapong (Mahidol University, Thailand), Steve Lindsay, James Logan (London School of Hygiene and Tropical Medicine, UK), Christoph Hatz, Andreas Neumayr (Swiss Tropical and Public Health Institute), Paul Reiter (Institut Pasteur, France), Yesim Tozan, Valérie R. Louis (Heidelberg University Hospital), Duane Gubler (Duke-NUS Graduate Medical School Singapore), Eduardo Massad (University of Sao Paolo), Antonio Tenorio (Instituto de Salud Carlos III), Christophe Lagneau, Grégory L'Ambert (Entente Inter-Départementale pour la Démoustication du littoral Mediterranéen), European Project: 281803,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,IDAMS(2011), European Project: 282378,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENFREE(2012), European Project: 282589,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENGUETOOLS(2011), Microbes in Health and Disease (MHD), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Medical Research Council (MRC)

Subjects
Economic growth, Biomedical Research, Infektionsmedicin, MESH: Dengue/prevention & control, Dengue virus, medicine.disease_cause, Dengue fever, Capital Financing, Dengue, IDAMS, 0302 clinical medicine, DENFREE, 030212 general & internal medicine, Chikungunya, MESH: Capital Financing, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), media_common, Disease surveillance, education.field_of_study, lcsh:Public aspects of medicine, Health Policy, Public Health, Global Health, Social Medicine and Epidemiology, 11 Medical And Health Sciences, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, epidemiology, MESH: Health Policy, DengueTools, Infectious Medicine, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, 030231 tropical medicine, Population, MESH: Dengue/epidemiology, Biology, 03 medical and health sciences, Tropical Medicine, MESH: Biomedical Research/trends, MESH: European Union, medicine, media_common.cataloged_instance, Humans, European Union, European union, education, Health policy, MESH: Humans, business.industry, Policy Platform, Public Health, Environmental and Occupational Health, International health, lcsh:RA1-1270, 06 Biological Sciences, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 13. Climate action, business
Abstract

Dengue is a major international public health concern and one of the most important arthropod-borne diseases [1]. Approximately 2.5 billion people—40% of the world's population, in over 100 countries—are at risk of dengue virus (DENV) infection [2]. In recent years the average annual incidence of dengue-related serious disease in many tropical counties has been rising dramatically, with the infection becoming endemic in areas where its occurrence was once sporadic [3]. The exponential increase over the last decade has been connected to societal changes, such as population growth and increasing urbanization [4]. In addition, it has been suggested that rising temperatures and global climate change may lead to the expansion of the range of major mosquito vectors into new areas, extension of the transmission season in current endemic areas, and increase in the mosquito species vectorial capacity [5]–[7]. Human migration (likely including infected hosts) and international travel are constantly introducing new vectors and pathogens into novel geographic areas [8]. For example, chikungunya virus was introduced into northeastern Italy in 2007, causing an outbreak with local transmission due to the presence of Aedes albopictus, a vector also capable of transmitting dengue virus [9]. In 2010, three authochthonous cases of dengue were reported in Europe, thereby highlighting the potential for global spread of this disease [10], [11]. The island of Madeira, where the mosquito vector Aedes aegypti is present, experienced a major dengue outbreak in the fall of 2012 [12], highlighting that the introduction of dengue to non-endemic areas is a real threat. Dengue has been neglected for many years. Major research gaps for dengue exist in the areas of epidemiology under changing climate conditions, clinical management, pathogenesis, vector control, surveillance and response, vaccines, drugs, and health policy research [13]. The European Commission (EC) launched a call under the Seventh Framework Programme with the title of “Comprehensive control of Dengue fever under changing climatic conditions” (http://ec.europa.eu/research/participants/portal/page/cooperation?callIdentifier=FP7-HEALTH-2011-single-stage). The focus of this call is summarized in Box 1. Within this framework, in 2011, the EC awarded a total of approximately €18 million to three consortia. The hosting institutions are Heidelberg University Hospital (Germany), the Institute Pasteur (Paris, France), and Umea University (Sweden). Each consortium has partners from countries with endemic and epidemic dengue. In total, the consortia comprise 38 partners from 21 countries, of which 11 are from Asia and Latin America, the current hotspots of dengue endemicity, and one from Africa (Figure 1). Figure 1 The world map of the three EU-funded dengue consortia. Box 1. European Commission Seventh Framework Programme FP7 Cooperation - Health HEALTH.2011.2.3.3-2: Comprehensive control of Dengue fever under changing climatic conditions. FP7-HEALTH-2011-single-stage Research should develop innovative tools for one or more of the following aspects: better diagnosis, surveillance, development of treatment, prevention and vaccination strategies, prevention, and/or prediction and prevention of the spread of dengue fever to previously uninfected regions (including Europe), in the context of climate change. Research may also include studies on the underlying pathogenesis with respect to viral and host factors that can predict disease severity and prepare for further development of new vaccines, antiviral compounds, and more targeted treatment schemes. Funding Scheme Specific International Cooperation Action (SICA) Collaborative Project (small- or medium-scale focused research project) target regions: Latin America and/or Asia. SICA aims to bring about the balanced participation of third countries in collaboration with European partners. Expected Impact Better tools, and the use thereof, for improved comprehensive control of dengue fever at a global level. Participation from both SICA target regions and Small and Medium Enterprises SMEs in the projects should help ensure innovation and exploitation of the results in this area/topic. The degree of such participation will be considered during the evaluation. Source: http://ec.europa.eu/research/health/infectious-diseases/emerging-epidemics/call-for-proposals_en.html The funding of such a large and complex research programme focusing on a single disease highlights the emphasis that the European Commission has put on dengue and its potential threat to Europe. In this paper, we present these three consortia and outline their scientific strategies and potential role within the international dengue research community.

Published
2013

40. T cell responses and dengue haemorrhagic fever

Author

Gavin, Screaton and Juthathip, Mongkolsapaya

Subjects
Immunity, Cellular, T-Lymphocytes, Cytokines, Humans, Severe Dengue, Dengue Virus
Abstract

The enhancement of severe disease upon secondary infection makes dengue almost unique among infectious pathogens and presents a serious challenge to vaccine design. Several key observations have been made which shed light onto this phenomenon particularly that antibodies can enhance Fc receptor-dependent uptake of virus into macrophages thereby increasing virus replication. Furthermore there seems to be a relationship between the peak virus load and disease severity. However, a second key feature of dengue is that the life-threatening symptoms do not correlate with the period of high viraemia; instead they occur at a time when the virus load is in steep decline. The coincidence of severe disease manifestations with defervescence and virus control suggests that the symptoms may be a consequence of the immune response to the virus rather than virus induced cytopathology. One of the key elements in the immune response to viruses are T cells which can both secrete a host of inflammatory cytokines and also be directly cytotoxic to infected cells. There are a number of experimental models of T cell-induced immunopathology including in responses to viruses. Particularly interesting in this respect are models of RSV-induced immunopathology, which have direct relevance to vaccine design as a formalin-inactivated vaccine to RSV actually enhanced disease in children when they became naturally infected with RSV, an echo of the disease enhancement seen in dengue. We will present an analysis of CD8+ T cell responses to a number of novel T cell epitopes during dengue infection and also analyse the function and cytokine secretion of these cells. We suggest that an exaggerated and partially misdirected T cell response seen in secondary dengue infection may be part of the complex series of events leading to dengue haemorrhagic fever and shock.

Published
2007

41. The influence of CD25+ cells on the generation of immunity to tumour cell lines in mice

Author

Emma, Jones, Denise, Golgher, Anna Katharina, Simon, Michaela, Dahm-Vicker, Gavin, Screaton, Tim, Elliott, and Awen, Gallimore

Subjects
Mice, Antigens, Neoplasm, Cell Line, Tumor, Neoplasms, T-Lymphocytes, Immunity, Animals, Humans, Receptors, Interleukin-2, Lymphocyte Depletion
Abstract

CD25+ regulatory T cells comprise 5-10% of CD4+ T cells in naïve mice and have been shown in several in vivo murine models to prevent the induction of autoimmune disease and inflammatory disease. Since T cells, which mediate autoimmunity, can through recognition of self-antigens also target tumour cells, it was postulated that CD25+ regulatory cells would also inhibit the generation of immune responses to rumours. Depletion of these cells using CD25-specific monoclonal antibodies has indeed been shown to promote rejection of several transplantable murine tumour cell lines including melanoma, leukaemia and colorectal carcinoma. Results obtained using these models indicate that in the absence of regulatory cells, CD4+ T cells mediate tumour immunity, although the precise mechanisms through which these cells result in tumour rejection have not yet been elucidated. The target antigens recognized by these CD4+ T cells have also not yet been identified. Immunization of mice with tumour cells in the absence of CD25+ regulatory cells does, however, induce immunity against a variety of different tumour cell lines indicating that the target antigen(s) are shared amongst tumours of distinct histological origins. Since CD25+ regulatory cells have been identified in humans, the possibility that the cells inhibit immune responses to shared rejection antigens expressed by human tumours is worthy of investigation.

Published
2004

42. Lymphocyte inhibitor of TRAIL (TNF-related apoptosis-inducing ligand): a new receptor protecting lymphocytes from the death ligand TRAIL

Author

Mongkolsapaya J, Ae, Cowper, Xn, Xu, Morris G, Aj, Mcmichael, Ji, Bell, and Gavin Screaton

Subjects
Membrane Glycoproteins, Sequence Homology, Amino Acid, Tumor Necrosis Factor-alpha, Molecular Sequence Data, Membrane Proteins, Apoptosis, TNF-Related Apoptosis-Inducing Ligand, Humans, Tissue Distribution, Amino Acid Sequence, Receptors, Immunologic, Apoptosis Regulatory Proteins, Sequence Alignment, Repetitive Sequences, Nucleic Acid
Abstract

Apoptosis can be triggered by the engagement of cell surface receptors by their ligands. A growing number of receptors belonging to the TNF receptor family have been identified that contain a conserved cytoplasmic death domain. These include Fas, TNF-R1, lymphocyte-associated receptor of death (LARD), DR4, and TNF-related apoptosis-inducing ligand receptor inducer of cell killing-2 (TRICK2). The latter two are receptors for the cytotoxic ligand TNF-related apoptosis-inducing ligand (TRAIL), and one of the paradoxes raised by the cloning of these molecules was why do most cells not die upon contact with the widely expressed TRAIL molecule? This is a particular problem for lymphocytes that express DR4 and TRICK2 and are in constant circulation through TRAIL-expressing tissues. We have cloned LIT (lymphocyte inhibitor of TRAIL), which lacks a death domain. LIT is expressed predominantly on PBL, where it can competitively inhibit TRAIL-induced apoptosis through DR4/TRICK2, and may function to modulate lymphocyte sensitivity to TRAIL.

Published
1998

43. Antibody responses to dengue infection (67.9)

Author

Wanwisa Dejnirattisai, Prida Malasit, Juthathip Mongkolsapaya, and Gavin Screaton

Subjects
Immunology, Immunology and Allergy
Abstract

Dengue virus infection is a major public health problem in tropical and subtropical countries. Around 50 million people are infected per year of which 500,000 cases develop into the severe form, dengue hemorrhagic fever (DHF). Dengue is a flavivirus circulating as 4 serotypes with an average of 30% amino acid difference between each other, and infection with one serotype dose not provide protective immunity to the others, so secondary infection is very common. So far, the mechanisms involved in the pathogenesis of DHF are not well understood, but the key epidemiological studies indicate that it usually occurs in subsequent heterotypic dengue infection. Antibody dependent enhancement (ADE) is one of the hypotheses where preexisting antibodies from primary infection may be unable to neutralise other serotype from secondary infection but may instead form dengue/antibody complexes which will be taken up by Fc-bearing cells such as monocytes and macrophages leading to increase viral production. In this study, we have generated a panel of human monoclonal antibodies against dengue virus from B cells isolated from dengue infected patients. Neutralizing, enhancing and cross-reactive activity of these antibodies have been characterized and shown different patterns of functioanl properties.

Published
2011

44. T1214 Peripheral Blood from Crohn's Disease Patients Demonstrate Both IL-17 Expressing CD4+ Lymphocytes and IL-17 and Interferon-Gamma Double Expressing CD4+ Lymphocytes

Author

Gavin Screaton, Julian R.F. Walters, Subrata Ghosh, Vinod K. Patel, and Vieira L. Pedro

Subjects
Crohn's disease, Hepatology, business.industry, Immunology, Gastroenterology, Medicine, Interferon gamma, Interleukin 17, business, medicine.disease, Peripheral blood mononuclear cell, Peripheral blood, medicine.drug
Published
2008

45. The identification of a new alternative exon with highly restricted tissue expression in transcripts encoding the mouse Pgp-1 (CD44) homing receptor. Comparison of all 10 variable exons between mouse, human, and rat

Author

Gavin Screaton, Mv, Bell, Ji, Bell, and Dg, Jackson

Subjects
Base Sequence, Sequence Homology, Amino Acid, Transcription, Genetic, Molecular Sequence Data, Receptors, Lymphocyte Homing, Exons, Polymerase Chain Reaction, Rats, Alternative Splicing, Mice, Oligodeoxyribonucleotides, Molecular Probes, Sequence Homology, Nucleic Acid, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Codon
Abstract

The human CD44 cell surface glycoprotein family which has been implicated in lymphocyte homing, tumor metastasis, and extracellular matrix attachment consists of a large number of related isoforms that derive from the differential splicing of a single CD44 gene transcript. Recent mapping of the CD44 locus in man indicated the presence of at least nine alternative exons within the region of the gene encoding the variable membrane proximal extracellular domain. Here we report the identification of a 10th alternative exon (termed V1) in the mouse, human, and rat CD44 genes. We demonstrate tissue-specific patterns of expression for transcripts containing exons V1-V10 in the mouse and a highly restricted usage of exon V1 in transcripts from mouse gastric tissue. Close sequence homology between exons V1-V10 from mouse rat and human points to a specific functional role rather than a purely structural role for the membrane proximal extracellular domain of the CD44 molecule.

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