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1. Emerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection

Author: Chang Liu, Raksha Das, Aiste Dijokaite-Guraliuc, Daming Zhou, Alexander J. Mentzer, Piyada Supasa, Muneeswaran Selvaraj, Helen M. E. Duyvesteyn, Thomas G. Ritter, Nigel Temperton, Paul Klenerman, Susanna J. Dunachie, Neil G. Paterson, Mark A. Williams, David R. Hall, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, and Gavin R. Screaton
Subjects: Science
Abstract: Abstract The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called ‘FLip’ mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86.
Published: 2024
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2. The SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86

Author: Daming Zhou, Piyada Supasa, Chang Liu, Aiste Dijokaite-Guraliuc, Helen M. E. Duyvesteyn, Muneeswaran Selvaraj, Alexander J. Mentzer, Raksha Das, Wanwisa Dejnirattisai, Nigel Temperton, Paul Klenerman, Susanna J. Dunachie, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, and Gavin R. Screaton
Subjects: Science
Abstract: Abstract Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the receptor binding domain which has become heavily mutated. Here we study responses to a conserved epitope in sub-domain-1 (SD1) of spike which have become more prominent because of mutational escape from antibodies directed to the receptor binding domain. Some SD1 reactive mAbs show potent and broad neutralization of SARS-CoV-2 variants. We structurally map the dominant SD1 epitope and provide a mechanism of action by blocking interaction with ACE2. Mutations in SD1 have not been sustained to date, but one, E554K, leads to escape from mAbs. This mutation has now emerged in several sublineages including BA.2.86, reflecting selection pressure on the virus exerted by the increasing prominence of the anti-SD1 response.
Published: 2024
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3. 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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4. 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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5. Generation of SARS-CoV-2 escape mutations by monoclonal antibody therapy

Author: Manon Ragonnet-Cronin, Rungtiwa Nutalai, Jiandong Huo, Aiste Dijokaite-Guraliuc, Raksha Das, Aekkachai Tuekprakhon, Piyada Supasa, Chang Liu, Muneeswaran Selvaraj, Natalie Groves, Hassan Hartman, Nicholas Ellaby, J. Mark Sutton, Mohammad W. Bahar, Daming Zhou, Elizabeth Fry, Jingshan Ren, Colin Brown, Paul Klenerman, Susanna J. Dunachie, Juthathip Mongkolsapaya, Susan Hopkins, Meera Chand, David I. Stuart, Gavin R. Screaton, and Sakib Rokadiya
Subjects: Science
Abstract: Abstract COVID-19 patients at risk of severe disease may be treated with neutralising monoclonal antibodies (mAbs). To minimise virus escape from neutralisation these are administered as combinations e.g. casirivimab+imdevimab or, for antibodies targeting relatively conserved regions, individually e.g. sotrovimab. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to detect emerging drug resistance in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the antibody epitopes and for casirivimab+imdevimab multiple mutations are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.
Published: 2023
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6. Serum HCoV-spike specific antibodies do not protect against subsequent SARS-CoV-2 infection in children and adolescents

Author: Helen Ratcliffe, Karen S. Tiley, Stephanie Longet, Claire Tonry, Cathal Roarty, Chris Watson, Gayatri Amirthalingam, Iason Vichos, Ella Morey, Naomi L. Douglas, Spyridoula Marinou, Emma Plested, Parvinder K. Aley, Eva Galiza, Saul N. Faust, Stephen Hughes, Clare Murray, Marion R. Roderick, Fiona Shackley, Sam Oddie, Tim W.R. Lee, David P.J. Turner, Mala Raman, Stephen Owens, Paul J. Turner, Helen Cockerill, Jamie Lopez Bernal, Samreen Ijaz, John Poh, Justin Shute, Ezra Linley, Ray Borrow, Katja Hoschler, Kevin E. Brown, Miles W. Carroll, Paul Klenerman, Susanna J. Dunachie, Mary Ramsay, Merryn Voysey, Thomas Waterfield, and Matthew D. Snape
Subjects: Health sciences, Medicine, Medical specialty, Immunology, Virology, Science
Abstract: Summary: SARS-CoV-2 infections in children are generally asymptomatic or mild and rarely progress to severe disease and hospitalization. Why this is so remains unclear. Here we explore the potential for protection due to pre-existing cross-reactive seasonal coronavirus antibodies and compare the rate of antibody decline for nucleocapsid and spike protein in serum and oral fluid against SARS-CoV-2 within the pediatric population. No differences in seasonal coronaviruses antibody concentrations were found at baseline between cases and controls, suggesting no protective effect from pre-existing immunity against seasonal coronaviruses. Antibodies against seasonal betacoronaviruses were boosted in response to SARS-CoV-2 infection. In serum, anti-nucleocapsid antibodies fell below the threshold of positivity more quickly than anti-spike protein antibodies. These findings add to our understanding of protection against infection with SARS-CoV-2 within the pediatric population, which is important when considering pediatric SARS-CoV-2 immunization policies.
Published: 2023
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7. Deciphering the human antibody response against Burkholderia pseudomallei during melioidosis using a comprehensive immunoproteome approach

Author: Gabriel E. Wagner, Thomas Franz Paul Stanjek, Dirk Albrecht, Michaela Lipp, Susanna J. Dunachie, Esther Föderl-Höbenreich, Katharina Riedel, Anne Kohler, Ivo Steinmetz, and Christian Kohler
Subjects: Burkholderia pseudomallei, immunoproteomics, melioidosis, dot blot, Western blot, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionThe environmental bacterium Burkholderia pseudomallei causes the often fatal and massively underreported infectious disease melioidosis. Antigens inducing protective immunity in experimental models have recently been identified and serodiagnostic tools have been improved. However, further elucidation of the antigenic repertoire of B. pseudomallei during human infection for diagnostic and vaccine purposes is required. The adaptation of B. pseudomallei to very different habitats is reflected by a huge genome and a selective transcriptional response to a variety of conditions. We, therefore, hypothesized that exposure of B. pseudomallei to culture conditions mimicking habitats encountered in the human host might unravel novel antigens that are recognized by melioidosis patients.Methods and resultsIn this study, B. pseudomallei was exposed to various stress and growth conditions, including anaerobiosis, acid stress, oxidative stress, iron starvation and osmotic stress. Immunogenic proteins were identified by probing two-dimensional Western blots of B. pseudomallei intracellular and extracellular protein extracts with sera from melioidosis patients and controls and subsequent MALDI-TOF MS. Among B. pseudomallei specific immunogenic signals, 90 % (55/61) of extracellular immunogenic proteins were identified by acid, osmotic or oxidative stress. A total of 84 % (44/52) of intracellular antigens originated from the stationary growth phase, acidic, oxidative and anaerobic conditions. The majority of the extracellular and intracellular protein antigens were identified in only one of the various stress conditions. Sixty-three immunoreactive proteins and an additional 38 candidates from a literature screening were heterologously expressed and subjected to dot blot analysis using melioidosis sera and controls. Our experiments confirmed melioidosis-specific signals in 58 of our immunoproteome candidates. These include 15 antigens with average signal ratios (melioidosis:controls) greater than 10 and another 26 with average ratios greater than 5, including new promising serodiagnostic candidates with a very high signal-to-noise ratio.ConclusionOur study shows that a comprehensive B. pseudomallei immunoproteomics approach, using conditions which are likely to be encountered during infection, can identify novel antibody targets previously unrecognized in human melioidosis.
Published: 2023
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8. Antigenic characterization of SARS-CoV-2 Omicron subvariant BA.4.6

Author: Aiste Dijokaite-Guraliuc, Raksha Das, Rungtiwa Nutalai, Daming Zhou, Alexander J. Mentzer, Chang Liu, Piyada Supasa, Susanna J. Dunachie, Teresa Lambe, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, Jiandong Huo, David I. Stuart, and Gavin R. Screaton
Subjects: Cytology, QH573-671
Published: 2022
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9. Identification and function of a novel human memory-like NK cell population expressing CD160 in melioidosis

Author: Anucha Preechanukul, Barbara Kronsteiner, Natnaree Saiprom, Kitilak Rochaikun, Boonthanom Moonmueangsan, Rungnapa Phunpang, Orawan Ottiwet, Yuphin Kongphrai, Soonthon Wapee, Kesinee Chotivanich, Chumpol Morakot, Rachan Janon, Susanna J. Dunachie, and Narisara Chantratita
Subjects: Immunology, Immunity, Microbiology, Cell biology, Science
Abstract: Summary: NK cells are endowed with immunological memory to a range of pathogens but the development of NK cell memory in bacterial infections remains elusive. Here, we establish an assay inducing memory-like NK cell response to Burkholderia pseudomallei, the causative agent of the severe bacterial disease called melioidosis, and explore NK cell memory in a melioidosis patient cohort. We show that NK cells require bacteria-primed monocytes to acquire memory-like properties, demonstrated by bacteria-specific responses, features that strongly associate with CD160 expression. Induction of this memory-like NK cell is partly dependent on CD160 and IL-12R. Importantly, CD160 expression identifies memory-like NK cells in a cohort of recovered melioidosis patients with heightened responses maintained at least 3 months post hospital admission and reduced numbers of this cell population independently correlate with recurrent melioidosis. These newly identified memory-like NK cells are a promising target for future vaccine design and for monitoring protection against infection.
Published: 2023
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10. Impact of shipping temperature on cell viability and T cell responses to bacterial antigens [version 1; peer review: 2 approved]

Author: Susanna J. Dunachie, Barbara Kronsteiner, and Patpong Rongkard
Subjects: IFN-gamma, ELISpot, PBMC, cryopreservation, shipping, storage, eng, Medicine, Science
Abstract: Background: Interferon-γ (IFN-γ) secretion by T cells is a key correlate of immune protection against many pathogens including tuberculosis and the neglected tropical disease melioidosis. Clinical studies in tropical regions of immune responses to pathogens and vaccine monitoring studies require the collection of samples in resource-limited rural areas and subsequent shipment to central laboratories for downstream assays and long-term storage. Here, we studied the impact of two different shipping temperatures on the viability, composition and function of peripheral blood mononuclear cells (PBMC) using multi-colour flow cytometry and IFN-g enzyme-linked immunospot assay (IFN-g ELISpot), in order to provide guidance on sample shipment conditions for future clinical studies. Methods: Paired peripheral blood mononuclear cell (PBMC) samples from recovered melioidosis patients were stored in liquid nitrogen (-196°C) and then shipped from Bangkok, Thailand to Oxford, UK at either -80°C (dry ice) or -196°C (dry shipper). After thawing, cell viability and composition were assessed by flow cytometry and antigen specific responses to Burkholderia pseudomallei (BP) were measured using IFN-g ELISpot. Results: We observed modest lowering of viability in the majority of samples and a reduction in IFN-g responses to BP which correlated to a decrease of monocytes and natural killer cells in samples shipped at -80°C compared to -196°C. Despite being lower in magnitude antigen-specific responses remained detectable in the majority of samples. Conclusions: Here we demonstrate that shipment of cryopreserved PBMC at -196°C has a benefit on cell viability, recovery and T cell responses to bacterial antigens, although useful information can still be obtained from samples shipped at -80°C, thus providing important guidance for sample management in future clinical trials.
Published: 2023
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11. Rapid escape of new SARS-CoV-2 Omicron variants from BA.2-directed antibody responses

Author: Aiste Dijokaite-Guraliuc, Raksha Das, Daming Zhou, Helen M. Ginn, Chang Liu, Helen M.E. Duyvesteyn, Jiandong Huo, Rungtiwa Nutalai, Piyada Supasa, Muneeswaran Selvaraj, Thushan I. de Silva, Megan Plowright, Thomas A.H. Newman, Hailey Hornsby, Alexander J. Mentzer, Donal Skelly, Thomas G. Ritter, Nigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Cornelius Roemer, Thomas P. Peacock, Neil G. Paterson, Mark A. Williams, David R. Hall, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, Gavin R. Screaton, Christopher Conlon, Alexandra Deeks, John Frater, Siobhan Gardiner, Anni Jämsén, Katie Jeffery, Tom Malone, Eloise Phillips, Barbara Kronsteiner-Dobramysl, Priyanka Abraham, Sagida Bibi, Teresa Lambe, Stephanie Longet, Tom Tipton, Miles Carrol, and Lizzie Stafford
Subjects: CP: Immunology, CP: Microbiology, Biology (General), QH301-705.5
Abstract: Summary: In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titer of vaccine or BA.1, BA.2, or BA.4/5 immune serum.
Published: 2023
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12. Divergent trajectories of antiviral memory after SARS-CoV-2 infection

Author: Adriana Tomic, Donal T. Skelly, Ane Ogbe, Daniel O’Connor, Matthew Pace, Emily Adland, Frances Alexander, Mohammad Ali, Kirk Allott, M. Azim Ansari, Sandra Belij-Rammerstorfer, Sagida Bibi, Luke Blackwell, Anthony Brown, Helen Brown, Breeze Cavell, Elizabeth A. Clutterbuck, Thushan de Silva, David Eyre, Sheila Lumley, Amy Flaxman, James Grist, Carl-Philipp Hackstein, Rachel Halkerston, Adam C. Harding, Jennifer Hill, Tim James, Cecilia Jay, Síle A. Johnson, Barbara Kronsteiner, Yolanda Lie, Aline Linder, Stephanie Longet, Spyridoula Marinou, Philippa C. Matthews, Jack Mellors, Christos Petropoulos, Patpong Rongkard, Cynthia Sedik, Laura Silva-Reyes, Holly Smith, Lisa Stockdale, Stephen Taylor, Stephen Thomas, Timothy Tipoe, Lance Turtle, Vinicius Adriano Vieira, Terri Wrin, OPTIC Clinical Group, PITCH Study Group, C-MORE Group, Andrew J. Pollard, Teresa Lambe, Chris P. Conlon, Katie Jeffery, Simon Travis, Philip Goulder, John Frater, Alex J. Mentzer, Lizzie Stafford, Miles W. Carroll, William S. James, Paul Klenerman, Eleanor Barnes, Christina Dold, and Susanna J. Dunachie
Subjects: Science
Abstract: The engagement of immunological memory is a key component to the protective anti-SARS-CoV-2 B and T cell responses. Here the authors assess the B and T cells of a cohort of UK healthcare workers in response to infection and longitudinally track the compartment showing distinct trajectories following early priming.
Published: 2022
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13. Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

Author: Donal T. Skelly, Adam C. Harding, Javier Gilbert-Jaramillo, Michael L. Knight, Stephanie Longet, Anthony Brown, Sandra Adele, Emily Adland, Helen Brown, Medawar Laboratory Team, Tom Tipton, Lizzie Stafford, Alexander J. Mentzer, Síle A. Johnson, Ali Amini, OPTIC (Oxford Protective T cell Immunology for COVID-19) Clinical Group, Tiong Kit Tan, Lisa Schimanski, Kuan-Ying A. Huang, Pramila Rijal, PITCH (Protective Immunity T cells in Health Care Worker) Study Group, C-MORE/PHOSP-C Group, John Frater, Philip Goulder, Christopher P. Conlon, Katie Jeffery, Christina Dold, Andrew J. Pollard, Alex Sigal, Tulio de Oliveira, Alain R. Townsend, Paul Klenerman, Susanna J. Dunachie, Eleanor Barnes, Miles W. Carroll, and William S. James
Subjects: Science
Abstract: Understanding the effect of vaccination on emerging SARS-CoV-2 variants of concern is of increasing importance. Here, James et al. report that two doses of vaccination with the Pfizer-BioNTech vaccine induce more robust immune responses to the B.1.1.7 and B.1.351 SARS-CoV-2 lineages than does natural infection.
Published: 2021
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14. A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model

Author: Manutsanun Inthawong, Piyanate Sunyakumthorn, Sirima Wongwairot, Tippawan Anantatat, Susanna J. Dunachie, Rawiwan Im-Erbsin, James W. Jones, Carl J. Mason, Luis A. Lugo, Stuart D. Blacksell, Nicholas P. J. Day, Piengchan Sonthayanon, Allen L. Richards, and Daniel H. Paris
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: Background Scrub typhus is a vector-borne febrile illness caused by Orientia tsutsugamushi transmitted by the bite of Trombiculid mites. O. tsutsugamushi has a high genetic diversity and is increasingly recognized to have a wider global distribution than previously assumed. Methodology/principle findings We evaluated the clinical outcomes and host immune responses of the two most relevant human pathogenic strains of O. tsutsugamushi; Karp (n = 4) and Gilliam (n = 4) in a time-course study over 80 days post infection (dpi) in a standardized scrub typhus non-human primate rhesus macaque model. We observed distinct features in clinical progression and immune response between the two strains; Gilliam-infected macaques developed more pronounced systemic infection characterized by an earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. C-reactive protein (CRP) plasma levels, interferon gamma (IFN-γ, interleukin-1 receptor antagonist (IL-1ra), IL-15 serum concentrations, CRP/IL10- and IFN-γ/IL-10 ratios correlated positively with bacterial load in blood, implying activation of the innate immune response and preferential development of a T helper-type 1 immune response. The O. tsutsugamushi-specific immune memory responses in cells isolated from skin and lymph nodes at 80 dpi were more markedly elevated in the Gilliam-infected macaques than in the Karp-infected group. The comparative cytokine response dynamics of both strains revealed significant up-regulation of IFN-γ, tumor necrosis factor (TNF), IL-15, IL-6, IL-18, regulatory IL-1ra, IL-10, IL-8 and granulocyte-colony-stimulating factor (G-CSF). These data suggest that the clinical outcomes and host immune responses to scrub typhus could be associated with counter balancing effects of pro- and anti-inflammatory cytokine-mediated responses. Currently, no data on characterized time-course comparisons of O. tsutsugamushi strains regarding measures of disease severity and immune response is available. Our study provides evidence for the strain-specificity of host responses in scrub typhus, which supports our understanding of processes at the initial inoculation site (eschar), systemic disease progression, protective and/or pathogenic host immune mechanisms and cellular immune memory function. Conclusions/significance This study characterised an improved intradermal rhesus macaque challenge model for scrub typhus, whereby the Gilliam strain infection associated with higher disease severity in the rhesus macaque model than the previous Karp strain infection. Difficulties associated with inoculum quantitation for obligate-intracellular bacteria were overcome by using functional inoculum titrations in outbred mice. The Gilliam-based rhesus macaque model provides improved endpoint measurements and contributes towards the identification of correlates of protection for future vaccine development. Author summary Scrub typhus is a mite-borne rickettsial illness, which is potentially severe if untreated or diagnosis is delayed or missed. This easily treatable disease is endemic in southeastern and eastern parts of Asia, but is increasingly recognised to have a global distribution. In endemic areas, where infected vectors transmit different strains of Orientia tsutsugamushi—the causative pathogen of scrub typhus—the diversity of these bacterial strains poses a serious obstacle for developing effective diagnostics and a universal scrub typhus vaccine. Comparison studies on the host immune responses against various strains are rare and there is limited evidence on strain-specific immune responses over the disease course. In this study, we characterized the clinical disease progression from the start of infection to full convalescence in a well-characterised non-human primate rhesus macaque model, infected with the two most prevalent O. tsutsugamushi strains; Karp and Gillam, and compared the time course dynamics of bacteremia with correlations of various immune response mechanisms. We found that Gilliam strain infection associated with higher disease severity, earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. The findings suggest that a Gilliam strain infection in rhesus macaques provides improved endpoint measurements when compared to Karp strain infections, which is useful for future vaccine development.
Published: 2022

15. Human Immune Responses to Melioidosis and Cross-Reactivity to Low-Virulence Burkholderia Species, Thailand

Author: Patpong Rongkard, Barbara Kronsteiner, Viriya Hantrakun, Kemajittra Jenjaroen, Manutsanun Sumonwiriya, Panjaporn Chaichana, Suchintana Chumseng, Narisara Chantratita, Vanaporn Wuthiekanun, Helen A. Fletcher, Prapit Teparrukkul, Direk Limmathurotsakul, Nicholas P.J. Day, and Susanna J. Dunachie
Subjects: Burkholderia pseudomallei, Burkholderia thailandensis, Burkholderia thailandensis CPS variant, melioidosis, capsular polysaccharide, immune cross-reactivity, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: Melioidosis is a neglected tropical disease with an estimated annual mortality rate of 89,000 in 45 countries across tropical regions. The causative agent is Burkholderia pseudomallei, a gram-negative soil-dwelling bacterium. In Thailand, B. pseudomallei can be found across multiple regions, along with the low-virulence B. thailandensis and the recently discovered B. thailandensis variant (BTCV), which expresses B. pseudomallei–like capsular polysaccharide. Comprehensive studies of human immune responses to B. thailandensis variants and cross-reactivity to B. pseudomallei are not complete. We evaluated human immune responses to B. pseudomallei, B. thailandensis, and BTCV in melioidosis patients and healthy persons in B. pseudomallei–endemic areas using a range of humoral and cellular immune assays. We found immune cross-reactivity to be strong for both humoral and cellular immunity among B. pseudomallei, B. thailandensis, and BTCV. Our findings suggest that environmental exposure to low-virulence strains may build cellular immunity to B. pseudomallei.
Published: 2020
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16. BpOmpW Antigen Stimulates the Necessary Protective T-Cell Responses Against Melioidosis

Author: Julen Tomás-Cortázar, Lorenzo Bossi, Conor Quinn, Catherine J. Reynolds, David K. Butler, Niamh Corcoran, Maitiú Ó Murchú, Eve McMahon, Mahavir Singh, Patpong Rongkard, Juan Anguita, Alfonso Blanco, Susanna J. Dunachie, Daniel Altmann, Rosemary J. Boyton, Johan Arnold, Severine Giltaire, and Siobhán McClean
Subjects: melioidosis, vaccine, Burkholderia pseudomallei, T-cell responses, IFN-γ, type 2 diabetes, Immunologic diseases. Allergy, RC581-607
Abstract: Melioidosis is a potentially fatal bacterial disease caused by Burkholderia pseudomallei and is estimated to cause 89,000 deaths per year in endemic areas of Southeast Asia and Northern Australia. People with diabetes mellitus are most at risk of melioidosis, with a 12-fold increased susceptibility for severe disease. Interferon gamma (IFN-γ) responses from CD4 and CD8 T cells, but also from natural killer (NK) and natural killer T (NKT) cells, are necessary to eliminate the pathogen. We previously reported that immunization with B. pseudomallei OmpW (BpOmpW antigen) protected mice from lethal B. pseudomallei challenge for up to 81 days. Elucidating the immune correlates of protection of the protective BpOmpW vaccine is an essential step prior to clinical trials. Thus, we immunized either non-insulin-resistant C57BL/6J mice or an insulin-resistant C57BL/6J mouse model of type 2 diabetes (T2D) with a single dose of BpOmpW. BpOmpW induced strong antibody responses, stimulated effector CD4+ and CD8+ T cells and CD4+ CD25+ Foxp3+ regulatory T cells, and produced higher IFN-γ responses in CD4+, CD8+, NK, and NKT cells in non-insulin-resistant mice. The T-cell responses of insulin-resistant mice to BpOmpW were comparable to those of non-insulin-resistant mice. In addition, as a precursor to its evaluation in human studies, humanized HLA-DR and HLA-DQ (human leukocyte antigen DR and DQ isotypes, respectively) transgenic mice elicited IFN-γ recall responses in an enzyme-linked immune absorbent spot (ELISpot)-based study. Moreover, human donor peripheral blood mononuclear cells (PBMCs) exposed to BpOmpW for 7 days showed T-cell proliferation. Finally, plasma from melioidosis survivors with diabetes recognized our BpOmpW vaccine antigen. Overall, the range of approaches used strongly indicated that BpOmpW elicits the necessary immune responses to combat melioidosis and bring this vaccine closer to clinical trials.
Published: 2021
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17. Mitochondrial Ultrastructure and Activity Are Differentially Regulated by Glycolysis-, Krebs Cycle-, and Microbiota-Derived Metabolites in Monocytes

Author: C. Angélica Pérez-Hernández, M. Maximina Bertha Moreno-Altamirano, Edgar O. López-Villegas, Egle Butkeviciute, Mohammad Ali, Barbara Kronsteiner, Susanna J. Dunachie, Hazel M. Dockrell, Steven G. Smith, and F. Javier Sánchez-García
Subjects: innate immunity, mitochondria, glycolysis, Krebs cycle, short-chain fatty acids, mitochondrial reprogramming, Biology (General), QH301-705.5
Abstract: Several intermediate metabolites harbour cell-signalling properties, thus, it is likely that specific metabolites enable the communication between neighbouring cells, as well as between host cells with the microbiota, pathogens, and tumour cells. Mitochondria, a source of intermediate metabolites, participate in a wide array of biological processes beyond that of ATP production, such as intracellular calcium homeostasis, cell signalling, apoptosis, regulation of immune responses, and host cell–microbiota crosstalk. In this regard, mitochondria’s plasticity allows them to adapt their bioenergetics status to intra- and extra-cellular cues, and the mechanisms driving such plasticity are currently a matter of intensive research. Here, we addressed whether mitochondrial ultrastructure and activity are differentially shaped when human monocytes are exposed to an exogenous source of lactate (derived from glycolysis), succinate, and fumarate (Krebs cycle metabolic intermediates), or butyrate and acetate (short-chain fatty acids produced by intestinal microbiota). It has previously been shown that fumarate induces mitochondrial fusion, increases the mitochondrial membrane potential (Δψm), and reshapes the mitochondrial cristae ultrastructure. Here, we provide evidence that, in contrast to fumarate, lactate, succinate, and butyrate induce mitochondrial fission, while acetate induces mitochondrial swelling. These traits, along with mitochondrial calcium influx kinetics and glycolytic vs. mitochondrial ATP-production rates, suggest that these metabolites differentially shape mitochondrial function, paving the way for the understanding of metabolite-induced metabolic reprogramming of monocytes and its possible use for immune-response intervention.
Published: 2022
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18. Serum From Melioidosis Survivors Diminished Intracellular Burkholderia pseudomallei Growth in Macrophages: A Brief Research Report

Author: Panjaporn Chaichana, Barbara Kronsteiner, Patpong Rongkard, Prapit Teparrukkul, Direk Limmathurotsakul, Narisara Chantratita, Nicholas P. J. Day, Helen A. Fletcher, and Susanna J. Dunachie
Subjects: melioidosis, functional antibodies, opsonization, phagocytosis, Burkholderia pseudomallei, growth inhibition, Microbiology, QR1-502
Abstract: Melioidosis is a neglected tropical disease with high mortality rate. It is caused by the Gram-negative, CDC category B select agent Burkholderia pseudomallei (B. ps) that is intrinsically resistant to first-line antibiotics. An antibody-based vaccine is likely to be the most effective control measure. Previous studies have demonstrated significant mechanistic roles of antibodies in protection against death in animal models, but data from human melioidosis is scarce. Herein, we used in-vitro antibody-dependent cellular phagocytosis and growth inhibition assays to assess the mechanism of protective antibodies in patients with acute melioidosis. We found that serum from patients who survived the disease enable more live B. ps to be engulfed by THP-1 derived macrophages (median 1.7 × 103 CFU/ml, IQR 1.1 × 103-2.5 × 103 CFU/ml) than serum from patients who did not survive (median 1.2 × 103 CFU/ml, IQR 0.7 × 103-1.8 × 103, p = 0.02). In addition, the intracellular growth rate of B. ps pre-opsonized with serum from survivors (median 7.89, IQR 5.58–10.85) was diminished when compared with those with serum from non-survivors (median 10.88, IQR 5.42–14.88, p = 0.04). However, the difference of intracellular bacterial growth rate failed to reach statistical significance when using purified IgG antibodies (p = 0.09). These results provide new insights into a mechanistic role of serum in protection against death in human melioidosis for antibody-based vaccine development.
Published: 2020
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19. Melioidosis in Bangladesh: A Clinical and Epidemiological Analysis of Culture-Confirmed Cases

Author: Fazle Rabbi Chowdhury, Md. Shariful Alam Jilani, Lovely Barai, Tanjila Rahman, Mili Rani Saha, Md. Robed Amin, Kaniz Fatema, K. M. Shahidul Islam, M. A. Faiz, Susanna J. Dunachie, and David A. B. Dance
Subjects: melioidosis, Burkholderia, Bangladesh, Medicine
Abstract: Melioidosis is known to occur in Bangladesh, but there are few reports about the condition in the published international literature. We set out to review all known cases of melioidosis in the country to date, using both retrospective and prospective data. A web-based literature search was conducted to identify all published case reports, original articles and conference abstracts. Cases were also included from a prospective study conducted in 2017. Fifty-one cases were identified between 1961 and 2017. Cases have been reported from sixteen out of the 64 districts of Bangladesh. The median age of the patients at presentation was 45 years (IQR 37–52), with a significant male (77%) predominance. Many patients (14/39; 36%) were farmers and 83% had diabetes mellitus. A skin/soft tissue abscess was the most common primary clinical presentation (13/49; 27%), followed by septic arthritis (10/49; 20%), pneumonia, and a deep-seated abscess/organ abscess (7/49; 14%). The major challenges to the diagnosis and treatment of melioidosis in Bangladesh are the lack of resources and the lack of awareness of melioidosis. Capacity development programs are urgently required to define the burden of disease and to tackle the mortality rates.
Published: 2018
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20. Correction: Quantitative PCR Evaluation of Cellular Immune Responses in Kenyan Children Vaccinated with a Candidate Malaria Vaccine.

Author: Jedidah Mwacharo, Susanna J. Dunachie, Oscar Kai, Adrian V. S. Hill, Philip Bejon, and Helen A. Fletcher
Subjects: Medicine, Science
Published: 2011
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21. Global mortality associated with 33 bacterial pathogens in 2019

Author: Kevin S Ikuta, Lucien R Swetschinski, Gisela Robles Aguilar, Fablina Sharara, Tomislav Mestrovic, Authia P Gray, Nicole Davis Weaver, Eve E Wool, Chieh Han, Anna Gershberg Hayoon, Amirali Aali, Semagn Mekonnen Abate, Mohsen Abbasi-Kangevari, Zeinab Abbasi-Kangevari, Sherief Abd-Elsalam, Getachew Abebe, Aidin Abedi, Amir Parsa Abhari, Hassan Abidi, Richard Gyan Aboagye, Abdorrahim Absalan, Hiwa Abubaker Ali, Juan Manuel Acuna, Tigist Demssew Adane, Isaac Yeboah Addo, Oyelola A Adegboye, Mohammad Adnan, Qorinah Estiningtyas Sakilah Adnani, Muhammad Sohail Afzal, Saira Afzal, Zahra Babaei Aghdam, Bright Opoku Ahinkorah, Aqeel Ahmad, Araz Ramazan Ahmad, Rizwan Ahmad, Sajjad Ahmad, Sohail Ahmad, Sepideh Ahmadi, Ali Ahmed, Haroon Ahmed, Jivan Qasim Ahmed, Tarik Ahmed Rashid, Marjan Ajami, Budi Aji, Mostafa Akbarzadeh-Khiavi, Chisom Joyqueenet Akunna, Hanadi Al Hamad, Fares Alahdab, Ziyad Al-Aly, Mamoon A Aldeyab, Alicia V Aleman, Fadwa Alhalaiqa Naji Alhalaiqa, Robert Kaba Alhassan, Beriwan Abdulqadir Ali, Liaqat Ali, Syed Shujait Ali, Yousef Alimohamadi, Vahid Alipour, Atiyeh Alizadeh, Syed Mohamed Aljunid, Kasim Allel, Sami Almustanyir, Edward Kwabena Ameyaw, Arianna Maever L Amit, Nivedita Anandavelane, Robert Ancuceanu, Catalina Liliana Andrei, Tudorel Andrei, Dewi Anggraini, Adnan Ansar, Anayochukwu Edward Anyasodor, Jalal Arabloo, Aleksandr Y Aravkin, Demelash Areda, Timur Aripov, Anton A Artamonov, Judie Arulappan, Raphael Taiwo Aruleba, Muhammad Asaduzzaman, Tahira Ashraf, Seyyed Shamsadin Athari, Daniel Atlaw, Sameh Attia, Marcel Ausloos, Tewachew Awoke, Beatriz Paulina Ayala Quintanilla, Tegegn Mulatu Ayana, Sina Azadnajafabad, Amirhossein Azari Jafari, Darshan B B, Muhammad Badar, Ashish D Badiye, Nayereh Baghcheghi, Sara Bagherieh, Atif Amin Baig, Indrajit Banerjee, Aleksandra Barac, Mainak Bardhan, Francesco Barone-Adesi, Hiba Jawdat Barqawi, Amadou Barrow, Pritish Baskaran, Saurav Basu, Abdul-Monim Mohammad Batiha, Neeraj Bedi, Melaku Ashagrie Belete, Uzma Iqbal Belgaumi, Rose G Bender, Bharti Bhandari, Dinesh Bhandari, Pankaj Bhardwaj, Sonu Bhaskar, Krittika Bhattacharyya, Suraj Bhattarai, Saeid Bitaraf, Danilo Buonsenso, Zahid A Butt, Florentino Luciano Caetano dos Santos, Jiao Cai, Daniela Calina, Paulo Camargos, Luis Alberto Cámera, Rosario Cárdenas, Muge Cevik, Joshua Chadwick, Jaykaran Charan, Akhilanand Chaurasia, Patrick R Ching, Sonali Gajanan Choudhari, Enayet Karim Chowdhury, Fazle Rabbi Chowdhury, Dinh-Toi Chu, Isaac Sunday Chukwu, Omid Dadras, Fentaw Teshome Dagnaw, Xiaochen Dai, Saswati Das, Anna Dastiridou, Sisay Abebe Debela, Fitsum Wolde Demisse, Solomon Demissie, Diriba Dereje, Msganaw Derese, Hardik Dineshbhai Desai, Fikadu Nugusu Dessalegn, Samuel Abebe A Dessalegni, Belay Desye, Kartik Dhaduk, Meghnath Dhimal, Sameer Dhingra, Nancy Diao, Daniel Diaz, Shirin Djalalinia, Milad Dodangeh, Deepa Dongarwar, Bezabih Terefe Dora, Fariba Dorostkar, Haneil Larson Dsouza, Eleonora Dubljanin, Susanna J Dunachie, Oyewole Christopher Durojaiye, Hisham Atan Edinur, Habtamu Bekele Ejigu, Michael Ekholuenetale, Temitope Cyrus Ekundayo, Hassan El-Abid, Muhammed Elhadi, Mohamed A Elmonem, Amir Emami, Luchuo Engelbert Bain, Daniel Berhanie Enyew, Ryenchindorj Erkhembayar, Babak Eshrati, Farshid Etaee, Adeniyi Francis Fagbamigbe, Shahab Falahi, Aida Fallahzadeh, Emerito Jose A Faraon, Ali Fatehizadeh, Ginenus Fekadu, João C Fernandes, Allegra Ferrari, Getahun Fetensa, Irina Filip, Florian Fischer, Masoud Foroutan, Peter Andras Gaal, Muktar A Gadanya, Abhay Motiramji Gaidhane, Balasankar Ganesan, Mesfin Gebrehiwot, Reza Ghanbari, Mohammad Ghasemi Nour, Ahmad Ghashghaee, Ali Gholamrezanezhad, Abdolmajid Gholizadeh, Mahaveer Golechha, Pouya Goleij, Davide Golinelli, Amador Goodridge, Damitha Asanga Gunawardane, Yuming Guo, Rajat Das Gupta, Sapna Gupta, Veer Bala Gupta, Vivek Kumar Gupta, Alemu Guta, Parham Habibzadeh, Atlas Haddadi Avval, Rabih Halwani, Asif Hanif, Md. Abdul Hannan, Harapan Harapan, Shoaib Hassan, Hadi Hassankhani, Khezar Hayat, Behzad Heibati, Golnaz Heidari, Mohammad Heidari, Reza Heidari-Soureshjani, Claudiu Herteliu, Demisu Zenbaba Heyi, Kamal Hezam, Praveen Hoogar, Nobuyuki Horita, Md Mahbub Hossain, Mehdi Hosseinzadeh, Mihaela Hostiuc, Sorin Hostiuc, Soodabeh Hoveidamanesh, Junjie Huang, Salman Hussain, Nawfal R Hussein, Segun Emmanuel Ibitoye, Olayinka Stephen Ilesanmi, Irena M Ilic, Milena D Ilic, Mohammad Tarique Imam, Mustapha Immurana, Leeberk Raja Inbaraj, Arnaud Iradukunda, Nahlah Elkudssiah Ismail, Chidozie C D Iwu, Chinwe Juliana Iwu, Linda Merin J, Mihajlo Jakovljevic, Elham Jamshidi, Tahereh Javaheri, Fatemeh Javanmardi, Javad Javidnia, Sathish Kumar Jayapal, Umesh Jayarajah, Rime Jebai, Ravi Prakash Jha, Tamas Joo, Nitin Joseph, Farahnaz Joukar, Jacek Jerzy Jozwiak, Salah Eddine Oussama Kacimi, Vidya Kadashetti, Laleh R Kalankesh, Rohollah Kalhor, Vineet Kumar Kamal, Himal Kandel, Neeti Kapoor, Samad Karkhah, Bekalu Getnet Kassa, Nicholas J Kassebaum, Patrick DMC Katoto, Mohammad Keykhaei, Himanshu Khajuria, Abbas Khan, Imteyaz A Khan, Maseer Khan, Md Nuruzzaman Khan, Moien AB Khan, Moawiah Mohammad Khatatbeh, Mona M Khater, Hamid Reza Khayat Kashani, Jagdish Khubchandani, Hanna Kim, Min Seo Kim, Ruth W Kimokoti, Niranjan Kissoon, Sonali Kochhar, Farzad Kompani, Soewarta Kosen, Parvaiz A Koul, Sindhura Lakshmi Koulmane Laxminarayana, Fiorella Krapp Lopez, Kewal Krishan, Vijay Krishnamoorthy, Vishnutheertha Kulkarni, Naveen Kumar, Om P Kurmi, Ambily Kuttikkattu, Hmwe Hmwe Kyu, Dharmesh Kumar Lal, Judit Lám, Iván Landires, Savita Lasrado, Sang-woong Lee, Jacopo Lenzi, Sonia Lewycka, Shanshan Li, Stephen S Lim, Wei Liu, Rakesh Lodha, Michael J Loftus, Ayush Lohiya, László Lorenzovici, Mojgan Lotfi, Ata Mahmoodpoor, Mansour Adam Mahmoud, Razzagh Mahmoudi, Azeem Majeed, Jamal Majidpoor, Alaa Makki, Galana Ayana Mamo, Yosef Manla, Miquel Martorell, Clara N Matei, Barney McManigal, Entezar Mehrabi Nasab, Ravi Mehrotra, Addisu Melese, Oliver Mendoza-Cano, Ritesh G Menezes, Alexios-Fotios A Mentis, Georgia Micha, Irmina Maria Michalek, Ana Carolina Micheletti Gomide Nogueira de Sá, Neda Milevska Kostova, Shabir Ahmad Mir, Mojgan Mirghafourvand, Seyyedmohammadsadeq Mirmoeeni, Erkin M Mirrakhimov, Mohammad Mirza-Aghazadeh-Attari, Abay Sisay Misganaw, Awoke Misganaw, Sanjeev Misra, Esmaeil Mohammadi, Mokhtar Mohammadi, Abdollah Mohammadian-Hafshejani, Shafiu Mohammed, Syam Mohan, Mohammad Mohseni, Ali H Mokdad, Sara Momtazmanesh, Lorenzo Monasta, Catrin E Moore, Maryam Moradi, Mostafa Moradi Sarabi, Shane Douglas Morrison, Majid Motaghinejad, Haleh Mousavi Isfahani, Amin Mousavi Khaneghah, Seyed Ali Mousavi-Aghdas, Sumaira Mubarik, Francesk Mulita, Getaneh Baye B Mulu, Sandra B Munro, Saravanan Muthupandian, Tapas Sadasivan Nair, Atta Abbas Naqvi, Himanshi Narang, Zuhair S Natto, Muhammad Naveed, Biswa Prakash Nayak, Shumaila Naz, Ionut Negoi, Seyed Aria Nejadghaderi, Sandhya Neupane Kandel, Che Henry Ngwa, Robina Khan Niazi, Antonio Tolentino Nogueira de Sá, Nafise Noroozi, Hasti Nouraei, Ali Nowroozi, Virginia Nuñez-Samudio, Jerry John Nutor, Chimezie Igwegbe Nzoputam, Ogochukwu Janet Nzoputam, Bogdan Oancea, Rahman Md Obaidur, Vivek Anand Ojha, Akinkunmi Paul Okekunle, Osaretin Christabel Okonji, Andrew T Olagunju, Bolajoko Olubukunola Olusanya, Ahmed Omar Bali, Emad Omer, Nikita Otstavnov, Bilcha Oumer, Mahesh P A, Jagadish Rao Padubidri, Keyvan Pakshir, Tamás Palicz, Adrian Pana, Shahina Pardhan, Jose L Paredes, Utsav Parekh, Eun-Cheol Park, Seoyeon Park, Ashish Pathak, Rajan Paudel, Uttam Paudel, Shrikant Pawar, Hamidreza Pazoki Toroudi, Minjin Peng, Umberto Pensato, Veincent Christian Filipino Pepito, Marcos Pereira, Mario F P Peres, Norberto Perico, Ionela-Roxana Petcu, Zahra Zahid Piracha, Indrashis Podder, Nayanum Pokhrel, Ramesh Poluru, Maarten J Postma, Naeimeh Pourtaheri, Akila Prashant, Ibrahim Qattea, Mohammad Rabiee, Navid Rabiee, Amir Radfar, Saber Raeghi, Sima Rafiei, Pankaja Raghav Raghav, Leila Rahbarnia, Vafa Rahimi-Movaghar, Mosiur Rahman, Muhammad Aziz Rahman, Amir Masoud Rahmani, Vahid Rahmanian, Pradhum Ram, Muhammad Modassar Ali Nawaz Ranjha, Sowmya J Rao, Mohammad-Mahdi Rashidi, Azad Rasul, Zubair Ahmed Ratan, Salman Rawaf, Reza Rawassizadeh, Mohammad Sadegh Razeghinia, Elrashdy Moustafa Mohamed Redwan, Misganu Teshoma Regasa, Giuseppe Remuzzi, Melese Abate Reta, Nazila Rezaei, Aziz Rezapour, Abanoub Riad, Rezaul Karim Ripon, Kristina E Rudd, Basema Saddik, Saeid Sadeghian, Umar Saeed, Mohsen Safaei, Azam Safary, Sher Zaman Safi, Maryam Sahebazzamani, Amirhossein Sahebkar, Harihar Sahoo, Saina Salahi, Sarvenaz Salahi, Hedayat Salari, Sana Salehi, Hossein Samadi Kafil, Abdallah M Samy, Nima Sanadgol, Senthilkumar Sankararaman, Francesco Sanmarchi, Brijesh Sathian, Monika Sawhney, Ganesh Kumar Saya, Subramanian Senthilkumaran, Allen Seylani, Pritik A Shah, Masood Ali Shaikh, Elaheh Shaker, Murad Ziyaudinovich Shakhmardanov, Mequannent Melaku Sharew, Athena Sharifi-Razavi, Purva Sharma, Rahim Ali Sheikhi, Ali Sheikhy, Pavanchand H Shetty, Mika Shigematsu, Jae Il Shin, Hesamaddin Shirzad-Aski, K M Shivakumar, Parnian Shobeiri, Seyed Afshin Shorofi, Sunil Shrestha, Migbar Mekonnen Sibhat, Negussie Boti Sidemo, Mustafa Kamal Sikder, Luís Manuel Lopes Rodrigues Silva, Jasvinder A Singh, Paramdeep Singh, Surjit Singh, Md Shahjahan Siraj, Samarjeet Singh Siwal, Valentin Yurievich Skryabin, Anna Aleksandrovna Skryabina, Bogdan Socea, Damtew Damtew Solomon, Yimeng Song, Chandrashekhar T Sreeramareddy, Muhammad Suleman, Rizwan Suliankatchi Abdulkader, Saima Sultana, Miklós Szócska, Seyed-Amir Tabatabaeizadeh, Mohammad Tabish, Majid Taheri, Elahe Taki, Ker-Kan Tan, Sarmila Tandukar, Nathan Y Tat, Vivian Y Tat, Belay Negash Tefera, Yibekal Manaye Tefera, Gebremaryam Temesgen, Mohamad-Hani Temsah, Samar Tharwat, Arulmani Thiyagarajan, Imad I Tleyjeh, Christopher E Troeger, Krishna Kishore Umapathi, Era Upadhyay, Sahel Valadan Tahbaz, Pascual R Valdez, Jef Van den Eynde, H. Rogier van Doorn, Siavash Vaziri, Georgios-Ioannis Verras, Harimadhav Viswanathan, Bay Vo, Abdul Waris, Gizachew Tadesse Wassie, Nuwan Darshana Wickramasinghe, Sajad Yaghoubi, Gahin Abdulraheem Tayib Yahya Yahya, Seyed Hossein Yahyazadeh Jabbari, Arzu Yigit, Vahit Yiğit, Dong Keon Yon, Naohiro Yonemoto, Mazyar Zahir, Burhan Abdullah Zaman, Sojib Bin Zaman, Moein Zangiabadian, Iman Zare, Mikhail Sergeevich Zastrozhin, Zhi-Jiang Zhang, Peng Zheng, Chenwen Zhong, Mohammad Zoladl, Alimuddin Zumla, Simon I Hay, Christiane Dolecek, Benn Sartorius, Christopher J L Murray, Mohsen Naghavi, Ikuta, Kevin S, Swetschinski, Lucien R, Robles Aguilar, Gisela, Sharara, Fablina, Mestrovic, Tomislav, Gray, Authia P, Davis Weaver, Nicole, Wool, Eve E, Han, Chieh, Gershberg Hayoon, Anna, Aali, Amirali, Abate, Semagn Mekonnen, Abbasi-Kangevari, Mohsen, Abbasi-Kangevari, Zeinab, Abd-Elsalam, Sherief, Abebe, Getachew, Abedi, Aidin, Abhari, Amir Parsa, Abidi, Hassan, Aboagye, Richard Gyan, Absalan, Abdorrahim, Abubaker Ali, Hiwa, Acuna, Juan Manuel, Adane, Tigist Demssew, Addo, Isaac Yeboah, Adegboye, Oyelola A, Adnan, Mohammad, Adnani, Qorinah Estiningtyas Sakilah, Afzal, Muhammad Sohail, Afzal, Saira, Aghdam, Zahra Babaei, Ahinkorah, Bright Opoku, Ahmad, Aqeel, Ahmad, Araz Ramazan, Ahmad, Rizwan, Ahmad, Sajjad, Ahmad, Sohail, Ahmadi, Sepideh, Ahmed, Ali, Ahmed, Haroon, Ahmed, Jivan Qasim, Ahmed Rashid, Tarik, Ajami, Marjan, Aji, Budi, Akbarzadeh-Khiavi, Mostafa, Akunna, Chisom Joyqueenet, Al Hamad, Hanadi, Alahdab, Fare, Al-Aly, Ziyad, Aldeyab, Mamoon A, Aleman, Alicia V, Alhalaiqa, Fadwa Alhalaiqa Naji, Alhassan, Robert Kaba, Ali, Beriwan Abdulqadir, Ali, Liaqat, Ali, Syed Shujait, Alimohamadi, Yousef, Alipour, Vahid, Alizadeh, Atiyeh, Aljunid, Syed Mohamed, Allel, Kasim, Almustanyir, Sami, Ameyaw, Edward Kwabena, Amit, Arianna Maever L, Anandavelane, Nivedita, Ancuceanu, Robert, Andrei, Catalina Liliana, Andrei, Tudorel, Anggraini, Dewi, Ansar, Adnan, Anyasodor, Anayochukwu Edward, Arabloo, Jalal, Aravkin, Aleksandr Y, Areda, Demelash, Aripov, Timur, Artamonov, Anton A, Arulappan, Judie, Aruleba, Raphael Taiwo, Asaduzzaman, Muhammad, Ashraf, Tahira, Athari, Seyyed Shamsadin, Atlaw, Daniel, Attia, Sameh, Ausloos, Marcel, Awoke, Tewachew, Ayala Quintanilla, Beatriz Paulina, Ayana, Tegegn Mulatu, Azadnajafabad, Sina, Azari Jafari, Amirhossein, B, Darshan B, Badar, Muhammad, Badiye, Ashish D, Baghcheghi, Nayereh, Bagherieh, Sara, Baig, Atif Amin, Banerjee, Indrajit, Barac, Aleksandra, Bardhan, Mainak, Barone-Adesi, Francesco, Barqawi, Hiba Jawdat, Barrow, Amadou, Baskaran, Pritish, Basu, Saurav, Batiha, Abdul-Monim Mohammad, Bedi, Neeraj, Belete, Melaku Ashagrie, Belgaumi, Uzma Iqbal, Bender, Rose G, Bhandari, Bharti, Bhandari, Dinesh, Bhardwaj, Pankaj, Bhaskar, Sonu, Bhattacharyya, Krittika, Bhattarai, Suraj, Bitaraf, Saeid, Buonsenso, Danilo, Butt, Zahid A, Caetano dos Santos, Florentino Luciano, Cai, Jiao, Calina, Daniela, Camargos, Paulo, Cámera, Luis Alberto, Cárdenas, Rosario, Cevik, Muge, Chadwick, Joshua, Charan, Jaykaran, Chaurasia, Akhilanand, Ching, Patrick R, Choudhari, Sonali Gajanan, Chowdhury, Enayet Karim, Chowdhury, Fazle Rabbi, Chu, Dinh-Toi, Chukwu, Isaac Sunday, Dadras, Omid, Dagnaw, Fentaw Teshome, Dai, Xiaochen, Das, Saswati, Dastiridou, Anna, Debela, Sisay Abebe, Demisse, Fitsum Wolde, Demissie, Solomon, Dereje, Diriba, Derese, Msganaw, Desai, Hardik Dineshbhai, Dessalegn, Fikadu Nugusu, Dessalegni, Samuel Abebe A, Desye, Belay, Dhaduk, Kartik, Dhimal, Meghnath, Dhingra, Sameer, Diao, Nancy, Diaz, Daniel, Djalalinia, Shirin, Dodangeh, Milad, Dongarwar, Deepa, Dora, Bezabih Terefe, Dorostkar, Fariba, Dsouza, Haneil Larson, Dubljanin, Eleonora, Dunachie, Susanna J, Durojaiye, Oyewole Christopher, Edinur, Hisham Atan, Ejigu, Habtamu Bekele, Ekholuenetale, Michael, Ekundayo, Temitope Cyru, El-Abid, Hassan, Elhadi, Muhammed, Elmonem, Mohamed A, Emami, Amir, Engelbert Bain, Luchuo, Enyew, Daniel Berhanie, Erkhembayar, Ryenchindorj, Eshrati, Babak, Etaee, Farshid, Fagbamigbe, Adeniyi Franci, Falahi, Shahab, Fallahzadeh, Aida, Faraon, Emerito Jose A, Fatehizadeh, Ali, Fekadu, Ginenu, Fernandes, João C, Ferrari, Allegra, Fetensa, Getahun, Filip, Irina, Fischer, Florian, Foroutan, Masoud, Gaal, Peter Andra, Gadanya, Muktar A, Gaidhane, Abhay Motiramji, Ganesan, Balasankar, Gebrehiwot, Mesfin, Ghanbari, Reza, Ghasemi Nour, Mohammad, Ghashghaee, Ahmad, Gholamrezanezhad, Ali, Gholizadeh, Abdolmajid, Golechha, Mahaveer, Goleij, Pouya, Golinelli, Davide, Goodridge, Amador, Gunawardane, Damitha Asanga, Guo, Yuming, Gupta, Rajat Da, Gupta, Sapna, Gupta, Veer Bala, Gupta, Vivek Kumar, Guta, Alemu, Habibzadeh, Parham, Haddadi Avval, Atla, Halwani, Rabih, Hanif, Asif, Hannan, Md. Abdul, Harapan, Harapan, Hassan, Shoaib, Hassankhani, Hadi, Hayat, Khezar, Heibati, Behzad, Heidari, Golnaz, Heidari, Mohammad, Heidari-Soureshjani, Reza, Herteliu, Claudiu, Heyi, Demisu Zenbaba, Hezam, Kamal, Hoogar, Praveen, Horita, Nobuyuki, Hossain, Md Mahbub, Hosseinzadeh, Mehdi, Hostiuc, Mihaela, Hostiuc, Sorin, Hoveidamanesh, Soodabeh, Huang, Junjie, Hussain, Salman, Hussein, Nawfal R, Ibitoye, Segun Emmanuel, Ilesanmi, Olayinka Stephen, Ilic, Irena M, Ilic, Milena D, Imam, Mohammad Tarique, Immurana, Mustapha, Inbaraj, Leeberk Raja, Iradukunda, Arnaud, Ismail, Nahlah Elkudssiah, Iwu, Chidozie C D, Iwu, Chinwe Juliana, J, Linda Merin, Jakovljevic, Mihajlo, Jamshidi, Elham, Javaheri, Tahereh, Javanmardi, Fatemeh, Javidnia, Javad, Jayapal, Sathish Kumar, Jayarajah, Umesh, Jebai, Rime, Jha, Ravi Prakash, Joo, Tama, Joseph, Nitin, Joukar, Farahnaz, Jozwiak, Jacek Jerzy, Kacimi, Salah Eddine Oussama, Kadashetti, Vidya, Kalankesh, Laleh R, Kalhor, Rohollah, Kamal, Vineet Kumar, Kandel, Himal, Kapoor, Neeti, Karkhah, Samad, Kassa, Bekalu Getnet, Kassebaum, Nicholas J, Katoto, Patrick DMC, Keykhaei, Mohammad, Khajuria, Himanshu, Khan, Abba, Khan, Imteyaz A, Khan, Maseer, Khan, Md Nuruzzaman, Khan, Moien AB, Khatatbeh, Moawiah Mohammad, Khater, Mona M, Khayat Kashani, Hamid Reza, Khubchandani, Jagdish, Kim, Hanna, Kim, Min Seo, Kimokoti, Ruth W, Kissoon, Niranjan, Kochhar, Sonali, Kompani, Farzad, Kosen, Soewarta, Koul, Parvaiz A, Koulmane Laxminarayana, Sindhura Lakshmi, Krapp Lopez, Fiorella, Krishan, Kewal, Krishnamoorthy, Vijay, Kulkarni, Vishnutheertha, Kumar, Naveen, Kurmi, Om P, Kuttikkattu, Ambily, Kyu, Hmwe Hmwe, Lal, Dharmesh Kumar, Lám, Judit, Landires, Iván, Lasrado, Savita, Lee, Sang-woong, Lenzi, Jacopo, Lewycka, Sonia, Li, Shanshan, Lim, Stephen S, Liu, Wei, Lodha, Rakesh, Loftus, Michael J, Lohiya, Ayush, Lorenzovici, László, Lotfi, Mojgan, Mahmoodpoor, Ata, Mahmoud, Mansour Adam, Mahmoudi, Razzagh, Majeed, Azeem, Majidpoor, Jamal, Makki, Alaa, Mamo, Galana Ayana, Manla, Yosef, Martorell, Miquel, Matei, Clara N, McManigal, Barney, Mehrabi Nasab, Entezar, Mehrotra, Ravi, Melese, Addisu, Mendoza-Cano, Oliver, Menezes, Ritesh G, Mentis, Alexios-Fotios A, Micha, Georgia, Michalek, Irmina Maria, Micheletti Gomide Nogueira de Sá, Ana Carolina, Milevska Kostova, Neda, Mir, Shabir Ahmad, Mirghafourvand, Mojgan, Mirmoeeni, Seyyedmohammadsadeq, Mirrakhimov, Erkin M, Mirza-Aghazadeh-Attari, Mohammad, Misganaw, Abay Sisay, Misganaw, Awoke, Misra, Sanjeev, Mohammadi, Esmaeil, Mohammadi, Mokhtar, Mohammadian-Hafshejani, Abdollah, Mohammed, Shafiu, Mohan, Syam, Mohseni, Mohammad, Mokdad, Ali H, Momtazmanesh, Sara, Monasta, Lorenzo, Moore, Catrin E, Moradi, Maryam, Moradi Sarabi, Mostafa, Morrison, Shane Dougla, Motaghinejad, Majid, Mousavi Isfahani, Haleh, Mousavi Khaneghah, Amin, Mousavi-Aghdas, Seyed Ali, Mubarik, Sumaira, Mulita, Francesk, Mulu, Getaneh Baye B, Munro, Sandra B, Muthupandian, Saravanan, Nair, Tapas Sadasivan, Naqvi, Atta Abba, Narang, Himanshi, Natto, Zuhair S, Naveed, Muhammad, Nayak, Biswa Prakash, Naz, Shumaila, Negoi, Ionut, Nejadghaderi, Seyed Aria, Neupane Kandel, Sandhya, Ngwa, Che Henry, Niazi, Robina Khan, Nogueira de Sá, Antonio Tolentino, Noroozi, Nafise, Nouraei, Hasti, Nowroozi, Ali, Nuñez-Samudio, Virginia, Nutor, Jerry John, Nzoputam, Chimezie Igwegbe, Nzoputam, Ogochukwu Janet, Oancea, Bogdan, Obaidur, Rahman Md, Ojha, Vivek Anand, Okekunle, Akinkunmi Paul, Okonji, Osaretin Christabel, Olagunju, Andrew T, Olusanya, Bolajoko Olubukunola, Omar Bali, Ahmed, Omer, Emad, Otstavnov, Nikita, Oumer, Bilcha, P A, Mahesh, Padubidri, Jagadish Rao, Pakshir, Keyvan, Palicz, Tamá, Pana, Adrian, Pardhan, Shahina, Paredes, Jose L, Parekh, Utsav, Park, Eun-Cheol, Park, Seoyeon, Pathak, Ashish, Paudel, Rajan, Paudel, Uttam, Pawar, Shrikant, Pazoki Toroudi, Hamidreza, Peng, Minjin, Pensato, Umberto, Pepito, Veincent Christian Filipino, Pereira, Marco, Peres, Mario F P, Perico, Norberto, Petcu, Ionela-Roxana, Piracha, Zahra Zahid, Podder, Indrashi, Pokhrel, Nayanum, Poluru, Ramesh, Postma, Maarten J, Pourtaheri, Naeimeh, Prashant, Akila, Qattea, Ibrahim, Rabiee, Mohammad, Rabiee, Navid, Radfar, Amir, Raeghi, Saber, Rafiei, Sima, Raghav, Pankaja Raghav, Rahbarnia, Leila, Rahimi-Movaghar, Vafa, Rahman, Mosiur, Rahman, Muhammad Aziz, Rahmani, Amir Masoud, Rahmanian, Vahid, Ram, Pradhum, Ranjha, Muhammad Modassar Ali Nawaz, Rao, Sowmya J, Rashidi, Mohammad-Mahdi, Rasul, Azad, Ratan, Zubair Ahmed, Rawaf, Salman, Rawassizadeh, Reza, Razeghinia, Mohammad Sadegh, Redwan, Elrashdy Moustafa Mohamed, Regasa, Misganu Teshoma, Remuzzi, Giuseppe, Reta, Melese Abate, Rezaei, Nazila, Rezapour, Aziz, Riad, Abanoub, Ripon, Rezaul Karim, Rudd, Kristina E, Saddik, Basema, Sadeghian, Saeid, Saeed, Umar, Safaei, Mohsen, Safary, Azam, Safi, Sher Zaman, Sahebazzamani, Maryam, Sahebkar, Amirhossein, Sahoo, Harihar, Salahi, Saina, Salahi, Sarvenaz, Salari, Hedayat, Salehi, Sana, Samadi Kafil, Hossein, Samy, Abdallah M, Sanadgol, Nima, Sankararaman, Senthilkumar, Sanmarchi, Francesco, Sathian, Brijesh, Sawhney, Monika, Saya, Ganesh Kumar, Senthilkumaran, Subramanian, Seylani, Allen, Shah, Pritik A, Shaikh, Masood Ali, Shaker, Elaheh, Shakhmardanov, Murad Ziyaudinovich, Sharew, Mequannent Melaku, Sharifi-Razavi, Athena, Sharma, Purva, Sheikhi, Rahim Ali, Sheikhy, Ali, Shetty, Pavanchand H, Shigematsu, Mika, Shin, Jae Il, Shirzad-Aski, Hesamaddin, Shivakumar, K M, Shobeiri, Parnian, Shorofi, Seyed Afshin, Shrestha, Sunil, Sibhat, Migbar Mekonnen, Sidemo, Negussie Boti, Sikder, Mustafa Kamal, Silva, Luís Manuel Lopes Rodrigue, Singh, Jasvinder A, Singh, Paramdeep, Singh, Surjit, Siraj, Md Shahjahan, Siwal, Samarjeet Singh, Skryabin, Valentin Yurievich, Skryabina, Anna Aleksandrovna, Socea, Bogdan, Solomon, Damtew Damtew, Song, Yimeng, Sreeramareddy, Chandrashekhar T, Suleman, Muhammad, Suliankatchi Abdulkader, Rizwan, Sultana, Saima, Szócska, Mikló, Tabatabaeizadeh, Seyed-Amir, Tabish, Mohammad, Taheri, Majid, Taki, Elahe, Tan, Ker-Kan, Tandukar, Sarmila, Tat, Nathan Y, Tat, Vivian Y, Tefera, Belay Negash, Tefera, Yibekal Manaye, Temesgen, Gebremaryam, Temsah, Mohamad-Hani, Tharwat, Samar, Thiyagarajan, Arulmani, Tleyjeh, Imad I, Troeger, Christopher E, Umapathi, Krishna Kishore, Upadhyay, Era, Valadan Tahbaz, Sahel, Valdez, Pascual R, Van den Eynde, Jef, van Doorn, H. Rogier, Vaziri, Siavash, Verras, Georgios-Ioanni, Viswanathan, Harimadhav, Vo, Bay, Waris, Abdul, Wassie, Gizachew Tadesse, Wickramasinghe, Nuwan Darshana, Yaghoubi, Sajad, Yahya, Gahin Abdulraheem Tayib Yahya, Yahyazadeh Jabbari, Seyed Hossein, Yigit, Arzu, Yiğit, Vahit, Yon, Dong Keon, Yonemoto, Naohiro, Zahir, Mazyar, Zaman, Burhan Abdullah, Zaman, Sojib Bin, Zangiabadian, Moein, Zare, Iman, Zastrozhin, Mikhail Sergeevich, Zhang, Zhi-Jiang, Zheng, Peng, Zhong, Chenwen, Zoladl, Mohammad, Zumla, Alimuddin, Hay, Simon I, Dolecek, Christiane, Sartorius, Benn, Murray, Christopher J L, and Naghavi, Mohsen
Subjects: Male, Bacteria, Syndrome, Bacterial Infections, General Medicine, Global Health, Global Burden of Disease, Risk Factors, Sepsis, Humans, Female, Mortality, Child, Africa South of the Sahara
Abstract: Background: Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes. Methods: We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest. Findings: From an estimated 13·7 million (95% UI 10·9–17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7–10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2–18·1) of all global deaths and 56·2% (52·1–60·1) of all sepsis-related deaths in 2019. Five leading pathogens—Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa—were responsible for 54·9% (52·9–56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185–285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4–71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths. Interpretation: The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development. Funding: Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care, using UK aid funding managed by the Fleming Fund.
Published: 2022

22. Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis

Author: Yavuz F. Yazicioglu, Eros Marin, Ciaran Sandhu, Silvia Galiani, Iwan G. A. Raza, Mohammad Ali, Barbara Kronsteiner, Ewoud B. Compeer, Moustafa Attar, Susanna J. Dunachie, Michael L. Dustin, and Alexander J. Clarke
Subjects: Immunology, Immunology and Allergy
Abstract: Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.
Published: 2023
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23. 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
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24. Dynamic mitochondrial transcription and translation in B cells control germinal centre entry and lymphomagenesis

Author: Yavuz F Yazicioglu, Eros M Marin, Ciaran Sandhu, Silvia Galiani, Iwan G A Raza, Mohammad Ali, Barbara Kronsteiner, Ewoud B Compeer, Moustafa Attar, Susanna J Dunachie, Michael L Dustin, and Alexander J Clarke
Abstract: Germinal centre (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment, but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor mitochondrial A (TFAM). TFAM, whilst also necessary for normal B cell development, is required for entry of activated GC-precursor B cells into the germinal centre reaction, and deletion ofTfamsignificantly impairs GC formation, function, and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signalling, leading to their spatial disorganisation. We show that B cell lymphoma substantially increases mitochondrial translation, and deletion ofTfamin B cells is protective against the development of lymphoma in a c-Myc transgenic model. Finally, we show that pharmacologic inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells, and induces similar defects in the actin cytoskeleton.
Published: 2022
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25. Infectious Disease

Author: Susanna J. Dunachie, Hanif Esmail, Ruth Corrigan, and Maria Dudareva
Published: 2022
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26. Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum

Author: Aekkachai Tuekprakhon, Rungtiwa Nutalai, Aiste Dijokaite-Guraliuc, Daming Zhou, Helen M. Ginn, Muneeswaran Selvaraj, Chang Liu, Alexander J. Mentzer, Piyada Supasa, Helen M.E. Duyvesteyn, Raksha Das, Donal Skelly, Thomas G. Ritter, Ali Amini, Sagida Bibi, Sandra Adele, Sile Ann Johnson, Bede Constantinides, Hermione Webster, Nigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Derrick Crook, Andrew J. Pollard, Teresa Lambe, Philip Goulder, Neil G. Paterson, Mark A. Williams, David R. Hall, Elizabeth E. Fry, Jiandong Huo, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, Gavin R. Screaton, Christopher Conlon, Alexandra Deeks, John Frater, Lisa Frending, Siobhan Gardiner, Anni Jämsén, Katie Jeffery, Tom Malone, Eloise Phillips, Lucy Rothwell, Lizzie Stafford, and Consortium, OPTIC
Subjects: QR355, South Africa, Neutralization Tests, SARS-CoV-2, COVID-19, Humans, Viral Vaccines, Antibodies, Viral, Antibodies, Neutralizing, General Biochemistry, Genetics and Molecular Biology
Abstract: The Omicron lineage of SARS-CoV-2, which was first described in November 2021, spread rapidly to become globally dominant and has split into a number of sublineages. 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 sublineages, 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, they contain further mutations in the receptor-binding domain of their spikes. 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 the serum from individuals vaccinated with triple doses of AstraZeneca or Pfizer vaccine compared with BA.1 and BA.2. Furthermore, using the 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

27. SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

Author: Wanwisa Dejnirattisai, Jiandong Huo, Daming Zhou, Jiří Zahradník, Piyada Supasa, Chang Liu, Helen M.E. Duyvesteyn, Helen M. Ginn, Alexander J. Mentzer, Aekkachai Tuekprakhon, Rungtiwa Nutalai, Beibei Wang, Aiste Dijokaite, Suman Khan, Ori Avinoam, Mohammad Bahar, Donal Skelly, Sandra Adele, Sile Ann Johnson, Ali Amini, Thomas G. Ritter, Chris Mason, Christina Dold, Daniel Pan, Sara Assadi, Adam Bellass, Nicola Omo-Dare, David Koeckerling, Amy Flaxman, Daniel Jenkin, Parvinder K. Aley, Merryn Voysey, Sue Ann Costa Clemens, Felipe Gomes Naveca, Valdinete Nascimento, Fernanda Nascimento, Cristiano Fernandes da Costa, Paola Cristina Resende, Alex Pauvolid-Correa, Marilda M. Siqueira, Vicky Baillie, Natali Serafin, Gaurav Kwatra, Kelly Da Silva, Shabir A. Madhi, Marta C. Nunes, Tariq Malik, Peter J.M. Openshaw, J. Kenneth Baillie, Malcolm G. Semple, Alain R. Townsend, Kuan-Ying A. Huang, Tiong Kit Tan, Miles W. Carroll, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Bede Constantinides, Hermione Webster, Derrick Crook, Andrew J. Pollard, Teresa Lambe, Neil G. Paterson, Mark A. Williams, David R. Hall, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, Gideon Schreiber, David I. Stuart, Gavin R. Screaton, Christopher Conlon, Alexandra S. Deeks, John Frater, Lisa Frending, Siobhan Gardiner, Anni Jämsén, Katie Jeffery, Tom Malone, Eloise Phillips, Lucy Rothwell, Lizzie Stafford, J Kenneth Baillie, Peter JM. Openshaw, Gail Carson, Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, Wendy S. Barclay, Debby Bogaert, Meera Chand, Kanta Chechi, Graham S. Cooke, Ana da Silva Filipe, Thushan de Silva, Annemarie B. Docherty, Gonçalo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christoper A. Green, William Greenhalf, Julian L. Griffin, Rishi K. Gupta, Ewen M. Harrison, Julian A. Hiscox, Antonia Ying Wai Ho, Peter W. Horby, Samreen Ijaz, Saye Khoo, Andrew Law, Matthew R. Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Laura Merson, Alison M. Meynert, Shona C. Moore, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A. Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L. Robertson, Clark D. Russell, Vanessa Sancho-Shimizu, Caroline J. Sands, Janet T. Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Olivia V. Swann, Zoltan Takats, Panteleimon Takis, Richard S. Tedder, AA Roger Thompson, Emma C. Thomson, Ryan S. Thwaites, Lance CW. Turtle, Maria Zambon, Hayley Hardwick, Chloe Donohue, Fiona Griffiths, Wilna Oosthuyzen, Cara Donegan, Rebecca G. Spencer, Lisa Norman, Riinu Pius, Thomas M. Drake, Cameron J. Fairfield, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Catherine A. Shaw, Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Daniel Plotkin, James Lee, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, Victoria Shaw, Sarah E. McDonald, Seán Keating, Katie A. Ahmed, Jane A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L. Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin WA. Catterall, Jordan J. Clark, Emily A. Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis WS. Fisher, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Rebecca L. Jensen, Christopher B. Jones, Trevor R. Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A. Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S. Miah, Joanna Middleton, Joyce Mitchell, Ellen G. Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P. Matthew Ridley, Debby Sales, Victoria E. Shaw, Rebecca K. Shears, Benjamin Small, Krishanthi S. Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. Eunice Zhang, Lisa Flaherty, Nicole Maziere, Emily Cass, Alejandra Doce Carracedo, Nicola Carlucci, Anthony Holmes, Hannah Massey, Lee Murphy, Sarah McCafferty, Richard Clark, Angie Fawkes, Kirstie Morrice, Alan Maclean, Nicola Wrobel, Lorna Donnelly, Audrey Coutts, Katarzyna Hafezi, Louise MacGillivray, Tammy Gilchrist, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Sam Allen, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Colin Berry, Nicola Best, Pieter Bothma, David Chadwick, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Andrew Drummond, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Clive Graham, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B. Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Mariyam Mirfenderesky, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Lillian Norris, Matthew K. O’Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Tim Planche, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Bobby Ruge, Brendan Ryan, Taranprit Saluja, Matthias L. Schmid, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Manu Shankar-Hari, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Nick Vallotton, Rama Vancheeswaran, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Padmasayee Papineni, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G. Wootton, Andrew Workman, Bryan Yates, Peter Young, National Institute for Health Research, UK Research and Innovation, UKRI MRC COVID-19 Rapid Response Call, University of Oxford, Northwestern Polytechnical University (NPU), Charles University [Prague] (CU), Division of Immunology and Inflammation, Department of Medicine, Imperial College London-Hammersmith Hospital Campus, University of Dayton, Universiteit Gent = Ghent University (UGENT), Computational & Applied Vegetation Ecology (CAVElab), Nanjing University of Science and Technology (NJUST), Weizmann Institute of Science [Rehovot, Israël], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Imperial College London, and Apollo - University of Cambridge Repository
Subjects: variants, receptor interaction, Omicron, SARS-CoV-2, [SDV]Life Sciences [q-bio], OPTIC Consortium, Spike, vaccines, 06 Biological Sciences, Article, General Biochemistry, Genetics and Molecular Biology, RBD, ISARIC4C Consortium, 11 Medical and Health Sciences, immune evasion, Developmental Biology
Abstract: On the 24th November 2021 the sequence of a new SARS CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses., A comprehensive analysis of sera from vaccinees, convalescent patients infected previously by multiple variants and potent monoclonal antibodies from early in the COVID-19 pandemic reveals a substantial overall reduction the ability to neutralize the SARS-CoV-2 Omicron variant, which a third vaccine dose seems to ameliorate. Structural analyses of the Omicron RBD suggest a selective pressure enabling the virus bind ACE2 with increased affinity that is offset by other changes in the receptor binding motif that facilitates immune escape.
Published: 2022
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28. Global burden of bacterial antimicrobial resistance in 2019 : a systematic analysis

Author: Christopher J L Murray, Kevin Shunji Ikuta, Fablina Sharara, Lucien Swetschinski, Gisela Robles Aguilar, Authia Gray, Chieh Han, Catherine Bisignano, Puja Rao, Eve Wool, Sarah C Johnson, Annie J Browne, Michael Give Chipeta, Frederick Fell, Sean Hackett, Georgina Haines-Woodhouse, Bahar H Kashef Hamadani, Emmanuelle A P Kumaran, Barney McManigal, Sureeruk Achalapong, Ramesh Agarwal, Samuel Akech, Samuel Albertson, John Amuasi, Jason Andrews, Aleskandr Aravkin, Elizabeth Ashley, François-Xavier Babin, Freddie Bailey, Stephen Baker, Buddha Basnyat, Adrie Bekker, Rose Bender, James A Berkley, Adhisivam Bethou, Julia Bielicki, Suppawat Boonkasidecha, James Bukosia, Cristina Carvalheiro, Carlos Castañeda-Orjuela, Vilada Chansamouth, Suman Chaurasia, Sara Chiurchiù, Fazle Chowdhury, Rafai Clotaire Donatien, Aislinn J Cook, Ben Cooper, Tim R Cressey, Elia Criollo-Mora, Matthew Cunningham, Saffiatou Darboe, Nicholas P J Day, Maia De Luca, Klara Dokova, Angela Dramowski, Susanna J Dunachie, Thuy Duong Bich, Tim Eckmanns, Daniel Eibach, Amir Emami, Nicholas Feasey, Natasha Fisher-Pearson, Karen Forrest, Coralith Garcia, Denise Garrett, Petra Gastmeier, Ababi Zergaw Giref, Rachel Claire Greer, Vikas Gupta, Sebastian Haller, Andrea Haselbeck, Simon I Hay, Marianne Holm, Susan Hopkins, Yingfen Hsia, Kenneth C Iregbu, Jan Jacobs, Daniel Jarovsky, Fatemeh Javanmardi, Adam W J Jenney, Meera Khorana, Suwimon Khusuwan, Niranjan Kissoon, Elsa Kobeissi, Tomislav Kostyanev, Fiorella Krapp, Ralf Krumkamp, Ajay Kumar, Hmwe Hmwe Kyu, Cherry Lim, Kruy Lim, Direk Limmathurotsakul, Michael James Loftus, Miles Lunn, Jianing Ma, Anand Manoharan, Florian Marks, Jürgen May, Mayfong Mayxay, Neema Mturi, Tatiana Munera-Huertas, Patrick Musicha, Lilian A Musila, Marisa Marcia Mussi-Pinhata, Ravi Narayan Naidu, Tomoka Nakamura, Ruchi Nanavati, Sushma Nangia, Paul Newton, Chanpheaktra Ngoun, Amanda Novotney, Davis Nwakanma, Christina W Obiero, Theresa J Ochoa, Antonio Olivas-Martinez, Piero Olliaro, Ednah Ooko, Edgar Ortiz-Brizuela, Pradthana Ounchanum, Gideok D Pak, Jose Luis Paredes, Anton Yariv Peleg, Carlo Perrone, Thong Phe, Koukeo Phommasone, Nishad Plakkal, Alfredo Ponce-de-Leon, Mathieu Raad, Tanusha Ramdin, Sayaphet Rattanavong, Amy Riddell, Tamalee Roberts, Julie Victoria Robotham, Anna Roca, Victor Daniel Rosenthal, Kristina E Rudd, Neal Russell, Helio S Sader, Weerawut Saengchan, Jesse Schnall, John Anthony Gerard Scott, Samroeng Seekaew, Mike Sharland, Madhusudhan Shivamallappa, Jose Sifuentes-Osornio, Andrew J Simpson, Nicolas Steenkeste, Andrew James Stewardson, Temenuga Stoeva, Nidanuch Tasak, Areerat Thaiprakong, Guy Thwaites, Caroline Tigoi, Claudia Turner, Paul Turner, H Rogier van Doorn, Sithembiso Velaphi, Avina Vongpradith, Manivanh Vongsouvath, Huong Vu, Timothy Walsh, Judd L Walson, Seymour Waner, Tri Wangrangsimakul, Prapass Wannapinij, Teresa Wozniak, Tracey E M W Young Sharma, Kalvin C Yu, Peng Zheng, Benn Sartorius, Alan D Lopez, Andy Stergachis, Catrin Moore, Christiane Dolecek, Mohsen Naghavi, Antimicrobial Resistance Collaborators, and Collaborators, Antimicrobial Resistance
Subjects: METHICILLIN-RESISTANT, Models, Statistical, Science & Technology, SEPSIS, UNITED-STATES, ANTIBIOTIC-RESISTANCE, General Medicine, Bacterial Infections, systematic analysis, Global Health, Anti-Bacterial Agents, Global Burden of Disease, DEFINITIONS, Medicine, General & Internal, INFECTIONS, General & Internal Medicine, VACCINES, Drug Resistance, Bacterial, bacterial antimicrobial resistance, Humans, Human medicine, Life Sciences & Biomedicine, STAPHYLOCOCCUS-AUREUS
Abstract: Background Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date. Methods We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level. Findings On the basis of our predictive statistical models, there were an estimated 4·95 million (3·62–6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27·3 deaths per 100 000 (20·9–35·3), and lowest in Australasia, at 6·5 deaths (4·3–9·4) per 100 000. Lower respiratory infections accounted for more than 1·5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000–1 270 000) deaths attributable to AMR and 3·57 million (2·62–4·78) deaths associated with AMR in 2019. One pathogen–drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000–100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistant E coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae. Interpretation To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen–drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programmes, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasising the need to expand microbiology laboratory capacity and data collection systems to improve our understanding of this important human health threat. Funding Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.
Published: 2022

29. A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75

Author: Jiandong Huo, Aiste Dijokaite-Guraliuc, Chang Liu, Daming Zhou, Helen M. Ginn, Raksha Das, Piyada Supasa, Muneeswaran Selvaraj, Rungtiwa Nutalai, Aekkachai Tuekprakhon, Helen M.E. Duyvesteyn, Alexander J. Mentzer, Donal Skelly, Thomas G. Ritter, Ali Amini, Sagida Bibi, Sandra Adele, Sile Ann Johnson, Neil G. Paterson, Mark A. Williams, David R. Hall, Megan Plowright, Thomas A.H. Newman, Hailey Hornsby, Thushan I. de Silva, Nigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Andrew J. Pollard, Teresa Lambe, Philip Goulder, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, and Gavin R. Screaton
Subjects: General Biochemistry, Genetics and Molecular Biology
Abstract: Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape.
Published: 2023
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30. Divergent trajectories of antiviral memory after SARS-Cov-2 infection

Author: Adriana Tomic, Donal T. Skelly, Ane Ogbe, Daniel O'Connor, Matthew Pace, Emily Adland, Frances Alexander, Mohammad Ali, Kirk Allott, M. Azim Ansari, null Sandra Belij-Rammerstorfer, Sagida Bibi, Luke Blackwell, Anthony Brown, Helen Brown, Breeze Cavell, Elizabeth A. Clutterbuck, Thushan I de Silva, David Eyre, null Amy Flaxman, James Grist, Carl-Philipp Hackstein, null Rachel Halkerston, Adam C. Harding, Jennifer Hill, Tim James, null Cecilia Jay, Síle A. Johnson, Barbara Kronsteiner, Yolanda Lie, Aline Linder, Stephanie Longet, Spyridoula Marinou, Philippa C. Matthews, Jack Mellors, Christos Petropoulos, Patpong Rongkard, null Cynthia Sedik, Laura Silva-Reyes, Holly Smith, null Lisa Stockdale, Stephen Taylor, Stephen Thomas, Timothy Tipoe, Lance Turtle, Vinicius Adriano Vieira, null Terri Wrin, OPTIC Clinical Group, PITCH Study Group, C-MORE Group, Andrew J. Pollard, Teresa Lambe, null Christopher P. Conlon, Katie Jeffery, Simon Travis, Philip J. Goulder, John Frater, Alexander J. Mentzer, Lizzie Stafford, Miles W. Carroll, William S. James, Paul Klenerman, Eleanor Barnes, Christina Dold, and Susanna J. Dunachie
Subjects: biology, business.industry, ELISPOT, T cell, Antiviral antibody, Acquired immune system, Vaccination, Immune system, medicine.anatomical_structure, Immunity, Immunology, biology.protein, medicine, Antibody, business
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is normally controlled by effective host immunity including innate, humoral and cellular responses. However, the trajectories and correlates of acquired immunity, and the capacity of memory responses months after infection to neutralise variants of concern - which has important public health implications - is not fully understood. To address this, we studied a cohort of 78 UK healthcare workers who presented in April to June 2020 with symptomatic PCR-confirmed infection or who tested positive during an asymptomatic screening programme and tracked virus-specific B and T cell responses longitudinally at 5-6 time points each over 6 months, prior to vaccination. We observed a highly variable range of responses, some of which - T cell interferon-gamma (IFN-γ) ELISpot, N-specific antibody waned over time across the cohort, while others (spike-specific antibody, B cell memory ELISpot) were stable. In such cohorts, antiviral antibody has been linked to protection against re-infection. We used integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling Over Night) to explore this heterogeneity and to identify predictors of sustained immune responses. Hierarchical clustering defined a group of high and low antibody responders, which showed stability over time regardless of clinical presentation. These antibody responses correlated with IFN-γ ELISpot measures of T cell immunity and represent a subgroup of patients with a robust trajectory for longer term immunity. Importantly, this immune-phenotype associates with higher levels of neutralising antibodies not only against the infecting (Victoria) strain but also against variants B.1.1.7 (alpha) and B.1.351 (beta). Overall memory responses to SARS-CoV-2 show distinct trajectories following early priming, that may define subsequent protection against infection and severe disease from novel variants.* These authors contributed equally.# These authors jointly supervised this work and contributed equally.Corresponding authors: Eleanor Barnes, email: ellie.barnes@ndm.ox.ac.ukand Adriana Tomic, email: 19info@adrianatomic.com
Published: 2021
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31. 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
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32. Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection

Author: Donal T. Skelly, Adam C. Harding, Javier Gilbert-Jaramillo, Michael L. Knight, Stephanie Longet, null Anthony Brown, Sandra Adele, Emily Adland, Helen Brown, Medawar Laboratory Team, null Tom Tipton, Lizzie Stafford, Síle A. Johnson, Ali Amini, OPTIC Clinical Group, Tiong Kit Tan, Lisa Schimanski, Kuan-Ying A. Huang, Pramila Rijal, PITCH Study Group, CMORE/PHOSP-C Group, John Frater, Philip Goulder, Christopher P. Conlon, Katie Jeffery, Christina Dold, Andrew J. Pollard, Alex Sigal, Tulio de Oliveira, Alain R. Townsend, Paul Klenerman, Susanna J . Dunachie, Eleanor Barnes, Miles W. Carroll, and William S. James
Subjects: Vaccination, Immune system, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Biology, Virology
Abstract: Both natural infection with SARS-CoV-2 and immunization with vaccines induce protective immunity. However, the extent to which such immune responses protect against emerging variants is of increasing importance. Such variants of concern (VOC) include isolates of lineage B.1.1.7, first identified in the UK, and B.1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417, escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks of the receptor-binding domain. To address the potential threat posed by VOC, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort sampled in the early convalescent stages after natural infection in the first wave of the pandemic in Spring 2020. We tested antibody and T cell responses against a reference isolate of the original circulating lineage, B, and the impact of sequence variation in the B.1.1.7 and B.1.351 VOC. Neutralization of the VOC compared to B isolate was reduced, and this was most evident for the B.1.351 isolate. This reduction in antibody neutralization was less marked in post-boost vaccine-induced responses compared to naturally induced immune responses and could be largely explained by the potency of the homotypic antibody response. After a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOC was completely abrogated in the majority of vaccinees. Importantly, high magnitude T cell responses were generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. These data indicate that VOC may evade protective neutralizing responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine dose, but the impact of the VOC on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants.
Published: 2021
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33. Natural and vaccine-induced antibody and cellular responses against emerging SARS-CoV-2 variants of concern

Author: Donal T. Skelly, Adam C. Harding, Javier Gilbert-Jaramillo, Michael L. Knight, Stephanie Longet, Anthony Brown, Sandra Adele, Emily Adland, Helen Brown, Medawar Laboratory Team, Tom Tipton, Lizzie Stafford, Síle A. Johnson, Ali Amini, OPTIC Clinical Group, Tiong Kit Tan, Lisa Schimanski, Kuan-Ying A. Huang, Pramila Rijal, PITCH Study Group, University of Oxford, John Frater, Philip Goulder, Chris Conlon, Katie Jeffery, Christina Dold, Andrew J. Pollard, Alain R. Townsend, Paul Klenerman, Susanna J. Dunachie, Eleanor Barnes, Miles W. Carroll, and William James
Subjects: biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), biology.protein, Medicine, Antibody, business, Virology
Abstract: Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.
Published: 2021
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34. Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern

Author: Donal T. Skelly, Adam C. Harding, Javier Gilbert-Jaramillo, Michael L. Knight, Stephanie Longet, null Anthony Brown, Sandra Adele, Emily Adland, Helen Brown, Medawar Laboratory Team, null Tom Tipton, Lizzie Stafford, Síle A. Johnson, Ali Amini, OPTIC Clinical Group, Tiong Kit Tan, Lisa Schimanski, Kuan-Ying A. Huang, Pramila Rijal, PITCH Study Group, CMORE/PHOSP-C Group, John Frater, Philip Goulder, Christopher P. Conlon, Katie Jeffery, Christina Dold, Andrew J. Pollard, Alain R. Townsend, Paul Klenerman, Susanna J . Dunachie, Eleanor Barnes, Miles W. Carroll, and William S. James
Subjects: Immunity, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Biology, Virology
Abstract: Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.Authorship note: Donal T. Skelly and Adam C. Harding contributed equally; Miles W. Carroll and William S. James contributed equally
Published: 2021
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35. Potent cross-reactive antibodies following Omicron breakthrough in vaccinees

Author: Rungtiwa Nutalai, Daming Zhou, Aekkachai Tuekprakhon, Helen M. Ginn, Piyada Supasa, Chang Liu, Jiandong Huo, Alexander J. Mentzer, Helen M.E. Duyvesteyn, Aiste Dijokaite-Guraliuc, Donal Skelly, Thomas G. Ritter, Ali Amini, Sagida Bibi, Sandra Adele, Sile Ann Johnson, Bede Constantinides, Hermione Webster, Nigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Derrick Crook, Andrew J. Pollard, Teresa Lambe, Philip Goulder, Neil G. Paterson, Mark A. Williams, David R. Hall, Juthathip Mongkolsapaya, Elizabeth E. Fry, Wanwisa Dejnirattisai, Jingshan Ren, David I. Stuart, Gavin R. Screaton, consortium, OPTIC, and consortium, ISARIC4C
Subjects: QR355, Epitopes, COVID-19 Vaccines, Neutralization Tests, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Antibodies, Monoclonal, COVID-19, Humans, Angiotensin-Converting Enzyme 2, Antibodies, Viral, General Biochemistry, Genetics and Molecular Biology
Abstract: Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.
Published: 2022
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36. 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
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37. 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

38. Correction: The association between temperature, rainfall and humidity with common climate-sensitive infectious diseases in Bangladesh

Author: Fazle Rabbi Chowdhury, Quazi Shihab Uddin Ibrahim, Md. Shafiqul Bari, M. M. Jahangir Alam, Susanna J. Dunachie, Alfonso J. Rodriguez-Morales, and Md. Ismail Patwary
Subjects: Multidisciplinary, Science, Medicine
Abstract: [This corrects the article DOI: 10.1371/journal.pone.0199579.].
Published: 2020

39. A clinical trial of prime-boost immunisation with the candidate malaria vaccines RTS,S/AS02A and MVA-CS

Author: Susanna J, Dunachie, Michael, Walther, Jenni M, Vuola, Daniel P, Webster, Sheila M, Keating, Tamara, Berthoud, Laura, Andrews, Philip, Bejon, Ian, Poulton, Geoffrey, Butcher, Katherine, Watkins, Robert E, Sinden, Amanda, Leach, Philippe, Moris, Nadia, Tornieporth, Joerg, Schneider, Filip, Dubovsky, Eveline, Tierney, Jack, Williams, D Gray, Heppner, Sarah C, Gilbert, Joe, Cohen, and Adrian V S, Hill
Subjects: Adult, Male, Adolescent, T cell, T-Lymphocytes, Immunization, Secondary, Heterologous, Priming (immunology), Antibodies, Protozoan, Vaccinia virus, complex mixtures, Interferon-gamma, parasitic diseases, Malaria Vaccines, medicine, Humans, General Veterinary, General Immunology and Microbiology, biology, business.industry, Immunogenicity, ELISPOT, Public Health, Environmental and Occupational Health, RTS,S, Plasmodium falciparum, Middle Aged, biology.organism_classification, Virology, Malaria, Vaccination, Infectious Diseases, medicine.anatomical_structure, Immunology, Molecular Medicine, Female, business
Abstract: Heterologous prime-boost immunisation with RTS,S/AS02A and the poxvirus MVA-CS was evaluated in 18 healthy malaria-naïve subjects in Oxford. Both priming with RTS,S and boosting MVA-CS, and the reverse, were found to be safe and well tolerated. T cell responses as measured by IFN-gamma ex vivo ELISPOT were induced, but the responses were low to moderate in both groups, with heterologous boosting yielding only small increments in T cell immunogenicity and no increased antibody response. Protection against 3D7 Plasmodium falciparum sporozoite challenge 4 weeks after the final vaccination was equal for both regimens at 33% (95% C.I. 4.3-77.7%), with one subject remaining fully protected on rechallenge at 5 months.
Published: 2005

40. Prime-boost strategies for malaria vaccine development

Author: Susanna J. Dunachie and Adrian V. S. Hill
Subjects: Cellular immunity, Plasmodium, Physiology, Immunization, Secondary, Antigens, Protozoan, Aquatic Science, Biology, CD8-Positive T-Lymphocytes, Epitope, DNA vaccination, Viral vector, Antigen, Immunity, Malaria Vaccines, medicine, Animals, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Clinical Trials as Topic, Immunity, Cellular, Malaria vaccine, medicine.disease, Malaria, Disease Models, Animal, Insect Science, Immunology, Animal Science and Zoology
Abstract: SUMMARY Malaria is an intracellular pathogen, for which an effective vaccine is likely to require induction of cell-mediated immunity. Immunisation approaches that stimulate strong and persistent levels of effector T-cells are being sought by many researchers. DNA vaccines, recombinant protein and viral vectors were amongst the vaccine delivery systems that appeared promising for the generation of cellular immunity, and in some initial studies in small animals this goal was achieved. However, clinical trials of these candidate vaccines when used alone or in repeated homologous boosting regimes have been disappointing, with short-lived low levels of induced specific T-cell responses. Recent years have seen the development of immunisation strategies using a combination of different antigen delivery systems encoding the same epitopes or antigen, delivered at an interval of a few weeks apart. This sequential immunisation approach with different vectors is known as heterologous prime-boosting and is capable of inducing greatly enhanced and persistent levels of CD8+ T-cells and Th1-type CD4+ T-cells compared to homologous boosting. This review will summarise the key pre-clinical studies of prime-boost strategy and outline recent progress in clinical trials of this approach. Possible mechanisms of action and potential improvements to existing delivery systems will be discussed. The prime-boost approach represents an encouraging step towards establishing an effective preventative vaccine to one of the world's greatest killers.
Published: 2003

41. 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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42. Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records

Author: Liam Smeeth, Nish Chaturvedi, Carol Brayne, Rohini Mathur, Krishnan Bhaskaran, Rutendo Muzambi, Charlotte Warren-Gash, Christopher T Rentsch, Dylan M Williams, Susanna J Dunachie, William Doran, Louis Tunnicliffe, and Sophie V Eastwood
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Introduction 4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs).Research design and methods We conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification.Results We included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)).Conclusions Metformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality.
Published: 2024
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43. T cell immune memory after covid-19 and vaccination

Author: Paul Klenerman, Lance Turtle, Alex Richter, Lulu Wang, Alex Nicols, Christopher JA Duncan, Susanna J Dunachie, and Rebecca P Payne
Subjects: Medicine
Abstract: The T cell memory response is a crucial component of adaptive immunity responsible for limiting or preventing viral reinfection. T cell memory after infection with the SARS-CoV-2 virus or vaccination is broad, and spans multiple viral proteins and epitopes, about 20 in each individual. So far the T cell memory response is long lasting and provides a high level of cross reactivity and hence resistance to viral escape by variants of the SARS-CoV-2 virus, such as the omicron variant. All current vaccine regimens tested produce robust T cell memory responses, and heterologous regimens will probably enhance protective responses through increased breadth. T cell memory could have a major role in protecting against severe covid-19 disease through rapid viral clearance and early presentation of epitopes, and the presence of cross reactive T cells might enhance this protection. T cell memory is likely to provide ongoing protection against admission to hospital and death, and the development of a pan-coronovirus vaccine might future proof against new pandemic strains.
Published: 2023
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44. Correction: A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model.

Author: Manutsanun Inthawong, Piyanate Sunyakumthorn, Sirima Wongwairot, Tippawan Anantatat, Susanna J Dunachie, Rawiwan Im-Erbsin, James W Jones, Carl J Mason, Luis A Lugo, Stuart D Blacksell, Nicholas P J Day, Piengchan Sonthayanon, Allen L Richards, and Daniel H Paris
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: [This corrects the article DOI: 10.1371/journal.pntd.0010611.].
Published: 2023
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45. A whole blood intracellular cytokine assay optimised for field site studies demonstrates polyfunctionality of CD4+ T cells in acute scrub typhus.

Author: Manutsanun Inthawong, Nattapon Pinthong, Areerat Thaiprakhong, Tri Wangrangsimakul, Piyanate Sunyakumthorn, Jennifer Hill, Piengchan Sonthayanon, Daniel H Paris, Susanna J Dunachie, and Barbara Kronsteiner
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: BackgroundAssessment of cellular immune responses by combining intracellular cytokine staining and immunophenotyping using flow cytometry enables the simultaneous measurement of T cell phenotype and effector function in response to pathogens and vaccines. The use of whole blood samples rather than peripheral blood mononuclear cells avoids both the need for immediate processing and loss of functional antigen presenting cells due to processing and cryopreservation. Using whole blood provides the possibility to stimulate peripheral T cells in situ, and is more suitable for studies where sample volume is limited, such as those involving children, the elderly and critically ill patients. The aim of this study was to provide a robust tool for the assessment of antigen-specific T cell responses in a field site setting with limited resources.Methodology/principle findingsWe optimised a flow cytometry-based whole blood intracellular cytokine assay (WBA) with respect to duration of antigen stimulation and intracellular protein retention time. We demonstrate the ability of the WBA to capture polyfunctional T cell responses in the context of acute scrub typhus infection, by measuring IFN-γ, TNF and IL-2 in CD4+ and CD8+ T cells in response to the causative agent O. tsutsugamushi (OT). Using an optimised OT antigen preparation, we demonstrate the presence of polyfunctional antigen-specific memory CD4+ T cells in the blood of scrub typhus patients.Conclusions/significanceIn conclusion, this flow cytometry-based WBA is well-suited for use at field study sites, and enables the assessment of polyfunctional T cell responses to infectious agents and vaccines through delineation of antigen-specific cytokine secretion at the single cell level.
Published: 2023
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46. Role of Burkholderia pseudomallei–Specific IgG2 in Adults with Acute Melioidosis, Thailand

Author: Panjaporn Chaichana, Kemajittra Jenjaroen, Suchintana Chumseng, Manutsanun Sumonwiriya, Patpong Rongkard, Barbara Kronsteiner, Prapit Teparrukkul, Direk Limmathurotsakul, Nicholas P.J. Day, Narisara Chantratita, and Susanna J Dunachie
Subjects: bacteria, antimicrobial resistance, melioidosis, Burkholderia pseudomallei, antibodies, IgG subclasses, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: Melioidosis is a life-threatening infectious disease caused by the gram-negative bacillus Burkholderia pseudomallei. An effective vaccine is needed, but data on protective immune responses in human melioidosis are lacking. We used ELISA and an antibody-dependent cellular phagocytosis assay to identify the major features of protective antibodies in patients with acute melioidosis in Thailand. We found that high levels of B. pseudomallei–specific IgG2 are associated with protection against death in a multivariable logistic regression analysis adjusting for age, diabetes, renal disease, and neutrophil count. Serum from melioidosis survivors enhanced bacteria uptake into human monocytes expressing FcγRIIa-H/R131, an intermediate-affinity IgG2-receptor, compared with serum from nonsurvivors. We did not find this enhancement when using monocytes carrying the low IgG2–affinity FcγRIIa-R131 allele. The findings indicate the importance of IgG2 in protection against death in human melioidosis, a crucial finding for antibody-based therapeutics and vaccine development.
Published: 2021
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47. Melioidosis DS rapid test: A standardized serological dipstick assay with increased sensitivity and reliability due to multiplex detection.

Author: Gabriel E Wagner, Esther Föderl-Höbenreich, Karoline Assig, Michaela Lipp, Andreas Berner, Christian Kohler, Sabine Lichtenegger, Julia Stiehler, Wisansanee Karoonboonyanan, Nida Thanapattarapairoj, Chidchanok Promkong, Sirikamon Koosakulnirand, Panjaporn Chaichana, Ralf Ehricht, Anne-Marie Gad, Hans H Söffing, Susanna J Dunachie, Narisara Chantratita, and Ivo Steinmetz
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: BackgroundMelioidosis, caused by Burkholderia pseudomallei, is a severe infectious disease with high mortality rates, but is under-recognized worldwide. In endemic areas, there is a great need for simple, low-cost and rapid diagnostic tools. In a previous study we showed, that a protein multiplex array with 20 B. pseudomallei-specific antigens detects antibodies in melioidosis patients with high sensitivity and specificity. In a subsequent study the high potential of anti-B. pseudomallei antibody detection was confirmed using a rapid Hcp1 single protein-based assay. Our protein array also showed that the antibody profile varies between patients, possibly due to a combination of host factors but also antigen variations in the infecting B. pseudomallei strains. The aim of this study was to develop a rapid test, combining Hcp1 and the best performing antigens BPSL2096, BPSL2697 and BPSS0477 from our previous study, to take advantage of simultaneous antibody detection.Methods and principal findingsThe 4-plex dipstick was validated with sera from 75 patients on admission plus control groups, achieving 92% sensitivity and 97-100% specificity. We then re-evaluated melioidosis sera with the 4-plex assay that were previously misclassified by the monoplex Hcp1 rapid test. 12 out of 55 (21.8%) false-negative samples were positive in our new dipstick assay. Among those, 4 sera (7.3%) were Hcp1 positive, whereas 8 (14.5%) sera remained Hcp1 negative but gave a positive reaction with our additional antigens.ConclusionsOur dipstick rapid test represents an inexpensive, standardized and simple diagnostic tool with an improved serodiagnostic performance due to multiplex detection. Each additional band on the test strip makes a false-positive result more unlikely, contributing to its reliability. Future prospective studies will seek to validate the gain in sensitivity and specificity of our multiplex rapid test approach in different melioidosis patient cohorts.
Published: 2020
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48. Characterization of the rhesus macaque (Macaca mulatta) scrub typhus model: Susceptibility to intradermal challenge with the human pathogen Orientia tsutsugamushi Karp.

Author: Piyanate Sunyakumthorn, Suwit J Somponpun, Rawiwan Im-Erbsin, Tippawan Anantatat, Kemajittra Jenjaroen, Susanna J Dunachie, Eric D Lombardini, Robin L Burke, Stuart D Blacksell, James W Jones, Carl J Mason, Allen L Richards, Nicholas P J Day, and Daniel H Paris
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: Scrub typhus is an important endemic disease in tropical Asia caused by Orientia tsutsugamushi for which no effective broadly protective vaccine is available. The successful evaluation of vaccine candidates requires well-characterized animal models and a better understanding of the immune response against O. tsutsugamushi. While many animal species have been used to study host immunity and vaccine responses in scrub typhus, only limited data exists in non-human primate (NHP) models.In this study we evaluated a NHP scrub typhus disease model based on intradermal inoculation of O. tsutsugamushi Karp strain in rhesus macaques (n = 7). After an intradermal inoculation with 106 murine LD50 of O. tsutsugamushi at the anterior thigh (n = 4) or mock inoculum (n = 3), a series of time course investigations involving hematological, biochemical, molecular and immunological assays were performed, until day 28, when tissues were collected for pathology and immunohistochemistry. In all NHPs with O. tsutsugamushi inoculation, but not with mock inoculation, the development of a classic eschar with central necrosis, regional lymphadenopathy, and elevation of body temperature was observed on days 7-21 post inoculation (pi); bacteremia was detected by qPCR on days 6-18 pi; and alteration of liver enzyme function and increase of white blood cells on day 14 pi. Immune assays demonstrated raised serum levels of soluble cell adhesion molecules, anti-O. tsutsugamushi-specific antibody responses (IgM and IgG) and pathogen-specific cell-mediated immune responses in inoculated macaques. The qPCR assays detected O. tsutsugamushi in eschar, spleen, draining and non-draining lymph nodes, and immuno-double staining demonstrated intracellular O. tsutsugamushi in antigen presenting cells of eschars and lymph nodes.These data show the potential of using rhesus macaques as a scrub typhus model, for evaluation of correlates of protection in both natural and vaccine induced immunity, and support the evaluation of future vaccine candidates against scrub typhus.
Published: 2018
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49. The association between temperature, rainfall and humidity with common climate-sensitive infectious diseases in Bangladesh.

Author: Fazle Rabbi Chowdhury, Quazi Shihab Uddin Ibrahim, Md Shafiqul Bari, M M Jahangir Alam, Susanna J Dunachie, Alfonso J Rodriguez-Morales, and Md Ismail Patwary
Subjects: Medicine, Science
Abstract: Bangladesh is one of the world's most vulnerable countries for climate change. This observational study examined the association of temperature, humidity and rainfall with six common climate-sensitive infectious diseases in adults (malaria, diarrheal disease, enteric fever, encephalitis, pneumonia and bacterial meningitis) in northeastern Bangladesh. Subjects admitted to the adult medicine ward of a tertiary referral hospital in Sylhet, Bangladesh from 2008 to 2012 with a diagnosis of one of the six chosen climate-sensitive infectious diseases were enrolled in the study. Climate-related data were collected from the Bangladesh Meteorological Institute. Disease incidence was then analyzed against mean temperature, humidity and average rainfall for the Sylhet region. Statistical significance was determined using Mann-Whitney test, Chi-square test and ANOVA testing. 5033 patients were enrolled (58% male, 42% female, ratio 1.3:1). All six diseases showed highly significant (p = 0.01) rises in incidence between the study years 2008 (540 cases) and 2012 (1330 cases), compared with no significant rise in overall all-cause hospital admissions in the same period (p = 0.19). The highest number of malaria (135), diarrhea (266) and pneumonia (371) cases occurred during the rainy season. On the other hand, the maximum number of enteric fever (408), encephalitis (183) and meningitis (151) cases occurred during autumn, which follows the rainy season. A positive (P = 0.01) correlation was observed between increased temperature and the incidence of malaria, enteric fever and diarrhea, and a negative correlation with encephalitis, meningitis and pneumonia. Higher humidity correlated (P = 0.01) with a higher number of cases of malaria and diarrhea, but inversely correlated with meningitis and encephalitis. Higher incidences of encephalitis and meningitis occurred while there was low rainfall. Incidences of diarrhea, malaria and enteric fever, increased with rainfall, and then gradually decreased. The findings support a relationship between weather patterns and disease incidence, and provide essential baseline data for future large prospective studies.
Published: 2018
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50. Immune response to recombinant Burkholderia pseudomallei FliC.

Author: Sirikamon Koosakulnirand, Phornpun Phokrai, Kemajittra Jenjaroen, Rosemary A Roberts, Pongsak Utaisincharoen, Susanna J Dunachie, Paul J Brett, Mary N Burtnick, and Narisara Chantratita
Subjects: Medicine, Science
Abstract: Burkholderia pseudomallei is a flagellated Gram-negative bacterium which is the causative agent of melioidosis. The disease poses a major public health problem in tropical regions and diabetes is a major risk factor. The high mortality rate of melioidosis is associated with severe sepsis which involves the overwhelming production of pro-inflammatory cytokines. Bacterial flagellar protein (flagellin) activates Toll-like receptor 5 (TLR5)-mediated innate immune signaling pathways and induces adaptive immune response. However, previous studies of TLR5 signaling in melioidosis have been performed using recombinant flagellin from Salmonella Typhimurium instead of B. pseudomallei. This study aimed to investigate human innate immune response and antibody response against a recombinant B. pseudomallei flagellin (rFliC). We prepared B. pseudomallei rFliC and used it to stimulate HEK-BlueTM-hTLR5 and THP1-DualTM cells to assess TLR5 activation. Subsequently, whole blood stimulation assays with rFliC were performed ex vivo. TLR5-flagellin interactions trigger activation of transcription factor NF-κB in HEK-BlueTM-hTLR5 cells. Pro-inflammatory cytokine (IL-1β, IL-6, and TNF-α) productions from whole blood in response to rFliC differed between fourteen healthy individuals. The levels of these cytokines changed in a dose and time-dependent manner. ELISA was used to determine rFliC-specific antibodies in serum samples from different groups of melioidosis patients and healthy subjects. IgG antibody to rFliC in melioidosis patients with diabetes were higher compared with non-diabetic patients. Our results show that B. pseudomallei flagellin is a potent immune stimulator and that the immune responses to rFliC are different among individuals. This may provide valuable insights toward the potential use of rFliC in vaccine development.
Published: 2018
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