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1. Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

Author

Robert H Shaw, Xinxue Liu, Arabella S V Stuart, Melanie Greenland, Parvinder K Aley, Nick J Andrews, J Claire Cameron, Sue Charlton, Elizabeth A Clutterbuck, Andrea M Collins, Wanwisa Dejnirattisai, Tanya Dinesh, Saul N Faust, Daniela M Ferreira, Adam Finn, Christopher A Green, Bassam Hallis, Paul T Heath, Helen Hill, Teresa Lambe, Rajeka Lazarus, Vincenzo Libri, Fei Long, Yama F Mujadidi, Emma L Plested, Ella R Morey, Samuel Provstgaard-Morys, Maheshi N Ramasamy, Mary Ramsay, Robert C Read, Hannah Robinson, Gavin R Screaton, Nisha Singh, David P J Turner, Paul J Turner, Iason Vichos, Laura L Walker, Rachel White, Jonathan S Nguyen-Van-Tam, Matthew D Snape, Alasdair P.S. Munro, Jazz Bartholomew, Laura Presland, Sarah Horswill, Sarah Warren, Sophie Varkonyi-Clifford, Stephen Saich, Kirsty Adams, Marivic Ricamara, Nicola Turner, Nicole Y. Yee Ting, Sarah Whittley, Tommy Rampling, Amisha Desai, Claire H. Brown, Ehsaan Qureshi, Karishma Gokani, Kush Naker, Johanna K. Kellett Wright, Rachel L. Williams, Tawassal Riaz, Florentina D. Penciu, Amy Carson, Claudio Di Maso, Gracie Mead, Elizabeth G. Howe, Mujtaba Ghulam Farooq, Rabiullah Noristani, Xin L. Yao, Neil J. Oldfield, Daniel Hammersley, Sue Belton, Simon Royal, Alberto San Francisco Ramos, Cecilia Hultin, Eva P. Galiza, Rebecca Crook, Marcin Bula, Fred Fyles, Hassan Burhan, Flora Maelin, Elen Hughes, Emmanuel Okenyi, Group, Com-COV Study, and National Institute for Health and Care Research

Subjects
Pulmonary and Respiratory Medicine, Adult, COVID-19 Vaccines, wa_115, SARS-CoV-2, COVID-19/prevention & control, Com-COV Study Group, Immunization, Secondary, COVID-19, Covid19, 1103 Clinical Sciences, Antibodies, Viral, qw_806, qw_805, 1117 Public Health and Health Services, ChAdOx1 nCoV-19, Immunoglobulin G, wc_506, Humans, BNT162 Vaccine, COVID-19 Vaccines/adverse effects, 1199 Other Medical and Health Sciences
Abstract

Background Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33). Findings Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Funding UK Vaccine Taskforce and National Institute for Health and Care Research.

Published
2022

2. Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial

Author

Katrina M. Pollock, Hannah M. Cheeseman, Alexander J. Szubert, Vincenzo Libri, Marta Boffito, David Owen, Henry Bern, Leon R. McFarlane, Jessica O'Hara, Nana-Marie Lemm, Paul McKay, Tommy Rampling, Yee Ting N. Yim, Ana Milinkovic, Cherry Kingsley, Tom Cole, Susanne Fagerbrink, Marites Aban, Maniola Tanaka, Savviz Mehdipour, Alexander Robbins, William Budd, Saul Faust, Hana Hassanin, Catherine A. Cosgrove, Alan Winston, Sarah Fidler, David Dunn, Sheena McCormack, Robin J. Shattock, Kirsty Adams, Fahimah Amini, Nafisah B Atako, Amalina Bakri, Wendy Barclay, Elizabeth Brodnicki, Jonathan C Brown, Ruth Byrne, Rowena Chilvers, Sofia Coelho, Suzanne Day, Monica Desai, Eleanor Dorman, Tamara Elliott, Katie E Flight, James Fletcher, John Galang, Jagruti Gohil, Aneta Gupta, Chris Harlow, Kai Hu, Mohini Kalyan, Dominic Lagrue, Ely Liscano, Cecilia Njenga, Krunal Polra, Derecia A Powlette, Paul Randell, Mary Rauchenberger, Ianto Redknap, Maravic Ricamara, Paul Rogers, Hadijatou Sallah, Karnyart Samnuan, Michael Schumacher, Zareena Shah, Rachel Shaw, Thomas Shaw, Stefan Sivapatham, Susie Slater, Kim Sorley, Regina Storch, Elizabeth Tan, Tricia Tan, Lieze Thielemans, Sarah Whitely, Charlotte Valentine, Jeeva Varghese, Asha Vikraman, Martin Wilkins, The Sir Joseph Hotung Charitable Settlement, and National Institute for Health Research

Subjects
NSP, non-structural protein, medicine.medical_specialty, Medicine (General), Coronavirus disease 2019 (COVID-19), Article, AEs, adverse events, R5-920, Internal medicine, Medicine, Seroconversion, Adverse effect, biology, LNP, lipid nanoparticle, business.industry, GOI, gene of Interest, Immunogenicity, General Medicine, Vaccination, Clinical research, biology.protein, Antibody, business, COVAC1 study Group, saRNA, saRNA, self-amplifying RNA, VEEV, Venezuelan equine encephalitis virus
Abstract

Summary: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0·1-10·0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p

Published
2022

3. Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

Author

Phedra Marius, Lynne Grundy, Nabeela Nazir Ahmed, Margaret Irwin, Jeanette Thorpe, Hannah Robinson, Helen Thorp, Maria Moon, Sadaf Farooqi, Nick Andrews, Louise Haskell, Bea Choi, Helen Beckett, Sharon Davies-Dear, Victoria Cornelius, Tracey Dare, Sunder Chita, Stephen Singh, Chris Twelves, John Haughney, Patrick S. Moore, Maja dabagh, Xinxue Liu, S Bibi, Suzanne Wilkins, Mohammed Khan, Charlotte Trinham, Emily Brunt, Edwin Justice, Hanna Nguyen, Andrew Gowland, Andrew Riordan, Tanveer Bawa, Daniel Pan, Ceri Davies, Suahil Aslam, Chris A Rogers, Dileep Kumar, Yvanne Enever, Siobhan Roche, Karen Bisnauthsing, Hayley Tulloch, Andrew Ustianowski, Steve Hurdover, Ehsaan Qureshi, Akamino Egbo, Ingrid Seath, Jo Salkeld, Carla Ferreira Da Silva, Ray Sheridan, Samantha Keenan, Shama Hamal, Jo Piper, Kerry Godwin, Sara Bennett, Liliana Cifuentes, Nicholas Ronan, Nicki Lakeman, Lona Tudor Jones, Ian Bentley, Rachel White, Chloe McDonnell, Nina Parungao, Emma Plested, Kyra Holliday, Lisa Berry, Christine Minnis, Victoria Graham, Christopher J Edwards, Beth Giddins, Tara Watson, Suzie Colquhoun, Johanna Mouland, Marion K Campbell, Rostam Osanlou, Carlota Pereira Dias Alves, Simon Fowler, Becky Mansfield, Sally Batham, Orod Osanlou, Arpan Guha, Stephen Saich, Kush Naker, Marcin Bula, Igor Starinskij, Bassam Hallis, Sonia Baryschpolec, Shirley Todd, Agatha A. van der Klaauw, Claire Brown, Emma Snashall, Andrew Seaton, Helen Radford, John Hladkiwskyj, Rachael Drake-Brockman, Matilda lang, Linda Harndahl, Holly Burton, Tim Whitbred, Sue Charlton, Mushiya Mpelembue, Anna Stewart, Anil Shenoy, Zalina Rashid-Gardner, Joseph Newman, John Gavin, Mary Savage, Julie Evans, Aidan Lingwood, Lauren Allen, Parvinder K. Aley, Rebecca Lyon, Rachel Bousfield, Robert C. Read, Joanne Spencer, David Baxter, Anastasia de la Haye, James Calderwood, Emily Chiplin, Evgenia Kourampa, Helen Gutteridge, Jade Gouriet, Trishna Champaneri, Javier Magan, Luke Vamplew, Abigail Oliver, Sally Reeder, Sunil Sharma, Nicola Turner, Yukari Sakagami, Mikayala King, Steve Thomas, Chanice Knight, Samantha Broadhead, Erica Peters, Dennyl Vail, Marta Merida-Morillas, Emily Locke, Krishna Chatterjee, Debbie Suggitt, Sara Fraser, Mihaela Pacurar, Kerry Hughes, Jessica Hailstone, Eleni Ladikou, Leah Richmond, Wythehi Ambihapathy, Kari Nightingale, Chris Cooper, Victoria Wenn, Kimberley Driver, Rachel Hughes, Filipa Dos Santos, Michael Singh, Ben Gardside, Donna Wixted, Jessica Lewis-Taylor, Jason Domingo, Scott Elliott, Wiesia Woodyatt, Jonathan Kwok, Subarna Roy, Amisha Desai, Iryna Boubriak, Helen Haydock, Arabella Stuart, Amy Ross-Russell, Rossana Romani, Lauren Fox, Gillian McMillan, Angela M. Minassian, Ann Sturdy, R. A. James, Valerie Renals, Stephanie Leung, Lillian Goncalves cordeiro, Fran Westwell, Robert Shaw, Anna L. Goodman, Katrina Cathie, Ryan Stephen Elliott, Adrian Palfreeman, Phillip Brown, Kim En Lee, Farida khan, Suzanne Tasker, Anna Hardy, Elisa Nanino, Donald van Welsenes, Adam Farrier, Antonette Andrews, Jacqueline Brandon, Alicja Kownacka, Jennifer Murira, Kate Dodd, Emily Horsfall, Chantelle Moorbey, Alison Hogan, Lynda Wagstaff, Gita Patel, Rebecca Cutts, Matthew D. Snape, Karen Regan, Beverley Longhurst, Saul N. Faust, Vincenzo Libri, Andrea Mazzella, Michael Stackpoole, Carool Osuji, Jonathan Baker, Teona Serafimova, Tumena Corrah, Sophie E. Moore, Sarah Warren, Christopher Herbert, Laura Presland, Daniel R. Owens, Colin Hale, Beth Jackson, Fran Hall, Debbie Branney, Martha Nabunjo, Mehmood Mughal, Laura Longshaw, Holly Baker, Elizabeth A. Clutterbuck, Eloise Summerton, Rowena Weighell, Fiona Makia, Alexander Hicks, Leila Janani, Matthew Stokes, Amanda Buadi, E. Thomson, Jennifer Gibney, Jane Hall, Tricia Coughlan, Bridget Tandy, Kelly Littlewood, Christopher A Green, Mary Ramsay, Lorinda Pickup, Karren Buttigieg, Gavin Babbage, Todd Rawlins, Simon Tunstall, Dominique Barker, Martin J. Llewelyn, James Cullinane, Judith Bell, Elizabeth Gordon, Andrew L. Freedman, Martin Wiselka, Mohammed Kamal, Sarah Whittley, Natalie Baker, Jorden Frankham, Malathi Munusamy, Karen Underwood, Dinesh Saralaya, Olivia Chalwin, Tommy Rampling, Rachael Phillips, Sarah Garrahy, Yee Ting Nicole Yim, Charlotte Sabine, Haniah Habash-Bailey, Ashley Whittington, Benjamin Welham, Patrick Kinch, Avril Bonnaud, Jonathan Macdonald, NinaSimone Hopkins, Kim Storton, Stephen Hughes, Enya Cooney, Alasdair Munro, Christine Cole, John Paul Seenan, Kim Appleby, Laurence John, David J. Smith, Lara Barcella, Imam Shaik, Kate Ellis, Olumide Adebambo, Jane Stockport, Gertraud Morshead, Paminder Lall, Stephen E. Cox, Daniel Hansen, Jonathan Perkins, Yama F Mujadidi, Thomas Honey, Alan Magee, Jonathan S. Nguyen-Van-Tam, Mwila Kasanyinga, Marivic Ricamara, Jaimie Wilson-Goldsmith, Alastair McGregor, Djamila Shamtally, Helena Baker, Tom Eadsforth, Dee Mullan, Karishma Gokani, Kirsty Adams, and Dominic Galvin

Subjects
Adult, Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Population, Immunization, Secondary, Department of Error, Group A, Group B, COV-BOOST study group, Medicine, General & Internal, Immunogenicity, Vaccine, General & Internal Medicine, ChAdOx1 nCoV-19, Internal medicine, Safety, immunogenicity, COVID-19, vaccines, booster, Humans, Medicine, Adverse effect, education, Pandemics, BNT162 Vaccine, 11 Medical and Health Sciences, Aged, Aged, 80 and over, education.field_of_study, Science & Technology, Booster (rocketry), Reactogenicity, SARS-CoV-2, business.industry, Immunogenicity, COVID-19, General Medicine, Articles, Middle Aged, United Kingdom, Female, Patient Safety, business, Life Sciences & Biomedicine
Abstract

Background: \ud Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT).\ud \ud Methods: \ud COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130.\ud \ud Findings: \ud Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44–61) in the younger age group and 76 years (73–78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41–59) in the younger age group and 78 years (75–82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5–2·3) in the half VLA group to 32·3 (24·8–42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7–1·6) for ChAd to 3·6 (2·4–5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0–1·5) in the half VLA group to 11·5 (9·4–14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7–1·6) for half VLA to 4·7 (3·1–7·1) for m1273. The results were similar between those aged 30–69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30–69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273.\ud \ud Interpretation: \ud All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination.\ud \ud Funding: \ud UK Vaccine Taskforce and National Institute for Health Research.

Published
2021

4. Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

Author

Sophie Varkonyi-Clifford, Sue Charlton, Anna England, Matthew D. Snape, Parvinder K. Aley, Elizabeth A. Clutterbuck, Pauline Ambrose, Eva P. Galiza, Adam Finn, Laura L. Walker, Emma Plested, Ehsaan Qureshi, Chanice Knight, David P. J. Turner, Lisa Hitchins, Mujtaba Ghulam Farooq, Christopher A Green, Melanie Greenland, J. Claire Cameron, Stephanie Leung, Karen Buttigieg, Jonathan S. Nguyen-Van-Tam, Cecilia Hultin, Florentina D Penciu, Jazz Bartholomew, Yama F Mujadidi, Nisha Singh, Sarah Horswill, Tommy Rampling, Kush Naker, Rabiullah Noristani, Xinxue Liu, Marivic Ricamara, Tawassal Riaz, Phill Brown, Rajeka Lazarus, Imam Shaik, Johanna K Kellett Wright, Kerry Godwin, Kelly Davies, Robert Shaw, Paminder Lall, Neil J. Oldfield, Farah Shiham, Sue Belton, Karishma Gokani, Carla Solórzano, Mary Ramsay, Kirsty Adams, Ross Fothergill, Hannah Robinson, Claudio Di Maso, Rachel Williams, Lauren Allen, Paul T. Heath, Sarah Whittley, Stephen Saich, E Howe, Bassam Hallis, Alberto San Francisco Ramos, Simon Royal, Alasdair Munro, Tanya Dinesh, Vincenzo Libri, Helen Hill, Arabella Stuart, Samuel Provstgaard-Morys, Xin L Yao, Andrea M. Collins, Rachel White, Paul Turner, Teresa Lambe, Nick Andrews, Iason Vichos, Daniela M. Ferreira, Natalie Baker, Nicole Y Yee Ting, Claire Brown, M N Ramasamy, Sarah Warren, Amisha Desai, Fei Long, Laura Presland, Hannah Sainsbury, Daniel Hammersley, Saul N. Faust, Robert C. Read, Nicola Turner, Group, Com-COV Study, and Department of Health

Subjects
Male, COVID-19/prevention & control, Antibodies, Viral, law.invention, Antibodies, Viral/blood, Immunogenicity, Vaccine, Randomized controlled trial, law, qv_771, wc_505, Single-Blind Method, 11 Medical and Health Sciences, COVID-19 Vaccines/administration & dosage, education.field_of_study, Immunogenicity, General Medicine, Middle Aged, Intention to Treat Analysis, Vaccination, Spike Glycoprotein, Coronavirus, Female, Life Sciences & Biomedicine, medicine.medical_specialty, COVID-19 Vaccines, Population, REACTOGENICITY, Equivalence Trials as Topic, qw_806, Medicine, General & Internal, General & Internal Medicine, Internal medicine, ChAdOx1 nCoV-19, parasitic diseases, medicine, Humans, education, BNT162 Vaccine, Immunization Schedule, Aged, Science & Technology, Intention-to-treat analysis, Reactogenicity, business.industry, Com-COV Study Group, Comment, qu_58, COVID-19, EFFICACY, Clinical trial, Regimen, Immunoglobulin G/blood, Immunoglobulin G, Spike Glycoprotein, Coronavirus/immunology, business
Abstract

Background Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Funding UK Vaccine Task Force and National Institute for Health Research.

Published
2021

5. 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

6. Optimizing the Mizoroki–Heck reaction of cyclic allyl amines: Gram-scale synthesis of preclamol without protecting groups

Author

Kirsty Adams, Bimod Thapa, Fanny Tran, Joseph B. Sweeney, Robert Crook, and Julien Doulcet

Subjects
chemistry.chemical_classification, 010405 organic chemistry, Chemistry, Alkene, Heck reaction, Heteroatom, Physical and Theoretical Chemistry, 010402 general chemistry, 01 natural sciences, Combinatorial chemistry, Catalysis, 0104 chemical sciences
Abstract

Though a widely used metal-catalyzed cross-coupling process, the Mizoroki–Heck (MH) reaction can be a capricious transformation. This is particularly true for oxidation-prone alkene substrates containing ligating heteroatoms, as in the case of N-alkyl tetrahydropyridines, whose MH reactions have been underexplored due to the many side reactions that hamper the process. Since the products of tetrahydropyridine Heck reactions are direct precursors to potent pharmacophores, and therefore of commercial value, this is a significant drawback. We report here the results of our study designed to deliver an optimized, scalable MH procedure for N-alkyltetrahydropyridines and its exemplification in a gram-scale synthesis of the drug substance preclamol.

Published
2018

7. An iron-catalysed C–C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks

Author

Nathan J. Patmore, Piotr Raubo, Joseph B. Sweeney, Ben Chappell, James J. Ryan, Lee Brown, Kirsty Adams, P. K. Tony Lo, James Birkett, Craig R. Rice, Anthony K. Ball, and Duncan M. Gill

Subjects
010405 organic chemistry, General Chemical Engineering, Aryl, Molecular Conformation, Stereoisomerism, General Chemistry, 010402 general chemistry, Ferric Compounds, 01 natural sciences, Catalysis, 0104 chemical sciences, chemistry.chemical_compound, Monomer, chemistry, Cascade reaction, Cyclization, Heterocyclic Compounds, Cascade, Reagent, Organic chemistry, Spiro Compounds, Stereoselectivity, Amines, Ethers
Abstract

Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3 -carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac) 3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.

Published
2016

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