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

BackgroundPriming 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).MethodsCom-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).FindingsBetween 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.InterpretationThese 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

Semmaphorin 3 A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells.

Acknowledgements: The authors wish to thank members of the Vincenzo Cerundolo and Tudor A. Fulga laboratories, University of Oxford, for helpful discussions and suggestions. Simon Davis and Oliver Bannard, University of Oxford, for helpful advice and guidance. The staff of the University of Oxford Department of Biomedical Services for animal husbandry. Christoffer Lagerholm and Dominic Waithe of the Wolfson Imaging Centre at University of Oxford for microscopy training and support. Helena Coker and Kseniya Korobchevskaya from the Oxford-ZEISS Centre of Excellence in Biomedical Imaging at Kennedy Institute of Rheumatology which is supported by the Kennedy Trust for Rheumatology Research, IDRM and Carl Zeiss GMBH. The Medical Research Council (MRC) WIMM Flow Cytometry Facility for training and support. The Oxford Centre for Histopathology Research and the Oxford Radcliffe Biobank, which are supported by the NIHR Oxford Biomedical Research Centre. Lisa Browning, Oxford University Hospital, for examination of histology samples. David Pinto, University of Oxford, for code for analysis of CDR3 sequences. This work was supported by the U.K. MRC (MRC Human Immunology Unit), the Oxford Biomedical Research Centre, and Cancer Research UK (CRUK) through CRUK Cancer Centre (C399/A2291 to V.C.; C38302/A17319 to V.K.W.; C375/A17721 to E.Y.J.; 29549 to A.G.; CTRQQR-2021\100002 to J.A.B.); the Wellcome Trust (212343/Z/18/Z to M.F.; 100262Z/12/Z to M.L.D. and S.V.) and Kennedy Trust for Rheumatology Research (to M.F., M.L.D., S.V., A.G., J.M.M.), European Commission (ERC-2014-AdG_670930 to M.L.D. and V.M.), Cancer Research Institute (to V.M.), and EPSRC (EP/S004459/1 to M.F. and H.C.Y). The Wellcome Centre for Human Genetics is supported by Wellcome Trust Centre grant 203141/Z/16/Z. P.S.M. is supported by a Jean Shanks Foundation/Pathological Society of Great Britain & Ireland Clinical Research Training Fellowship. C.K. is supported by a Wellcome Studentship (105401/Z/14/Z). V.J. is supported by an EMBO Long-Term Fellowship (ALTF 1061–2017). J.A.B. is supported by EPSRC/MRC Centre for Doctoral Training in Systems Approaches to Biomedical Science (EP/G037280/1) and the EPSRC Impact Acceleration Account (EP/R511742/1). L.R.O. is supported by the Independent Research Fund Denmark (8048-00078B). V.K.W. is supported by CRUK Oxford Centre Prize DPhil Studentship. M.B.B. is supported by Early-Career Clinician Scientists fellowship from the Lundbeck Foundation (R381-2021-1278). A.V.H. was supported by a Wellcome Trust Clinical Research Fellowship (106287/Z/14/Z) and an A.G. Leventis Foundation Scholarship. A.V.H. is currently supported by a NIHR/University of Cambridge Clinical Lectureship (RC30016) and a Clinical Lecturer Starter Grant from the Academy Of Medical Sciences (G122195; RDAG/600).Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours

Semmaphorin 3 A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells.

Acknowledgements: The authors wish to thank members of the Vincenzo Cerundolo and Tudor A. Fulga laboratories, University of Oxford, for helpful discussions and suggestions. Simon Davis and Oliver Bannard, University of Oxford, for helpful advice and guidance. The staff of the University of Oxford Department of Biomedical Services for animal husbandry. Christoffer Lagerholm and Dominic Waithe of the Wolfson Imaging Centre at University of Oxford for microscopy training and support. Helena Coker and Kseniya Korobchevskaya from the Oxford-ZEISS Centre of Excellence in Biomedical Imaging at Kennedy Institute of Rheumatology which is supported by the Kennedy Trust for Rheumatology Research, IDRM and Carl Zeiss GMBH. The Medical Research Council (MRC) WIMM Flow Cytometry Facility for training and support. The Oxford Centre for Histopathology Research and the Oxford Radcliffe Biobank, which are supported by the NIHR Oxford Biomedical Research Centre. Lisa Browning, Oxford University Hospital, for examination of histology samples. David Pinto, University of Oxford, for code for analysis of CDR3 sequences. This work was supported by the U.K. MRC (MRC Human Immunology Unit), the Oxford Biomedical Research Centre, and Cancer Research UK (CRUK) through CRUK Cancer Centre (C399/A2291 to V.C.; C38302/A17319 to V.K.W.; C375/A17721 to E.Y.J.; 29549 to A.G.; CTRQQR-2021\100002 to J.A.B.); the Wellcome Trust (212343/Z/18/Z to M.F.; 100262Z/12/Z to M.L.D. and S.V.) and Kennedy Trust for Rheumatology Research (to M.F., M.L.D., S.V., A.G., J.M.M.), European Commission (ERC-2014-AdG_670930 to M.L.D. and V.M.), Cancer Research Institute (to V.M.), and EPSRC (EP/S004459/1 to M.F. and H.C.Y). The Wellcome Centre for Human Genetics is supported by Wellcome Trust Centre grant 203141/Z/16/Z. P.S.M. is supported by a Jean Shanks Foundation/Pathological Society of Great Britain & Ireland Clinical Research Training Fellowship. C.K. is supported by a Wellcome Studentship (105401/Z/14/Z). V.J. is supported by an EMBO Long-Term Fellowship (ALTF 1061–2017). J.A.B. is supported by EPSRC/MRC Centre for Doctoral Training in Systems Approaches to Biomedical Science (EP/G037280/1) and the EPSRC Impact Acceleration Account (EP/R511742/1). L.R.O. is supported by the Independent Research Fund Denmark (8048-00078B). V.K.W. is supported by CRUK Oxford Centre Prize DPhil Studentship. M.B.B. is supported by Early-Career Clinician Scientists fellowship from the Lundbeck Foundation (R381-2021-1278). A.V.H. was supported by a Wellcome Trust Clinical Research Fellowship (106287/Z/14/Z) and an A.G. Leventis Foundation Scholarship. A.V.H. is currently supported by a NIHR/University of Cambridge Clinical Lectureship (RC30016) and a Clinical Lecturer Starter Grant from the Academy Of Medical Sciences (G122195; RDAG/600).Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours

Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8 + T cells

Acknowledgements: The authors wish to thank members of the Vincenzo Cerundolo and Tudor A. Fulga laboratories, University of Oxford, for helpful discussions and suggestions. Simon Davis and Oliver Bannard, University of Oxford, for helpful advice and guidance. The staff of the University of Oxford Department of Biomedical Services for animal husbandry. Christoffer Lagerholm and Dominic Waithe of the Wolfson Imaging Centre at University of Oxford for microscopy training and support. Helena Coker and Kseniya Korobchevskaya from the Oxford-ZEISS Centre of Excellence in Biomedical Imaging at Kennedy Institute of Rheumatology which is supported by the Kennedy Trust for Rheumatology Research, IDRM and Carl Zeiss GMBH. The Medical Research Council (MRC) WIMM Flow Cytometry Facility for training and support. The Oxford Centre for Histopathology Research and the Oxford Radcliffe Biobank, which are supported by the NIHR Oxford Biomedical Research Centre. Lisa Browning, Oxford University Hospital, for examination of histology samples. David Pinto, University of Oxford, for code for analysis of CDR3 sequences. This work was supported by the U.K. MRC (MRC Human Immunology Unit), the Oxford Biomedical Research Centre, and Cancer Research UK (CRUK) through CRUK Cancer Centre (C399/A2291 to V.C.; C38302/A17319 to V.K.W.; C375/A17721 to E.Y.J.; 29549 to A.G.; CTRQQR-2021\100002 to J.A.B.); the Wellcome Trust (212343/Z/18/Z to M.F.; 100262Z/12/Z to M.L.D. and S.V.) and Kennedy Trust for Rheumatology Research (to M.F., M.L.D., S.V., A.G., J.M.M.), European Commission (ERC-2014-AdG_670930 to M.L.D. and V.M.), Cancer Research Institute (to V.M.), and EPSRC (EP/S004459/1 to M.F. and H.C.Y). The Wellcome Centre for Human Genetics is supported by Wellcome Trust Centre grant 203141/Z/16/Z. P.S.M. is supported by a Jean Shanks Foundation/Pathological Society of Great Britain & Ireland Clinical Research Training Fellowship. C.K. is supported by a Wellcome Studentship (105401/Z/14/Z). V.J. is supported by an EMBO Long-Term Fellowship (ALTF 1061–2017). J.A.B. is supported by EPSRC/MRC Centre for Doctoral Training in Systems Approaches to Biomedical Science (EP/G037280/1) and the EPSRC Impact Acceleration Account (EP/R511742/1). L.R.O. is supported by the Independent Research Fund Denmark (8048-00078B). V.K.W. is supported by CRUK Oxford Centre Prize DPhil Studentship. M.B.B. is supported by Early-Career Clinician Scientists fellowship from the Lundbeck Foundation (R381-2021-1278). A.V.H. was supported by a Wellcome Trust Clinical Research Fellowship (106287/Z/14/Z) and an A.G. Leventis Foundation Scholarship. A.V.H. is currently supported by a NIHR/University of Cambridge Clinical Lectureship (RC30016) and a Clinical Lecturer Starter Grant from the Academy Of Medical Sciences (G122195; RDAG/600).Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours

Semmaphorin 3 A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8⁺ T cells

Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours.</p

Influence of intracerebral hemorrhage location on incidence, characteristics, and outcome

Background and Purpose— The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. Methods— In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. Results— There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.8 [95% confidence interval, 7.7–12.4] versus 8.6 [95% confidence interval, 6.7–11.1] per 100 000 adults/y). At baseline, adults with lobar ICH were more likely to have preceding dementia (21% versus 5%; P=0.01), lower Glasgow Coma Scale scores (median, 13 versus 14; P=0.03), larger ICHs (median, 38 versus 11 mL; P<0.001), subarachnoid extension (57% versus 5%; P<0.001), and subdural extension (15% versus 3%; P=0.02) than those with nonlobar ICH. One-year case fatality was lower after lobar ICH than after nonlobar ICH (adjusted odds ratio for death at 1 year: lobar versus nonlobar ICH 0.21; 95% confidence interval, 0.07–0.63; P=0.006, after adjustment for known predictors of outcome). There were 4 recurrent ICHs, which occurred exclusively in survivors of lobar ICH (annual risk of recurrent ICH after lobar ICH, 11.8%; 95% confidence interval, 4.6%–28.5% versus 0% after nonlobar ICH; log-rank P=0.04). Conclusions— The baseline characteristics and outcome of lobar ICH differ from other locations

Association of baseline hematoma and edema volumes with one-year outcome and long-term survival after spontaneous intracerebral hemorrhage: A community-based inception cohort study

Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author. </jats:sec