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  1. Article ; Online: Application of HLA molecular level mismatching in ethnically diverse kidney transplant recipients receiving a steroid-sparing immunosuppression protocol.

    Santos, Eva / Spensley, Katrina / Gunby, Nicola / Worthington, Judith / Roufosse, Candice / Anand, Arthi / Willicombe, Michelle

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

    2024  

    Abstract: Defining HLA mismatch at the molecular compared with the antigen level has been shown to be superior in predicting alloimmune responses, although data from across different patient populations are lacking. Using HLA-Matchmaker, HLA-EMMA and PIRCHE-II, ... ...

    Abstract Defining HLA mismatch at the molecular compared with the antigen level has been shown to be superior in predicting alloimmune responses, although data from across different patient populations are lacking. Using HLA-Matchmaker, HLA-EMMA and PIRCHE-II, this study reports on the association between molecular mismatch (MolMM) and de novo donor-specific antibody (dnDSA) in an ethnically diverse kidney transplant population receiving a steroid-sparing immunosuppression protocol. Of the 419 patients, 51 (12.2%) patients had dnDSA. De novo DSA were seen more frequently with males, primary transplants, patients receiving tacrolimus monotherapy, and unfavorably HLA-matched transplants. There was a strong correlation between MolMM load and antigen mismatch, although significant variation of MolMM load existed at each antigen mismatch. MolMM loads differed significantly by recipient ethnicity, although ethnicity alone was not associated with dnDSA. On multivariate analysis, increasing MolMM loads associated with dnDSA, whereas antigen mismatch did not. De novo DSA against 8 specific epitopes occurred at high frequency; of the 51 patients, 47 (92.1%) patients with dnDSA underwent a pretreatment biopsy, with 21 (44.7%) having evidence of alloimmune injury. MolMM has higher specificity than antigen mismatching at identifying recipients who are at low risk of dnDSA while receiving minimalist immunosuppression. Immunogenicity consideration is important, with more work needed on identification, especially across different ethnic groups.
    Language English
    Publishing date 2024-02-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2060594-8
    ISSN 1600-6143 ; 1600-6135
    ISSN (online) 1600-6143
    ISSN 1600-6135
    DOI 10.1016/j.ajt.2024.02.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Steroid Sparing Maintenance Immunosuppression in Highly Sensitised Patients Receiving Alemtuzumab Induction.

    Santos, Eva / Spensley, Katrina / Gunby, Nicola / Clarke, Candice / Anand, Arthi / Roufosse, Candice / Willicombe, Michelle

    Transplant international : official journal of the European Society for Organ Transplantation

    2023  Volume 36, Page(s) 11056

    Abstract: This analysis reports on the outcomes of two different steroid sparing immunosuppression protocols used in the management of 120 highly sensitised patients (HSPs) with cRF>85% receiving Alemtuzumab induction, 53 maintained on tacrolimus (FK) monotherapy ... ...

    Abstract This analysis reports on the outcomes of two different steroid sparing immunosuppression protocols used in the management of 120 highly sensitised patients (HSPs) with cRF>85% receiving Alemtuzumab induction, 53 maintained on tacrolimus (FK) monotherapy and 67 tacrolimus plus mycophenolate mofetil (FK + MMF). There was no difference in the median cRF or mode of sensitisation between the two groups, although the FK + MMF cohort received more poorly matched grafts. There was no difference in one-year patient or allograft survival, however rejection free survival was inferior with FK monotherapy compared with FK + MMF at 65.4% and 91.4% respectively,
    MeSH term(s) Humans ; Alemtuzumab/therapeutic use ; Immunosuppressive Agents/therapeutic use ; Tacrolimus/therapeutic use ; Kidney Transplantation/methods ; Immunosuppression Therapy/methods ; Steroids ; Mycophenolic Acid/therapeutic use ; Graft Rejection/prevention & control ; Graft Survival
    Chemical Substances Alemtuzumab (3A189DH42V) ; Immunosuppressive Agents ; Tacrolimus (WM0HAQ4WNM) ; Steroids ; Mycophenolic Acid (HU9DX48N0T)
    Language English
    Publishing date 2023-06-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 639435-8
    ISSN 1432-2277 ; 0934-0874
    ISSN (online) 1432-2277
    ISSN 0934-0874
    DOI 10.3389/ti.2023.11056
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Lack of seroresponse to SARS-CoV-2 booster vaccines given early post-transplant in patients primed pre-transplantation.

    Gleeson, Sarah / Martin, Paul / Thomson, Tina / Spensley, Katrina J / Goodall, Dawn / Bedi, Rachna / Thind, Amarpreet Kaur / Seneschall, Charlotte / Gan, Jaslyn / McAdoo, Stephen / Lightstone, Liz / Kelleher, Peter / Prendecki, Maria / Willicombe, Michelle

    Frontiers in immunology

    2023  Volume 13, Page(s) 1083167

    Abstract: SARS-CoV-2 vaccines are recommended pre-transplantation, however, waning immunity and evolving variants mandate booster doses. Currently there no data to inform the optimal timing of booster doses post-transplant, in patients primed pre-transplant. We ... ...

    Abstract SARS-CoV-2 vaccines are recommended pre-transplantation, however, waning immunity and evolving variants mandate booster doses. Currently there no data to inform the optimal timing of booster doses post-transplant, in patients primed pre-transplant. We investigated serial serological samples in 204 transplant recipients who received 2 or 3 SARS-CoV-2 vaccines pre-transplant. Spike protein antibody concentrations, [anti-S], were measured on the day of transplantation and following booster doses post-transplant. In infection-naïve patients, post-booster [anti-S] did not change when V3 (1
    MeSH term(s) Humans ; COVID-19 Vaccines ; SARS-CoV-2 ; COVID-19/prevention & control ; Transplants ; Transplant Recipients ; Antibodies
    Chemical Substances COVID-19 Vaccines ; Antibodies
    Language English
    Publishing date 2023-01-16
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.1083167
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Comparison of Vaccine Effectiveness Against the Omicron (B.1.1.529) Variant in Hemodialysis Patients.

    Spensley, Katrina J / Gleeson, Sarah / Martin, Paul / Thomson, Tina / Clarke, Candice L / Pickard, Graham / Thomas, David / McAdoo, Stephen P / Randell, Paul / Kelleher, Peter / Bedi, Rachna / Lightstone, Liz / Prendecki, Maria / Willicombe, Michelle

    Kidney international reports

    2022  Volume 7, Issue 6, Page(s) 1406–1409

    Language English
    Publishing date 2022-04-13
    Publishing country United States
    Document type Journal Article
    ISSN 2468-0249
    ISSN (online) 2468-0249
    DOI 10.1016/j.ekir.2022.04.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients.

    Thomson, Tina / Prendecki, Maria / Gleeson, Sarah / Martin, Paul / Spensley, Katrina / De Aguiar, Rute Cardoso / Sandhu, Bynvant / Seneschall, Charlotte / Gan, Jaslyn / Clarke, Candice L / Lewis, Shanice / Pickard, Graham / Thomas, David / McAdoo, Stephen P / Lightstone, Liz / Cox, Alison / Kelleher, Peter / Willicombe, Michelle

    EClinicalMedicine

    2022  Volume 53, Page(s) 101642

    Abstract: Background: Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant ... ...

    Abstract Background: Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population.
    Methods: We undertook a single centre cohort study of 724 kidney transplant recipients prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their first dose of vaccine.
    Findings: 586/724 (80.9%) patients were infection-naïve post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001.Post-V4, 45/239 (18.8%) infection-naïve patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type.
    Interpretation: A significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection. As such alternative strategies are required to provide protection to this vulnerable group.
    Funding: MW/PK received study support from Oxford Immunotec.
    Language English
    Publishing date 2022-09-09
    Publishing country England
    Document type Journal Article
    ISSN 2589-5370
    ISSN (online) 2589-5370
    DOI 10.1016/j.eclinm.2022.101642
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Comparison of immunogenicity and clinical effectiveness between BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines in people with end-stage kidney disease receiving haemodialysis: A prospective, observational cohort study.

    Martin, Paul / Gleeson, Sarah / Clarke, Candice L / Thomson, Tina / Edwards, Helena / Spensley, Katrina / Mortimer, Paige / McIntyre, Stacey / Cox, Alison / Pickard, Graham / Lightstone, Liz / Thomas, David / McAdoo, Stephen P / Kelleher, Peter / Prendecki, Maria / Willicombe, Michelle

    The Lancet regional health. Europe

    2022  Volume 21, Page(s) 100478

    Abstract: Background: People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical effectiveness of BNT162B2 versus ChAdOx1 in ... ...

    Abstract Background: People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical effectiveness of BNT162B2 versus ChAdOx1 in haemodialysis patients.
    Methods: In this observational cohort study, 1021 patients were followed-up from time of vaccination until December 2021. All patients underwent weekly RT-PCR screening. Patients were assessed for nucleocapsid(anti-NP) and spike(anti-S) antibodies at timepoints after second(V2) and third(V3) vaccinations. 191 patients were investigated for T-cell responses. Vaccine effectiveness (VE) for prevention of infection, hospitalisation and mortality was evaluated using the formula VE=(1-adjustedHR)x100.
    Findings: 45.7% (467/1021) had evidence of prior infection. There was no difference in the proportion of infection-naïve patients who seroconverted by vaccine type, but median anti-S antibody titres were higher post-BNT162b2 compared with ChAdOx1; 462(152-1171) and 78(20-213) BAU/ml respectively,
    Interpretation: Serum anti-S concentrations predict risk of breakthrough infection. Anti-S responses vary dependent upon clinical features, infection history and vaccine type. Monitoring of serological responses may enable individualised approaches to vaccine boosters in at risk populations.
    Funding: National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.
    Language English
    Publishing date 2022-09-10
    Publishing country England
    Document type Journal Article
    ISSN 2666-7762
    ISSN (online) 2666-7762
    DOI 10.1016/j.lanepe.2022.100478
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Kidney Transplant Recipients and Omicron: Outcomes, effect of vaccines and the efficacy and safety of novel treatments

    Gleeson, Sarah / Martin, Paul / Thomson, Tina / Thind, Amarpreet / Prendecki, Maria / Spensley, Katrina J / Clarke, Candice / Roufosse, Candice / Pickard, Graham / Thomas, David / McAdoo, Stephen P / Lightstone, Liz / Kelleher, Peter / Willicombe, Michelle

    medRxiv

    Abstract: We aimed to describe the outcomes of Omicron infection in kidney transplant recipients (KTR), compare the efficacy of the community therapeutic interventions and report the safety profile of molnupiravir. From 142 KTRs diagnosed with COVID-19 infection ... ...

    Abstract We aimed to describe the outcomes of Omicron infection in kidney transplant recipients (KTR), compare the efficacy of the community therapeutic interventions and report the safety profile of molnupiravir. From 142 KTRs diagnosed with COVID-19 infection after Omicron had become the dominant variant in the UK, 116 (78.9%) cases were diagnosed in the community; 47 receiving sotrovimab, 21 molnupiravir and 48 no treatment. 10 (20.8%) non-treated patients were hospitalised following infection, which was significantly higher than the sotrovimab group (2.1%), p=0.0048, but not the molnupiravir treated group (14.3%), p=0.47. The only admission following sotrovimab occurred in a patient infected with BA.2. One patient from the molnupiravir and no-treatment groups required ICU support, and both subsequently died, with one other death in the no-treatment group. No patient receiving sotrovimab died. 6/116 (5.2%) patients required dialysis following their diagnosis; 2 (9.5%) patients receiving molnupiravir and 4 (8.3%) no-treatment. This requirement was significantly higher in the molnupiravir group compared with the sotrovimab treated patients, in whom no patient required dialysis, p=0.035. Both molnupiravir treated patients requiring dialysis had features of systemic thrombotic microangiopathy. Post-vaccination serostatus was available in 110 patients. Seropositive patients were less likely to require hospital admission compared with seronegative patients, 6 (7.0%) and 6 (25.0%) respectively, p=0.023. Seropositive patients were also less likely to require dialysis therapy, (p=0.016). In conclusion, sotrovimab treatment in the community was associated with superior patient and transplant outcomes; its clinical efficacy against the BA.2 variant requires a rapid review. The treatment benefit of molnupiravir was not evident, and wider safety reporting in transplant patients is needed.
    Keywords covid19
    Language English
    Publishing date 2022-05-03
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2022.05.03.22274524
    Database COVID19

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  8. Article ; Online: Comparison of vaccine effectiveness against the Omicron (B.1.1.529) variant in patients receiving haemodialysis

    Spensley, Katrina / Gleeson, Sarah / Martin, Paul / Thomson, Tina / Clarke, Candice L / Pickard, Graham / Thomas, David C / McAdoo, Stephen P / Randell, Paul / Kelleher, Peter / Bedi, Rachna / Lightstone, Liz / Prendecki, Maria / Willicombe, Michelle

    medRxiv

    Abstract: Background Emerging data suggest a reduction in SARS-CoV-2 vaccine effectiveness against Omicron SARS-CoV-2 infection. There is also evidence to show that Omicron is less pathogenic than previous variants. For clinically vulnerable populations, a less ... ...

    Abstract Background Emerging data suggest a reduction in SARS-CoV-2 vaccine effectiveness against Omicron SARS-CoV-2 infection. There is also evidence to show that Omicron is less pathogenic than previous variants. For clinically vulnerable populations, a less pathogenic variant may still have significant impact on morbidity and mortality. Herein we assess the clinical impact of Omicron infection, and vaccine effectiveness, in an in-centre haemodialysis (IC-HD) population. Methods One thousand, one hundred and twenty-one IC-HD patients were included in the analysis, all patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between 1st December 2021 and 16th January 2022. Screening for infection via weekly RT-PCR testing and 3-monthly serological assessment started prior to the vaccine roll out in 2020. Results Omicron infection was diagnosed in 145/1121 (12.9%) patients over the study period, equating to an infection rate of 3.1 per 1000 patient days. Vaccine effectiveness (VE) against Omicron infection in patients who had received a booster vaccine was 58 (23-75)%, p=0.002; VE was seen in patients who received either ChAdOx1, VE of 47(2-70)%, p=0.034, or BNT162b2, VE of 66 (36-81)%, p=0.0005, as their first two doses. No protection against infection was seen in patients who were partially vaccinated (2-doses), p=0.83. Prior infection was associated with reduced likelihood of Omicron infection, HR 0.69 (0.50-0.96), p=0.0289. Four (2.8%) patients died within 28 days of infection diagnosis, with no excess mortality was seen in patients with infection. Conclusion 3-doses of SARS-CoV-2 vaccines are required in ICHD to provide protection against Omicron infection.
    Keywords covid19
    Language English
    Publishing date 2022-01-26
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2022.01.25.22269804
    Database COVID19

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  9. Article ; Online: Reverse immunodynamics: a new method for identifying targets of protective immunity.

    Spensley, Katrina J / Wikramaratna, Paul S / Penman, Bridget S / Walker, Andrew / Smith, Adrian L / Pybus, Oliver G / Jean, Létitia / Gupta, Sunetra / Lourenço, José

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 2164

    Abstract: Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. Epidemiological models predict that strong immune selection ... ...

    Abstract Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. Epidemiological models predict that strong immune selection can cause antigenic variants to structure into genetically discordant sets of antigenic types (e.g. serotypes). A corollary of this theory is that targets of immunity may be identified by searching for non-overlapping associations of amino acids among co-circulating antigenic variants. We propose a novel population genetics methodology that combines such predictions with phylogenetic analyses to identify genetic loci (epitopes) under strong immune selection. We apply this concept to the AMA-1 protein of the malaria parasite Plasmodium falciparum and find evidence of epitopes among certain regions of low variability which could render them ideal vaccine candidates. The proposed method can be applied to a myriad of multi-strain pathogens for which vast amounts of genetic data has been collected in recent years.
    MeSH term(s) Antigens, Protozoan/genetics ; Antigens, Protozoan/immunology ; Epitopes/genetics ; Epitopes/immunology ; Genetics, Population/methods ; Genotype ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Plasmodium falciparum/immunology ; Protozoan Proteins/genetics ; Protozoan Proteins/immunology ; Selection, Genetic
    Chemical Substances Antigens, Protozoan ; Epitopes ; Membrane Proteins ; Protozoan Proteins ; apical membrane antigen I, Plasmodium
    Language English
    Publishing date 2019-02-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-37288-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients

    Thomson, Tina / Prendecki, Maria / Gleeson, Sarah / Martin, Paul / Spensley, Katrina J / Cardoso De Aguiar, Rute / Sandhu, Bynvant / Seneschall, Charlotte / Gan, Jaslyn / Clarke, Candice L / Lewis, Shanice / Pickard, Graham / Thomas, David / McAdoo, Stephen P / Lightstone, Liz / Cox, Alison / Kelleher, Peter / Willicombe, Michelle

    medRxiv

    Abstract: Background Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population. ...

    Abstract Background Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population. Methods 724 kidney transplant recipients were prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their 1st dose of vaccine. Results 586/724 (80.9%) patients were infection-naive post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001. Post-V4, 45/239 (18.8%) infection-naive patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients who were seronegative post-V3. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. Anti-S post-V4 were sequentially greater in those seroconverting post V2- compared with V3- , and V3- compared with V4-, at 1561 (567-5211), 379 (101-851) and 19 (9.7-48) BAU/ml respectively. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type. Conclusion A significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection.
    Keywords covid19
    Language English
    Publishing date 2022-05-01
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2022.04.29.22274396
    Database COVID19

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