Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression.

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.

Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

Clinical impact of early post-transplant red cell transfusions in kidney transplantation: a systematic review and meta-analysis.

Introduction: Red blood cell transfusions (RBCT) represent a potentially modifiable risk factor for HLA sensitisation and adverse outcomes post transplantation. Evidence of the clinical impact of post-transplant RBCT has been infrequently reported. Herein, we performed a systematic review of available literature to assess the prevalence of RBCT post kidney transplant, and the effect of transfusion on transplant outcomes. Methods: We included studies from 2000 to July 2022, published on Medline, Embase and the Transplant Library. Results: Ten studies were analysed which included a total of 32,817 kidney transplant recipients, with a median transfusion prevalence of 40% (range 18-64%). There was significant heterogeneity between studies in terms of patient and allograft characteristics, immunological risk, and immunosuppression protocols. Analysis of unadjusted outcomes showed that post-transplant RBCTs are associated with inferior patient survival, allograft loss, rejection and donor specific antibodies. Adjusted outcomes were described where available, and supported the adverse associations seen in the unadjusted models in many studies. Discussion: This review demonstrates that RBCT post-transplant are common and maybe associated with inferior outcomes, highlighting the urgent need for high quality prospective evidence of the effect of RBCTs on transplant outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier, CRD42022348763767.

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.

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, p<0.001.  Concomitant immunosuppressant use was a risk factor for non-response, OR 0.12[95% CI 0.05-0.25] p<0.001.  Post-V3 (all BNT162b2), median anti-S antibody titres remained higher in those receiving BNT162b2 versus ChAdOx1 as primary doses; 2756(187-1246) and 1250(439-2635) BAU/ml respectively, p=0.003.Anti-S antibodies waned over time. Hierarchical levels of anti-S post-V2 predicted risk of infection; patients with no/low anti-S being at highest risk. VE for preventing infection, hospitalisation and death was 53% (95% CI 6-75), 77% (95% CI 30-92) and 93% (95% CI 59-99) respectively, with no difference seen by vaccine type. 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.

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

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 (1st booster) was given at 116(78-150) days post-transplant, falling from 122(32-574) to 111(34-682) BAU/ml, p=0.78. Similarly, in infection-experienced patients, [anti-S] on Day-0 and post-V3 were 1090(133-3667) and 2207(650-5618) BAU/ml respectively, p=0.26. In patients remaining infection-naïve, [anti-S] increased post-V4 (as 2nd booster) when given at 226(208-295) days post-transplant, rising from 97(34-1074) to 5134(229-5680) BAU/ml, p=0.0016. Whilst in patients who had 3 vaccines pre-transplant, who received V4 (as 1st booster) at 82(49-101) days post-transplant, [anti-S] did not change, falling from 981(396-2666) to 871(242-2092) BAU/ml, p=0.62. Overall, infection pre-transplant and [anti-S] at the time of transplantation predicted post-transplant infection risk. As [Anti-S] fail to respond to SARS-CoV-2 booster vaccines given early post-transplant, passive immunity may be beneficial to protect patients during this period.

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

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow assay for antibody prevalence studies following vaccination: a diagnostic accuracy study.

Background: Lateral flow immunoassays (LFIAs) are able to achieve affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Methods: This was a prospective diagnostic accuracy study. Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following two doses of SARS-CoV-2 vaccine, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination and subsequent follow up. During the participants visit, finger-prick blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG was detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. A total of 186 paired samples were collected. The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay Results: The LFIA had an estimated sensitivity of 92.0% (114/124; 95% confidence interval [CI] 85.7% to 96.1%) and specificity of 93.6% (58/62; 95% CI 84.3% to 98.2%) using the Abbott assay as reference standard (using the threshold for positivity of 7.10 BAU/ml) Conclusions: Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveillance but does not meet criteria for individual testing.

Cohort Study of Outpatient Hemodialysis Management Strategies for COVID-19 in North-West London.

BACKGROUND: Dialysis patients are at risk of severe coronavirus disease 2019 (COVID-19). We managed COVID-19 hemodialysis outpatients in dedicated satellite dialysis units. This provided rare opportunity to study early disease progress in community-based patients. We aimed to (i) understand COVID-19 progression, (ii) identify markers of future clinical severity, and (iii) assess associations between dialysis management strategies and COVID-19 clinical outcomes. METHODS: We conducted a cohort study of all outpatients managed at a COVID-19 hemodialysis unit. We analyzed data recorded as part of providing COVID-19 clinical care. We analyzed associations between features at diagnosis and the first 3 consecutive hemodialysis sessions in patients who required future hospital admission, and those who had died at 28 days. RESULTS: Isolated outpatient hemodialysis was provided to 106 patients over 8 weeks. No patients received antiviral medication or hydroxychloroquine. Twenty-one patients (20%) were admitted at COVID-19 diagnosis; 29 of 85 patients (34%) were admitted after initial outpatient management; 16 patients (15%) died. By multivariate analysis, nonactive transplant list status, use of institutional transport, and increased white cell count associated with future hospitalization and increased age associated with death. Oxygen saturations progressively decreased over the first 3 dialysis sessions in the cohorts that progressed to future hospital admission or death. Mean ultrafiltration volume of the first 3 hemodialysis sessions was reduced in the same cohorts. CONCLUSIONS: Outpatient hemodialysis in patients with COVID-19 is safe for patients and staff. Features at the first 3 dialysis sessions can identify individuals at risk of future hospitalization and death from COVID-19.