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ObjectiveThere is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination.MethodsSerological 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.ResultsFollowing 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.ConclusionSARS-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.

BackgroundLimited data exists on the immunogenicity of vector-based SARS-CoV-2 vaccines in patients with kidney disease. Given their use in over 180 countries, such data is of upmost importance to inform policy on optimal vaccination strategies. This study compares the immunogenicity of BNT162b2 with ChAdOx1 in patients receiving haemodialysis.Methods1021 patients were screened for spike protein antibodies (anti-S) following 2 doses of either BNT162b2 (n=523) or ChAdOx1 (n=498). 191 patients underwent assessment with T-cell ELISpot assays. 65 health care workers were used as a control group.ResultsAnti-S was detected in 936 (91.2%) of patients post-vaccination. There was no difference in seroconversion rates between infection-naïve patients who received BNT162b2, 248/281 (88.3%), compared with ChAdOx1, 227/272 (83.5%), p=0.11. Anti-S concentrations were higher following BNT162b, 462(152-1171) BAU/ml, compared with ChAdOx-1 79(20-213) BAU/ml, pOnly 73 (38.2%) of patients had detectable T-cell responses post-vaccination, with no proportional difference between infection-naïve patients who received BNT162b2, 2/19 (10.5%), versus ChAdOx1, 15/75 (20.0%), p=0.34. There were no quantitative differences in T-cell responses in infection-naïve patients, with a median 2(0-16) SFU/106PBMCs and 10(4-28) SFU/106PBMCs in those receiving BNT162b2 and ChAdOx1 respectively, p=0.35. These responses were significantly weaker compared with healthy controls.ConclusionsEnhanced immunogenicity was seen with BNT162b2 compared with ChAdOx1, driven by superior humoral responses, with attenuated T-cell responses to both vaccines. Comparative data on clinical efficacy is now required.Significance StatementLimited data exist on the immunogenicity of vector-based SARS-CoV-2 vaccines in patients with kidney disease. Given their use in over 180 countries worldwide, such data are of upmost importance to inform policy on optimal vaccination strategies. This study compares the immunogenicity of BNT162b2 (n=523) against the adenovirus vector vaccine, ChAdOx1 (n=498), in 1021 haemodialysis patients. In infection-naïve patients, overall seroconversion rates were comparable, however, spike protein antibody concentrations were significantly higher following BNT162b2. No difference in T-cell responses was seen, however, all naïve patients had weaker responses compared with healthy controls. Equivalent attenuated cellular responses to both vaccines, with greater humoral responses to BNT162b2, suggests BNT162b2 has superior immunogenicity in this patient population, with data on clinical efficacy required.

End-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We measured 436 circulating proteins in serial blood samples from hospitalised and non-hospitalised ESKD patients with COVID-19 (n = 256 samples from 55 patients). Comparison to 51 non-infected patients revealed 221 differentially expressed proteins, with consistent results in a separate subcohort of 46 COVID-19 patients. Two hundred and three proteins were associated with clinical severity, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g. proteinase-3), and epithelial injury (e.g. KRT19). Machine-learning identified predictors of severity including IL18BP, CTSD, GDF15, and KRT19. Survival analysis with joint models revealed 69 predictors of death. Longitudinal modelling with linear mixed models uncovered 32 proteins displaying different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. These data implicate epithelial damage, innate immune activation, and leucocyte–endothelial interactions in the pathology of severe COVID-19 and provide a resource for identifying drug targets., eLife digest COVID-19 varies from a mild illness in some people to fatal disease in others. Patients with severe disease tend to be older and have underlying medical problems. People with kidney failure have a particularly high risk of developing severe or fatal COVID-19. Patients with severe COVID-19 have high levels of inflammation, causing damage to tissues around the body. Many drugs that target inflammation have already been developed for other diseases. Therefore, to repurpose existing drugs or design new treatments, it is important to determine which proteins drive inflammation in COVID-19. Here, Gisby, Clarke, Medjeral-Thomas et al. measured 436 proteins in the blood of patients with kidney failure and compared the levels between patients who had COVID-19 to those who did not. This revealed that patients with COVID-19 had increased levels of hundreds of proteins involved in inflammation and tissue injury. Using a combination of statistical and machine learning analyses, Gisby et al. probed the data for proteins that might predict a more severe disease progression. In total, over 200 proteins were linked to disease severity, and 69 with increased risk of death. Tracking how levels of blood proteins changed over time revealed further differences between mild and severe disease. Comparing this data with a similar study of COVID-19 in people without kidney failure showed many similarities. This suggests that the findings may apply to COVID-19 patients more generally. Identifying the proteins that are a cause of severe COVID-19 – rather than just correlated with it – is an important next step that could help to select new drugs for severe COVID-19.

End-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We performed dense serial blood sampling in hospitalised and non-hospitalised ESKD patients with COVID-19 (n=256 samples from 55 patients) and used Olink immunoassays to measure 436 circulating proteins. Comparison to 51 non-infected ESKD patients revealed 221 proteins differentially expressed in COVID-19, of which 69.7% replicated in an independent cohort of 46 COVID-19 patients. 203 proteins were associated with clinical severity scores, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g proteinase-3) and epithelial injury (e.g. KRT19). Random Forests machine learning identified predictors of current or future severity such as KRT19, PARP1, PADI2, CCL7, and IL1RL1 (ST2). Survival analysis with joint models revealed 69 predictors of death including IL22RA1, CCL28, and the neutrophil-derived chemotaxin AZU1 (Azurocidin). Finally, longitudinal modelling with linear mixed models uncovered 32 proteins that display different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. Our findings point to aberrant innate immune activation and leucocyte-endothelial interactions as central to the pathology of severe COVID-19. The data from this unique cohort of high-risk individuals provide a valuable resource for identifying drug targets in COVID-19.