Optimal time for COVID-19 vaccination in rituximab-treated dermatologic patients.

Background: By depleting circulating B lymphocytes, rituximab time-dependently suppresses coronavirus disease 2019 (COVID-19) vaccines' humoral immunogenicity for a prolonged period. The optimal time to vaccinate rituximab-exposed immune-mediated dermatologic disease (IMDD) patients is currently unclear. Objective: To estimate the vaccination timeframe that equalized the occurrence of humoral immunogenicity outcomes between rituximab-exposed and rituximab-naïve IMDD patients. Methods: This retrospective cohort study recruited rituximab-exposed and age-matched rituximab-naïve subjects tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunity post-vaccination. Baseline clinical and immunological data (i.e., immunoglobulin levels, lymphocyte immunophenotyping) and SARS-CoV-2-specific immunity levels were extracted. The outcomes compared were the percentages of subjects who produced neutralizing antibodies (seroconversion rates, SR) and SARS-CoV-2-specific IgG levels among seroconverters. The outcomes were first analyzed using multiple regressions adjusted for the effects of corticosteroid use, steroid-spearing agents, and pre-vaccination immunological status (i.e., IgM levels, the percentages of the total, naïve, and memory B lymphocytes) to identify rituximab-related immunogenicity outcomes. The rituximab-related outcome differences with a 95% confidence interval (CI) between groups were calculated, starting by including every subject and then narrowing down to those with longer rituximab-to-vaccination intervals (≥3, ≥6, ≥9, ≥12 months). The desirable cut-off performances were <25% outcome inferiority observed among rituximab-exposed subgroups compared to rituximab-naïve subjects, and the positive likelihood ratio (LR+) for the corresponding outcomes ≥2. Findings: Forty-five rituximab-exposed and 90 rituximab-naive subjects were included. The regression analysis demonstrated a negative association between rituximab exposure status and SR but not with SARS-CoV-2-specific IgG levels. Nine-month rituximab-to-vaccination cut-off fulfilled our prespecified diagnostic performance (SR difference between rituximab-exposed and rituximab-naïve group [95%CI]: -2.6 [-23.3, 18.1], LR+: 2.6) and coincided with the repopulation of naïve B lymphocytes in these patients. Conclusions: Nine months of rituximab-to-vaccination interval maximize the immunological benefits of COVID-19 vaccines while avoiding unnecessary delay in vaccination and rituximab treatment for IMDD patients.

A real-world prospective cohort study of immunogenicity and reactogenicity of ChAdOx1-S[recombinant] among patients with immune-mediated dermatological diseases.

BACKGROUND: Immunogenicity and reactogenicity of COVID-19 vaccines have been established in various groups of immunosuppressed patients; however, studies involving patients with immune-mediated dermatological diseases (IMDDs) are scarce. OBJECTIVES: To investigate the influence of IMDDs on the development of SARS-CoV-2-specific immunity and side-effects following ChAdOx1-S[recombinant] vaccination. METHODS: This prospective cohort study included 127 patients with IMDDs and 97 participants without immune-mediated diseases who received ChAdOx1-S[recombinant]. SARS-CoV-2-specific immunity and side-effect profiles were assessed at 1 month postvaccination and compared between groups. Immunological (primary) outcomes were the percentages of participants who tested positive for neutralizing antibodies [seroconversion rate (SR)] and those who developed T-cell-mediated immunity demonstrated by an interferon-γ-releasing assay (IGRA) [positive IGRA rate (+IGRA)]. Reactogenicity-related (secondary) outcomes were the unsolicited adverse reactions and worsening of IMDD activity reflected by the uptitration of immunosuppressants during and within 1 month of vaccination. RESULTS: Overall, the SR for the IMDD group was similar to that of participants without immune-mediated conditions (75·6 vs. 84·5, P = 0·101), whereas + IGRA was lower (72·4 vs. 88·7, P = 0·003). Reactogenicity was similar between groups. No severe adverse reaction was reported. By stratifying the participants in the IMDD group according to individual disease, the immunogenicity of the vaccine was lowest in patients with autoimmune bullous diseases (AIBD) (SR 64·5%, +IGRA 62·9%) and highest in patients with psoriasis (SR 87·7%, +IGRA 80·7%). The reverse trend was found for vaccine-related reactions. Immunosuppressants were uptitrated in 15·8% of cases; 75% of these were patients with AIBD. CONCLUSIONS: Among participants with IMDDs, ChAdOx1-S[recombinant] showed good immunogenicity among patients with psoriasis, but demonstrated lower levels of immunogenicity for patients with AIBD. Some patients, especially patients with AIBD, should be closely monitored as they may require treatment escalation within 1 month postvaccination.

Humoral Immune Response of the Additional Chadox1 NCOV-19 Vaccine Following a Two-Dose Inactivated Whole-Virus SARS-COV-2 Vaccination in Patients on Dialysis

BACKGROUND AND AIMS Patients with end-stage kidney disease (ESKD) are at risk of coronavirus disease 2019 infection and its associated complications. A previous study demonstrated that patients with ESKD on dialysis generated suboptimal humoral immune response (HIR) and lower seroconversion rate after two-dose inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination as compared to healthy individuals. In this study, we examined HIR of the additional dose of ChAdOx1 nCoV-19 vaccine following a standard two-dose inactivated whole-virus SARS-CoV-2 vaccination in patients on dialysis, and compared to those of healthy controls. METHOD We recruited 59 patients with ESKD [31 patients on haemodialysis (HD) and 28 on peritoneal dialysis (PD)) and 16 healthy controls who received two doses of inactivated SARS-CoV-2 vaccine (V2) from Ramathibodi hospital and Banphaeo General Hospital, Bangkok, Thailand, from July 2021 to September 2021. All participants were administered a third dose of the ChAdOx1nCoV-19 vaccine (V3) with a 6-week interval between the V2 to V3. HIR was measured 2 weeks after V2 and V3 using SARS-CoV-2 immunoglobulin G (IgG) assay, which detects antibodies against the S1 receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Median anti-RBD IgG titer and seroconversion rate, defined as anti-RBD IgG titre ≥ 7.1 BAU/mL, were compared among ESKD patients and to those of healthy controls using the Kruskal–Wallis H test and the chi-squared test, respectively. RESULTS Baseline characteristics of patients on HD, PD and healthy controls are shown in Table 1. Demographic characteristics and baseline laboratory parameters were comparable between the HD and PD groups, except for a lower mean serum albumin level in the PD group (P < .001). None of the healthy controls were immunocompromised or receiving immunosuppressive therapies.Table 1.Clinical characteristics, n (%) HD (n = 31)PD (n = 28)Controls (n = 16)Age, years45 (10)41 (12)41 (9)Male, n (%) 23 (74)17 (61)5 (31)Body mass index, kg/m226 (5)24 (4)27 (6)Charlson Comorbidity Index, median (IQR) 3 (3–5)2.5 (2–4)0Comorbidities, n (%)  Diabetes mellitus HypertensionCardiovascular disease 14 (45)24 (77)7 (23)7 (25)25 (89)2 (7)1 (6)2 (13)0 Causes of ESKD, n (%) Diabetic nephropathy Hypertensive nephropathy Others Unknown6 (19)3 (10)5 (16)14 (45)5 (18)8 (29)8 (29)7 (25)NADialysis vintage, months, median (IQR)33 (17–84)34 (7–57)NATotal Kt/Vurea1.6 (0.3)2.0 (0.4)NALaboratories White blood cells, × 109/L Absolute lymphocyte count, × 109/L Haemoglobin, g/dL Ferritin, ng/mL, median (IQR) Albumin, g/L6.9 (1.9)1.6 (0.5)11 (2)301 (119–441)40 (4)7.3 (2.8)1.5 (0.8)10 (2)367 (156–751)33 (4)*7.7 (2.4)2.2 (0.9)NANANA *P < .05. At 2 weeks after V3, the median anti-RBD IgG titres were significantly increased in all groups compared to those levels after V2 (85[33–412] versus 1566 [861–3083] BAU/mL for patients on HD, 81 [15–144] versus 913 [293–1359] BAU/mL for patients on PD and 250 [92–603] versus 2210 [1531–2782] BAU/mL for healthy controls;P < .001 for all groups). Comparing antibody levels between groups after V3, patients on PD generated significantly lower anti-RBD IgG titer than patients on HD (P = .02) and healthy controls (P < .01) (Figure 1A). The seroconversion rate of the HD and PD groups improved from 94% and 82% after V2 to 100% after V3 in both groups (P = .16 and P = .03, respectively) (Figure 1B). All patients on dialysis who had anti-RBD IgG < 7.1 BAU/mL after V2 (7/59 patients) seroconverted after the additional dose of ChAdOx1 nCoV-19 vaccine. CONCLUSION We suggest that an additional ChAdOx1 nCoV-19 vaccine after a primary two doses inactivated SARS-CoV-2 vaccination could improve seroconversion rate and magnitude of humoral immune response in patients on dialysis. The durability of the immune response to this vaccination regimen requires further study.

An additional dose of viral vector COVID-19 vaccine and mRNA COVID-19 vaccine in kidney transplant recipients: A randomized controlled trial (CVIM 4 study).

Immunogenicity following an additional dose of Coronavirus disease 2019 (COVID-19) vaccine was investigated in an extended primary series among kidney transplant (KT) recipients. Eighty-five KT participants were randomized to receive either an mRNA (M group; n = 43) or viral vector (V group; n = 42) vaccine. Among them, 62% were male, with a median (IQR) age of 50 (43-59) years and post-transplantation duration of 46 (26-82) months. At 2 weeks post-additional dose, there was no difference in the seroconversion rate between the M and V groups (70% vs. 65%, p = .63). A median (IQR) of anti-RBD antibody level was not statistically different between the M group compared with the V group (51.8 [5.1-591] vs. 28.5 [2.9-119.3] BAU/ml, p = .18). Furthermore, the percentage of participants with positive SARS-CoV-2 surrogate virus neutralization test results was not statistically different between groups (20% vs. 15%, p = .40). S1-specific T cell and RBD-specific B cell responses were also comparable between the M and V groups (230 [41-420] vs. 268 [118-510], p = .65 and 2 [0-10] vs. 2 [0-13] spot-forming units/106 peripheral blood mononuclear cells, p = .60). In conclusion, compared with an additional dose of viral vector COVID-19 vaccine, a dose of mRNA COVID-19 vaccine did not elicit significantly different responses in KT recipients, regarding either humoral or cell-mediated immunity. (TCTR20211102003).

Durability of Humoral and Cellular Immunity after an Extended Primary Series with Heterologous Inactivated SARS-CoV-2 Prime-Boost and ChAdOx1 nCoV-19 in Dialysis Patients (ICON3).

The durability of a three-dose extended primary series of COVID-9 vaccine in dialysis patients remains unknown. Here, we assessed dynamic changes in SARS-CoV-2-specific humoral and cell-mediated immunity at baseline, 3 months, and 6 months after the extended primary series in 29 hemodialyzed (HD), 28 peritoneal dialyzed (PD) patients, and 14 healthy controls. Participants received two doses of inactivated SARS-CoV-2 vaccine followed by a dose of ChAdOx1 nCoV-19 vaccine. At 6 months, median anti-RBD IgG titers (IQR) significantly declined from baseline in the HD (1741 (1136-3083) BAU/mL vs. 373 (188-607) BAU/mL) and PD (1093 (617-1911) BAU/mL vs. 180 (126-320) BAU/mL) groups, as did the mean percent inhibition of neutralizing antibodies (HD: 96% vs. 81%; PD: 95% vs. 73%) (all p < 0.01). Age and post-vaccination serological response intensity were predictors of early humoral seroprotection loss. In contrast, cell-mediated immunity remained unchanged. In conclusion, humoral immunity declined substantially in dialysis patients, while cell-mediated immunity remained stable 6 months after the extended heterologous primary series of two inactivated SARS-CoV-2/ChAdOx1 nCoV-19 vaccine. A booster dose could be considered in dialysis patients 3 months after this unique regimen, particularly in the elderly or those with a modest initial humoral response.

Immunogenicity of ChAdOx1 nCoV-19 vaccine after a two-dose inactivated SARS-CoV-2 vaccination of dialysis patients and kidney transplant recipients.

Vaccination with inactivated SARS-CoV-2 virus produces suboptimal immune responses among kidney transplant (KT), peritoneal dialyzed (PD), and hemodialyzed (HD) patients. Participants were vaccinated with two-dose inactivated SARS-CoV-2 vaccine (V2) and a third dose of ChAdOx1 nCoV-19 vaccine (V3) at 1-2 months after V2. We enrolled 106 participants: 31 KT, 28 PD, and 31 HD patients and 16 controls. Among KT, PD, and HD groups, median (IQR) of anti-receptor binding domain antibody levels were 1.0 (0.4-26.8), 1092.5 (606.9-1927.2), and 1740.9 (1106-3762.3) BAU/mL, and percent neutralization was 0.9 (0-9.9), 98.8 (95.9-99.5), and 99.4 (98.8-99.7), respectively, at two weeks after V3. Both parameters were significantly increased from V2 across all groups (p < 0.05). Seroconversion and neutralization positivity rates in PD, HD, and control groups were 100% but were impaired in KT patients (39% and 16%, respectively). S1-specific T-cell counts were increased in PD and HD groups (p < 0.05) but not in KT patients. The positive S1-specific T-cell responder rate was > 90% in PD, HD, and control groups, which was higher than that in KT recipients (74%, p < 0.05). The heterologous inactivated virus/ChAdOx1 nCoV-19 vaccination strategy elicited greater immunogenicity among dialysis patients; however, inadequate responses remained among KT recipients (TCTR20210226002).

SARS-CoV-2 neutralizing antibodies decline over one year and patients with severe COVID-19 pneumonia display a unique cytokine profile.

OBJECTIVES: As coronavirus disease 2019 (COVID-19) rages on worldwide, there is an urgent need to characterize immune correlates of protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to identify immune determinants of COVID-19 severity. METHODS: This study examined the longitudinal profiles of neutralizing antibody (NAb) titers in hospitalized COVID-19 patients clinically diagnosed with mild symptoms, pneumonia, or severe pneumonia, up to 12 months after illness onset, using live-virus neutralization. Multiplex, correlation, and network analyses were used to characterize serum-derived inflammatory cytokine profiles in all severity groups. RESULTS: Peak NAb titers correlated with disease severity, and NAb titers declined over the course of 12 months regardless of severity. Multiplex analyses revealed that IP-10, IL-6, IL-7, and VEGF-α were significantly elevated in severe pneumonia cases compared to those with mild symptoms and pneumonia cases. Correlation and network analyses further suggested that cytokine network formation was distinct in different COVID-19 severity groups. CONCLUSIONS: The study findings inform on the long-term kinetics of naturally acquired serological immunity against SARS-CoV-2 and highlight the importance of identifying key cytokine networks for potential therapeutic immunomodulation.

Inactivated COVID-19 Vaccine Induces a Low Humoral Immune Response in a Subset of Dermatological Patients Receiving Immunosuppressants.

Inactivated Sinovac-CoronaVac vaccine (Sinovac Life Sciences, Beijing) for coronavirus disease 2019 (COVID-19) has been used in many countries. However, its immunogenicity profile in immunosuppressed dermatological patients is lacking. This prospective observational case-control study compared the humoral immune response between adult dermatological patients receiving systemic immunosuppressive therapies (n = 14) and those who did not (n = 18); excluding patients with HIV infection, cancer, non-dermatological autoimmune conditions, previous COVID-19 infection, and positive anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG prior to vaccination. The subjects were advised to withhold methotrexate for 1 week after each vaccine dose while continuing other therapies unadjusted. Anti-SARS-CoV-2 IgG antibody, surrogate neutralizing antibody (sNAb), and seroconversion rates (calculated from the percentages of participants in the group with positive sNAb) were used to assess immunogenicity. We found that participants using azathioprine, cyclosporin, mycophenolate mofetil, or prednisolone ≥ 10 mg/day had a lower level of serum anti-SARS-CoV-2 IgG antibody and sNAb than those received methotrexate ≤ 10 mg/week, prednisolone < 10 mg/day, or biologics (i.e., secukinumab, ixekizumab, omalizumab). Patients who received methotrexate ≤ 10 mg/week, prednisolone < 10 mg/day or the biologics had a similar immunogenicity profile to those without immunosuppressive therapies. Despite the lack of statistical significance, a reduction of humoral immune response was observed among the study participants who used ≥2 immunosuppressants or pemphigus patients. Our findings suggest that a subset of patients with immune-mediated skin conditions respond poorly to the vaccine despite having low-level immunosuppression. These patients could benefit from vaccines that trigger a greater level of immunogenicity or booster doses.

SARS-CoV-2-specific humoral and cell-mediated immune responses after immunization with inactivated COVID-19 vaccine in kidney transplant recipients (CVIM 1 study).

Immunogenicity following inactivated SARS-CoV-2 vaccination among solid organ transplant recipients has not been assessed. Seventy-five patients (37 kidney transplant [KT] recipients and 38 healthy controls) received two doses, at 4-week intervals, of an inactivated whole-virus SARS-CoV-2 vaccine. SARS-CoV-2-specific humoral (HMI) and cell-mediated immunity (CMI) were measured before, 4 weeks post-first dose, and 2 weeks post-second dose. The median (IQR) age of KT recipients was 50 (42-54) years and 89% were receiving calcineurin inhibitors/mycophenolate/corticosteroid regimens. The median (IQR) time since transplant was 4.5 (2-9.5) years. Among 35 KT patients, the median (IQR) of anti-RBD IgG level measured by CLIA after vaccination was not different from baseline, but was significantly lower than in controls (2.4 [1.1-3.7] vs. 1742.0 [747.7-3783.0] AU/ml, p < .01) as well as percentages of neutralizing antibody inhibition measured by surrogate viral neutralization test (0 [0-0] vs. 71.2 [56.8-92.2]%, p < .01). However, the median (IQR) of SARS-CoV-2 mixed peptides-specific T cell responses measured by ELISpot was significantly increased compared with baseline (30 [4-120] vs. 12 [0-56] T cells/106  PBMCs, p = .02) and not different from the controls. Our findings revealed weak HMI but comparable CMI responses in fully vaccinated KT recipients receiving inactivated SARS-CoV-2 vaccination compared to immunocompetent individuals (Thai Clinical Trials Registry, TCTR20210226002).

Short-Term Immunogenicity Profiles and Predictors for Suboptimal Immune Responses in Patients with End-Stage Kidney Disease Immunized with Inactivated SARS-CoV-2 Vaccine.

INTRODUCTION: Patients with end-stage kidney disease (ESKD) are at risk of severe coronavirus disease and mortality. Immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivated whole-virus vaccine in patients with ESKD has never been explored. METHODS: We conducted a prospective cohort study of 60 patients with ESKD and 30 healthy controls. All participants received two doses of an inactivated whole-virus SARS-CoV-2 vaccine (Sinovac Biotech Ltd) 4 weeks apart. SARS-CoV-2-specific humoral and cell-mediated immune responses were investigated and referenced with healthy controls. RESULTS: After two doses, an anti-receptor-binding domain immunoglobulin G of 50 AU/ml or greater was present in 53 of 60 patients (88%) in the ESKD group and all participants (100%) in the control group (P = 0.05). The percentage of patients with ESKD and controls with neutralizing antibodies of 35% threshold or greater was 58% and 88%, respectively (P = 0.01). Furthermore, the proportion of patients with ESKD and S1-specific T cell response was comparable with controls (82% vs. 77%, P = 0.45). Old age, high ferritin level, and low absolute lymphocyte count were independently associated with poor humoral immune responses. CONCLUSIONS: Patients with ESKD could develop similar SARS-CoV-2-specific cell-mediated immune responses compared to healthy controls, although suboptimal humoral immune responses were observed following two doses of SARS-CoV-2 vaccination. Therefore, patients with ESKD and the abovementioned factors are at risk of generating inadequate humoral immune responses, and a vaccine strategy to elicit greater immunogenicity among these relatively immunocompromised patients is warranted. (Thai Clinical Trials Registry, TCTR20210226002).