COVID-19 Vaccine Evolution and Beyond

Immune response to three doses of mRNA SARS-CoV-2 vaccines in CD19-targeted chimeric antigen receptor Tcell immunotherapy recipients.

Even though extreme containment and mitigation strategies were implemented by numerous governments around the world to slow down the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the number of critically ill patients and fatalities keeps rising. This crisis has highlighted the socioeconomic disparities of health care systems within and among countries. As new CoVID policies and responses are implemented to lessen the impact of the virus, it is imperative (1) to consider additional mitigation strategies critical for the development of effective countermeasures, (2) to promote long-term policies and strict regulations of the trade of wildlife and live animal markets, and (3) to advocate for necessary funding and investments in global health, specifically for the prevention of and response to natural and manmade pandemics. This document considers some of these challenges.

SARS-CoV-2 Vaccines: The Mucosal Immunity Imperative

Humoral Responses After SARS-CoV-2 mRNA Vaccination and Breakthrough Infection in Cancer Patients

Clinical Prioritization of Antispike Monoclonal Antibody Treatment of Mild to Moderate COVID-19

Linked articles: COVID‐19 SPECIAL FORUM. J Eur Acad Dermatol Venereol 2020; 34: e346–e380.

Background: Ozanimod, an oral S1P receptor modulator, is approved in the United States and European Union for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS). A previous analysis of data from UC and multiple sclerosis (MS) open-label extension (OLE) studies showed that most patients with confirmed coronavirus infection (COVID-19) had nonserious infections, recovered, and did not require ozanimod discontinuation. As some immunomodulators and biologics may attenuate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response, this analysis evaluated humoral immune responses and predictors of response to SARS-CoV-2 vaccination in patients with RMS treated with ozanimod. Methods: RMS participants who completed a phase 1-3 ozanimod trial could enter an OLE trial (DAYBREAK; NCT02576717) of ozanimod 0.92 mg/d. This analysis (January 2020‒October 2021) included DAYBREAK participants receiving mRNA or non-mRNA SARS-CoV-2 vaccines (1 or 2 doses, vaccine-dependent) and had serum samples available postvaccination. Receptor binding domain (RBD) antibody titers were analyzed (Elecsys Anti-SARS-CoV-2 assay; Roche Diagnostics, Basel, Switzerland) prevaccination, after 1 dose, and at days 1–229 after full vaccination. Nucleocapsid antibody levels were measured before and after vaccination to confirm whether participants had a natural exposure to SARS-CoV-2, with nucleocapsid antibody negative indicating no exposure and nucleocapsid antibody positive indicating exposure to SARS-CoV-2. Fisher’s exact tests and regression models determined association with seroconversion and log2 antibody levels. Results: Demographics were similar between the mRNA and non-mRNA vaccine recipients without serological evidence of virus exposure. Seroconversion (≥0.8 U/mL spike RBD antibody) occurred in 100% (80/80) of fully vaccinated mRNA and 62% (18/29) of fully vaccinated non-mRNA vaccine recipients who were nucleocapsid antibody–negative. Additionally, seroconversion occurred in 100% (39/39) of nucleocapsid antibody–positive participants in both fully vaccinated mRNA and non-mRNA vaccine recipients. Higher spike RBD antibody levels were seen in participants with mRNA (grand mean: 512.6 U/mL, range: 1.3-4572) vs non-mRNA (grand mean: 39.3 U/mL, range: 0.4-368.5) vaccinations at all time points studied in nucleocapsid antibody–negative participants. Compared with nucleocapsid antibody–negative participants, spike RBD antibody levels were higher in fully vaccinated nucleocapsid antibody–positive participants in both mRNA and non-mRNA vaccine recipients. Vaccination with a non-mRNA vaccine predicted lower antibody levels (beta: -5.90 [95% CI: -6.99 to -4.82]; P < 0.0001) and less seroconversion (Fisher’s exact: P < 0.0001), whereas age, sex, body mass index, and absolute lymphocyte count (ALC) did not predict lower antibody levels in nucleocapsid antibody–negative participants. Conclusion(s): Participants receiving ozanimod developed humoral immune response to SARS-CoV-2 vaccines, with 100% seroconversion after mRNA vaccination; this was independent of demographic characteristics and ALC levels at time of vaccination. However, some participants developed low antibody concentrations and may benefit from booster doses. Fully vaccinated participants with confirmed evidence of natural infection had higher seroconversion rates and RBD antibody levels, possibly suggesting a primed immune response.

De Novo and Relapsing Glomerular Diseases After COVID-19 Vaccination: What Do We Know So Far?

Observations on improving COVID-19 vaccination responses in kidney transplant recipients: heterologous vaccination and immunosuppression modulation

Rear Window—What Can the Gut Tell Us About Long-COVID?

BackgroundThe mortality rate due to COVID-19 in kidney transplant recipients (KTRs) is 16.8 to 32%. Vaccination against COVID-19 is expected to contribute to the prevention of infection, severe disease, and mortality; however, it has been reported that the humoral response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in KTRs is poor. Vaccination strategies against COVID-19 vary from country to country, and in Japan, the third dose is given 6 months after the second dose. Few studies have evaluated long-term humoral responses after the second dose of SARS-CoV-2 mRNA vaccine. In addition, the superiority of BNT162b2 vaccine and mRNA-1,273 vaccine in KTRs regarding humoral response is controversial.MethodsNinety-four KTRs were administered a second dose of the BNT162b2 or mRNA-1,273 vaccines, and anti-spike (anti-S) and anti-nucleocapsid (anti-N) SARS-CoV-2 antibody levels were measured 5 months (149.2 ± 45.5 days) later. The cutoff value of anti-S antibodies was defined ≥50 AU/ml and 1.4 Index for anti-N antibodies. The primary outcome was the rate of seropositivity, and factors associated with an appropriate humoral response were assessed by univariate and multivariate analysis.ResultsOf 94 KTRs, only 45 (47.9%) patients were positive for anti-S antibodies. The median anti-S SARS-CoV-2 IgG antibody titers was 35.3 (Interquartile range 3.8 to 159.7). Anti-N SARS-CoV-2 IgG antibodies in all patients were < 1.4 Index. Response to SARS-CoV-2 mRNA vaccines were 43.2 and 65% for BNT162b2 and mRNA-1,273, respectively (p = 0.152). In comparison with high-dose, low-dose of mycophenolic acid was a robust factor associated with an adequate humoral response.ConclusionThe long-term humoral response after a second dose of SARS-CoV-2 mRNA vaccine in Japanese KTRs was poor. In comparison with high-dose, low-dose mycophenolic acid was related to an appropriate humoral response. Five months is too long to wait for a 3rd dose after 2nd dose of SARS-CoV-2 vaccine in KTRs. In this cohort, there was no statistical difference in humoral response to the BNT162b2 and mRNA-1,273 vaccines. Additional large observational studies and meta-analyses are needed to clarify the factors related to an appropriate humoral immune response to COVID-19 vaccination.

Patients with type 1 diabetes (T1D) may develop severe outcomes during coronavirus disease 2019 (COVID-19), but their ability to generate an immune response against the SARS-CoV-2 mRNA vaccines remains to be established. We evaluated the safety, immunogenicity, and glycometabolic effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in patients with T1D. A total of 375 patients (326 with T1D and 49 subjects without diabetes) who received two doses of the SARS-CoV-2 mRNA vaccines (mRNA-1273, BNT162b2) between March and April 2021 at ASST Fatebenefratelli Sacco were included in this monocentric observational study. Local and systemic adverse events were reported in both groups after SARS-CoV-2 mRNA vaccination, without statistical differences between them. While both patients with T1D and subjects without diabetes exhibited a parallel increase in anti-SARS-CoV-2 spike titers after vaccination, the majority of patients with T1D (70% and 78%, respectively) did not show any increase in the SARS-CoV-2-specific cytotoxic response compared with the robust increase observed in all subjects without diabetes. A reduced secretion of the T-cell-related cytokines interleukin-2 and tumor necrosis factor-α in vaccinated patients with T1D was also observed. No glycometabolic alterations were evident in patients with T1D using continuous glucose monitoring during follow-up. Administration of the SARS-CoV-2 mRNA vaccine is associated with an impaired cellular SARS-CoV-2-specific cytotoxic immune response in patients with T1D.

Immunocompetent people with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (convalescent individuals) have been shown to have a more robust antibody response to the first SARS-CoV-2 mRNA vaccine dose compared with previously uninfected people (naive individuals).1 Given limited immunogenicity of SARS-CoV-2 vaccines in solid organ transplant recipients,2,3 we sought to quantify the antibody response to vaccination among convalescent versus naive transplant recipients. Leveraging our ongoing prospective cohort of transplant recipients who underwent SARS-CoV-2 mRNA vaccination December 18, 2020–April 1, 2021,4 we compared antispike antibody titers after dose 1 in convalescent transplant recipients with prior polymerase chain reaction-confirmed SARS-CoV-2 infection at a median (interquartile range [IQR]) of 3.5 mo (2.6–5.3 mo) before vaccination (n = 28) versus naive recipients (n = 1012) using weighted-by-the-odds Poisson regression. As previously reported, serologic testing was conducted on the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (range, <0.4 to >250 U/mL [positive ≥0.8 U/mL]), which tests for antibodies against the receptor-binding domain of the spike protein, or the EUROIMMUN enzyme immunoassay (positive ≥1.1 AU), which tests for immunoglobulin G to the S1 domain of the spike protein. This study was approved by the Johns Hopkins Institutional Review Board. Convalescent vaccinees were more likely to have a positive antibody response to dose 1 compared with naive vaccinees (89% versus 18%, P < 0.001) (Table 1). After weighting to adjust for age, antimetabolite therapy, and organ transplant type, prior SARS-CoV-2 infection was associated with a 6.28-fold higher chance of a positive antibody response (weighted incidence rate ratio = 5.236.287.54, P < 0.001). Convalescent vaccinees also had a higher post–dose 1 antispike antibody titer than naive vaccinees (median [IQR], 250 [250–250] versus 7.63 [2.02–28.97], P < 0.001 [Roche] and 7.62 [7.44–9.14] versus 3.42 [2.3–5.16], P = 0.02 [EUROIMMUN]). In a sensitivity analysis restricting to only those with a confirmed prevaccine negative antibody result, convalescent recipients were still more likely to have a positive antibody response to dose 1 (75% versus 19%, P < 0.001). TABLE 1. - Demographics of study population stratified by prior SARS-CoV-2 infection status Previously uninfected Previously infected P n 1012 28 Kidney recipient 476 (48.0%) 14 (50.0%) 0.83 Age, median (IQR) 60.0 (45.7–68.1) (n = 1002) 56.6 (50.6–66.3) (n = 28) 0.45 Transplant type 0.88 Kidney 476 (47.0%) 14 (50.0%) Liver 215 (21.2%) 5 (17.9%) Pancreas 12 (1.2%) 0 (0.0%) Heart 145 (14.3%) 4 (14.3%) Lung 107 (10.6%) 3 (10.7%) Other 8 (0.8%) 0 (0.0%) Kidney/pancreas 29 (2.9%) 2 (7.1%) Not available 20 (2.0%) 0 (0.0%) Years since transplant, median (IQR) 6.2 (2.7–13.6) (n = 992) 6.1 (3.8–14.1) (n = 28) 0.56 White 889 (89.4%) 26 (92.9%) 0.56 Antimetabolite 699 (69.1%) 24 (85.7%) 0.059 Tacrolimus 813 (80.3%) 19 (67.9%) 0.15 Prevaccine antibody result <0.001 Positive 3 (0.3%) 8 (28.6%) Negative 495 (48.9%) 4 (14.3%) Not available 514 (50.8%) 16 (57.1%) Post–dose 1 testing platform 0.19 EUROIMMUN 264 (26.1%) 4 (14.3%) Roche 748 (73.9%) 24 (85.7%) Days between dose 1 and post-D1 Ab testing, median (IQR) 21 (19–26) (n = 1003) 21 (19–24.5) (n = 28) 0.93 Ab, antibody; IQR, interquartile range; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Prevaccine antispike antibody testing was available in 12 of the 28 convalescent recipients and detectable in 8 of 12 (67%). In this population, postvaccine titers were higher than those prevaccine (>250 versus 223.3 U/mL [Roche]; 9.14 versus 5.5 AU [EUROIMMUN]). Limitations include a convenience sample, which may limit generalizability; inclusion of late entries, which limited the availability of prevaccination titers; self-report of SARS-CoV-2, which may have led to information bias; and lack of data on whether antimetabolite immunosuppression was held at the time of SARS-CoV-2 infection. In this study of transplant recipients with prior SARS-CoV-2 infection, antibody response to vaccination was much stronger than in SARS-CoV-2 naive recipients. Furthermore, even in this population with some natural immunity, antibody titers were substantially boosted by 1 dose of a SARS-CoV-2 mRNA vaccine. Prior COVID-19 infection may prime the immune system in a similar way to the intended effect of dose 1 in uninfected patients.5

Decreased Antibody Responses to Ad26.COV2.S Relative to SARS-CoV-2 mRNA Vaccines in Patients With Inflammatory Bowel Disease

COVID-19 in Kidney Transplantation: Outcomes, Immunosuppression Management, and Operational Challenges.