ABSTRACT
Purpose: COVID-19-related morbidity and mortality is high among kidney patients. Several studies recently suggested low humoral and cellular immune responses after two doses of mRNA-1273 (Moderna) in these patients. Interleukin (IL)-21 is key in orchestrating an effective immune response against viral infections, is mainly produced by activated CD4+ T-cells and stimulates both humoral and cellular immunity. However, T-cell function may be impaired in kidney patients and this may explain the poor response to vaccination. Currently, there is limited data available on the vaccine-induced IL-21 memory T-cell response in these patients. We studied the induction of SARS-CoV-2-specific IL-21 memory T-cell response after mRNA- 1273 vaccination in 3 groups of kidney patients. Method(s): 113 participants were randomly selected from a prospective controlled multicenter cohort study, including 38 controls, 19 chronic kidney disease (CKD) stages G4/5 (eGFR <30 mL/min/1.73m2), 20 dialysis and 36 kidney transplant patients. All participants received 2 doses of mRNA-1273. To assess the vaccineinduced IL-21 memory T-cell response, we performed an IL-21 ELISpot (per 3.105 PBMCs) in these participants at baseline and 28 days after the second vaccination. SARS-CoV-2 S1-specific IgG antibody levels were already measured in the context of the multicenter cohort study. Result(s): Kidney transplant recipients had a significantly lower number of SARSCoV- 2-specific IL-21 producing memory T-cells when compared to controls (median of 46 versus 146, P<0.001). Participants with CKD G4/5 or on dialysis also had reduced SARS-CoV-2-specific IL-21 producing memory T-cells compared to controls (median of 128 [19-658] and 124 [7-654] versus 146 [10-635], p=0.43 and p=0.45, respectively), but the difference was less pronounced. In addition, a positive correlation was found between the number of SARS-CoV-2-specific IL-21 producing memory T-cells and SARS-CoV-2 S1-specific IgG antibody levels for all groups (Pearson correlation coefficient of 0.2, p=0.028). Conclusion(s): Kidney transplant recipients have an impaired antibody response after two doses of mRNA-1273 (Moderna), which correlates with poor SARS-CoV- 2-specific T-cell reactivity. These findings suggest that poor IL-21 memory T-cell response might hamper protection against COVID-19.
ABSTRACT
Background: Patients with cancer have an increased risk of complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Vaccination is recommended, but the impact of chemotherapy and immunotherapy on immunogenicity and safety is still unclear. Methods: This prospective multicenter non-inferiority trial comprises four cohorts: individuals without cancer (A) and patients with solid tumors who were treated with immunotherapy (B), chemotherapy (C) or chemo-immunotherapy (D). Participants received two mRNA-1273 vaccinations 28 days apart. The primary endpoint was SARS-CoV-2 Spike S1-specific IgG serum antibody response, defined as >10 binding antibody units (BAU)/ml 28 days after the second vaccination. We also assessed the virus neutralizing capacity of these antibodies, SARS-CoV-2 Spike-specific interferon-gamma T cell response, and adverse events. Results: Of the 791 participants enrolled, 743 were evaluable for the primary endpoint in cohort A (n=240), B (n=131), C (n=229) and D (n=143). A SARS-CoV-2-binding antibody response was found in 100%, 99.3%, 97.4%, and 100% of the participants in cohorts A, B, C, and D, respectively. To discriminate between suboptimal and adequate responders, we defined a cut-off level at 300 BAU/ml, based on neutralizing capacity. The antibody response was considered adequate after the first vaccination in 66.0%, 37.1%, 32.5%, and 33.3% of the participants in cohorts A, B, C, and D, respectively. This raised 28 days after the second vaccination to respectively 99.6%, 93.1%, 83.8%, and 88.8% in cohorts A, B, C, and D. Spike-specific T cell responses were detected in 46.7% of suboptimal and non-responders. No new safety signals were observed. Conclusions: mRNA-1273 vaccination is safe in the patient populations studied. For each cohort, the proportion of patients with a SARS-CoV-2-binding antibody response after two vaccinations is non-inferior compared to individuals without cancer. However, a significant minority lacks an adequate response. Most patients have an antibody concentration increase after the second vaccination. Therefore, an additional booster may turn inadequate into adequate responders. Clinical trial identification: NCT04715438. Legal entity responsible for the study: University Medical Center Groningen, the Netherlands. Funding: ZonMw, The Netherlands Organisation for Health Research and Development. Disclosure: All authors have declared no conflicts of interest.
ABSTRACT
After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.