Antigenic cartography of SARS-CoV-2 reveals that Omicron BA.1 and BA.2 are antigenically distinct

The emergence and rapid spread of SARS-CoV-2 variants may affect vaccine efficacy substantially. The Omicron variant termed BA.2, which differs substantially from BA.1 based on genetic sequence, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed. Here, we used antigenic cartography to quantify and visualize antigenic differences between early SARS-CoV-2 variants (614G, Alpha, Beta, Gamma, Zeta, Delta, and Mu) using hamster antisera obtained after primary infection. We first verified that the choice of the cell line for the neutralization assay did not affect the topology of the map substantially. Antigenic maps generated using pseudo-typed SARS-CoV-2 on the widely used VeroE6 cell line and the human airway cell line Calu-3 generated similar maps. Maps made using authentic SARS-CoV-2 on Calu-3 cells also closely resembled those generated with pseudo-typed viruses. The antigenic maps revealed a central cluster of SARS-CoV-2 variants, which grouped on the basis of mutual spike mutations. Whereas these early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape vaccine-induced antibody responses as a result of different antigenic characteristics. Thus, antigenic cartography could be used to assess antigenic properties of future SARS-CoV-2 variants of concern that emerge and to decide on the composition of novel spike-based (booster) vaccines.

High TTV Load Before First Vaccine Dose is Associated with Poor Serological Response to Covid-19 Vaccination in Lung Transplant Recipients

Purpose: Torque tenovirus (TTV), a highly prevalent virus which is not known to cause pathology in humans, is currently being investigated as a marker of immunosuppression. In this study we investigated if the TTV load measured prior to COVID-19 vaccination can predict the serological response to the COVID-19 vaccine, measured 28 days after the second vaccination dose. Method(s): The humoral response to the mRNA 1273 vaccine (Moderna) was assessed in Lung transplant recipients (LTR) who received a transplant between 4 and 237 months prior, by measuring Spike-specific IgG levels at 28 days after the second vaccination. Antibody concentrations of >10 BAU/ml were considered reactive. TTV loads were determined by PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load. Patient characteristics, including reasons for transplantation, antirejection treatment, age and time since transplantation, were recorded to assess associations between these factors and vaccination response or TTV levels. Result(s): 103 LTR were included of which 41 (40%) showed some response (>10 BAU/ml) to the vaccine at 28 days after the second vaccination. 61 (60%) were non-responders. TTV loads at baseline varied between negative and 10E9 copies/ ml. The TTV loads were found to correlate with IgG levels and the with the percentage of responders 28 days after the second vaccination (=<0.001). TTV loads also correlated strongly with the time since transplantation. High TTV levels occurred predominantly in patients who were shorter after transplantation (p=0.0001). Conclusion(s): This study shows an association between pre-vaccination TTV load and humoral response to the SARS-CoV-2 vaccine, which correlate with the time after transplantation. We recommend that TTV load measurements are included in further vaccination efficacy studies in immunocompromised cohorts. If the TTV load is indeed a predictor of vaccine response, this could be used as a potential guidance for optimizing vaccination response.

COVID-19 Vaccination Induces a Poor Interleukin-21 Memory T-cell Response in Kidney Transplant Recipients

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.

Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.

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.