T cell responses against SARS-CoV-2 and its Omicron variant in a patient with B cell lymphoma after multiple doses of a COVID-19 mRNA vaccine.

Anti-SARS-CoV-2 antibodies are crucial for protection from future COVID-19 infections, limiting disease severity, and control of viral transmission. While patients with the most common type of hematologic malignancy, B cell lymphoma, often develop insufficient antibody responses to messenger RNA (mRNA) vaccines, vaccine-induced T cells would have the potential to 'rescue' protective immunity in patients with B cell lymphoma. Here we report the case of a patient with B cell lymphoma with profound B cell depletion after initial chemoimmunotherapy who received a total of six doses of a COVID-19 mRNA vaccine. The patient developed vaccine-induced anti-SARS-CoV-2 antibodies only after the fifth and sixth doses of the vaccine once his B cells had started to recover. Remarkably, even in the context of severe treatment-induced suppression of the humoral immune system, the patient was able to mount virus-specific CD4+ and CD8+ responses that were much stronger than what would be expected in healthy subjects after two to three doses of a COVID-19 mRNA vaccine and which were even able to target the Omicron 'immune escape' variant of the SARS-CoV-2 virus. These findings not only have important implications for anti-COVID-19 vaccination strategies but also for future antitumor vaccines in patients with cancer with profound treatment-induced immunosuppression.

Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine.

Objectives: Solid organ transplant recipients (SOTR) receiving post-transplant immunosuppression show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines can overcome the reduced immune responsiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Methods: We analysed humoral immune responses against SARS-CoV-2 and its variants in 53 SOTR receiving SARS-CoV-2 vaccination. Results: Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titres against SARS-CoV-2 and its delta variants and fewer linear B-cell epitopes, indicating reduced B-cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti-SARS-CoV-2 CD4+ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS-CoV-2 and the improvement in neutralising activity was much less pronounced than for all the other variants. Conclusion: Only a small subgroup of solid organ transplant recipients is able to generate functional antibodies after an initial vaccine series; however, an additional vaccine dose resulted in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron where antibody responses and neutralising activity remained suboptimal.

Prolonged Lenalidomide Induction Does Not Significantly Impair Stem Cell Collection in Multiple Myeloma Patients Mobilized With Cyclophosphamide or Plerixafor: A Report From The Covid Era.

INTRODUCTION: Induction therapy for multiple myeloma is traditionally capped at 6 cycles of lenalidomide due to concerns that longer treatment compromises the ability to collect sufficient stem cells for autologous stem cell transplantation (ASCT). However, during the COVID-19 pandemic, many of our patients received prolonged lenalidomide induction due to concerns about proceeding to ASCT. We investigated whether prolonged induction with lenalidomide affects the efficacy of stem cell collection among patients mobilized with cyclophosphamide and/or plerixafor. PATIENTS AND METHODS: This single center, retrospective study included patients who were treated with lenalidomide induction regimens, received mobilization with cyclophosphamide or plerixafor, and underwent apheresis in preparation for ASCT. 94 patients were included, 40 of whom received prolonged induction with >6 cycles of lenalidomide containing regimen. RESULTS: Patients who received prolonged induction were more likely to require >1 day of apheresis (38% vs. 15%; OR 3.45; P = .0154), and there was a significant correlation between the duration of lenalidomide treatment and the apheresis time required to collect sufficient cells for transplant (R2 = 0.06423, P = .0148). However, there was no significant difference between patients who received prolonged induction and those who did not with respect to CD34+ stem cell yields at completion of apheresis (9.99 vs. 10.46 cells/Kg, P = .5513) or on the first day of collection (8.29 vs. 9.59 cells/Kg, P = .1788). CONCLUSION: Among patients treated with >6 cycles of lenalidomide, mobilization augmented with cyclophosphamide and/or plerixafor will likely facilitate sufficient stem cell harvest to permit ASCT.

Deep dissection of the antiviral immune profile of patients with COVID-19.

In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 "South African" variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-ß) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.

Anti-SARS-CoV-2 Immune Responses in Patients Receiving an Allogeneic Stem Cell or Organ Transplant.

Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.