Post-vaccination SARS-Cov-2 T-cell receptor repertoires in patients with multiple sclerosis and related disorders.

BACKGROUND: Attenuation in post-vaccination SARS-CoV-2 humoral responses has been demonstrated in people treated with either anti-CD20 therapies or sphingosine-1-phosphate (S1P) receptor modulators. In the setting of disease modifying therapy (DMT) use, humoral response may not correlate with effective immunity, and analysis of vaccine-mediated SARS-CoV-2-specific memory T-cell responses is crucial. While vaccination in patients treated with anti-CD20 agents leads to deficient antibody production, emerging data from live cell assays suggests intact T-cell responses to vaccination. We evaluated post-vaccination SARS-CoV-2 T-cell receptor (TCR) repertoires in DMT-treated patients using the ImmunoSeqR assay, an assay that does not require live cells. METHODS: Adults 18-80 years old without prior COVID-19, with neuroimmune conditions, who had been vaccinated with two doses of Pfizer-BioNTech or Moderna mRNA vaccines at least 3 weeks and up to 6 months prior, were recruited. Whole blood was obtained for immunosequencing, and matched serum was obtained for humoral analysis. Immunosequencing of the CDR3 regions of human TCRß chains was completed using the immunoSEQR Assay (Adaptive Biotechnologies). TCR sequences were mapped across a set of TCR sequences reactive to SARS-CoV-2. Clonal diversity (breadth) and frequency (depth) of TCRs specific to SARS-CoV-2 spike protein were calculated and relationships with clinical variables were assessed. RESULTS: Forty patients were recruited into the study, aged 25-77, and 27 female. 37 had MS, 2 had neuromyelitis optica spectrum disorder (NMOSD), and 1 had hypophysitis. Subjects treated with anti-CD20 agents and S1P receptor modulators had severely attenuated humoral responses, but SARS-CoV-2-spike-specific TCR clonal depth and breadth were robust across all treatment classes except S1P modulators. No spike-specific or non-spike-specific SARS-CoV-2-associated TCRs were found in those treated with S1P modulators (p = 0.002 for both breadth and depth). Subjects treated with fumarates exhibited somewhat lower spike TCR breadth than subjects treated with other or no DMTs (median 2.27 × 10^-5 for fumarates and 4.96 × 10^-5 for all others, p = 0.008), but no statistically significant difference was demonstrated with spike TCR depth. No other significant associations with DMT type were found. We found no significant correlations between depth or breadth and age, duration of treatment, type of vaccination, or time interval since vaccination. CONCLUSION: This is the first study to characterize post-vaccination SARS-CoV-2 TCR repertoires in DMT-treated individuals. We demonstrated a dichotomous response to SARS-CoV-2 vaccination in anti-CD20-treated patients, with severely attenuated humoral response but intact TCR depth and breadth. It is unclear to what degree each arm of the adaptive immune system impacts post-vaccine immunity, both from the standpoint of incidence of post-vaccine infections and that of infection severity, and further clinical studies are necessary. S1P modulator-treated subjects exhibited both severely attenuated humoral responses and absent spike-specific TCR depth and breadth, information which is crucial for counseling of patients on these agents. Our methodology can be used in larger studies to determine the benefit of repeated vaccination doses, including those that are modified to better target modern or seasonal variants, without the use of live cell assays.

A Single-Health System Case Series of New-Onset CNS Inflammatory Disorders Temporally Associated With mRNA-Based SARS-CoV-2 Vaccines.

Background: Since 2020, over 250 million doses of mRNA-based SARS-CoV-2 vaccines have been administered in the United States and hundreds of millions worldwide between the Pfizer-BioNTech and Moderna SARS-CoV-2 vaccines. To date, there have been rare reports associating mRNA-based SARS-CoV-2 vaccines with episodes of inflammatory and autoimmune CNS disorders. We report a case series of five patients with new-onset neurological disorders of inflammatory or immunological origin temporally associated with these vaccines. Methods: A case-series of five patients within a single 23-hospital health system who developed new-onset CNS inflammatory disease within 2 weeks of receiving a dose of an mRNA-based SARS-CoV-2 vaccine. Results: Five cases of post-vaccination CNS disorders of immune origin (fatal ADEM; n = 1, new-onset NMOSD; n = 2, new-clinical onset MS-like syndrome but with preexisting clinically silent mild demyelination; n = 1, meningoencephalitis; n = 1) observed within 2 weeks of inoculation with either the first or second dose of mRNA-based SARS-CoV-2 vaccines (Moderna = 3, Pfizer = 2). Discussion: To our knowledge, these are among the emerging cases of CNS adverse events of immunological or inflammatory origin. These findings should be interpreted with great caution as they neither prove a mechanistic link nor imply a potential long-term increased risk in post-vaccination CNS autoimmunity. Larger prospective studies assessing the potential association between mRNA-based vaccination and the development of neurological adverse events of suspected immune origin, particularly among those with underlying CNS or systemic autoimmune disorders, are needed. The use of mRNA-based SARS-CoV-2 vaccines should continue to be strongly encouraged given their high efficacy in overcoming this pandemic.

Case Report: HSV-2 Encephalitis Presenting With Chorea; Effects of Infection Alone or Combination of Infection and Autoimmunity?

Background: Chorea as a symptom of late-onset post-infectious autoimmune encephalitis has been reported with HSV-1 but not HSV-2 encephalitis. Extrapyramidal symptoms are typically associated with the presence of anti-NMDA receptor antibodies but may also exist in antibody-negative individuals. Case: This case highlights a patient who presented with mental status changes and chorea as the initial manifestation of HSV-2 encephalitis. The choreiform movements failed to respond to antiviral medications but were rapidly responsive to plasmapheresis, which, together with abnormal intrathecal immunoglobulin synthesis, suggests a potential contribution of parainfectious immune-mediated process. The patient made a full recovery and a complete resolution of the chorea. Discussion: This is the first case associating HSV-2 encephalitis presentation with chorea. The neurological complications, including chorea, are largely related to active CNS HSV-2 infection, possibly together with triggered CNS autoimmunity despite undetectable CSF neuronal autoantibodies and normal neuroimaging. Early diagnosis and treatment with antiviral agent and immune therapies might be pivotal to optimize the clinical outcome.

Five-year follow-up of concomitant accelerated hypofractionated radiation in advanced squamous cell carcinoma of the buccal mucosa: a retrospective cohort study.

In resource limited settings, induction chemotherapy with Gemcitabine and Cisplatinum and concurrent hypofractionated chemoradiation for locally advanced carcinoma of buccal mucosa (BMSCC) are a cost effective option but remain under reported. The objective of this study was to report long term survival outcome after concurrent hypofractionated radiotherapy in locally advanced BMSCC. Between February 2005 and 2009, 63 patients received treatment. Induction chemotherapy (IC) regimen consisted of two drugs: Gemcitabine and Cisplatin. All patients received 55 Gy of radiation in 20 fractions with concurrent single agent Cisplatin (75 mg/m(2)). Five-year overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were determined. Based on AJCC staging, 7 (11%) patients were stage III, 31 (49%) stage IV a, and 25 (40%) stage IVb at presentation. After IC, 8 (18%) patients had complete radiological response, 33 (73%) had partial response, and 4 (9%) had stable disease. After concurrent hypofractionated chemoradiation, thirty-nine (62%) patients were complete responders and 24 (38%) had stable disease. With a minimum follow-up of 60 months, 5-year OS, DFS, and PFS were 30%, 49%, and 30%, respectively. In locally advanced buccal mucosa squamous cell carcinoma, concurrent hypofractionated chemoradiation results in acceptable survival and regimen related toxicity.