Discordant humoral and cell-mediated responses to SARS-CoV-2 vaccination in people with multiple sclerosis on B cell depleting agents

Introduction: Sphingosine-1-phosphate receptor (S1P) modulators and B cell depleting agents significantly impair humoral responses to SARS-CoV-2 mRNA vaccines. Whether disease modifying therapies (DMTs) impact cell-mediated immune (CMI) response to vaccination is unknown. Objectives/ Aims: To evaluate humoral and CMI response to SARS CoV-2 vaccination in people with MS and the impact of specific DMTs on these responses. Methods: We recruited participants from the Johns Hopkins MS center who underwent phlebotomy either 4 or 8 weeks following the terminal vaccine dose. Blood was processed to isolate serum and peripheral blood mononuclear cells (PBMCs). We measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. Blinded experimenters measured CMI responses using FluoroSpot assay for interferon gamma (IFN-γ) (Mabtech,Sweden) using cryopreserved PBMCs rested overnight and then incubated in cRPMI with 1μg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools of 158 peptides each). Plates were read on an AID iSpot Spectrum. Results were expressed as spot forming cells (SFC)/106 PBMCs. We evaluated concordance between humoral and CMI responses and tested for differences across DMTs using linear models. Results: We included 102 participants (82% female;mean age 49.5y [SD: 10.4y];94% mRNA vaccine recipients) who were on average 6.8 weeks post-vaccine. 22/39 (56%) of participants exposed to B-cell depleting agents exhibited a humoral response to the vaccine, whereas all participants on no (n=13), injectable (n=16), or natalizumab (n=17) therapies and most (12/14;86%) on non-S1P modulating orals responded. In a subset (n=58) with CMI response data, a lack of humoral immunity was marginally associated with an 120.3% greater IFN-γ SFC counts (120.3% higher;95% CI: -25.2%, 542.4%;p=0.09). B-cell depleting agents were associated with greater IFN-γ SFC counts relative to those on no DMT or other DMTs (for B-cell vs. no DMT: 270.6% higher [95% CI: 0.0%, 1373.2%];p=0.05;for B-cell vs. other DMTs: 182.9% higher [95% CI: 15.0%, 609.9%];p=0.03). Updated CMI data with 48 additional patients will be presented. Conclusions: We noted a robust CMI response in MS patients on B-cell depleting agents despite the lack of a humoral response in about half of these patients. Follow up studies are needed to determine if this translates to protection against clinical COVID-19 infection.

Assessment of neurological manifestations in hospitalized patients with COVID-19.

BACKGROUND AND PURPOSE: The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. METHODS: Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. RESULTS: In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. CONCLUSIONS: Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

Does SARS-Cov-2 invade the brain? Translational lessons from animal models.

The current coronavirus disease (COVID-19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS-CoV-2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS-CoV-2. One key finding that may unify these pathogens is that all require angiotensin-converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS-CoV-2 binds to cell membranes, binds angiotensin-converting enzyme 2 with a higher affinity compared with SARS-CoV. The expression of this receptor in neurons and endothelial cells hints that SARS-CoV-2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune-mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune-mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID-19.