Preserved T cell but attenuated antibody response in MS patients on fingolimod and ocrelizumab following 2nd and 3rd SARS-CoV-2 mRNA vaccine.

Background: There is limited knowledge about T cell responses in patients with multiple sclerosis (MS) after 3 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Objectives: Assess the SARS-CoV-2 spike antibody and T cell responses in MS patients and healthy controls (HCs) after 2 doses (2-vax) and 3 doses (3-vax) of SARS-CoV-2 mRNA vaccination. Methods: We studied seroconversion rates and T cell responses by flow cytometry in HC and MS patients on fingolimod or ocrelizumab. Results: After 2-vax, 8/33 (24.2%) patients in ocrelizumab group, 5/7 (71.4%) in fingolimod group, and 29/29 (100%) in HC group (P = 5.7 × 10-11) seroconverted. After 3-vax, 9/22 (40.9%) patients in ocrelizumab group, 19/21 (90.5%) in fingolimod group, and 7/7 (100%) in HC group seroconverted (P = 0.0003). The percentage of SARS-CoV-2 peptide reactive total CD4+ T cells increased in HC and ocrelizumab group but not in fingolimod group after 2-vax and 3-vax (P < 0.0001). The percentage of IFNγ and TNFα producing total CD4+ and CD8+ T cells increased in fingolimod group as compared to HC and ocrelizumab group after 2-vax and 3-vax (P < 0.0001). Conclusions: MS patients on ocrelizumab and fingolimod had attenuated humoral responses, but preserved cytokine producing T cell responses compared to HCs after SARS-CoV-2 mRNA vaccination. Clinical Trials Registration: NCT05060354.

Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19.

T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 µg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7+ effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1, and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7, and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.

Humoral response to COVID-19 vaccination in MS patients on disease modifying therapy: Immune profiles and clinical outcomes.

BACKGROUND: Patients with multiple sclerosis (MS) on some disease modifying therapies (DMTs), particularly anti-CD20 and sphingosine-1-phosphate (S1P) modulators, are at increased risk of severe Coronavirus Disease 19 (COVID-19) and death. COVID-19 vaccinations are effective in preventing infection and severe disease, but humoral response to vaccination and outcomes of COVID-19 infection after vaccination in MS patients on DMTs remain less understood. METHODS: In this retrospective single-center study, patients enrolled in the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital) study and biorepository who had been vaccinated against COVID-19 and had SARS-CoV-2 spike antibody (anti-SARS-CoV-2 S Roche-Elecsys) testing were identified and compared to healthy controls. Demographic data, serum immune profiles including lymphocyte count, B-cell count, and immunoglobulins, and clinical outcome of COVID-19 infection were collected. RESULTS: 254 patients (73.2% female, mean (SD) age 52.9 (11.2) years) were identified. When controlling for age, time since vaccination, and vaccine type, patients on fingolimod, ocrelizumab, rituximab, mycophenolate mofetil, natalizumab and teriflunomide had significantly lower levels of spike antibodies compared to healthy controls (n = 34). Longer duration of treatment was associated with lower spike antibody levels in patients on anti-CD20 therapy (p = 0.016) and S1P modulators (p = 0.016) compared to healthy controls. In patients on anti-CD20 therapy, higher spike antibody levels were associated with higher CD20 cell count (p<0.001), and longer time since last anti-CD20 therapy infusion (p<0.001). 92.8% (13/14) vaccine responders (spike antibody titer >100 ug/dL) on anti-CD20 therapy demonstrated B-cell reconstitution (mean CD20 3.6%). Only 1 out of 86 patients with CD20 of 0% had a measurable spike antibody response to vaccination. During follow-up (mean 270 days), five patients were diagnosed with COVID-19 after vaccination (incidence 1.9%), all of whom had spike antibody < 20 ug/dL. No patients required ICU care or died. CONCLUSIONS: Patients on some DMTs demonstrate reduced humoral immunity after Sars-CoV-2 vaccination. Longer duration of anti-CD20 therapy and reduced CD20 cell count is associated with blunted humoral response to vaccination. CD20 reconstitution >0.1% appears necessary, but not always sufficient, for humoral response to vaccination. Breakthrough COVID-19 infection in our cohort of MS patients on DMT was higher than in population studies. We propose that adjustment of B-cell therapy administration to allow for B-cell reconstitution prior to vaccination should be considered.

Are We Forgetting About IgA? A Re-examination of Coronavirus Disease 2019 Convalescent Plasma.

BACKGROUND: While convalescent plasma (CP) may benefit patients with COVID-19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG-specific anti-SARS-CoV-2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP. STUDY DESIGN AND METHODS: Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti-SARS-CoV-2 antibody titers against the receptor-binding domain responsible for viral entry. Symptom onset was obtained by chart review. RESULTS: Increased IgA anti-SARS-CoV-2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID-19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation. CONCLUSIONS: IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID-19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity.

Comparison of Antibody Class-Specific SARS-CoV-2 Serologies for the Diagnosis of Acute COVID-19.

Accurate diagnosis of acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical for appropriate management of patients with this disease. We examined the possible complementary role of laboratory-developed class-specific clinical serology in assessing SARS-CoV-2 infection in hospitalized patients. Serological tests for immunoglobulin G (IgG), IgA, and IgM antibodies against the receptor binding domain (RBD) of SARS-CoV-2 were evaluated using samples from real-time reverse transcription-quantitative PCR (qRT-PCR)-confirmed inpatient coronavirus disease 2019 (COVID-19) cases. We analyzed the influence of timing and clinical severity on the diagnostic value of class-specific COVID-19 serology testing. Cross-sectional analysis revealed higher sensitivity and specificity at lower optical density cutoffs for IgA in hospitalized patients than for IgG and IgM serology (IgG area under the curve [AUC] of 0.91 [95% confidence interval {CI}, 0.89 to 0.93] versus IgA AUC of 0.97 [95% CI, 0.96 to 0.98] versus IgM AUC of 0.95 [95% CI, 0.92 to 0.97]). The enhanced performance of IgA serology was apparent in the first 2 weeks after symptom onset and the first week after PCR testing. In patients requiring intubation, all three tests exhibit enhanced sensitivity. Among PCR-negative patients under investigation for SARS-CoV-2 infection, 2 out of 61 showed clear evidence of seroconversion IgG, IgA, and IgM. Suspected false-positive results in the latter population were most frequently observed in IgG and IgM serology tests. Our findings suggest the potential utility of IgA serology in the acute setting and explore the benefits and limitations of class-specific serology as a complementary diagnostic tool to PCR for COVID-19 in the acute setting.