Three to four mRNA COVID-19 vaccines in multiple sclerosis patients on immunosuppressive drugs: Seroconversion and variant neutralization.

BACKGROUND AND PURPOSE: An enhanced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen could improve humoral vaccine response in patients with multiple sclerosis (MS) treated by anti-CD20. The aim was to evaluate the serological response and the neutralizing activity after BNT162b2 primary and booster vaccination in MS patients, including patients on anti-CD20 receiving a primary vaccine regimen enhanced with three injections. METHODS: In this prospective longitudinal cohort study of 90 patients (47 on anti-CD20, 10 on fingolimod, 33 on natalizumab, dimethylfumarate or teriflunomide), anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G antibodies were quantified and their neutralization capacity was evaluated by enzyme-linked immunosorbent assay (GenScript) and a virus neutralization test against B.1 historical strain, Delta and Omicron variants, before and after three to four BNT162b2 injections. RESULTS: After the primary vaccination scheme, the anti-RBD positivity rate was strongly decreased in patients on anti-CD20 (28% [15%; 44%] after two shots, 45% [29%; 62%] after three shots) and fingolimod (50% [16%; 84%]) compared to other treatments (100% [90%; 100%]). Neutralization activity was also decreased in patients on anti-CD20 and fingolimod, and notably low for the Omicron variant in all patients (0%-22%). Delayed booster vaccination was performed in 54 patients, leading to a mild increase of anti-RBD seropositivity in patients on anti-CD20 although it was still lower compared to other treatments (65% [43%; 84%] vs. 100% [87%; 100%] respectively). After a booster, Omicron neutralization activity remained low on anti-CD20 and fingolimod treated patients but was strongly increased in patients on other treatments (91% [72%; 99%]). DISCUSSION: In MS patients on anti-CD20, an enhanced primary vaccination scheme moderately increased anti-RBD seropositivity and anti-RBD antibody titre, but neutralization activity remained modest even after a fourth booster injection. TRIAL REGISTRATION INFORMATION: COVIVAC-ID, NCT04844489, first patient included on 20 April 2021.

Low rate of daily active tobacco smoking in patients with symptomatic COVID-19

Abstract Importance: As the pandemic of COVID-19 is still under progression, identification of prognostic factors remains a global challenge. The role of smoking has been suggested among the disease risk factors, although it is highly controversial. Objective: To evaluate whether the rate of daily smokers in patients with COVID-19 was different to that in the French population. Participants: COVID-19-infected in- and outpatients in a large French university hospital between February 28, 2020 and March 30, 2020 for outpatients and from March 23, till April 9, 2020 for inpatients. Design: We systematically interviewed the patients on their smoking status, use of e-cigarette and nicotinic substitutes. The rate of daily smokers in inpatients and outpatients were compared to those in the 2018 French general population, after standardization for sex and age. Results: The inpatient group was composed of 340 patients, median age 66 years: 203 men (59.7%, median age 66 years) and 137 women (40.3%, median age 66 years),with a rate of daily smokers of 4.1% CI95% [2.3 – 6.9] (5.4% of men and 2.2% of women). The outpatient group was composed of 139 patients, median age 44 years: 62 men (44.6%, median age 43 years, and 77 women (55.4 %, median age 44 years). The daily smokers' rate was 6.1 % CI95% [2.7 - 11.6] (5.1% of men and 6.8 % of women). In the French population, the daily smokers' rate was 25.4% (28.2% of men and 22.9% of women). The rate of daily smokers was significantly lower in COVID-19 patients, as compared to that in the French general population after standardization by age and sex, with Standardized Incidence Ratios of 0.23 [0.11 - 0.45] for outpatients and 0.23 [0.14 - 0.39] for inpatients. These ratios did not significantly differ between the two groups (P=0.94). Conclusions and relevance: This cross sectional study in both COVID-19 out- and inpatients shows that daily smokers rate in patients with symptomatic COVID-19 is lower as compared to the general population.

Low incidence of daily active tobacco smoking in patients with symptomatic COVID-19

Importance: As the pandemic of COVID-19 is still under progression, identification of prognostic factors remains a global challenge. The role of cigarette smoking has been suggested among the disease's epidemiological risk factors, although it is highly controversial. Objective: To evaluate the correlation of daily smoking with the susceptibility to develop SARS-CoV-2 infection. Participants: We estimated the rates of daily current smokers in COVID-19-infected patients in a large French university hospital between February 28th , 2020 and March 30th , 2020 for outpatients and from March 23rd , till April 9th , 2020 for inpatients. Design: The rates from both groups were compared to those of daily current smokers in the 2018 French general population, established in 2018, after standardization of the data for sex and age. Results: The inpatient group was composed of 343 patients, median age 65 yr: 206 men (601%, median age 66 years) and 137 women (39.9%, median age 65 years) with a rate of daily smokers of 4.4% (5.4% of men and 2.9% of women).The outpatient group was composed of 139 patients, median age 44 years: 62 men (44.6 %, median age 43 years, and 77 women (55.4 %, median age 44 years). The daily smokers rate was 5.3% (5.1% of men and 5.5 % of women). In the French population, the daily smokers rate was 25.4% (28.2% of men and 22.9% of women). The rate of current daily smokers was significantly lower in COVID-19 outpatients and inpatients (80.3% and 75.4%, respectively), as compared to that in the French general population with standardized incidence ratios according to sex and age of 0.197 [0.094 - 0.41] and 0.246 [0.148 - 0.408]. These ratios did not significantly differ between the two groups (P=0.63). Conclusions and relevance: Our cross sectional study in both COVID-19 out- and inpatients strongly suggests that daily smokers have a very much lower probability of developing symptomatic or severe SARS-CoV-2 infection as compared to the general population.

Prolonged replication of BA.1 and BA.2 Omicron lineages compared to Delta variant in nasopharyngeal samples from COVID-19 patients.

OBJECTIVES: We aimed to characterize and compare the viral loads (VL) of the Omicron BA.1 and BA.2 lineages and the Delta variant in nasopharyngeal samples from newly diagnosed COVID-19 patients and their kinetics over time. PATIENTS AND METHODS: The kinetics of the VL were measured on the CT data from 215 SARS-CoV-2 positive patients who presented at least two positive PCRs a day apart and were screened for SARS-CoV-2 viral lineages. RESULTS: We observed no significant difference in median CT value during the first diagnostic test between the Delta variant and the two Omicron lineages. However, the kinetics of CT decreases for the BA.1 and BA.2 lineage were significantly lengthier in time than the kinetics for the Delta variant. The BA.2 lineage presented lower median CT value (-2 CT) (inversely proportional to the VL) than the BA.1 lineage. CONCLUSIONS: BA.2 Omicron lineage presented higher VL than BA.1 Omicron lineage at diagnostic. Omicron BA.1 and BA.2 lineages have more prolonged replication than the Delta variant.

Time to negative PCR conversion amongst high-risk patients with mild-to-moderate Omicron BA.1 and BA.2 COVID-19 treated with sotrovimab or nirmatrelvir.

OBJECTIVES: Our aim was to compare the clinical and virological outcomes in Omicron BA.1- and BA.2-infected patients who received sotrovimab with those in patients who received nirmatrelvir for the prevention of severe COVID-19. METHODS: In this multi-centric, prospective ANRS 0003S CoCoPrev cohort study, patients at a high risk of progression of mild-to-moderate BA.1 or BA.2 COVID-19 who received sotrovimab or nirmatrelvir were included. The proportion of patients with progression to severe COVID-19, time between the start of treatment to negative PCR conversion, SARS-CoV-2 viral decay, and characterization of resistance variants were determined. A multi-variable Cox proportional hazard model was used to determine the time to negative PCR conversion and a mixed-effect model for the dynamics of viral decay. RESULTS: Amongst 255 included patients, 199 (80%) received ≥3 vaccine doses, 195 (76%) received sotrovimab, and 60 (24%) received nirmatrelvir. On day 28, new COVID-19-related hospitalization occurred in 4 of 193 (2%; 95% CI, 1-5%) sotrovimab-treated patients and 0 of 55 nirmatrelvir-treated patients (p 0.24). One out of the 55 nirmatrelvir-treated patients died (2%; 95% CI, 0-10%). The median time to negative PCR conversion was 11.5 days (95% CI, 10.5-13) in the sotrovimab-treated patients vs. 4 days (95% CI, 4-9) in the nirmatrelvir-treated patients (p < 0.001). Viral decay was faster in the patients who received nirmatrelvir (p < 0.001). In the multi-variable analysis, nirmatrelvir and nasopharyngeal PCR cycle threshold values were independently associated with faster conversion to negative PCR (hazard ratio, 2.35; 95% CI, 1.56-3.56; p < 0.0001 and hazard ratio, 1.05; 95% CI, 1.01-1.08; p 0.01, respectively). CONCLUSIONS: Early administration of nirmatrelvir in high-risk patients compared with that of sotrovimab was associated with faster viral clearance. This may participate to decrease transmission and prevent viral resistance.

High seroconversion rate and SARS-CoV-2 Delta neutralization in people with HIV vaccinated with BNT162b2.

OBJECTIVES: To assess humoral responses to SARS-CoV-2 Delta-variant in people with HIV (PWH) after BNT162b2-vaccination. DESIGN: Multicenter cohort study of PWH with CD4 + cell count less than 500 cells/µl and viral load less than 50 copies/ml on stable antiretroviral therapy for at least 3 months. METHODS: Anti-SARS-CoV-2 receptor-binding-domain IgG antibodies (anti-RBD IgG) were quantified and neutralization capacity was evaluated by ELISA/GenScript and virus-neutralization-test against the D614G-strain, beta and delta variants before vaccination (day 0) and 1 month after complete schedule (M1). RESULTS: We enrolled 97 PWH, 85 received two vaccine shots. The seroconversion rate for anti-RBD IgG was 97% [95% confidence interval (CI) 90-100%] at M1. Median (IQR) anti-RBD IgG titer was 0.97 (0.97-5.3) BAU/ml at D0 and 1219 (602-1929) at M1. Neutralization capacity improved between D0 (15%; 50% CI 8-23%) and M1 (94%; 95% CI 87-98%) ( P  < 0.0001). At M1, NAbs against the D614G strain, beta and delta variants were present in 82, 77, and 84% PWH, respectively. The seroconversion rate and median anti-RBD-IgG level were 91% and 852 BAU/ml, respectively, in PWH with CD4 + cell count less than 250 ( n  = 13) and 98% and 1270 BAU/ml for CD4 + greater than 250 ( n  = 64) ( P  = 0.3994). NAbs were present in 73% of PWH with CD4 + less than 250 and 97% of those with CD4 + cell count greater than 250 ( P  = 0.0130). NAbs against beta variant were elicited in 50% in PWH with CD4 + cell count less than 250 and in 81% of those with CD4 + cell count greater than 250 ( P  = 0.0292). CD4 + and CD8 + T-cell counts were unchanged, whereas CD19 + B-cell counts decreased after vaccination(208 ±â€Š124 at D0 vs. 188 ±â€Š112 at M1, P  < 0.01). No notable adverse effects or COVID-19 cases were reported. CONCLUSION: Seroconversion rates were high, with delta-neutralization rates similar to those for the D61G strain, after a two-dose BNT162b2 vaccination in PWH.

Lower Rate of Daily Smokers With Symptomatic COVID-19: A Monocentric Self-Report of Smoking Habit Study.

Background: Identification of prognostic factors in COVID-19 remains a global challenge. The role of smoking is still controversial. Methods: PCR-positive in- and outpatients with symptomatic COVID-19 from a large French University hospital were systematically interviewed for their smoking status, use of e-cigarette, and nicotinic substitutes. The rates of daily smokers in in- and outpatients were compared using the same smoking habit questionnaire to those in the 2019 French general population, after standardisation for sex and age. Results: The inpatient group was composed of 340 patients, median age of 66 years: 203 men (59.7%) and 137 women (40.3%), median age of both 66 years, with a rate of 4.1% daily smokers (CI 95% [2.3-6.9]) (5.4% of men and 2.2% of women). The outpatient group was composed of 139 patients, median age of 44 years: 62 men (44.6%, median age of 43 years) and 77 women (55.4%, median age of 44 years). The daily smoker rate was 6.1% (CI 95% [2.7-11.6], 5.1% of men and 6.8% of women). Amongst inpatients, daily smokers represented 2.2 and 3.4% of the 45 dead patients and of the 29 patients transferred to ICU, respectively. The rate of daily smokers was significantly lower in patients with symptomatic COVID-19, as compared to that in the French general population after standardisation by age and sex, with standardised incidence ratios (SIRs) of 0.24 [0.12-0.48] for outpatients and 0.24 [0.14-0.40] for inpatients. Conclusions: Daily smoker rate in patients with symptomatic COVID-19 is lower as compared to the French general population.

Cumulative incidence of SARS-CoV-2 infection and associated risk factors among frontline health care workers in Paris: the SEROCOV cohort study.

With the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern. In this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression. Among 1062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95% CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); current smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3. The rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk.Trial registration The study has been registered on ClinicalTrials.gov: NCT04304690 first registered on 11/03/2020.

Spike Gene Evolution and Immune Escape Mutations in Patients with Mild or Moderate Forms of COVID-19 and Treated with Monoclonal Antibodies Therapies.

We explored the molecular evolution of the spike gene after the administration of anti-spike monoclonal antibodies in patients with mild or moderate forms of COVID-19. Four out of the 13 patients acquired a mutation during follow-up; two mutations (G1204E and E406G) appeared as a mixture without clinical impact, while the Q493R mutation emerged in two patients (one receiving bamlanivimab and one receiving bamlanivimab/etesevimab) with fatal outcomes. Careful virological monitoring of patients treated with mAbs should be performed, especially in immunosuppressed patients.

LOX-1-Expressing Immature Neutrophils Identify Critically-Ill COVID-19 Patients at Risk of Thrombotic Complications.

Background: Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity. Objective: We investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients' clinical characteristics. Methods: We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients. Results: The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10-CD64+ immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1ß, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions. Conclusion: LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.

Anti-CD20 therapies decrease humoral immune response to SARS-CoV-2 in patients with multiple sclerosis or neuromyelitis optica spectrum disorders.

BACKGROUND: SARS-CoV-2 seroconversion rate after COVID-19 may be influenced by disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMO-SD). OBJECTIVE: To investigate the seroprevalence and the quantity of SARS-CoV-2 antibodies in a cohort of patients with MS or NMO-SD. METHODS: Blood samples were collected in patients diagnosed with COVID-19 between 19 February 2020 and 26 February 2021. SARS-CoV-2 antibody positivity rates and Ig levels (anti-S IgG titre, anti-S IgA index, anti-N IgG index) were compared between DMTs groups. Multivariate logistic and linear regression models were used to estimate the influence of DMTs and other confounding variables on SARS-CoV-2 serological outcomes. RESULTS: 119 patients (115 MS, 4 NMO, mean age: 43.0 years) were analysed. Overall, seroconversion rate was 80.6% within 5.0 (SD 3.4) months after infection. 20/21 (95.2%) patients without DMT and 66/77 (85.7%) patients on DMTs other than anti-CD20 had at least one SARS-CoV-2 Ig positivity, while this rate decreased to only 10/21 (47.6%) for patients on anti-CD20 (p<0.001). Being on anti-CD20 was associated with a decreased odd of positive serology (OR, 0.07 (95% CI 0.01 to 0.69), p=0.02) independently from time to COVID-19, total IgG level, age, sex and COVID-19 severity. Time between last anti-CD20 infusion and COVID-19 was longer (mean (SD), 3.7 (2.0) months) in seropositive patients compared with seronegative patients (mean (SD), 1.9 (1.5) months, p=0.04). CONCLUSIONS: SARS-CoV-2 antibody response was decreased in patients with MS or NMO-SD treated with anti-CD20 therapies. Monitoring long-term risk of reinfection and specific vaccination strategies in this population may be warranted. TRIAL REGISTRATION NUMBER: NCT04568707.

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-ß-1a and hydroxychloroquine in hospitalized patients with COVID-19.

OBJECTIVES: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-ß-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. METHODS: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. RESULTS: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-ß-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-ß-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. CONCLUSION: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Co-infection of SARS-CoV-2 with other respiratory viruses and performance of lower respiratory tract samples for the diagnosis of COVID-19.

OBJECTIVES: This study was performed during the early outbreak period of coronavirus disease 2019 (COVID-19) and the seasonal epidemics of other respiratory viral infections, in order to describe the extent of co-infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with other respiratory viruses. It also compared the diagnostic performances of upper respiratory tract (URT) and lower respiratory tract (LRT) samples for SARS-CoV-2 infection. METHODS: From 25 January to 29 March 2020, all URT and LRT samples collected from patients with suspected COVID-19 received in the virology laboratory of Pitié-Salpêtrière University Hospital (Paris, France) were simultaneously tested for SARS-CoV-2 and other respiratory viruses. RESULTS: A total of 1423 consecutive patients were tested: 677 (47.6%) males, 746 (52.4%) females, median age 50 (range, 1-103) years. Twenty-one (1.5%) patients were positive for both SARS-CoV-2 and other respiratory viruses. The detection rate of SARS-CoV-2 was significantly higher in LRT than in URT (53.6% vs. 13.4%; p<0.0001). The analysis of paired samples from 117 (8.2%) patients showed that SARS-CoV-2 load was lower in URT than in LRT samples in 65% of cases. CONCLUSION: The detection of other respiratory viruses in patients during this epidemic period could not rule out SARS-CoV-2 co-infection. Furthermore, LRT samples increased the accuracy of diagnosis of COVID-19.