Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron Variant of Concern

BackgroundRecent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting SARS-CoV-2 varies according to the Variant of Concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. MethodsThe MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with early COVID-19. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was COVID-19 progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. ResultsOverall, 319 patients were included. Among 141 patients infected with Delta, no disease progression was recorded and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.895). Among 170 patients infected with Omicron (80.6% BA.1, 19.4% BA.1.1), two disease progressions were recorded in the bamlanivimab/etesevimab group and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared to bamlanivimab/etesevimab and casirivimab/imdevimab (HR 0.526 and HR 0.451, 95% CI 0.359 - 0.77 and 95% CI 0.303 - 0.669, p 0.001 and 0.0001, respectively). ConclusionsThese results confirm the in-vitro data of superiority of sotrovimab versus casirivimab/imdevimab and bamlanivimab/etesivamab in reducing the time to recovery in patients infected with Omicron BA.1 and BA.1.1, while no difference was detected in Delta infections. Casirivimab/imdevimab seems to maintain a role in preventing severe COVID-19 in the Omicron population. Adaptive clinical trials comparing mAbs by VOC should be pursued to promptly inform clinical recommendations. FundingThis trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). The VOC identification was funded by the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Unions Horizon 2020 research and innovation programme under grant agreement No 101016167. Clinical trial numberNCT05205759

VALIDATION OF A SALIVA-BASED TEST FOR THE MOLECULAR DIAGNOSIS OF SARS-CoV-2 INFECTION

BackgroundSince the beginning of the pandemic, clinicians and researchers have been searching for alternative tests to improve screening and diagnosis of SARS-CoV-2 infection (Y. Yang et al., medRxiv 2020; W. Wang et al., 2020.3786; A Senok et al., Infect Drug Resist 2020). Currently, the gold standard for virus identification is the nasopharyngeal (NP) swab (N. Sethuraman et al., JAMA 2020; A.J. Jamal et al Clinical Infect Disease 2021). Saliva samples, however, offer clear practical and logistical advantages (K.K.W To et al, Clinical Microb and Infect; A.L. Wylle et al. N Engl J Med 2020; N. Matic et al, Eur J Clin 2021) but due to lack of collection, transport, and storage solutions, high-throughput saliva-based laboratory tests are difficult to scale up as a screening or diagnostic tool (D. Esser et al., Biomark Insights 2008; E. Kaufman et al., Crit Rev Oral Biol Med2002). With this study, we aimed to validate an intra-laboratory molecular detection method for SARS-CoV-2 on saliva samples collected in a new storage saline solution, comparing the results to NP swabs to determine the difference in sensitivity between the two tests. MethodsIn this study, 156 patients (cases) and 1005 asymptomatic subjects (controls) were enrolled and tested simultaneously for the detection of the SARS-CoV-2 viral genome by RT-PCR on both NP swab and saliva samples. Saliva samples were collected in a preservative and inhibiting saline solution (Biofarma Srl). Internal method validation was performed to standardize the entire workflow for saliva samples. ResultsThe identification of SARS-CoV-2 conducted on saliva samples showed a clinical sensitivity of 95.1% and specificity of 97.8% compared to NP swabs. The positive predictive value (PPV) was 81% while the negative predictive value (NPV) was 99.5%. Test concordance was 97.6% (Cohens Kappa=0.86; 95% CI 0.81-0.91). The LoD of the test was 5 viral copies for both samples. ConclusionsRT-PCR assays conducted on a stored saliva sample achieved similar performance to those on NP swabs and this may provide a very effective tool for population screening and diagnosis. Collection of saliva in a stabilizing solution makes the test more convenient and widely available; furthermore, the denaturing properties of the solution reduce the infective risks belonging to sample manipulation.

Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian Centre study on tocilizumab versus standard of care.

ObjectiveApproximately 5% of patients with coronavirus disease 2019 (COVID-19) develop a life-threatening pneumonia that often occurs in the setting of increased inflammation or "cytokine storm". Anti-cytokine treatments are being evaluated but optimal patient selection remains unclear, and the aim of our study is to address this point. MethodsBetween February 29 to April 6, 2020, 111 consecutive hospitalized patients with COVID-19 pneumonia were evaluated in a single centre retrospective study. Patients were divided in two groups: 42 severe cases (TOCI) with adverse prognostic features including raised CRP and IL-6 levels, who underwent anti-cytokine treatments, mostly tocilizumab, and 69 standard of care patients (SOC). ResultsIn the TOCI group, all received anti-viral therapy and 40% also received glucocorticoids. In TOCI, 62% of cases were ventilated and there were 3 deaths (17.8{+/-}10.6 days, mean follow up) with 7/26 cases remaining on ventilators, without improvement, and 17/26 developed bacterial superinfection. One fatality occurred in the 15 TOCI cases treated on noninvasive ventilation and 1 serious bacterial superinfection. Of the 69 cases in SOC, there was no fatalities and no bacterial complications. The TOCI group had higher baseline CRP and IL-6 elevations (p<0.0001 for both) and higher neutrophils and lower lymphocyte levels (p= 0.04 and p=0.001, respectively) with the TOCI ventilated patients having higher markers than non-ventilated TOCI patients. ConclusionHigher inflammatory markers, more infections and worse outcomes characterized ventilated TOCI cases compared to ward based TOCI. Despite the confounding factors, this suggests that therapy time in anti-cytokine randomized trials will be key. FundingThis research received no external funding. Conflicts of Interest"The authors declare no conflict of interest." HighlightsO_LIThere is an urgent need for markers of prognosis in COVID-19. C_LIO_LIHigher inflammatory markers best select tocilizumab treatment. C_LIO_LIThe ward based tocilizumab group showed better responses and less infections than ICU tocilizumab group. C_LIO_LIThe former group may be the best for evaluating the impact of anti-cytokine therapy in COVID-19. C_LIO_LIThe known poor risk factors for COVID-19 infection were present in the TOCI treated rather than in the good prognosis standard of care group. C_LI