Long Term Assessment of Anti-SARS-CoV-2 Immunogenicity after mRNA Vaccine in Persons Living with HIV.

(1) Background: Waning of neutralizing and cell-mediated immune response after the primary vaccine cycle (PVC) and the first booster dose (BD) is of concern, especially for PLWH with a CD4 count ≤200 cells/mm3. (2) Methods: Neutralizing antibodies (nAbs) titers by microneutralization assay against WD614G/Omicron BA.1 and IFNγ production by ELISA assay were measured in samples of PLWH at four time points [2 and 4 months post-PVC (T1 and T2), 2 weeks and 5 months after the BD (T3 and T4)]. Participants were stratified by CD4 count after PVC (LCD4, ≤200/mm3; ICD4, 201-500/mm3, and HCD4, >500/mm3). Mixed models were used to compare mean responses over T1-T4 across CD4 groups. (3) Results: 314 PLWH on ART (LCD4 = 56; ICD4 = 120; HCD4 = 138) were enrolled. At T2, levels of nAbs were significantly lower in LCD4 vs. ICD4/HCD4 (p = 0.04). The BD was crucial for increasing nAbs titers above 1:40 at T3 and up to T4 for WD614G. A positive T cell response after PVC was observed in all groups, regardless of CD4 (p = 0.31). (4) Conclusions: Waning of nAbs after PVC was more important in LCD4 group. The BD managed to re-establish higher levels of nAbs against WD614G, which were retained for 5 months, but for shorter time for Omicron BA.1. The T cellular response in the LCD4 group was lower than that seen in participants with higher CD4 count, but, importantly, it remained above detectable levels over the entire study period.

Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics.

Nirmatrelvir/ritonavir (N/R) is one of the most effective antiviral drugs against SARS-CoV-2. The preclinical development, pharmacodynamics and pharmacokinetics of N/R are reviewed herein. Randomized clinical trials have been conducted exclusively with pre-Omicron variants of concern, but in vitro studies show that efficacy against all Omicron sublineages is preserved, as confirmed by post-marketing observational studies. Nevertheless, investigations of large viral genome repositories have shown that mutation in the main protease causing resistance to N/R are increasingly frequent. In addition, virological and clinical rebounds after N/R discontinuation have been reported in immunocompetent patients. This finding is of concern when translated to immunocompromised patients, in whom N/R efficacy has not been formally investigated in clinical trials. Economical sustainability and perspectives for this therapeutic arena are discussed.

Performance Assessment of the LIAISON® SARS-CoV-2 Antigen Assay On Nasopharyngeal Swabs.

The SARS-CoV-2 pandemic is ongoing worldwide, causing prolonged pressure on molecular diagnostics. Viral antigen (Ag) assays have several advantages, ranging from lower cost to shorter turnaround time to detection. Given the rare occurrence of low-load viremia, antigen assays for SARSCoV-2 have focused on nasopharyngeal swab and saliva as biological matrices, but their effectiveness must be validated. We assayed here the performances of the novel quantitative Liaison® SARSCoV-2 Ag assay on 119 nasopharyngeal swabs and obtained results were compared with Hologic Panther and Abbott m2000 RT-qPCR. The Ag assay demonstrated a good correlation with viral load, shorter turnaround time, and favorable economics. The best performance was obtained in the acute phase of disease.

Patient-blood management for COVID19 convalescent plasma therapy: relevance of affinity and donor-recipient differences in concentration of neutralizing antibodies.

BACKGROUND: Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is being extensively investigated as a treatment, with mixed results to date. Overall, there has been a generalized lack of appropriateness in prescriptions, which, in the field of transfusion medicine, is termed patient-blood management. OBJECTIVES: We aimed to separate study design variables that could affect clinical outcome after CCP therapy. We focus here on variables such as pretransfusion antibody testing in recipients, dose adjustments and antibody affinity measurements. SOURCES: We searched PubMed and preprint servers for relevant preclinical and clinical studies discussing each of these variables in the field of CCP therapy. CONTENT: We show evidence that neglecting those variables has affected the outcomes of the vast majority of CCP clinical trials to date. IMPLICATIONS: A better understanding of such variables will improve the design of the next generation of CCP clinical trials. This will likely lead to better clinical outcomes and will minimize risks of immune evasion from subneutralizing doses of neutralizing antibodies.

Neutralising antibody escape of SARS-CoV-2 spike protein: Risk assessment for antibody-based Covid-19 therapeutics and vaccines.

The Spike protein is the target of both antibody-based therapeutics (convalescent plasma, polyclonal serum, monoclonal antibodies) and vaccines. Mutations in Spike could affect efficacy of those treatments. Hence, monitoring of mutations is necessary to forecast and readapt the inventory of therapeutics. Different phylogenetic nomenclatures have been used for the currently circulating SARS-CoV-2 clades. The Spike protein has different hotspots of mutation and deletion, the most dangerous for immune escape being the ones within the receptor binding domain (RBD), such as K417N/T, N439K, L452R, Y453F, S477N, E484K, and N501Y. Convergent evolution has led to different combinations of mutations among different clades. In this review we focus on the main variants of concern, that is, the so-called UK (B.1.1.7), South African (B.1.351) and Brazilian (P.1) strains.

Assessment of automated high-throughput serological assays for prediction of high-titer SARS-CoV-2 neutralizing antibody.

COVID19 convalescent patient plasma units with high titer neutralizing antibody can be used to treat patients with severe disease. Therefore, in order to select suitable donors, neutralizing antibody titer against SARS CoV-2 needs to be determined. Because the neutralization assay is highly demanding from several points of view, a pre-selection of sera would be desirable to minimize the number of sera to be tested. In this study, a total of 140 serum samples that had been titrated for SARS-CoV-2 neutralizing antibody by microneutralization assay were also tested for the presence of anti-SARS-CoV2 antibody using 5 different tests: Architect® immunoassay (Abbott Diagnostics), detecting IgG against the nucleocapsid protein, LIAISON XL® (Diasorin) detecting IgG against a recombinant form of the S1/S2 subunits of the spike protein, VITROS® (Ortho Clinical Diagnostics), detecting IgG against a recombinant form of the spike protein, and ELISA (Euroimmun AG), detecting IgA or IgG against a recombinant form of the S1 subunit. To determine which immunoassay had the highest chance to detect sera with neutralizing antibodies above a certain threshold, we compared the results obtained from the five immunoassays with the titers obtained by microneutralization assay by linear regression analysis and by using receiver operating characteristic curve and Youden's index. Our results indicate that the most suitable method to predict sera with high Nab titer is Euroimmun® IgG, followed closely by Ortho VITROS® Anti-SARS-CoV-2 IgG.

Assessment of the risk of polyomavirus JC reactivation in patients with immune-mediated diseases during long-term treatment with infliximab.

Polyomavirus JC (JCV) reactivation causing progressive multifocal leukoencephalopathy is a main concern during biological therapies. Here, JCV reactivation in patients suffering from immune-mediated diseases after a long-term treatment with anti-tumor necrosis factor alpha (TNF-α) inhibitor infliximab was investigated. Peripheral mononuclear blood cells (PBMC), plasma and urine samples were obtained from 61 immune-mediated diseases patients treated or not with infliximab in combination with steroid and other immunomodulators and from 20 healthy donors. JCV DNA was transiently detected in 12 PBMC of 40 patients at different doses of infliximab with a higher prevalence than that of the 21 patients untreated. Conversely, a stable JCV positivity in urine of treated and untreated patients was detected. Sequencing the noncoding control region (NCCR), all samples exhibited the archetype structure with few mutations in transcriptional factor binding regions. The consequence of anti-TNF-α treatment on viral persistence was examined monitoring Torquetenovirus viremia and investigating the TNF-α-induced microRNA regulators of transcriptional factors, with a binding site on NCCR. Although infliximab treatment in this study did not affect directly JCV reactivation, further investigation on host factor(s) regulated by it will be of warranty in the understanding the mechanism(s) that may affect viral persistence.