On variants and vaccines: The effectiveness of Covid-19 monoclonal antibody therapy during two distinct periods in the pandemic.

BACKGROUND: While Covid-19 monoclonal antibody therapies (Mab) have been available in the outpatient setting for over a year and a half, little is known about the impact of emerging variants and vaccinations on the effectiveness of Mab therapies. We sought to determine the effectiveness of Covid-19 Mab therapies during the first two waves of the pandemic in Los Angeles County and assess the impact of vaccines, variants, and other confounding factors. METHODS AND FINDINGS: We retrospectively examined records for 2209 patients of with confirmed positive molecular SARS-CoV2 test either referred for outpatient Mab therapy or receiving Mab treatment in the emergency department (ED) between December 2020 and 2021. Our primary outcome was the combined 30-day incidence of ED visit, hospitalization, or death following the date of referral. Additionally, SARS-CoV2 isolates of hospitalized patients receiving Mabs were sequenced. The primary outcome was significantly reduced with combination therapy compared to bamlanivimab or no treatment (aHR 0·60; 95% CI ·37, ·99), with greater benefit in unvaccinated, moderate-to-high-risk patients (aHR ·39; 95% CI ·20, ·77). Significant associations with the primary outcome included history of lung disease (HR 7·13; 95% CI 5·12, 9·95), immunocompromised state (HR 6·59; 95% CI 2·91-14·94), and high social vulnerability (HR 2·29, 95% CI 1·56-3·36). Two predominant variants were noted during the period of observation: the Epsilon variant and the Delta variant. CONCLUSIONS: Only select monoclonal antibody therapies significantly reduced ED visits, hospitalizations, and death due to COVID-19 during. Vaccination diminished effectiveness of Mabs. Variant data and vaccination status should be considered when assessing the benefit of novel COVID-19 treatments.

Txe, an endoribonuclease of the enterococcal Axe-Txe toxin-antitoxin system, cleaves mRNA and inhibits protein synthesis.

The axe-txe operon encodes a toxin-antitoxin (TA) pair, Axe-Txe, that was initially identified on the multidrug-resistance plasmid pRUM in Enterococcus faecium. In Escherichia coli, expression of the Txe toxin is known to inhibit cell growth, and co-expression of the antitoxin, Axe, counteracts the toxic effect of Txe. Here, we report the nucleotide sequence of pS177, a 39 kb multidrug-resistant plasmid isolated from vancomycin-resistant Ent. faecium, which harbours the axe-txe operon and the vanA gene cluster. RT-PCR analysis revealed that the axe-txe transcript is produced by strain S177 as well as by other vancomycin-resistant enteroccoci. Moreover, we determine the mechanism by which the Txe protein exerts its toxic activity. Txe inhibits protein synthesis in E. coli without affecting DNA or RNA synthesis, and inhibits protein synthesis in a cell-free system. Using in vivo primer extension analysis, we demonstrate that Txe preferentially cleaves single-stranded mRNA at the first base after an AUG start codon. We conclude that Txe is an endoribonuclease which cleaves mRNA and inhibits protein synthesis.