The recent development and use of protease inhibitors have demonstrated the essential role that combination therapy will play in the treatment of individuals infected with the human immunodeficiency virus type 1 (HIV-1). Past clinical experience suggests that due to the appearance of resistant HIV-1 variants, additional therapeutics will be required in the future. To identify new options for combination therapy, it is of paramount importance to pursue novel targets for drug development. Ribosomal frameshifting is one potential target that has not been fully explored. Data presented here demonstrate that small molecules can stimulate frameshifting, leading to an imbalance in the ratio of Gag to Gag-Pol and inhibiting HIV-1 replication at what appears to be the point of viral particle assembly. Thus, we propose that frameshifting represents a new target for the identification of novel anti-HIV-1 therapeutics.

Background Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public-health threat in sub-Saharan Africa. We present phase 3 efficacy data from an African trial of a Vi-polysaccharide typhoid conjugate vaccine (Vi-TCV). Methods Children aged 9 months to 12 years in Blantyre, Malawi were randomized (1:1) in a double-blind trial to receive Vi-TCV (single dose) or group-A meningococcal control vaccine (MenA).The primary outcome was blood culture-confirmed typhoid fever. We present the primary vaccine efficacy (VE) and safety outcomes after 18–24 months of follow-up. Results This intention-to-treat (ITT) analysis included 28,130 children, comprising 14,069 children who received Vi-TCV and 14,061 children who received MenA. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 per 100,000 person-years) and 62 children in the MenA group (243 per 100,000 person-years). Overall VE was 80.7% (95% confidence interval (CI): 64.2% to 89.6%) in an ITT analysis, and 83.7% (95% CI: 68.1%−91.6%) in a per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in Vi-TCV group and 78 in MenA group), including 6 deaths (all in MenA group). No serious adverse event was considered by the investigator as related to study vaccination. Conclusions Vi-TCV reduced blood culture-confirmed typhoid fever among Malawian children aged 9 months to 12 years. (Funded by the Bill & Melinda Gates Foundation; ClinicalTrials.gov number NCT03299426 .)

The Staphylococcus aureus MSCRAMM (microbial surface components recognizing adhesive matrix molecules) protein clumping factor A (ClfA) has been shown to be a critical virulence factor in several experimental models of infection. This report describes the generation, characterization, and in vivo evaluation of a murine monoclonal antibody (MAb) against ClfA. Flow cytometric analysis revealed that MAb 12-9 recognized ClfA protein expressed by all of the clinical S. aureus strains obtained from a variety of sources. In assays measuring whole-cell S. aureus binding to human fibrinogen, MAb 12-9 inhibited S. aureus binding by over 90% and displaced up to 35% of the previously adherent S. aureus bacteria. Furthermore, a single infusion of MAb 12-9 was protective against an intravenous challenge with a methicillin-resistant strain of S. aureus in a murine sepsis model (P < 0.0001). These data suggest that anti-ClfA MAb 12-9 should be further investigated as a novel immunotherapy for the treatment and prevention of life-threatening S. aureus infections.

We report the humanization and characterization of monoclonal antibody (MAb) T1-2 or tefibazumab, a monoclonal antibody that recognizes clumping factor A expressed on the surface of Staphylococcus aureus. We demonstrate that the binding kinetics of MAb T1-2 is indistinguishable compared to that of its murine parent. Furthermore, MAb T1-2 is shown to enhance the opsonophagocytic uptake of ClfA-coated latex beads, protect against an intravenous challenge in a prophylactic model of rabbit infective endocarditis, and enhance the efficacy of vancomycin therapy in a therapeutic model of established infective endocarditis.

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