ABSTRACT
COVID-19 has demonstrated the power of RNA vaccines as part of a pandemic response toolkit. Another virus with pandemic potential is influenza. Further development of RNA vaccines in advance of a future influenza pandemic will save time and lives. As RNA vaccines require formulation to enter cells and induce antigen expression, the aim of this study was to investigate the impact of a recently developed bioreducible cationic polymer, pABOL for the delivery of a self-amplifying RNA (saRNA) vaccine for seasonal influenza virus in mice and ferrets. Mice and ferrets were immunized with pABOL formulated saRNA vaccines expressing either haemagglutinin (HA) from H1N1 or H3N2 influenza virus in a prime boost regime. Antibody responses, both binding and functional were measured in serum after immunization. Animals were then challenged with a matched influenza virus either directly by intranasal inoculation or in a contact transmission model. While highly immunogenic in mice, pABOL-formulated saRNA led to variable responses in ferrets. Animals that responded to the vaccine with higher levels of influenza virus-specific neutralizing antibodies were more protected against influenza virus infection. pABOL-formulated saRNA is immunogenic in ferrets, but further optimization of RNA vaccine formulation and constructs is required to increase the quality and quantity of the antibody response to the vaccine.
ABSTRACT
PURPOSE: Cycloserine has been used previously in some areas of the world for the treatment of urinary tract infections. The emergence of multi-resistant strains of Enterobacteriaceae and the lack of new agents in the development pipeline has prompted a need to review the activity of older agents. Susceptibility testing of cycloserine has traditionally been problematic owing to testing in standard media, containing competitive alanine, thus presenting falsely elevated minimum inhibitory concentrations (MICs). This study tests urinary coliforms against cycloserine in both standard and minimal media. METHODS: Susceptibilities were performed on 500 "wild type" UTI coliforms using Mueller-Hinton broth in the range 0.008-128 µg/ml in accordance with ISO guidelines. Cycloserine was also tested in Minimal Salts medium + 2 % 1 M glucose + 0.2 % 1 M magnesium sulphate. MICs were recorded after 18 h of incubation at 35 °C and interpreted with EUCAST breakpoints (where available). RESULTS: Cycloserine MIC50 for the "wild type" coliforms was 32 µg/ml in Mueller-Hinton broth compared with 2 µg/ml in Minimal Salts. Eighty-seven per cent of "wild type" UTI coliforms show cycloserine MICs < = 8 µg/ml in Minimal Salts. The epidemiological cut-off values for cycloserine for E. coli in this study were 64 µg/ml using Mueller-Hinton broth and 8 µg/ml using Minimal Salts medium. Ninety-four per cent of trimethoprim-resistant and 82 % of third generation cephalosporin-resistant E. coli had MICs in Minimal Salts ≤ 8 µg/ml. CONCLUSION: Cycloserine is still licensed in some countries for the treatment of urinary infections and the data presented here suggest that it may play a role in the management of infections resistant to trimethoprim and third generation cephalosporins.
