Leanne Marsay1, Christina Dold1, Gavin K Paterson2, Yuko Yamaguchi2, Jeremy P Derrick3, Hannah Chan4, Ian M Feavers4, Martin C J Maiden5, David Wyllie2, Adrian V Hill2, Andrew J Pollard1, Christine S Rollier6. 1. Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, CCVTM, Churchill Lane, Oxford OX3 7LE, United Kingdom. 2. Jenner Institute, University of Oxford, Old Road Campus Research Building, OX3 7DQ, United Kingdom. 3. Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, United Kingdom. 4. National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, United Kingdom. 5. Department of Zoology, University of Oxford, 11a Mansfield Road, Oxford OX1 3SZ, United Kingdom. 6. Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, CCVTM, Churchill Lane, Oxford OX3 7LE, United Kingdom; Section of Immunology, Department of Biochemical sciences, School of Biosciences & Medicine, Faculty of Health and Medical Sciences, University of Surrey, Dorothy Hodgkin Building (AY), Guildford, Surrey GU2 7XH, United Kingdom. Electronic address: c.rollier@surrey.ac.uk.
Abstract
OBJECTIVE: Adenoviral vectored vaccines, with the appropriate gene insert, induce cellular and antibody responses against viruses, parasites and intracellular pathogens such as Mycobacterium tuberculosis. Here we explored their capacity to induce functional antibody responses to meningococcal transmembrane outer membrane proteins. METHODS: Vectors expressing porin A and ferric enterobactin receptor A antigens were generated, and their immunogenicity assessed in mice using binding and bactericidal assays. RESULTS: The viral vectors expressed the bacterial proteins in an in vitro cell-infection assay and, after immunisation of mice, induced higher titres (>105 end-point titre) and longer lasting (>32 weeks) transgene-specific antibody responses in vivo than did outer membrane vesicles containing the same antigens. However, bactericidal antibodies, which are the primary surrogate of protection against meningococcus, were undetectable, despite different designs to support the presentation of the protective B-cell epitopes. CONCLUSION: These results demonstrate that, while the transmembrane bacterial proteins expressed by the viral vector induced strong and persistent antigen-specific antibodies, this platform failed to induce bactericidal antibodies. The results suggest that conformation or post-translational modifications of bacterial outer membrane antigens produced in eukaryote cells might not result in presentation of the necessary epitopes for induction of functional antibodies.
OBJECTIVE: Adenoviral vectored vaccines, with the appropriate gene insert, induce cellular and antibody responses against viruses, parasites and intracellular pathogens such as Mycobacterium tuberculosis. Here we explored their capacity to induce functional antibody responses to meningococcal transmembrane outer membrane proteins. METHODS: Vectors expressing porin A and ferric enterobactin receptor A antigens were generated, and their immunogenicity assessed in mice using binding and bactericidal assays. RESULTS: The viral vectors expressed the bacterial proteins in an in vitro cell-infection assay and, after immunisation of mice, induced higher titres (>105 end-point titre) and longer lasting (>32 weeks) transgene-specific antibody responses in vivo than did outer membrane vesicles containing the same antigens. However, bactericidal antibodies, which are the primary surrogate of protection against meningococcus, were undetectable, despite different designs to support the presentation of the protective B-cell epitopes. CONCLUSION: These results demonstrate that, while the transmembrane bacterial proteins expressed by the viral vector induced strong and persistent antigen-specific antibodies, this platform failed to induce bactericidal antibodies. The results suggest that conformation or post-translational modifications of bacterial outer membrane antigens produced in eukaryote cells might not result in presentation of the necessary epitopes for induction of functional antibodies.
Authors: Ann E Sluder; Susan Raju Paul; Leonard Moise; Christina Dold; Guilhem Richard; Laura Silva-Reyes; Laurie A Baeten; Anja Scholzen; Patrick M Reeves; Andrew J Pollard; Anja Garritsen; Richard A Bowen; Anne S De Groot; Christine Rollier; Mark C Poznansky Journal: Front Immunol Date: 2022-05-16 Impact factor: 8.786