title: Germinal Center B Cell and T Follicular Helper Cell Responses to Viral Vector and Protein-in-Adjuvant Vaccines.
abstract: There is great interest in the development of Ab-inducing subunit vaccines targeting infections, including HIV, malaria, and Ebola. We previously reported that adenovirus vectored vaccines are potent in priming Ab responses, but uncertainty remains regarding the optimal approach for induction of humoral immune responses. In this study, using OVA as a model Ag, we assessed the magnitude of the primary and anamnestic Ag-specific IgG responses of mice to four clinically relevant vaccine formulations: replication-deficient adenovirus; modified vaccinia Ankara (a poxvirus); protein with alum; and protein in the squalene oil-in-water adjuvant Addavax. We then used flow cytometric assays capable of measuring total and Ag-specific germinal center (GC) B cell and follicular Th cell responses to compare the induction of these responses by the different formulations. We report that adenovirus vectored vaccines induce Ag insert-specific GC B cell and Ab responses of a magnitude comparable to those induced by a potent protein/squalene oil-in-water formulation whereas-despite a robust overall GC response-the insert-specific GC B cell and Ab responses induced by modified vaccinia Ankara were extremely weak. Ag-specific follicular Th cell responses to adenovirus vectored vaccines exceeded those induced by other platforms at day 7 after immunization. We found little evidence that innate immune activation by adenovirus may act as an adjuvant in such a manner that the humoral response to a recombinant protein may be enhanced by coadministering with an adenovirus lacking a transgene of interest. Overall, these studies provide further support for the use of replication-deficient adenoviruses to induce humoral responses.
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; and.
authors.forename: Chuan
authors.identifier: 0000-0003-3552-4747
authors.initials: C
authors.lastname: Wang
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; and.
authors.forename: Matthew
authors.identifier: 0000-0001-7770-0142
authors.initials: M
authors.lastname: Hart
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors.forename: Cecilia
authors.identifier: 0000-0002-8888-6779
authors.initials: C
authors.lastname: Chui
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; and.
authors.forename: Augustine
authors.initials: A
authors.lastname: Ajuogu
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; and.
authors.forename: Iona J
authors.identifier: 0000-0002-2287-9488
authors.initials: IJ
authors.lastname: Brian
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; and.
authors.forename: Simone C
authors.initials: SC
authors.lastname: de Cassan
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors.forename: Persephone
authors.identifier: 0000-0002-3877-9780
authors.initials: P
authors.lastname: Borrow
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; and.
authors.forename: Simon J
authors.identifier: 0000-0002-9415-1357
authors.initials: SJ
authors.lastname: Draper
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; and sandy.douglas@ndm.ox.ac.uk.
authors.forename: Alexander D
authors.identifier: 0000-0002-5410-7562
authors.initials: AD
authors.lastname: Douglas
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D018858:Germinal Center / Q000276:immunology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D014765:Viral Vaccines; D010047:Ovalbumin